key: cord-0777593-q6e6oi1w
authors: El-Masry, Rana M.; Kadry, Hanan H.; Taher, Azza T.; Abou-Seri, Sahar M.
title: Comparative Study of the Synthetic Approaches and Biological Activities of the Bioisosteres of 1,3,4-Oxadiazoles and 1,3,4-Thiadiazoles over the Past Decade
date: 2022-04-22
journal: Molecules
DOI: 10.3390/molecules27092709
sha: e5b8172452d7e9ea7643e3b06bf5aff8a7098b67
doc_id: 777593
cord_uid: q6e6oi1w

The bioisosteres of 1,3,4-oxadiazoles and 1,3,4-thiadiazoles are well-known pharmacophores for many medicinally important drugs. Throughout the past 10 years, 1,3,4-oxa-/thiadiazole nuclei have been very attractive to researchers for drug design, synthesis, and the study of their potential activity towards a variety of diseases, including microbial and viral infections, cancer, diabetes, pain, and inflammation. This work is an up-to-date comparative study that identifies the differences between 1,3,4-thiadiazoles and 1,3,4-oxadiazoles concerning their methods of synthesis from different classes of starting compounds under various reaction conditions, as well as their biological activities and structure–activity relationship.

The nitrogen-containing five-membered heterocycles, particularly 1,3,4-oxadiazoles and 1,3,4-thiadiazoles, have received considerable attention because of their versatile biological properties and applications in drug discovery [1, 2] . Based on bioisosterism between sulfur and oxygen atoms [3] , 2-amino-1,3,4-thiadiazole could act as a bioisostere of 2-amino-1,3,4-oxadiazole and, therefore, produce biological properties broadly similar to those of the latter [4] . Moreover, these moieties are used as pharmacophores due to their favorable metabolic profile and ability to form hydrogen bonds [5, 6] . Different substituted 1,3,4-oxadiazole molecules possess antimicrobial [7, 8] , antitubercular [9] , antimalarial [10] , analgesic [11] , anticonvulsant [12] , anti-inflammatory [13] , antihepatitis B virus [14] , anti-severe acute respiratory syndrome coronavirus 2 (anti-SARS-CoV-2) [15] , anticancer [10, 16] , and antioxidant activities [17] . The antioxidants prevent the onset and propagation of oxidative disorders like autoimmune, cardiovascular, neurovascular diseases [2] .

The potent pharmacological activity of 1,3,4-oxadiazoles can be attributed to the presence of the toxophoric -N=C-O-linkage, which may react with the nucleophilic centers of the cell [18, 19] . Some of the drugs that contain an oxadiazole nucleus ( Figure 1 ) are Furamizole, a nitrofuran derivative with a strong antibacterial activity [20, 21] ; Nesapidil, a well-established vasodilating agent [22] ; Raltegravir, also known as MK-0518, which was the first FDA-approved HIV-1 integrase (IN) inhibitor launched by Merck & Co to treat HIV infection [23] ; Tiodazosin, an α1-adrenergic receptor antagonist used to treat hypertension [24, 25] ; Fenadiazole, a hypnotic drug [26, 27] ; Zibotentan, an anticancer Compared to 1,3,4-oxadiazole, the sulfur atom of 1,3,4-thiadiazole imparts improved lipid solubility, and the mesoionic nature of 1,3,4-thiadiazole makes this class of compounds show good tissue permeability [6] . Thus, the 1,3,4-thiadiazole fragment appears in many clinically used drugs (Figure 2 ), such as the diuretic drugs Acetazolamide and Methazolamide; Cefazolin CFZL and Cefazedone CFZD, which are first-generation cephalosporins; Atibeprone, an anti-depressant drug; antidiabetic agents Glybuthiazole and Glybuzole; antiprotozoal drug Megazol [31] ; and BMS341, a glucocorticoid receptor modulator [32] . Moreover, 1,3,4-thiadiazole derivatives are reported to possess anticancer [33] , antioxidant [34] , antimicrobial [35] , antidepressant [36] , anticonvulsant [37] , analgesic, and anti-inflammatory activities [38] . Compared to 1,3,4-oxadiazole, the sulfur atom of 1,3,4-thiadiazole imparts improved lipid solubility, and the mesoionic nature of 1,3,4-thiadiazole makes this class of compounds show good tissue permeability [6] . Thus, the 1,3,4-thiadiazole fragment appears in many clinically used drugs (Figure 2 ), such as the diuretic drugs Acetazolamide and Methazolamide; Cefazolin CFZL and Cefazedone CFZD, which are first-generation cephalosporins; Atibeprone, an anti-depressant drug; antidiabetic agents Glybuthiazole and Glybuzole; antiprotozoal drug Megazol [31] ; and BMS341, a glucocorticoid receptor modulator [32] . Moreover, 1,3,4-thiadiazole derivatives are reported to possess anticancer [33] , antioxidant [34] , antimicrobial [35] , antidepressant [36] , anticonvulsant [37] , analgesic, and anti-inflammatory activities [38] .

At the molecular level, 1,3,4-oxadiazole 1 is a thermally stable neutral aromatic molecule. It has four possible aromatic systems, 1-4: 1,3,4-oxadiazole 1, which is widely exploited for various applications; 1,3,4-oxadiazolines 2; 1,3,4-oxadiazolium cations 3; and the exocyclic-conjugated mesoionic 1,3,4-oxadiazole 4 ( Figure 3 ) [39] .

The linked substituents to 1,3,4-oxadiazole aromatic moieties normally appearing at positions C2, C5, and N3 may be represented by the following structural features 1,5-7 ( Figure 4 ) [39] . At the molecular level, 1,3,4-oxadiazole 1 is a thermally stable neutral aromatic molecule. It has four possible aromatic systems, 1-4: 1,3,4-oxadiazole 1, which is widely exploited for various applications; 1,3,4-oxadiazolines 2; 1,3,4-oxadiazolium cations 3; and the exocyclic-conjugated mesoionic 1,3,4-oxadiazole 4 ( Figure 3 ) [39] . The linked substituents to 1,3,4-oxadiazole aromatic moieties normally appearing at positions C2, C5, and N3 may be represented by the following structural features 1,5-7 ( Figure 4 ) [39] . At the molecular level, 1,3,4-oxadiazole 1 is a thermally stable neutral aromatic molecule. It has four possible aromatic systems, 1-4: 1,3,4-oxadiazole 1, which is widely exploited for various applications; 1,3,4-oxadiazolines 2; 1,3,4-oxadiazolium cations 3; and the exocyclic-conjugated mesoionic 1,3,4-oxadiazole 4 ( Figure 3 ) [39] . The linked substituents to 1,3,4-oxadiazole aromatic moieties normally appearing at positions C2, C5, and N3 may be represented by the following structural features 1,5-7 ( Figure 4 ) [39] . The electronic distribution in 1,3,4-oxadiazole has been calculated by various Selfconsistent Field Molecular Orbital (SCF-MO) methods [40] . Other structural parameters, the dipole moment, and data on its ultraviolet-visible (λ max calculated to be in the region 193-203 nm), NMR, NQR, and microwave spectra have been derived. Studies on 1,3,4oxadiazole indicate a maximum positive charge at the 2-position [41] . Molecular diagrams for 1,3,4-oxadiazole, 2-phenyl-and 2,5-diphenyl-1,3,4-oxadiazole, and oligomeric oxadiazoles have been derived, and conjugation between the rings was found to be similar to that in polyphenyls [42] .

Tautomerism in 2-hydroxy 8a, 2-mercapto 8b, and 2-amino-1,3,4-oxadiazole 8c is in equilibrium with the tautomeric oxadiazolines 2a, 2b, and 2c, respectively ( Figure 5 ) [43] . Evidence from UV, IR, 1 H-NMR, and 13 C-NMR spectra supports structure 2b for 1,3,4- The electronic distribution in 1,3,4-oxadiazole has been calculated by various Selfconsistent Field Molecular Orbital (SCF-MO) methods [40] . Other structural parameters, the dipole moment, and data on its ultraviolet-visible (λ max calculated to be in the region 193-203 nm), NMR, NQR, and microwave spectra have been derived. Studies on 1,3,4-oxadiazole indicate a maximum positive charge at the 2-position [41] . Molecular diagrams for 1,3,4-oxadiazole, 2-phenyl-and 2,5-diphenyl-1,3,4-oxadiazole, and oligomeric oxadiazoles have been derived, and conjugation between the rings was found to be similar to that in polyphenyls [42] .

Tautomerism in 2-hydroxy 8a, 2-mercapto 8b, and 2-amino-1,3,4-oxadiazole 8c is in equilibrium with the tautomeric oxadiazolines 2a, 2b, and 2c, respectively ( Figure 5 ) [43] . Evidence from UV, IR, 1 H-NMR, and 13 C-NMR spectra supports structure 2b for 1,3,4oxadiazoline-5-thione [44] . The electronic distribution in 1,3,4-oxadiazole has been calculated by various Selfconsistent Field Molecular Orbital (SCF-MO) methods [40] . Other structural parameters, the dipole moment, and data on its ultraviolet-visible (λ max calculated to be in the region 193-203 nm), NMR, NQR, and microwave spectra have been derived. Studies on 1,3,4oxadiazole indicate a maximum positive charge at the 2-position [41] . Molecular diagrams for 1,3,4-oxadiazole, 2-phenyl-and 2,5-diphenyl-1,3,4-oxadiazole, and oligomeric oxadiazoles have been derived, and conjugation between the rings was found to be similar to that in polyphenyls [42] .

Tautomerism in 2-hydroxy 8a, 2-mercapto 8b, and 2-amino-1,3,4-oxadiazole 8c is in equilibrium with the tautomeric oxadiazolines 2a, 2b, and 2c, respectively ( Figure 5 ) [43] . Evidence from UV, IR, 1 H-NMR, and 13 C-NMR spectra supports structure 2b for 1,3,4oxadiazoline-5-thione [44] . The development of 1,3,4-thiadiazole chemistry is linked to the discovery of phenylhydrazines and hydrazine in the late 19 th century. The first 1,3,4-thiadiazole was described by Fischer in 1882 and further developed by Bush and coworkers [45] , but the true nature of the ring system was demonstrated first in 1956 by Goerdler et al., [46] Similar to 1,3,4-oxadiazoles, the 1,3,4-thiadiazole derivatives are conveniently divided into three subclasses ( Figure 6 ):

a

Aromatic systems that include the neutral thiadiazoles 9 [45] . b

Mesoionic systems that are defined as a poly-heteroatomic system containing a fivemembered heterocyclic ring associated with conjugated p and π electrons and distinct regions of positive and negative charges 10. Mesoionic systems are dense and highly polarizable, with a net neutral electron charge; these characteristics allow mesoionic compounds to cross cellular membranes and interact with biological targets with distinct affinities [31] . c 1,3,4-thiadiazol-2-one(thione) 11a,b [47] . Further, the 1,3,4-thiadiazole ring system, with three heteroatoms, does not exhibit tautomerism in its fully conjugated form 9. However, when certain substituents are present, tautomerism is possible. 1,3,4-Thiadiazolin-2-ones 11a and -2-thione 11b exist in The development of 1,3,4-thiadiazole chemistry is linked to the discovery of phenylhydrazines and hydrazine in the late 19th century. The first 1,3,4-thiadiazole was described by Fischer in 1882 and further developed by Bush and coworkers [45] , but the true nature of the ring system was demonstrated first in 1956 by Goerdler et al. [46] . Similar to 1,3,4-oxadiazoles, the 1,3,4-thiadiazole derivatives are conveniently divided into three subclasses ( Figure 6 ):

a

Aromatic systems that include the neutral thiadiazoles 9 [45] . b

Mesoionic systems that are defined as a poly-heteroatomic system containing a fivemembered heterocyclic ring associated with conjugated p and π electrons and distinct regions of positive and negative charges 10. Mesoionic systems are dense and highly polarizable, with a net neutral electron charge; these characteristics allow mesoionic compounds to cross cellular membranes and interact with biological targets with distinct affinities [31] . c 1,3,4-thiadiazol-2-one(thione) 11a,b [47] .

The electronic distribution in 1,3,4-oxadiazole has been calculated by various Selfconsistent Field Molecular Orbital (SCF-MO) methods [40] . Other structural parameters, the dipole moment, and data on its ultraviolet-visible (λ max calculated to be in the region 193-203 nm), NMR, NQR, and microwave spectra have been derived. Studies on 1,3,4oxadiazole indicate a maximum positive charge at the 2-position [41] . Molecular diagrams for 1,3,4-oxadiazole, 2-phenyl-and 2,5-diphenyl-1,3,4-oxadiazole, and oligomeric oxadiazoles have been derived, and conjugation between the rings was found to be similar to that in polyphenyls [42] .

Tautomerism in 2-hydroxy 8a, 2-mercapto 8b, and 2-amino-1,3,4-oxadiazole 8c is in equilibrium with the tautomeric oxadiazolines 2a, 2b, and 2c, respectively ( Figure 5 ) [43] . Evidence from UV, IR, 1 H-NMR, and 13 C-NMR spectra supports structure 2b for 1,3,4oxadiazoline-5-thione [44] . The development of 1,3,4-thiadiazole chemistry is linked to the discovery of phenylhydrazines and hydrazine in the late 19 th century. The first 1,3,4-thiadiazole was described by Fischer in 1882 and further developed by Bush and coworkers [45] , but the true nature of the ring system was demonstrated first in 1956 by Goerdler et al., [46] Similar to 1,3,4-oxadiazoles, the 1,3,4-thiadiazole derivatives are conveniently divided into three subclasses ( Figure 6 ):

a

Aromatic systems that include the neutral thiadiazoles 9 [45] . b

Mesoionic systems that are defined as a poly-heteroatomic system containing a fivemembered heterocyclic ring associated with conjugated p and π electrons and distinct regions of positive and negative charges 10. Mesoionic systems are dense and highly polarizable, with a net neutral electron charge; these characteristics allow mesoionic compounds to cross cellular membranes and interact with biological targets with distinct affinities [31] . c 1,3,4-thiadiazol-2-one(thione) 11a,b [47] . Further, the 1,3,4-thiadiazole ring system, with three heteroatoms, does not exhibit tautomerism in its fully conjugated form 9. However, when certain substituents are present, tautomerism is possible. 1,3,4-Thiadiazolin-2-ones 11a and -2-thione 11b exist in Further, the 1,3,4-thiadiazole ring system, with three heteroatoms, does not exhibit tautomerism in its fully conjugated form 9. However, when certain substituents are present, tautomerism is possible. 1,3,4-Thiadiazolin-2-ones 11a and -2-thione 11b exist in the oxo 12a and thione 12b forms, respectively [47] . 2-Amino-1,3,4-thiadiazoles exist in the amino form 13 in solution and in the solid state ( Figure 7 ) [48] . Various synthetic routes for the synthesis of different classes of 1,3,4-oxadiazoles 1,3,4-thiadiazoles from diverse starting materials are illustrated in this collective (Figure 8) and are discussed in detail in this review. The biological activities of diff 1,3,4-oxadiazole and 1,3,4-thiadiazole classes are also summarized herein. 

The synthetic approaches adopted for the preparation of 1,3,4-oxadiazole and 1,3,4thiadiazole derivatives can be classified according to the starting material as follows:

Sulphonylmethyl-1,3,4-oxadiazole derivatives are synthesized by cyclocondensation of sulfonyl acetic acid hydrazide with derivatives of carboxylic acids or sulfonyl acetic acids. The most common reagent used for cyclocondensation is POCl 3 (Figure 9 ). The 1,3,4oxadiazole can then be interconverted to the 1,3,4-thiadiazole analog using thiourea and tetrahydrofuran (THF) [6] .

In 2019, Sekhar et al. [6] reported the cyclocondensation of E-aroylethene (14a-c) or E-arylsulfonylethene (15a-c) sulfonylacetic acid hydrazides with substituted cinnamic acid (16a-c) using the conventional method by reflux in POCl 3 to produce the 5-styryl-1,3,4oxadiazole derivatives (17a-c, 18a-c) in moderate yields. Interconversion of oxadiazole to thiadiazole was affected by the reaction of (17a-c, 18a-c) with thiourea in refluxing tetrahydrofuran to obtain 5-styryl-1,3,4-thiadiazole (19a-c, 20a-c) in moderate yields. However, all synthesized compounds were obtained in higher yields and in shorter reaction times by the ultrasound irradiation method when compared to the conventional method (Scheme 1). thiadiazole derivatives can be classified according to the starting material as follows:

Sulphonylmethyl-1,3,4-oxadiazole derivatives are synthesized by cyclocondensati of sulfonyl acetic acid hydrazide with derivatives of carboxylic acids or sulfonyl ace acids. The most common reagent used for cyclocondensation is POCl3 (Figure 9 ). The 1,3 oxadiazole can then be interconverted to the 1,3,4-thiadiazole analog using thiourea a tetrahydrofuran (THF) [6] . . Proposed mechanism for the synthesis of 1,3,4-oxadiazole derivatives using sulfonyl ace acid hydrazide based on the reported mechanism of formation of oxadiazole from hydrazide a and carboxylic acid [49] .

In 2019, Sekhar et al., [6] reported the cyclocondensation of E-aroylethene (14a-c) E-arylsulfonylethene (15a-c) sulfonylacetic acid hydrazides with substituted cinnam acid (16a-c) using the conventional method by reflux in POCl3 to produce the 5-styr 1,3,4-oxadiazole derivatives (17a-c, 18a-c) in moderate yields. Interconversion oxadiazole to thiadiazole was affected by the reaction of (17a-c, 18a-c) with thiourea refluxing tetrahydrofuran to obtain 5-styryl-1,3,4-thiadiazole (19a-c, 20a-c) in moder yields. However, all synthesized compounds were obtained in higher yields and shorter reaction times by the ultrasound irradiation method when compared to t conventional method (Scheme 1). Scheme 1. Synthetic pathway for compounds 17a-c-20a-c. . Proposed mechanism for the synthesis of 1,3,4-oxadiazole derivatives using sulfonyl acetic acid hydrazide based on the reported mechanism of formation of oxadiazole from hydrazide acid and carboxylic acid [49] .

acids. The most common reagent used for cyclocondensation is POCl3 (Figure 9 ). The 1,3,4oxadiazole can then be interconverted to the 1,3,4-thiadiazole analog using thiourea and tetrahydrofuran (THF) [6] . . Proposed mechanism for the synthesis of 1,3,4-oxadiazole derivatives using sulfonyl acetic acid hydrazide based on the reported mechanism of formation of oxadiazole from hydrazide acid and carboxylic acid [49] .

In 2019, Sekhar et al., [6] reported the cyclocondensation of E-aroylethene (14a-c) or E-arylsulfonylethene (15a-c) sulfonylacetic acid hydrazides with substituted cinnamic acid (16a-c) using the conventional method by reflux in POCl3 to produce the 5-styryl-1,3,4-oxadiazole derivatives (17a-c, 18a-c) in moderate yields. Interconversion of oxadiazole to thiadiazole was affected by the reaction of (17a-c, 18a-c) with thiourea in refluxing tetrahydrofuran to obtain 5-styryl-1,3,4-thiadiazole (19a-c, 20a-c) in moderate yields. However, all synthesized compounds were obtained in higher yields and in shorter reaction times by the ultrasound irradiation method when compared to the conventional method (Scheme 1). Similarly, a new class of sulfone/sulfonamide-linked bis(1,3,4-oxadiazoles) (24a-c, 25a-c) was prepared by the cyclocondensation of arylsulfonylacetic acid hydrazide (21a-c) or arylaminosulfonylacetic acid hydrazide (22a-c) with sulfonyldiacetic acid 23 in the presence of POCl 3 . Then, the bis(1,3,4-oxadiazoles) (24a-c, 25a-c) were converted to bis(1,3,4-thiadiazoles) (26a-c, 27a-c) by heating with thiourea in THF (Scheme 2) [2] .

The same methodology was used by Padmaja et al., in the preparation of styrylsulfonylmethyl 1,3,4-oxadiazoles (30a-c) through cyclocondensation of the intermediate arylaminosulfonylacetic acid hydrazides (28a-c) with Z-styrylsulfonylacetic acid (29a-c). The obtained oxadiazoles were then treated with thiourea in THF to undergo interconversion to the corresponding thiadiazoles (31a-c) (Scheme 3) [49] .

Similarly, a new class of sulfone/sulfonamide-linked bis(1,3,4-oxadiazoles) (24a-c 25a-c) was prepared by the cyclocondensation of arylsulfonylacetic acid hydrazide (21a c) or arylaminosulfonylacetic acid hydrazide (22a-c) with sulfonyldiacetic acid 23 in the presence of POCl3. Then, the bis(1,3,4-oxadiazoles) (24a-c, 25a-c) were converted to bis(1,3,4-thiadiazoles) (26a-c, 27a-c) by heating with thiourea in THF (Scheme 2) [2] .

The same methodology was used by Padmaja et al., in the preparation o styrylsulfonylmethyl 1,3,4-oxadiazoles (30a-c) through cyclocondensation of the intermediate arylaminosulfonylacetic acid hydrazides (28a-c) with Z-styrylsulfonylaceti acid (29a-c). The obtained oxadiazoles were then treated with thiourea in THF to undergo interconversion to the corresponding thiadiazoles (31a-c) (Scheme 3) [49] . In 2010, Padmavathi et al., synthesized a series of 2-arylaminosulfonylmethyl-5-aryl 1,3,4-oxadiazoles (33a-c) and 2-arylaminosulfonylmethyl-5-arylsulfonylmethyl-1,3,4 oxadiazoles (34a-c) by the cyclocondensation of arylaminosulfonylacetic acids (32a-c with different aryl acid hydrazides and arylsulfonylacetic acid hydrazides in the presence presence of POCl3. Then, the bis(1,3,4-oxadiazoles) (24a-c, 25a-c) were converted to bis(1,3,4-thiadiazoles) (26a-c, 27a-c) by heating with thiourea in THF (Scheme 2) [2] . The same methodology was used by Padmaja et al., in the preparation of styrylsulfonylmethyl 1,3,4-oxadiazoles (30a-c) through cyclocondensation of the intermediate arylaminosulfonylacetic acid hydrazides (28a-c) with Z-styrylsulfonylacetic acid (29a-c). The obtained oxadiazoles were then treated with thiourea in THF to undergo interconversion to the corresponding thiadiazoles (31a-c) (Scheme 3) [49] . In 2010, Padmavathi et al., synthesized a series of 2-arylaminosulfonylmethyl-5-aryl-1,3,4-oxadiazoles (33a-c) and 2-arylaminosulfonylmethyl-5-arylsulfonylmethyl-1,3,4oxadiazoles (34a-c) by the cyclocondensation of arylaminosulfonylacetic acids (32a-c) with different aryl acid hydrazides and arylsulfonylacetic acid hydrazides in the presence In 2010, Padmavathi et al., synthesized a series of 2-arylaminosulfonylmethyl-5aryl-1,3,4-oxadiazoles (33a-c) and 2-arylaminosulfonylmethyl-5-arylsulfonylmethyl-1,3,4oxadiazoles (34a-c) by the cyclocondensation of arylaminosulfonylacetic acids (32a-c) with different aryl acid hydrazides and arylsulfonylacetic acid hydrazides in the presence of POCl 3 , respectively. Interconversion of (33a-c, 34a-c) to thiadiazoles (35a-c, 36a-c) was affected by treatment with thiourea in THF (Scheme 4) [50] . of POCl3, respectively. Interconversion of (33a-c, 34a-c) to thiadiazoles (35a-c, 36a-c) was affected by treatment with thiourea in THF (Scheme 4) [50] .

A variety of symmetrical 2,4-bis-oxazolyl/thiazolyl/imidazolylacetamidosulfonylmethyl 1,3,4-oxadiazoles (43a-c, 44a-c, 45a-c) were prepared via a one-step route through the reaction of different 2-((4-aryl(oxazole or thiazole or 1H-imidazole)-2ylcarbamoyl)methylsulfonyl)-acetic acid derivatives (37a-c, 38a-c, 39a-c) with the respective acetohydrazides (40a-c, 41a-c, 42a-c) upon heating under reflux in POCl3 (Scheme 5). A variety of symmetrical 2,4-bis-oxazolyl/thiazolyl/imidazolylacetamido-sulfonylmethyl 1,3,4-oxadiazoles (43a-c, 44a-c, 45a-c) were prepared via a one-step route through the reaction of different 2-((4-aryl(oxazole or thiazole or 1H-imidazole)-2-ylcarbamoyl)methylsulfonyl)acetic acid derivatives (37a-c, 38a-c, 39a-c) with the respective acetohydrazides (40a-c, 41a-c, 42a-c) upon heating under reflux in POCl 3 (Scheme 5). of POCl3, respectively. Interconversion of (33a-c, 34a-c) to thiadiazoles (35a-c, 36a-c) was affected by treatment with thiourea in THF (Scheme 4) [50] . A variety of symmetrical 2,4-bis-oxazolyl/thiazolyl/imidazolylacetamidosulfonylmethyl 1,3,4-oxadiazoles (43a-c, 44a-c, 45a-c) were prepared via a one-step route through the reaction of different 2-((4-aryl(oxazole or thiazole or 1H-imidazole)-2ylcarbamoyl)methylsulfonyl)-acetic acid derivatives (37a-c, 38a-c, 39a-c) with the respective acetohydrazides (40a-c, 41a-c, 42a-c) upon heating under reflux in POCl3 (Scheme 5). For the thiadiazole analogs, a two-step route that involved the synthesis of the bis-hydrazide intermediate followed by cyclization was adopted. The bis-hydrazides (46a-c, 47a-c, 48a-c) were prepared by coupling the carboxylic acid derivatives (37a-c, 38a-c, 39a-c) with the acetohydrazide derivatives (40a-c, 41a-c, 42a-c) in the presence of 1-[bis(dimethylamino)methylene]-1H1,2,3-triazolo [4,5-b] pyridinium-3-oxid hexafluorophosphate (HATU) and N,N-diisopropyl ethylamine (DIPEA) in DMF. Then, cyclocondensation of (46a-c, 47a-c, 48a-c) with Lawesson's reagent (LR), propylphosphonic anhydride (T 3 P) and TEA produced the corresponding 1,3,4-thiadiazole (49a-c, 50a-c, 51a-c) (Scheme 6) [51] . For the thiadiazole analogs, a two-step route that involved the synthesis of the bishydrazide intermediate followed by cyclization was adopted. The bis-hydrazides (46a-c, 47a-c, 48a-c) were prepared by coupling the carboxylic acid derivatives (37a-c, 38a-c, 39ac) with the acetohydrazide derivatives (40a-c, 41a-c, 42a-c) in the presence of 1-[bis(dimethylamino)methylene]-1H1,2,3-triazolo [4,5-b] pyridinium-3-oxid hexafluorophosphate (HATU) and N,N-diisopropyl ethylamine (DIPEA) in DMF. Then, cyclocondensation of (46a-c, 47a-c, 48a-c) with Lawesson's reagent (LR), propylphosphonic anhydride (T3P) and TEA produced the corresponding 1,3,4thiadiazole (49a-c, 50a-c, 51a-c) (Scheme 6) [51] . Scheme 6. Synthetic pathway for compounds 49a-c-51a-c.

1,2-Diacylhydrazines ( Figure 10 ) can undergo dehydrocyclization reaction, forming 1,3,4-oxadiazoles using cyclodehydrating agents such as POCl3, P2O5, polyphosphoric acid (PPA) [52] , N,N′-dicyclohexylcarbodiimide (DCC) [53] , or ethyl-3-(3dimethylaminopropyl) carbodiimide (EDC) [54] (Figure 11 ). They can also be converted to the 1,3,4-thiadiazole ring by dehydrosulfurization reaction using Lawesson's reagent (LR) [55] or P2S5 [56] (Figure 12 ). 

1,2-Diacylhydrazines ( Figure 10 ) can undergo dehydrocyclization reaction, forming 1,3,4-oxadiazoles using cyclodehydrating agents such as POCl 3 , P 2 O 5 , polyphosphoric acid (PPA) [52] , N,N -dicyclohexylcarbodiimide (DCC) [53] , or ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) [54] (Figure 11 ). They can also be converted to the 1,3,4-thiadiazole ring by dehydrosulfurization reaction using Lawesson's reagent (LR) [55] or P 2 S 5 [56] ( Figure 12 ). For the thiadiazole analogs, a two-step route that involved the synthesis of the bishydrazide intermediate followed by cyclization was adopted. The bis-hydrazides (46a-c, 47a-c, 48a-c) were prepared by coupling the carboxylic acid derivatives (37a-c, 38a-c, 39ac) with the acetohydrazide derivatives (40a-c, 41a-c, 42a-c) in the presence of 1-[bis(dimethylamino)methylene]-1H1,2,3-triazolo [4,5-b] pyridinium-3-oxid hexafluorophosphate (HATU) and N,N-diisopropyl ethylamine (DIPEA) in DMF. Then, cyclocondensation of (46a-c, 47a-c, 48a-c) with Lawesson's reagent (LR), propylphosphonic anhydride (T3P) and TEA produced the corresponding 1,3,4thiadiazole (49a-c, 50a-c, 51a-c) (Scheme 6) [51] . Scheme 6. Synthetic pathway for compounds 49a-c-51a-c.

1,2-Diacylhydrazines ( Figure 10 ) can undergo dehydrocyclization reaction, forming 1,3,4-oxadiazoles using cyclodehydrating agents such as POCl3, P2O5, polyphosphoric acid (PPA) [52] , N,N′-dicyclohexylcarbodiimide (DCC) [53] , or ethyl-3-(3dimethylaminopropyl) carbodiimide (EDC) [54] (Figure 11 ). They can also be converted to the 1,3,4-thiadiazole ring by dehydrosulfurization reaction using Lawesson's reagent (LR) [55] or P2S5 [56] (Figure 12 ). s-Tetrazine-3,6-dicarbohydrazides (52a-c) can be reacted at high temperature with cyclodehydrating reagents such as POCl3 or DCC in dry toluene to obtain conjugated stetrazine-1,3,4-oxadiazole hybrids. This reaction was unsuccessful under conventional conditions; however, employing microwave irradiation led to the desired 1,3,4oxadiazoles (53a-c) in good yields. S-Tetrazine-3,6-dicarbohydrazides (52a-c) were also treated with LR in dry toluene under conventional heating and microwave irradiation, with both methods resulting in the formation of s-tetrazine-1,3,4-thiadiazole derivatives (54a-c) in satisfactory yields (Scheme 7) [53] . The key intermediate N-(5-methyl-2-nitrobenzoyl)-2-substituted carbohydrazides (55a-e) were treated separately with POCl3 and LR to obtain the desired 2-aryl-5- Figure 11 . Mechanism of dehydrocyclization of 1,2-diacylhydrazines to 1,3,4-oxadiazoles [53] .

Molecules 2022, 27, x FOR PEER REVIEW 10 of 59 Figure 11 . Mechanism of dehydrocyclization of 1,2-diacylhydrazines to 1,3,4-oxadiazoles [53] . s-Tetrazine-3,6-dicarbohydrazides (52a-c) can be reacted at high temperature with cyclodehydrating reagents such as POCl3 or DCC in dry toluene to obtain conjugated stetrazine-1,3,4-oxadiazole hybrids. This reaction was unsuccessful under conventional conditions; however, employing microwave irradiation led to the desired 1,3,4oxadiazoles (53a-c) in good yields. S-Tetrazine-3,6-dicarbohydrazides (52a-c) were also treated with LR in dry toluene under conventional heating and microwave irradiation, with both methods resulting in the formation of s-tetrazine-1,3,4-thiadiazole derivatives (54a-c) in satisfactory yields (Scheme 7) [53] . The key intermediate N-(5-methyl-2-nitrobenzoyl)-2-substituted carbohydrazides (55a-e) were treated separately with POCl3 and LR to obtain the desired 2-aryl-5- s-Tetrazine-3,6-dicarbohydrazides (52a-c) can be reacted at high temperature with cyclodehydrating reagents such as POCl 3 or DCC in dry toluene to obtain conjugated s-tetrazine-1,3,4-oxadiazole hybrids. This reaction was unsuccessful under conventional conditions; however, employing microwave irradiation led to the desired 1,3,4-oxadiazoles (53a-c) in good yields. S-Tetrazine-3,6-dicarbohydrazides (52a-c) were also treated with LR in dry toluene under conventional heating and microwave irradiation, with both methods resulting in the formation of s-tetrazine-1,3,4-thiadiazole derivatives (54a-c) in satisfactory yields (Scheme 7) [53] .

Molecules 2022, 27, x FOR PEER REVIEW 10 of 59 Figure 11 . Mechanism of dehydrocyclization of 1,2-diacylhydrazines to 1,3,4-oxadiazoles [53] . s-Tetrazine-3,6-dicarbohydrazides (52a-c) can be reacted at high temperature with cyclodehydrating reagents such as POCl3 or DCC in dry toluene to obtain conjugated stetrazine-1,3,4-oxadiazole hybrids. This reaction was unsuccessful under conventional conditions; however, employing microwave irradiation led to the desired 1,3,4oxadiazoles (53a-c) in good yields. S-Tetrazine-3,6-dicarbohydrazides (52a-c) were also treated with LR in dry toluene under conventional heating and microwave irradiation, with both methods resulting in the formation of s-tetrazine-1,3,4-thiadiazole derivatives (54a-c) in satisfactory yields (Scheme 7) [53] . The key intermediate N-(5-methyl-2-nitrobenzoyl)-2-substituted carbohydrazides (55a-e) were treated separately with POCl3 and LR to obtain the desired 2-aryl-5-Scheme 7. Synthetic pathway for compounds 53a-c and 54a-c.

The key intermediate N-(5-methyl-2-nitrobenzoyl)-2-substituted carbohydrazides (55a-e) were treated separately with POCl 3 and LR to obtain the desired 2-aryl-5-substituted-1,3,4-oxadiazoles (56a-e) and thiadiazoles (57a-e), respectively. The yields of 1,3,4-thiadiazoles were low compared to those of oxadiazoles (Scheme 8) [55] . Two series of novel diosgenin derivatives bearing 1,3,4-oxadiazole (59a-e) or 1,3,4thiadiazole (60a-e) moieties were designed and synthesized. The cyclodehydration of the N,N'-disubstituted hydrazine intermediates (58a-e) with POCl3 furnished the corresponding 1,3,4-oxadiazoles (59a-e) in high yields. On the other hand, heating intermediates (58a-e) with LR in dry toluene under reflux conditions induced dehydrosulfurization into the 1,3,4-thiadiazole counterparts (60a-e) in moderate yields (Scheme 9) [58] . Similarly, a series of 4-oxo-4H-pyrido [1,2-a]pyrimidine derivatives containing the 1,3,4-oxadiazole (62a-c) or 1,3,4-thiadiazole (63a-c) ring were synthesized from the corresponding diacylhydrazines (61a-e) by dehydrocyclization using P2O5 in toluene and dehydrosulfurization by LR in THF (Scheme 10) [59] . Two series of novel diosgenin derivatives bearing 1,3,4-oxadiazole (59a-e) or 1,3,4thiadiazole (60a-e) moieties were designed and synthesized. The cyclodehydration of the N,N -disubstituted hydrazine intermediates (58a-e) with POCl 3 furnished the corresponding 1,3,4-oxadiazoles (59a-e) in high yields. On the other hand, heating intermediates (58a-e) with LR in dry toluene under reflux conditions induced dehydrosulfurization into the 1,3,4-thiadiazole counterparts (60a-e) in moderate yields (Scheme 9) [58] .

substituted-1,3,4-oxadiazoles (56a-e) and thiadiazoles (57a-e), respectively. The yields 1,3,4-thiadiazoles were low compared to those of oxadiazoles (Scheme 8) [55] . Two series of novel diosgenin derivatives bearing 1,3,4-oxadiazole (59a-e) or 1,3 thiadiazole (60a-e) moieties were designed and synthesized. The cyclodehydration of t N,N'-disubstituted hydrazine intermediates (58a-e) with POCl3 furnished t corresponding 1,3,4-oxadiazoles (59a-e) in high yields. On the other hand, heati intermediates (58a-e) with LR in dry toluene under reflux conditions induc dehydrosulfurization into the 1,3,4-thiadiazole counterparts (60a-e) in moderate yiel (Scheme 9) [58] . Similarly, a series of 4-oxo-4H-pyrido [1,2-a]pyrimidine derivatives containing t 1,3,4-oxadiazole (62a-c) or 1,3,4-thiadiazole (63a-c) ring were synthesized from t corresponding diacylhydrazines (61a-e) by dehydrocyclization using P2O5 in toluene a dehydrosulfurization by LR in THF (Scheme 10) [59] . Similarly, a series of 4-oxo-4H-pyrido [1,2-a]pyrimidine derivatives containing the 1,3,4-oxadiazole (62a-c) or 1,3,4-thiadiazole (63a-c) ring were synthesized from the corresponding diacylhydrazines (61a-e) by dehydrocyclization using P 2 O 5 in toluene and dehydrosulfurization by LR in THF (Scheme 10) [59] . Orthogonally protected 1,3,4-thiadiazole and 1,3,4-oxadiazole-tether dipeptidomimetics were synthesized from a set of protected diacylhydrazines (64a derived from amino acids in good to high yield with good purities and with no detectab enantiomerization. The 1,3,4-thiadiazolo-dipeptides (66a-h) were formed by refluxi (64a-h) with LR in THF. Furthermore, refluxing (64a-h) in dry CH2Cl2 in the presence EDC and TEA resulted in the formation of 1,3,4-oxadiazolo-peptides (65a-h) cyclodehydration (Scheme 11) [54] . A series of mesogenic bent-shaped 2-(4-nitrophenyl)-5-(4-n-alkoxyphenyl)-1,3 oxadiazoles (68a-f) was synthesized by refluxing the analogous diacylhydrazi intermediates (67a-f) with POCl3. The 1,3,4-thiadiazole analogs (69a-f) were obtained dehydrosulfurization of the same intermediates through heating under reflux with P2S5 dry pyridine (Scheme 12) [56] . Orthogonally protected 1,3,4-thiadiazole and 1,3,4-oxadiazole-tethered dipeptidomimetics were synthesized from a set of protected diacylhydrazines (64a-h) derived from amino acids in good to high yield with good purities and with no detectable enantiomerization. The 1,3,4-thiadiazolo-dipeptides (66a-h) were formed by refluxing (64a-h) with LR in THF. Furthermore, refluxing (64a-h) in dry CH 2 Cl 2 in the presence of EDC and TEA resulted in the formation of 1,3,4-oxadiazolo-peptides (65a-h) by cyclodehydration (Scheme 11) [54] .

x FOR PEER REVIEW 12 of 59 Scheme 10. Synthetic pathway for compounds 62a-e and 63a-e.

Orthogonally protected 1,3,4-thiadiazole and 1,3,4-oxadiazole-tethered dipeptidomimetics were synthesized from a set of protected diacylhydrazines (64a-h) derived from amino acids in good to high yield with good purities and with no detectable enantiomerization. The 1,3,4-thiadiazolo-dipeptides (66a-h) were formed by refluxing (64a-h) with LR in THF. Furthermore, refluxing (64a-h) in dry CH2Cl2 in the presence of EDC and TEA resulted in the formation of 1,3,4-oxadiazolo-peptides (65a-h) by cyclodehydration (Scheme 11) [54] . A series of mesogenic bent-shaped 2-(4-nitrophenyl)-5-(4-n-alkoxyphenyl)-1,3,4oxadiazoles (68a-f) was synthesized by refluxing the analogous diacylhydrazine intermediates (67a-f) with POCl3. The 1,3,4-thiadiazole analogs (69a-f) were obtained by dehydrosulfurization of the same intermediates through heating under reflux with P2S5 in dry pyridine (Scheme 12) [56] . A series of mesogenic bent-shaped 2-(4-nitrophenyl)-5-(4-n-alkoxyphenyl)-1,3,4-oxadiazoles (68a-f) was synthesized by refluxing the analogous diacylhydrazine intermediates (67a-f) with POCl 3. The 1,3,4-thiadiazole analogs (69a-f) were obtained by dehydrosulfurization of the same intermediates through heating under reflux with P 2 S 5 in dry pyridine (Scheme 12) [56] . A solvent-free solid-state method was developed to synthesize a series of substituted 1,3,4-oxadiazoles (71a-k) and 1,3,4-thiadiazoles (72a-d,f-j) derivatives in high yields by cyclodehydration of N,N'-bishydrazide derivatives (70a-k). For cyclization to 1,3,4oxadiazoles (71a-k), three kinds of cyclizing agents, P2O5, PPA, and POCl3, were used. It was found that the three reagents worked well and provided the products with high yields. On the other hand, P2S5 and thiourea were used as cyclizing agents to promote the cyclization to 1,3,4-thiadiazoles (72a-d,f-j). Due to the decomposition of thiourea at high temperatures, the reaction yield using thiourea was lower than that of P2S5. Generally, P2O5 and P2S5 act not only as cyclizing agents but also as dehydrating agents, which further promote cyclodehydration (Scheme 13) [52] . Scheme 13. Synthetic pathway for compounds 71a-k and 72a-d,f-j.

Aryl amino-1,3,4-oxadiazoles can be cyclized from acyl semicarbazides under the effect of acid through treatment with POCl3 [60] ; likewise, acyl thiosemicarbazides can be dehydrocyclized to aryl amino 1,3,4-thiadiazoles under acidic conditions using conc. H2SO4 [61] , H3PO4 [60] , POCl3 [62] , p-TsCl in TEA [63] , or acetic anhydride [64] (Figure 13 ). A solvent-free solid-state method was developed to synthesize a series of substituted 1,3,4-oxadiazoles (71a-k) and 1,3,4-thiadiazoles (72a-d,f-j) derivatives in high yields by cyclodehydration of N,N'-bishydrazide derivatives (70a-k). For cyclization to 1,3,4oxadiazoles (71a-k), three kinds of cyclizing agents, P 2 O 5 , PPA, and POCl 3 , were used. It was found that the three reagents worked well and provided the products with high yields. On the other hand, P 2 S 5 and thiourea were used as cyclizing agents to promote the cyclization to 1,3,4-thiadiazoles (72a-d,f-j). Due to the decomposition of thiourea at high temperatures, the reaction yield using thiourea was lower than that of P 2 S 5 . Generally, P 2 O 5 and P 2 S 5 act not only as cyclizing agents but also as dehydrating agents, which further promote cyclodehydration (Scheme 13) [52] . A solvent-free solid-state method was developed to synthesize a series of substituted 1,3,4-oxadiazoles (71a-k) and 1,3,4-thiadiazoles (72a-d,f-j) derivatives in high yields by cyclodehydration of N,N'-bishydrazide derivatives (70a-k). For cyclization to 1,3,4oxadiazoles (71a-k), three kinds of cyclizing agents, P2O5, PPA, and POCl3, were used. It was found that the three reagents worked well and provided the products with high yields. On the other hand, P2S5 and thiourea were used as cyclizing agents to promote the cyclization to 1,3,4-thiadiazoles (72a-d,f-j). Due to the decomposition of thiourea at high temperatures, the reaction yield using thiourea was lower than that of P2S5. Generally, P2O5 and P2S5 act not only as cyclizing agents but also as dehydrating agents, which further promote cyclodehydration (Scheme 13) [52] . Scheme 13. Synthetic pathway for compounds 71a-k and 72a-d,f-j.

Aryl amino-1,3,4-oxadiazoles can be cyclized from acyl semicarbazides under the effect of acid through treatment with POCl3 [60] ; likewise, acyl thiosemicarbazides can be dehydrocyclized to aryl amino 1,3,4-thiadiazoles under acidic conditions using conc. H2SO4 [61] , H3PO4 [60] , POCl3 [62] , p-TsCl in TEA [63] , or acetic anhydride [64] (Figure 13 ). Scheme 13. Synthetic pathway for compounds 71a-k and 72a-d,f-j.

Aryl amino-1,3,4-oxadiazoles can be cyclized from acyl semicarbazides under the effect of acid through treatment with POCl 3 [60] ; likewise, acyl thiosemicarbazides can be dehydrocyclized to aryl amino 1,3,4-thiadiazoles under acidic conditions using conc. H 2 SO 4 [61] , H 3 PO 4 [60] , POCl 3 [62] , p-TsCl in TEA [63] , or acetic anhydride [64] (Figure 13 ).

1,3,4-Oxadiazoles can be also synthesized from acyl thiosemicarbazides through oxidative desulfurization reaction using one of the following reagents: I 2 /KI in NaOH [61] , HgO in ethanol [62] , Hg(OAc) 2 in ethanol [66] , HgCl 2 in triethylamine (TEA) [67] , or EDC.HCl in DMSO ( Figure 14 ) [63] . Molecules 2022, 27, x FOR PEER REVIEW 14 of 59 Figure 13 . Proposed mechanism for the synthesis of 2,5-disubstituted-1,3,4-oxa-/thiadiazoles using acyl semi/thiosemicarbazides based on the reported mechanism for synthesis of 2,5-disubstituted-1,3,4-thiadiazoles from acyl thiosemicarbazide [65] .

1,3,4-Oxadiazoles can be also synthesized from acyl thiosemicarbazides through oxidative desulfurization reaction using one of the following reagents: I2/KI in NaOH [61] , HgO in ethanol [62] , Hg(OAc)2 in ethanol [66] , HgCl2 in triethylamine (TEA) [67] , or EDC.HCl in DMSO ( Figure 14 ) [63] . Proposed mechanism for the synthesis of 2,5-disubstituted-1,3,4-oxa-/thiadiazoles using acyl semi/thiosemicarbazides based on the reported mechanism for synthesis of 2,5-disubstituted-1,3,4-thiadiazoles from acyl thiosemicarbazide [65] .

Molecules 2022, 27, x FOR PEER REVIEW 14 Figure 13 . Proposed mechanism for the synthesis of 2,5-disubstituted-1,3,4-oxa-/thiadiazoles acyl semi/thiosemicarbazides based on the reported mechanism for synthesis of 2,5-disubstit 1,3,4-thiadiazoles from acyl thiosemicarbazide [65] .

1,3,4-Oxadiazoles can be also synthesized from acyl thiosemicarbazides thr oxidative desulfurization reaction using one of the following reagents: I2/KI in NaOH HgO in ethanol [62] , Hg(OAc)2 in ethanol [66] , HgCl2 in triethylamine (TEA) [67 EDC .HCl in DMSO ( Figure 14 ) [63] . . Proposed mechanism for the synthesis of 2,5-disubstituted-1,3,4-oxa-/thiadiazoles using acyl semi/thiosemicarbazides based on the reported mechanism for synthesis of 2,5-disubstituted-1,3,4-thiadiazoles from acyl thiosemicarbazide [65] .

1,3,4-Oxadiazoles can be also synthesized from acyl thiosemicarbazides through oxidative desulfurization reaction using one of the following reagents: I2/KI in NaOH [61] , HgO in ethanol [62] , Hg(OAc)2 in ethanol [66] , HgCl2 in triethylamine (TEA) [67] , or EDC.HCl in DMSO ( Figure 14 ) [63] . Novel coumarin derivatives possessing 2-arylamino-1,3,4-thiadiazole (84a-e) and 1,3,4-oxadiazole (83a-e) moieties were efficiently synthesized through cyclization of thiosemicarbazides (82a-e) using conventional methods. The intramolecular cyclocondensation of (83a-e) in the presence of concentrated H2SO4 formed the corresponding 1,3,4-thiadiazoles (84a-e) in good yields, whereas the cyclocondensation of (82a-e) in the presence of NaOH/KI/I2 in ethanol formed the corresponding 1,3,4oxadiazoles (83a-e) in lower yields. Furthermore, the same compounds were also prepared by the microwave irradiation method and grinding method, with higher yields and shorter reaction times (Scheme 17) [70] . Novel coumarin derivatives possessing 2-arylamino-1,3,4-thiadiazole (84a-e) and 1,3,4-oxadiazole (83a-e) moieties were efficiently synthesized through cyclization of thiosemicarbazides (82a-e) using conventional methods. The intramolecular cyclocondensation of (83a-e) in the presence of concentrated H2SO4 formed the corresponding 1,3,4-thiadiazoles (84a-e) in good yields, whereas the cyclocondensation of (82a-e) in the presence of NaOH/KI/I2 in ethanol formed the corresponding 1,3,4oxadiazoles (83a-e) in lower yields. Furthermore, the same compounds were also prepared by the microwave irradiation method and grinding method, with higher yields and shorter reaction times (Scheme 17) [70] . Novel coumarin derivatives possessing 2-arylamino-1,3,4-thiadiazole (84a-e) and 1,3,4-oxadiazole (83a-e) moieties were efficiently synthesized through cyclization of thiosemicarbazides (82a-e) using conventional methods. The intramolecular cyclocondensation of (83a-e) in the presence of concentrated H 2 SO 4 formed the corresponding 1,3,4-thiadiazoles (84a-e) in good yields, whereas the cyclocondensation of (82a-e) in the presence of NaOH/KI/I 2 in ethanol formed the corresponding 1,3,4-oxadiazoles (83a-e) in lower yields. Furthermore, the same compounds were also prepared by the microwave irradiation method and grinding method, with higher yields and shorter reaction times (Scheme 17) [70] .

Similarly, benzimidazole derivatives featuring 1,3,4-oxadiazol-2-amine (86a-c) and 1,3,4-thiadiazol-2-amine (87a-c) heterocyclic moieties were prepared from acyl thiosemicarbazide intermediates (85a-c) via intramolecular cyclization with I 2 /KI/4N NaOH and conc. H 2 SO 4 , respectively (Scheme 18) [71] . Similarly, benzimidazole derivatives featuring 1,3,4-oxadiazol-2-amine (86a-c) and 1,3,4-thiadiazol-2-amine (87a-c) heterocyclic moieties were prepared from acyl thiosemicarbazide intermediates (85a-c) via intramolecular cyclization with I2/KI/4N NaOH and conc. H2SO4, respectively (Scheme 18) [71] . Series of substituted 1,4-dihydro-4-oxoquinoline bearing 2-arylamino-1,3,4oxadiazole (89a,b) or 1,3,4-thiadiazole (90a,b) were synthesized by El-Essawy et al., [72] . The 1,3,4-oxadiazole derivatives (89a,b) were obtained through oxidative cyclization of the acyl thiosemicarbazide intermediates (88a,b) using I2/KI in ethanolic NaOH. Intramolecular dehydration of (88a,b) with cold-concentrated H2SO4 furnished the 1,3,4thiadiazole counterparts (90a,b) (Scheme 19). Similarly, benzimidazole derivatives featuring 1,3,4-oxadiazol-2-amine (86a-c) and 1,3,4-thiadiazol-2-amine (87a-c) heterocyclic moieties were prepared from acyl thiosemicarbazide intermediates (85a-c) via intramolecular cyclization with I2/KI/4N NaOH and conc. H2SO4, respectively (Scheme 18) [71] . Series of substituted 1,4-dihydro-4-oxoquinoline bearing 2-arylamino-1,3,4oxadiazole (89a,b) or 1,3,4-thiadiazole (90a,b) were synthesized by El-Essawy et al., [72] . The 1,3,4-oxadiazole derivatives (89a,b) were obtained through oxidative cyclization of the acyl thiosemicarbazide intermediates (88a,b) using I2/KI in ethanolic NaOH. Intramolecular dehydration of (88a,b) with cold-concentrated H2SO4 furnished the 1,3,4thiadiazole counterparts (90a,b) (Scheme 19). Series of substituted 1,4-dihydro-4-oxoquinoline bearing 2-arylamino-1,3,4-oxadiazole (89a,b) or 1,3,4-thiadiazole (90a,b) were synthesized by El-Essawy et al. [72] . The 1,3,4oxadiazole derivatives (89a,b) were obtained through oxidative cyclization of the acyl thiosemicarbazide intermediates (88a,b) using I 2 /KI in ethanolic NaOH. Intramolecular dehydration of (88a,b) with cold-concentrated H 2 SO 4 furnished the 1,3,4-thiadiazole counterparts (90a,b) (Scheme 19). In a different study, the tetrahydropyrimidinone derivative bearing a 2-amino-1,3,4thiadiazole motif at position 5 93 was synthesized by treatment of the key intermediate tetrahydro pyrimidine-(5)-3-carbothioamide 91 with conc. H2SO4. Furthermore, the oxadiazole derivative 92 was prepared by heterocyclization of 91 when treated with I2/KI in a basic medium (10% NaOH) (Scheme 20) [73] . A series of N-substituted 2-amino-1,3,4-thiadiazoles (96a-c) and 1,3,4-oxadiazoles (95a-c) carrying an (R) 5-(1-(4-(5-chloro-3-fluoropyridin-2-yloxy)phenoxy)ethyl) moiety were synthesized from acyl thiosemicarbazide intermediates (94a-c) by cyclodehydration using conc. H2SO4 and cyclodesulfurization with alkaline iodine, respectively (Scheme 21) [74] . In a different study, the tetrahydropyrimidinone derivative bearing a 2-amino-1,3,4thiadiazole motif at position 5 93 was synthesized by treatment of the key intermediate tetrahydro pyrimidine-(5)-3-carbothioamide 91 with conc. H 2 SO 4 . Furthermore, the oxadiazole derivative 92 was prepared by heterocyclization of 91 when treated with I 2 /KI in a basic medium (10% NaOH) (Scheme 20) [73] . In a different study, the tetrahydropyrimidinone derivative bearing a 2-amino-1,3,4thiadiazole motif at position 5 93 was synthesized by treatment of the key intermediate tetrahydro pyrimidine-(5)-3-carbothioamide 91 with conc. H2SO4. Furthermore, the oxadiazole derivative 92 was prepared by heterocyclization of 91 when treated with I2/KI in a basic medium (10% NaOH) (Scheme 20) [73] . A series of N-substituted 2-amino-1,3,4-thiadiazoles (96a-c) and 1,3,4-oxadiazoles (95a-c) carrying an (R) 5-(1-(4-(5-chloro-3-fluoropyridin-2-yloxy)phenoxy)ethyl) moiety were synthesized from acyl thiosemicarbazide intermediates (94a-c) by cyclodehydration using conc. H2SO4 and cyclodesulfurization with alkaline iodine, respectively (Scheme 21) [74] . A series of N-substituted 2-amino-1,3,4-thiadiazoles (96a-c) and 1,3,4-oxadiazoles (95a-c) carrying an (R) 5-(1-(4-(5-chloro-3-fluoropyridin-2-yloxy)phenoxy)ethyl) moiety were synthesized from acyl thiosemicarbazide intermediates (94a-c) by cyclodehydration using conc. H 2 SO 4 and cyclodesulfurization with alkaline iodine, respectively (Scheme 21) [74] . In a different study, the tetrahydropyrimidinone derivative bearing a 2-amino-1,3,4thiadiazole motif at position 5 93 was synthesized by treatment of the key intermediate tetrahydro pyrimidine-(5)-3-carbothioamide 91 with conc. H2SO4. Furthermore, the oxadiazole derivative 92 was prepared by heterocyclization of 91 when treated with I2/KI in a basic medium (10% NaOH) (Scheme 20) [73] . A series of N-substituted 2-amino-1,3,4-thiadiazoles (96a-c) and 1,3,4-oxadiazoles (95a-c) carrying an (R) 5-(1-(4-(5-chloro-3-fluoropyridin-2-yloxy)phenoxy)ethyl) moiety were synthesized from acyl thiosemicarbazide intermediates (94a-c) by cyclodehydration using conc. H2SO4 and cyclodesulfurization with alkaline iodine, respectively (Scheme 21) [74] .

In a similar approach, Zoumpoulakis et al., synthesized a series of N,Ndimethylsulphonamide-based 1,3,4-thiadiazoles (99a-f) and 1,3,4-oxadiazoles (98a-f) utilizing the acylthiosemicarbazide intermediates (97a-f) through dehydrative cyclization in concentrated H 2 SO 4 and desulfurative cyclization with I 2 /NaOH, respectively (Scheme 22) [75] . In a similar approach, Zoumpoulakis et al., synthesized a series of N,Ndimethylsulphonamide-based 1,3,4-thiadiazoles (99a-f) and 1,3,4-oxadiazoles (98a-f) utilizing the acylthiosemicarbazide intermediates (97a-f) through dehydrative cyclization in concentrated H2SO4 and desulfurative cyclization with I2/NaOH, respectively (Scheme 22) [75] .

Thermal intramolecular cyclodehydration of the bis-acyl thiosemicarbazide intermediates (100a-c) was performed by the action of H2SO4 at 0 °C to furnish the corresponding 2-aminoalkyl/aryl-1,3,4-thiadiazoles (102a-c). Alternatively, compounds (100a-c) were oxidatively cyclized to the corresponding 2-alkyl/arylamino-1,3,4oxadiazoles (101a-c) in the presence of I2/KI in refluxing (4%) NaOH (Scheme 23) [76] . A series of 2-aminotetrahydrobenzothiophene linked to arylamino 1,3,4-oxadiazole (104a-e) and 1,3,4-thiadiazole (105a-e) moieties were synthesized from the precursor acylthiosemicarbazides (103a-e) by cyclization using I2/KI in NaOH and orthophosphoric acid, respectively (Scheme 24) [77] . Thermal intramolecular cyclodehydration of the bis-acyl thiosemicarbazide intermediates (100a-c) was performed by the action of H 2 SO 4 at 0 • C to furnish the corresponding 2-aminoalkyl/aryl-1,3,4-thiadiazoles (102a-c). Alternatively, compounds (100a-c) were oxidatively cyclized to the corresponding 2-alkyl/arylamino-1,3,4-oxadiazoles (101a-c) in the presence of I 2 /KI in refluxing (4%) NaOH (Scheme 23) [76] . In a similar approach, Zoumpoulakis et al., synthesized a series of N,Ndimethylsulphonamide-based 1,3,4-thiadiazoles (99a-f) and 1,3,4-oxadiazoles (98a-f) utilizing the acylthiosemicarbazide intermediates (97a-f) through dehydrative cyclization in concentrated H2SO4 and desulfurative cyclization with I2/NaOH, respectively (Scheme 22) [75] .

Thermal intramolecular cyclodehydration of the bis-acyl thiosemicarbazide intermediates (100a-c) was performed by the action of H2SO4 at 0 °C to furnish the corresponding 2-aminoalkyl/aryl-1,3,4-thiadiazoles (102a-c). Alternatively, compounds (100a-c) were oxidatively cyclized to the corresponding 2-alkyl/arylamino-1,3,4oxadiazoles (101a-c) in the presence of I2/KI in refluxing (4%) NaOH (Scheme 23) [76] . A series of 2-aminotetrahydrobenzothiophene linked to arylamino 1,3,4-oxadiazole (104a-e) and 1,3,4-thiadiazole (105a-e) moieties were synthesized from the precursor acylthiosemicarbazides (103a-e) by cyclization using I2/KI in NaOH and orthophosphoric acid, respectively (Scheme 24) [77] . A series of 2-aminotetrahydrobenzothiophene linked to arylamino 1,3,4-oxadiazole (104a-e) and 1,3,4-thiadiazole (105a-e) moieties were synthesized from the precursor acylthiosemicarbazides (103a-e) by cyclization using I 2 /KI in NaOH and orthophosphoric acid, respectively (Scheme 24) [77] . In a similar approach, Zoumpoulakis et al., synthesized a series of N,Ndimethylsulphonamide-based 1,3,4-thiadiazoles (99a-f) and 1,3,4-oxadiazoles (98a-f) utilizing the acylthiosemicarbazide intermediates (97a-f) through dehydrative cyclization in concentrated H2SO4 and desulfurative cyclization with I2/NaOH, respectively (Scheme 22) [75] .

Thermal intramolecular cyclodehydration of the bis-acyl thiosemicarbazide intermediates (100a-c) was performed by the action of H2SO4 at 0 °C to furnish the corresponding 2-aminoalkyl/aryl-1,3,4-thiadiazoles (102a-c). Alternatively, compounds (100a-c) were oxidatively cyclized to the corresponding 2-alkyl/arylamino-1,3,4oxadiazoles (101a-c) in the presence of I2/KI in refluxing (4%) NaOH (Scheme 23) [76] . A series of 2-aminotetrahydrobenzothiophene linked to arylamino 1,3,4-oxadiazole (104a-e) and 1,3,4-thiadiazole (105a-e) moieties were synthesized from the precursor acylthiosemicarbazides (103a-e) by cyclization using I2/KI in NaOH and orthophosphoric acid, respectively (Scheme 24) [77] . In 2020, Abu-Hashem synthesized a variety of heterocyclic compounds through acyl thiosemicarbazide intermediates (106a-c). Desulfurization of (106a-c) through refluxing with HgO in ethanol afforded 1,3,4-oxadiazoles (107a-c) in moderate yields. The treatment of (106a-c) with POCl 3 , led to the formation of 1,3,4-thiadiazoles (108a-c) in higher yields than those of oxadiazoles (Scheme 25) [62] . In 2020, Abu-Hashem synthesized a variety of heterocyclic compounds through acyl thiosemicarbazide intermediates (106a-c). Desulfurization of (106a-c) through refluxing with HgO in ethanol afforded 1,3,4-oxadiazoles (107a-c) in moderate yields. The treatment of (106a-c) with POCl3, led to the formation of 1,3,4-thiadiazoles (108a-c) in higher yields than those of oxadiazoles (Scheme 25) [62] . The synthesis of some 1,3,4-thia/oxadiazole derivatives containing arylsulphonylphenyl and 4-trifluoromethylphenyl or 2,4-difluorophenyl moieties was achieved through cyclization of hydrazinecarbothioamides (109a-f). Treatment of (109af) with POCl3 resulted in dehydrative cyclization obtaining the 2-arylamino-1,3,4thiadiazoles (111a-f) in moderate yields, while on refluxing of the same intermediates with HgO, desulfurative cyclization took place, resulting in the corresponding 2-arylamino-1,3,4-oxadiazoles (110a-f) being obtained in fair yields (Scheme 26) [78, 79] . The synthesis of some 1,3,4-thia/oxadiazole derivatives containing arylsulphonylphenyl and 4-trifluoromethylphenyl or 2,4-difluorophenyl moieties was achieved through cyclization of hydrazinecarbothioamides (109a-f). Treatment of (109a-f) with POCl 3 resulted in dehydrative cyclization obtaining the 2-arylamino-1,3,4-thiadiazoles (111a-f) in moderate yields, while on refluxing of the same intermediates with HgO, desulfurative cyclization took place, resulting in the corresponding 2-arylamino-1,3,4-oxadiazoles (110a-f) being obtained in fair yields (Scheme 26) [78, 79] . In 2020, Abu-Hashem synthesized a variety of heterocyclic compounds through acyl thiosemicarbazide intermediates (106a-c). Desulfurization of (106a-c) through refluxing with HgO in ethanol afforded 1,3,4-oxadiazoles (107a-c) in moderate yields. The treatment of (106a-c) with POCl3, led to the formation of 1,3,4-thiadiazoles (108a-c) in higher yields than those of oxadiazoles (Scheme 25) [62] . The synthesis of some 1,3,4-thia/oxadiazole derivatives containing arylsulphonylphenyl and 4-trifluoromethylphenyl or 2,4-difluorophenyl moieties was achieved through cyclization of hydrazinecarbothioamides (109a-f). Treatment of (109af) with POCl3 resulted in dehydrative cyclization obtaining the 2-arylamino-1,3,4thiadiazoles (111a-f) in moderate yields, while on refluxing of the same intermediates with HgO, desulfurative cyclization took place, resulting in the corresponding 2-arylamino-1,3,4-oxadiazoles (110a-f) being obtained in fair yields (Scheme 26) [78, 79] . Burbuliene et al., developed concise and efficient procedures for the synthesis of 1,3,4-oxadiazoles and 1,3,4-thiadiazoles bearing 4-pyrimidinylthio-and 2pyrimidinylthio-moieties by intramolecular cyclization of substituted acyl thiosemicarbazide precursors (115a-d). The cyclodesulfurization to form 1,3,4-oxadiazoles (116a-d) was conducted by treating (115a-d) with Hg(OAc)2 in ethanol. On the other hand, cyclodehydration of (115a-d) in acidic media using concentrated H2SO4 at ∼ 0 •C followed by neutralization with NH4OH provided the thiadiazoles (117a-d) in lower yields than those of the oxadiazole analogs (Scheme 28) [66] . Series of 1,3,4-thiadiazoles (120a-c) and 1,3,4-oxadiazoles (119a-c) containing isomeric pyridyl and cyclohexyl moieties were synthesized by intramolecular cyclization of 1,4-disubstituted acyl thiosemicarbazides (118a-c). The latter underwent cyclodehydration in the acid medium of conc. H2SO4 to form 1,3,4-thiadiazoles (120a-c). The 1,3,4-oxadiazoles (119a-c) were obtained from the corresponding thiosemicarbazides in the presence of Hg(OAc)2 as an oxidizing agent (Scheme 29) [81] . Burbuliene et al., developed concise and efficient procedures for the synthesis of 1,3,4-oxadiazoles and 1,3,4-thiadiazoles bearing 4-pyrimidinylthio-and 2-pyrimidinylthiomoieties by intramolecular cyclization of substituted acyl thiosemicarbazide precursors (115a-d). The cyclodesulfurization to form 1,3,4-oxadiazoles (116a-d) was conducted by treating (115a-d) with Hg(OAc) 2 in ethanol. On the other hand, cyclodehydration of (115a-d) in acidic media using concentrated H 2 SO 4 at ∼0 • C followed by neutralization with NH 4 OH provided the thiadiazoles (117a-d) in lower yields than those of the oxadiazole analogs (Scheme 28) [66] . Burbuliene et al., developed concise and efficient procedures for the synthesis of 1,3,4-oxadiazoles and 1,3,4-thiadiazoles bearing 4-pyrimidinylthio-and 2pyrimidinylthio-moieties by intramolecular cyclization of substituted acyl thiosemicarbazide precursors (115a-d). The cyclodesulfurization to form 1,3,4-oxadiazoles (116a-d) was conducted by treating (115a-d) with Hg(OAc)2 in ethanol. On the other hand, cyclodehydration of (115a-d) in acidic media using concentrated H2SO4 at ∼ 0 •C followed by neutralization with NH4OH provided the thiadiazoles (117a-d) in lower yields than those of the oxadiazole analogs (Scheme 28) [66] . Series of 1,3,4-thiadiazoles (120a-c) and 1,3,4-oxadiazoles (119a-c) containing isomeric pyridyl and cyclohexyl moieties were synthesized by intramolecular cyclization of 1,4-disubstituted acyl thiosemicarbazides (118a-c). The latter underwent cyclodehydration in the acid medium of conc. H2SO4 to form 1,3,4-thiadiazoles (120a-c). The 1,3,4-oxadiazoles (119a-c) were obtained from the corresponding thiosemicarbazides in the presence of Hg(OAc)2 as an oxidizing agent (Scheme 29) [81] . Series of 1,3,4-thiadiazoles (120a-c) and 1,3,4-oxadiazoles (119a-c) containing isomeric pyridyl and cyclohexyl moieties were synthesized by intramolecular cyclization of 1,4disubstituted acyl thiosemicarbazides (118a-c). The latter underwent cyclodehydration in the acid medium of conc. H 2 SO 4 to form 1,3,4-thiadiazoles (120a-c). The 1,3,4-oxadiazoles (119a-c) were obtained from the corresponding thiosemicarbazides in the presence of Hg(OAc) 2 as an oxidizing agent (Scheme 29) [81] . Novel heterocyclic derivatives of 2-arylamino-5-(pyridin-2-ylmethyl)-1,3,4oxadiazoles (122a-g) and thiadiazoles (123a-g) were efficiently synthesized through (pyridin-2-yl-acetyl)hydrazinecarbothioamide derivatives (121a-g). The method for obtaining 1,3,4-thiadiazole derivatives (123a-g) required cyclization under acidic conditions (conc. H2SO4), while oxadiazoles (122a-g) were prepared by a desulfurization/cyclization reaction of (121a-g) using HgCl2 with optional catalytic amounts of TEA (Scheme 30) [67] . Scheme 30. Synthetic pathway for compounds 122a-g and 123a-g.

Polymer-bound 2-amino-1,3,4-oxadiazoles (125a-d) and 1,3,4-thiadiazole 126 core skeleton resin were synthesized by solid-phase cyclization of acyl thiosemicarbazides (124a-e) with EDC·HCl and p-TsCl, respectively, followed by a functionalization reaction of the resulting core skeleton with various electrophiles such as alkyl halides and acid chlorides to generate N-alkylamino and N-acylamino-1,3,4-oxadiazole (127a-x and 128ax) and 1,3,4-thiadiazole (129a-j and 130a-j) resin, respectively. Finally, the desired 2-amino and 2-amido-1,3,4-oxadiazole (131a-x and 132a-x) and 1,3,4-thiadiazole (133a-j and 134aj) were then generated in high purities by cleavage of the resin under trifluoroacetic acid (TFA) in dichloromethane (DCM) (Scheme 31) [63] . Novel heterocyclic derivatives of 2-arylamino-5-(pyridin-2-ylmethyl)-1,3,4-oxadiazoles (122a-g) and thiadiazoles (123a-g) were efficiently synthesized through (pyridin-2-ylacetyl)hydrazinecarbothioamide derivatives (121a-g). The method for obtaining 1,3,4thiadiazole derivatives (123a-g) required cyclization under acidic conditions (conc. H 2 SO 4 ), while oxadiazoles (122a-g) were prepared by a desulfurization/cyclization reaction of (121a-g) using HgCl 2 with optional catalytic amounts of TEA (Scheme 30) [67] . Novel heterocyclic derivatives of 2-arylamino-5-(pyridin-2-ylmethyl)-1,3,4oxadiazoles (122a-g) and thiadiazoles (123a-g) were efficiently synthesized through (pyridin-2-yl-acetyl)hydrazinecarbothioamide derivatives (121a-g). The method for obtaining 1,3,4-thiadiazole derivatives (123a-g) required cyclization under acidic conditions (conc. H2SO4), while oxadiazoles (122a-g) were prepared by a desulfurization/cyclization reaction of (121a-g) using HgCl2 with optional catalytic amounts of TEA (Scheme 30) [67] . Scheme 30. Synthetic pathway for compounds 122a-g and 123a-g.

Polymer-bound 2-amino-1,3,4-oxadiazoles (125a-d) and 1,3,4-thiadiazole 126 core skeleton resin were synthesized by solid-phase cyclization of acyl thiosemicarbazides (124a-e) with EDC·HCl and p-TsCl, respectively, followed by a functionalization reaction of the resulting core skeleton with various electrophiles such as alkyl halides and acid chlorides to generate N-alkylamino and N-acylamino-1,3,4-oxadiazole (127a-x and 128ax) and 1,3,4-thiadiazole (129a-j and 130a-j) resin, respectively. Finally, the desired 2-amino and 2-amido-1,3,4-oxadiazole (131a-x and 132a-x) and 1,3,4-thiadiazole (133a-j and 134aj) were then generated in high purities by cleavage of the resin under trifluoroacetic acid (TFA) in dichloromethane (DCM) (Scheme 31) [63] . Scheme 30. Synthetic pathway for compounds 122a-g and 123a-g.

Polymer-bound 2-amino-1,3,4-oxadiazoles (125a-d) and 1,3,4-thiadiazole 126 core skeleton resin were synthesized by solid-phase cyclization of acyl thiosemicarbazides (124a-e) with EDC·HCl and p-TsCl, respectively, followed by a functionalization reaction of the resulting core skeleton with various electrophiles such as alkyl halides and acid chlorides to generate N-alkylamino and N-acylamino-1,3,4-oxadiazole (127a-x and 128a-x) and 1,3,4-thiadiazole (129a-j and 130a-j) resin, respectively. Finally, the desired 2-amino and 2-amido-1,3,4-oxadiazole (131a-x and 132a-x) and 1,3,4-thiadiazole (133a-j and 134a-j) were then generated in high purities by cleavage of the resin under trifluoroacetic acid (TFA) in dichloromethane (DCM) (Scheme 31) [63] .

In 2013, a regioselective, reagent-based method for the cyclization reaction of acyl thiosemicarbazide (135a-m) into 2-amino-1,3,4-oxadiazole (136a-m) and 2-amino-1,3,4thiadiazole (137a-m) core skeletons was described. The study showed that the use of EDC·HCl in DMSO as a desulfurizing agent led to 2-amino-1,3,4-oxadiazoles (136a-m) in quantitative yields (regioselectivity ratio = 100:0). However, the use of p-TsCl as a dehydrating agent and triethylamine in N-methyl-2-pyrrolidone as a polar solvent gave 2-amino-1,3,4-thiadiazoles (137a-m) as a major product with regioselectivity of 96:4 and a high yield (Scheme 32) [82] . In 2013, a regioselective, reagent-based method for the cyclization reaction of acyl thiosemicarbazide (135a-m) into 2-amino-1,3,4-oxadiazole (136a-m) and 2-amino-1,3,4thiadiazole (137a-m) core skeletons was described. The study showed that the use of EDC·HCl in DMSO as a desulfurizing agent led to 2-amino-1,3,4-oxadiazoles (136a-m) in quantitative yields (regioselectivity ratio = 100:0). However, the use of p-TsCl as a Long-chain 5-alkenyl/hydroxyalkenyl-2-phenylamine-1,3,4-oxadiazoles and 1,3,4thiadiazoles were synthesized from acyl semicarbazides and thiosemicarbazides, respectively. Refluxing semicarbazide (142a-d) with POCl3 yielded 2,5-disubstituted-1,3,4-oxadiazoles (143a-d) in good yields. The dehydrative cyclization of thiosemicarbazides (144a-d) by Ac2O produced 2,5-disubstituted-1,3,4-thiadiazoles (145a-d) in excellent yields (Scheme 34) [64] . Long-chain 5-alkenyl/hydroxyalkenyl-2-phenylamine-1,3,4-oxadiazoles and 1,3 thiadiazoles were synthesized from acyl semicarbazides and thiosemicarbazid respectively. Refluxing semicarbazide (142a-d) with POCl3 yielded 2,5-disubstitut 1,3,4-oxadiazoles (143a-d) in good yields. The dehydrative cyclization thiosemicarbazides (144a-d) by Ac2O produced 2,5-disubstituted-1,3,4-thiadiazo (145a-d) in excellent yields (Scheme 34) [64] . Long-chain 5-alkenyl/hydroxyalkenyl-2-phenylamine-1,3,4-oxadiazoles and 1,3,4thiadiazoles were synthesized from acyl semicarbazides and thiosemicarbazides, respectively. Refluxing semicarbazide (142a-d) with POCl 3 yielded 2,5-disubstituted-1,3,4oxadiazoles (143a-d) in good yields. The dehydrative cyclization of thiosemicarbazides (144a-d) by Ac 2 O produced 2,5-disubstituted-1,3,4-thiadiazoles (145a-d) in excellent yields (Scheme 34) [64] . 

Semi-/thiosemicarbazides are reacted with aldehydes in the presence of Na acetate in ethanol, forming the corresponding semi-/thiosemicarbazones, which can be used for the synthesis of 1,3,4-oxa-/thiadiazoles by oxidative cyclization using I2/K2CO3 [83] , Br2/CH3COOH [84] , or nitroalkanes in PPA [85] (Figure 15 ). The reaction of trifluoromethyl benzaldehyde 146 with semi-or thiosemicarbazide hydrochloride 147 and 148 formed the corresponding semi-and thiosemicarbazone 149 and 150. Cyclization using I2/dioxane produced the 1,3,4-oxadiazol-2-amine 151 and 1,3,4thiadiazol-2-amino 152, respectively, which were further reacted with aroyl chlorides to give the desired 1,3,4-oxadiazol-2-yl/1,3,4-thiadiazol-2-yl benzamides (153a-c) and 154b. Oxadiazoles were produced in higher yields than thiadiazoles (Scheme 35) [87] . 

Semi-/thiosemicarbazides are reacted with aldehydes in the presence of Na acetate in ethanol, forming the corresponding semi-/thiosemicarbazones, which can be used for the synthesis of 1,3,4-oxa-/thiadiazoles by oxidative cyclization using I 2 /K 2 CO 3 [83] , Br 2 /CH 3 COOH [84] , or nitroalkanes in PPA [85] (Figure 15 ). 

Semi-/thiosemicarbazides are reacted with aldehydes in the presence of Na acetate in ethanol, forming the corresponding semi-/thiosemicarbazones, which can be used for the synthesis of 1,3,4-oxa-/thiadiazoles by oxidative cyclization using I2/K2CO3 [83] , Br2/CH3COOH [84] , or nitroalkanes in PPA [85] (Figure 15 ). The reaction of trifluoromethyl benzaldehyde 146 with semi-or thiosemicarbazide hydrochloride 147 and 148 formed the corresponding semi-and thiosemicarbazone 149 and 150. Cyclization using I2/dioxane produced the 1,3,4-oxadiazol-2-amine 151 and 1,3,4thiadiazol-2-amino 152, respectively, which were further reacted with aroyl chlorides to give the desired 1,3,4-oxadiazol-2-yl/1,3,4-thiadiazol-2-yl benzamides (153a-c) and 154b. Oxadiazoles were produced in higher yields than thiadiazoles (Scheme 35) [87] . The reaction of trifluoromethyl benzaldehyde 146 with semi-or thiosemicarbazide hydrochloride 147 and 148 formed the corresponding semi-and thiosemicarbazone 149 and 150. Cyclization using I 2 /dioxane produced the 1,3,4-oxadiazol-2-amine 151 and 1,3,4thiadiazol-2-amino 152, respectively, which were further reacted with aroyl chlorides to give the desired 1,3,4-oxadiazol-2-yl/1,3,4-thiadiazol-2-yl benzamides (153a-c) and 154b. Oxadiazoles were produced in higher yields than thiadiazoles (Scheme 35) [87] . In 2015, 2-amino-substituted 1,3,4-oxadiazoles (159a-c) and 1,3,4-thiadiazoles (160a-c) were smoothly produced via condensation of semicarbazide hydrochloride/thiosemicarbazide 147 and 156 and the corresponding aldehydes (155a-c), followed by I 2 -mediated oxidative C−O/C−S bond formation using a mixture of I 2 and K 2 CO 3 in 1,4-dioxane. The 1,3,4oxadiazoles were produced in higher yields than the 1,3,4-thiadiazoles (Scheme 36) [83] . In 2015, 2-amino-substituted 1,3,4-oxadiazoles (159a-c) and 1,3,4-thiadiazoles (160ac)

were smoothly produced via condensation of semicarbazide hydrochloride/thiosemicarbazide 147 and 156 and the corresponding aldehydes (155a-c), followed by I2-mediated oxidative C−O/C−S bond formation using a mixture of I2 and K2CO3 in 1,4-dioxane. The 1,3,4-oxadiazoles were produced in higher yields than the 1,3,4thiadiazoles (Scheme 36) [83] . In 2017, Arafa and Abdelmagied reported that a rapid ultrasound accelerated the conversion of bis-semicarbazone derivatives (162a-f) into diverse novel substituted bis-2amino-1,3,4-oxadiazoles (164a-f) in quantitative yields using molecular iodine and potassium carbonate in dioxane as a solvent. Products (164a-f) could also be obtained in one-pot synthesis without the isolation of intermediates (162a-f). Replacing semicarbazide hydrochloride 147 with thiosemicarbazide 156 produced the desired bis-2-amino-1,3,4thiadiazoles (165a-f) in excellent yields (Scheme 37) [88] . In 2017, Arafa and Abdelmagied reported that a rapid ultrasound accelerated the conversion of bis-semicarbazone derivatives (162a-f) into diverse novel substituted bis-2amino-1,3,4-oxadiazoles (164a-f) in quantitative yields using molecular iodine and potassium carbonate in dioxane as a solvent. Products (164a-f) could also be obtained in one-pot synthesis without the isolation of intermediates (162a-f). Replacing semicarbazide hydrochloride 147 with thiosemicarbazide 156 produced the desired bis-2-amino-1,3,4thiadiazoles (165a-f) in excellent yields (Scheme 37) [88] . The reaction of pyrazole-4-carboxaldehyde derivatives bearing 2-hydroxyphenyl or 7-hydroxycoumarin-8-yl moiety (166a-k) with (semi)thiosemicarbazide hydrochloride 147 or 148 in the presence of sodium acetate in ethyl alcohol under reflux conditions afforded the corresponding semicarbazones (167a-k) and thiosemicarbazones (168a-k). Their oxidative cyclization using bromine as an oxidant in acetic acid at room temperature yielded the corresponding 1,3,4-oxadiazoles (169a-k) and 1,3,4-thiadiazoles (170a-k) (Scheme 38) [89, 84] . The reaction of pyrazole-4-carboxaldehyde derivatives bearing 2-hydroxyphenyl or 7hydroxycoumarin-8-yl moiety (166a-k) with (semi)thiosemicarbazide hydrochloride 147 or 148 in the presence of sodium acetate in ethyl alcohol under reflux conditions afforded the corresponding semicarbazones (167a-k) and thiosemicarbazones (168a-k). Their oxidative cyclization using bromine as an oxidant in acetic acid at room temperature yielded the corresponding 1,3,4-oxadiazoles (169a-k) and 1,3,4-thiadiazoles (170a-k) (Scheme 38) [84, 89] .

The reaction of pyrazole-4-carboxaldehyde derivatives bearing 2-hydroxyphenyl or 7-hydroxycoumarin-8-yl moiety (166a-k) with (semi)thiosemicarbazide hydrochloride 147 or 148 in the presence of sodium acetate in ethyl alcohol under reflux conditions afforded the corresponding semicarbazones (167a-k) and thiosemicarbazones (168a-k). Their oxidative cyclization using bromine as an oxidant in acetic acid at room temperature yielded the corresponding 1,3,4-oxadiazoles (169a-k) and 1,3,4-thiadiazoles (170a-k) (Scheme 38) [89, 84] . In 2020, Askenov et al., discovered an unusual reaction ( Figure 16 ) for the synthesis of 2-amino-1,3,4-oxa-/thiadiazoles via the electrophilic activation of nitroalkanes in the presence of polyphosphoric acid followed by a subsequent nucleophilic attack with semi/thiosemicarbazides. It was found that nitroalkanes 172 in PPA converted into phosphorylated nitronates showing strong electrophilic properties. Semicarbazides 171 and thiosemicarbazides 174 were employed as nucleophilic components in this cyclization reaction to access 2-amino-1,3,4-oxadiazoles (173a-d) and 2-amino-1,3,4-thiadiazoles (175a-g), respectively (Scheme 39) [85] . 

To date, various methods have been reported in the literature for generating 1,3,4oxa-/thiadiazoles from acid hydrazides ( Figure 17 ). 1,3,4-Oxadiazoles can be synthesized from acid hydrazides through treatment with tetramethylthiuram disulfide (TMTD) in DMF [91] , cyanogen bromide (CNBr) in aq. Dioxane [91] , coupling agent Scheme 40. Synthetic pathway for compounds 177, 182a-d, and 183a-d. 

To date, various methods have been reported in the literature for generating 1,3,4-oxa-/thiadiazoles from acid hydrazides ( Figure 17 ). 1,3,4-Oxadiazoles can be synthesized from acid hydrazides through treatment with tetramethylthiuram disulfide (TMTD) in DMF [91] , cyanogen bromide (CNBr) in aq. Dioxane [91] , coupling agent (CDI)/THF/POCl 3 [92] , CS 2 /KOH in ethanol [93] , or by reaction with triethyl orthoesters in glacial acetic acid [53] . On the other hand, 1,3,4-thiadiazoles can be synthesized through treatment of acid hydrazide with TMTD/DMF [91] , isothiocyanates/TEA [91] , CDI/DMF/P 2 S 5 [92] , by treatment with conc. H 2 SO 4 through the formation of acyl thiosemicarbazide intermediate [93] , or by reaction with triethylorthoesters/LR in glacial acetic acid [53] . Furthermore, TiCl 4mediated facile synthesis [94] and the palladium-catalyzed one-pot method [95] are used for the synthesis of 1,3,4-oxa-/thiadiazoles from acid/thionyl hydrazide. Oxadiazole was formed in a higher yield than thiadiazole (Scheme 41) [74] .

A series of 4,5-dihydro-1,5-diaryl-1H-pyrazole substituted at position 3 with functionalized 1,3,4-oxadiazole or 1,3,4-thiadiazole ring was synthesized from carbohydrazide precursors (188a,b) using variable reagents and conditions. The 2-hydroxy-1,3,4-oxadiazoles (189a,b) were prepared by reaction of carbonyldiimidazole with (188a,b) in tetrahydrofuran using triethylamine as a base. The 1,3,4-oxadiazole-2-thiols (190a,b) were obtained by reaction of (188a,b) with carbon disulfide employing KOH as a base catalyst. The l,3,4oxadiazole-2-amines (191a,b) resulted from the reaction of cyanogen bromide and NaHCO 3 with precursors (188a,b). The 5-methylthio-1,3,4-thiadiazoles (192a,b) were synthesized by reaction of hydrazide (188a,b) with carbon disulfide and KOH followed by methylation using methyl iodide. These compounds were further cyclized in refluxing toluene using p-toluene sulfonic acid (Scheme 42) [96] .

A series of 1,3,4-oxadiazole and 1,3,4-thiadiazole bearing an (R) 5-(1-(4-(5-chloro-3fluoropyridin-2-yloxy)phenoxy)ethyl) unit were synthesized from the corresponding acid hydrazide through the formation of the intermediate formylhydrazide. Prolonged reflux of hydrazide 184 in ethylorthoformate generated formylhydrazide 185 with subsequent cyclization to oxadiazole 186. Alternatively, sulfurative cyclization of formylhydrazide 185 to thiadiazole 187 was affected by heating with P2S5 in xylene under reflux conditions. Oxadiazole was formed in a higher yield than thiadiazole (Scheme 41) [74] . A series of 4,5-dihydro-1,5-diaryl-1H-pyrazole substituted at position 3 with functionalized 1,3,4-oxadiazole or 1,3,4-thiadiazole ring was synthesized from carbohydrazide precursors (188a,b) using variable reagents and conditions. The 2hydroxy-1,3,4-oxadiazoles (189a,b) were prepared by reaction of carbonyldiimidazole with (188a,b) in tetrahydrofuran using triethylamine as a base. The 1,3,4-oxadiazole-2thiols (190a,b) were obtained by reaction of (188a,b) with carbon disulfide employing KOH as a base catalyst. The l,3,4-oxadiazole-2-amines (191a,b) resulted from the reaction for compounds 199a,b and 200a,b. A series of benzosuberone analogs embedded with 1,3,4-oxadiazole or 1,3,4thiadiazole moieties were synthesized in high yields. The reaction of the hydrazides (201a,b) with phenyl isothiocyanate in ethanol gave the corresponding acylthiosemicarbazide (203a,b), which on treatment with conc. sulphuric acid yielded the required 1,3,4-thiadiazoles (204a,b), while oxadiazole analogs (202a,b) were obtained from (201a,b) directly by refluxing with carbon disulfide in the presence of alcoholic potassium hydroxide (Scheme 45) [98] . for compounds 199a,b and 200a,b. A series of benzosuberone analogs embedded with 1,3,4-oxadiazole or 1,3,4thiadiazole moieties were synthesized in high yields. The reaction of the hydrazides (201a,b) with phenyl isothiocyanate in ethanol gave the corresponding acylthiosemicarbazide (203a,b), which on treatment with conc. sulphuric acid yielded the required 1,3,4-thiadiazoles (204a,b), while oxadiazole analogs (202a,b) were obtained from (201a,b) directly by refluxing with carbon disulfide in the presence of alcoholic potassium hydroxide (Scheme 45) [98] . In 2020, (+)-sclareolide-based homodrimane sesquiterpenoids bearing 1,3,4-oxa-/ thiadiazole-2-thiols (206,207) were synthesized from acetohydrazide 205 through treatment with TMTD in DMF. Products were obtained selectively or in a mixture where the yield ratio between oxadiazole 206 and thiadiazole 207 was dependent on the amount of TMTD used in the reaction (Scheme 46) [91] . In 2020, (+)-sclareolide-based homodrimane sesquiterpenoids bearing 1,3,4-oxa-/thiadiazole-2-thiols (206,207) were synthesized from acetohydrazide 205 through treatment with TMTD in DMF. Products were obtained selectively or in a mixture where the yield ratio between oxadiazole 206 and thiadiazole 207 was dependent on the amount of TMTD used in the reaction (Scheme 46) [91] . Xiang et al., reported an efficient one-pot Pd-catalyzed carbonylative coupling reaction for the synthesis of 1,3,4-oxadiazoles (221a-o, 222a-j) from the reaction of benzohydrazides (219a-p) and iodobenzene (218a-j) with tert-butyl isocyanide 220 via isocyanide insertion/cyclization sequential reaction. The optimal reaction conditions were PdCl 2 and DPPP as the catalyst systems, with NaOAc as the base and DMF as the solvent, which furnished the products in moderate yields. Obtaining 1,3,4-thiadiazoles (224a-e) required replacement of benzohydrazides (219a-o) with benzothiohydrazides (223a-e), as well as changing the base from NaOAc to Na 2 CO 3 (Scheme 50) [95] . Xiang et al., reported an efficient one-pot Pd-catalyzed carbonylative coupling reaction for the synthesis of 1,3,4-oxadiazoles (221a-o, 222a-j) from the reaction of benzohydrazides (219a-p) and iodobenzene (218a-j) with tert-butyl isocyanide 220 via isocyanide insertion/cyclization sequential reaction. The optimal reaction conditions were PdCl2 and DPPP as the catalyst systems, with NaOAc as the base and DMF as the solvent, which furnished the products in moderate yields. Obtaining 1,3,4-thiadiazoles (224a-e) required replacement of benzohydrazides (219a-o) with benzothiohydrazides (223a-e), as well as changing the base from NaOAc to Na2CO3 (Scheme 50) [95] .

A series of benzimidazole derivatives bearing a 1,3,4-oxa-/thiadiazole core were synthesized by the precursor carbohydrazide 225 with substituted benzoic acid using the coupling agent CDI and POCl3 and P2S5 as cyclizing agents to yield the oxadiazole (226aj) and thiadiazole (227a,c,f,i) cores, respectively (Scheme 51) [92] . Scheme 51. Synthetic pathway for compounds 226a-j and 227a,c,f,i. 

A series of benzimidazole derivatives bearing a 1,3,4-oxa-/thiadiazole core were synthesized by the precursor carbohydrazide 225 with substituted benzoic acid using the coupling agent CDI and POCl 3 and P 2 S 5 as cyclizing agents to yield the oxadiazole (226a-j) and thiadiazole (227a,c,f,i) cores, respectively (Scheme 51) [92] . Xiang et al., reported an efficient one-pot Pd-catalyzed carbonylative coupling reaction for the synthesis of 1,3,4-oxadiazoles (221a-o, 222a-j) from the reaction of benzohydrazides (219a-p) and iodobenzene (218a-j) with tert-butyl isocyanide 220 via isocyanide insertion/cyclization sequential reaction. The optimal reaction conditions were PdCl2 and DPPP as the catalyst systems, with NaOAc as the base and DMF as the solvent, which furnished the products in moderate yields. Obtaining 1,3,4-thiadiazoles (224a-e) required replacement of benzohydrazides (219a-o) with benzothiohydrazides (223a-e), as well as changing the base from NaOAc to Na2CO3 (Scheme 50) [95] . A series of benzimidazole derivatives bearing a 1,3,4-oxa-/thiadiazole core were synthesized by the precursor carbohydrazide 225 with substituted benzoic acid using the coupling agent CDI and POCl3 and P2S5 as cyclizing agents to yield the oxadiazole (226aj) and thiadiazole (227a,c,f,i) cores, respectively (Scheme 51) [92] . Scheme 51. Synthetic pathway for compounds 226a-j and 227a,c,f,i.  Scheme 51. Synthetic pathway for compounds 226a-j and 227a,c,f,i. In 2020, s-tetrazine-1,3,4-oxadiazole hybrids (229a-d) were obtained by reaction of s-tetrazine-3,6-dicarbohydrazide 228 and triethylorthoesters in glacial acetic acid via conventional heating. S-tetrazine-1,3,4-thiadiazoles (230a-d) were synthesized by the same method with the addition of LR. The products were also obtained by microwave irradiation in similar yields, but in a very short reaction time (Scheme 52) [53] . In 2020, s-tetrazine-1,3,4-oxadiazole hybrids (229a-d) were obtained by reaction of stetrazine-3,6-dicarbohydrazide 228 and triethylorthoesters in glacial acetic acid via conventional heating. S-tetrazine-1,3,4-thiadiazoles (230a-d) were synthesized by the same method with the addition of LR. The products were also obtained by microwave irradiation in similar yields, but in a very short reaction time (Scheme 52) [53] . Scheme 52. Synthetic pathway for compounds 229a-d and 230a-d.

Over the past few decades, many 1,3,4-oxadiazoles and 1,3,4-thiadiazoles have been intensively studied for their broad biomedical applications, such as antimicrobial, antiviral, anticancer, antidiabetic, antioxidant, and analgesic activities ( Figure 18 ). 

In 2020, thirteen novel sclareolide-based homodrimane sesquiterpenoids bearing 1,3,4-oxadiazole or 1,3,4-thiadiazole moieties were synthesized and demonstrated promising antifungal and antibacterial activities toward fungal species Aspergillus niger, Fusarium solani, Penicillium chrysogenum, Penicillium frequentans, and Alternaria alternata and Gram-positive Bacillus species and Gram-negative Pseudomonas aeruginosa bacteria strains. On the basis of the SAR correlations, it was noticed that compounds having a 1,3,4thiadiazole moiety were more active compared with those having a 1,3,4-oxadiazole moiety. 

Over the past few decades, many 1,3,4-oxadiazoles and 1,3,4-thiadiazoles have been intensively studied for their broad biomedical applications, such as antimicrobial, antiviral, anticancer, antidiabetic, antioxidant, and analgesic activities ( Figure 18 ). In 2020, s-tetrazine-1,3,4-oxadiazole hybrids (229a-d) were obtained by reaction of stetrazine-3,6-dicarbohydrazide 228 and triethylorthoesters in glacial acetic acid via conventional heating. S-tetrazine-1,3,4-thiadiazoles (230a-d) were synthesized by the same method with the addition of LR. The products were also obtained by microwave irradiation in similar yields, but in a very short reaction time (Scheme 52) [53] . Scheme 52. Synthetic pathway for compounds 229a-d and 230a-d.

Over the past few decades, many 1,3,4-oxadiazoles and 1,3,4-thiadiazoles have been intensively studied for their broad biomedical applications, such as antimicrobial, antiviral, anticancer, antidiabetic, antioxidant, and analgesic activities ( Figure 18 ). 

In 2020, thirteen novel sclareolide-based homodrimane sesquiterpenoids bearing 1,3,4-oxadiazole or 1,3,4-thiadiazole moieties were synthesized and demonstrated promising antifungal and antibacterial activities toward fungal species Aspergillus niger, Fusarium solani, Penicillium chrysogenum, Penicillium frequentans, and Alternaria alternata and Gram-positive Bacillus species and Gram-negative Pseudomonas aeruginosa bacteria strains. On the basis of the SAR correlations, it was noticed that compounds having a 1,3,4thiadiazole moiety were more active compared with those having a 1,3,4-oxadiazole moiety. 

In 2020, thirteen novel sclareolide-based homodrimane sesquiterpenoids bearing 1,3,4oxadiazole or 1,3,4-thiadiazole moieties were synthesized and demonstrated promising antifungal and antibacterial activities toward fungal species Aspergillus niger, Fusarium solani, Penicillium chrysogenum, Penicillium frequentans, and Alternaria alternata and Grampositive Bacillus species and Gram-negative Pseudomonas aeruginosa bacteria strains. On the basis of the SAR correlations, it was noticed that compounds having a 1,3,4-thiadiazole moiety were more active compared with those having a 1,3,4-oxadiazole moiety.

Among the thiadiazole derivatives, compound 231 (Figure 19 ), featuring the 2-mercapto group, was the most potent, with promising broad-spectrum antifungal (MIC 0.032 µg/mL) and antibacterial (MIC 0.094 µg/mL) activities [91] .

olecules 2022, 27, x FOR PEER REVIEW Among the thiadiazole derivatives, compound 231 (Figure 19 ), fe mercapto group, was the most potent, with promising broad-spectrum an 0.032 µg/mL) and antibacterial (MIC 0.094 µg/mL) activities [91] . A series of 1,3,4-oxadiazoles/thiadiazoles bearing pyrazole scaffolds for their in vitro antimicrobial activity against S. aureus, E. coli, P. aeruginosa A. flavus bacteria, and C. albicans fungal species using Ciprofloxacin and F reference drugs. The tested compounds showed moderate to excellent an antifungal activities. The chloro-substituted oxadiazole 169d was equipote drugs Ciprofloxacin and Fluconazole MIC 12.5-25 μg/mL, while the chlo 1,3,4-oxadiazole 169j showed greater activity against Gram-negative E. coli fungi (MIC 12.5 μg/mL) than Ciprofloxacin and Fluconazole (MIC 25 a respectively). On the other hand, the chloro-substituted thiadiazoles (170 higher activity against Gram-positive S. aureus (MIC 12.5 μg/mL) compared Ciprofloxacin (MIC 25 μg/mL). Moreover, 170j was more potent against G E. coli (MIC 12.5 μg/mL) than Ciprofloxacin (MIC 25 μg/mL).

The comparative analysis illustrated that, among oxadiazoles and th In 2012, nalidixic acid-based 1,3,4-(oxa)thiadiazol-2-thione, their Mannich bases, Salkylated/arylated sulfides, and sulfones were synthesized and screened against Grampositive bacteria (S. aureus and B. subtilis) and Gram-negative bacteria (E. coli, P. aeruginosa, and K. pneumonia) using Streptomycin as the reference standard drug. According to evaluation results, the Mannich base 232 (Figure 20 ) emerged as a potent antibacterial agent against all test microorganisms except E. coli, with an MIC range of 6.25-12.5 µg/mL [93] . Among the thiadiazole derivatives, compound 231 (Figure 19 ), featuring the 2 mercapto group, was the most potent, with promising broad-spectrum antifungal (MIC 0.032 µg/mL) and antibacterial (MIC 0.094 µg/mL) activities [91] . A series of 1,3,4-oxadiazoles/thiadiazoles bearing pyrazole scaffolds were screened for their in vitro antimicrobial activity against S. aureus, E. coli, P. aeruginosa, A. niger, and A. flavus bacteria, and C. albicans fungal species using Ciprofloxacin and Fluconazole as reference drugs. The tested compounds showed moderate to excellent antibacterial and antifungal activities. The chloro-substituted oxadiazole 169d was equipotent to reference drugs Ciprofloxacin and Fluconazole MIC 12.5-25 μg/mL, while the chloro-substituted 1,3,4-oxadiazole 169j showed greater activity against Gram-negative E. coli and C. albicans fungi (MIC 12.5 μg/mL) than Ciprofloxacin and Fluconazole (MIC 25 and 50 μg/mL respectively). On the other hand, the chloro-substituted thiadiazoles (170d,j) showed a higher activity against Gram-positive S. aureus (MIC 12.5 μg/mL) compared with standard Ciprofloxacin (MIC 25 μg/mL). Moreover, 170j was more potent against Gram-negative E. coli (MIC 12.5 μg/mL) than Ciprofloxacin (MIC 25 μg/mL).

The comparative analysis illustrated that, among oxadiazoles and thiadiazoles, the sulfur moiety in 1, 3, 4-thiadiazoles acts as a potent inhibitor, while compounds containing moderately electronegative elements such as sulfur and chlorine (170d,j showed better in vitro activity than compounds with more electronegative elements, such as oxygen (169d,j) ( Figure 21 ) [89, 84] . A series of 1,3,4-oxadiazoles/thiadiazoles bearing pyrazole scaffolds were screened for their in vitro antimicrobial activity against S. aureus, E. coli, P. aeruginosa, A. niger, and A. flavus bacteria, and C. albicans fungal species using Ciprofloxacin and Fluconazole as reference drugs. The tested compounds showed moderate to excellent antibacterial and antifungal activities. The chloro-substituted oxadiazole 169d was equipotent to reference drugs Ciprofloxacin and Fluconazole MIC 12.5-25 µg/mL, while the chloro-substituted 1,3,4-oxadiazole 169j showed greater activity against Gram-negative E. coli and C. albicans fungi (MIC 12.5 µg/mL) than Ciprofloxacin and Fluconazole (MIC 25 and 50 µg/mL, respectively). On the other hand, the chloro-substituted thiadiazoles (170d,j) showed a higher activity against Gram-positive S. aureus (MIC 12.5 µg/mL) compared with standard Ciprofloxacin (MIC 25 µg/mL). Moreover, 170j was more potent against Gram-negative E. coli (MIC 12.5 µg/mL) than Ciprofloxacin (MIC 25 µg/mL).

The comparative analysis illustrated that, among oxadiazoles and thiadiazoles, the sulfur moiety in 1, 3, 4-thiadiazoles acts as a potent inhibitor, while compounds containing moderately electronegative elements such as sulfur and chlorine (170d,j) showed better in vitro activity than compounds with more electronegative elements, such as oxygen (169d,j) ( Figure 21 ) [84, 89] . Long-chain 5-alkenyl/hydroxyalkenyl-2-phenylamine-1,3,4-oxadiazoles and thiadiazoles were synthesized and screened as antimicrobial agents against S. pyogenes, S. aureus, P. aeruginosa, K. pneumoniae, and E. coli bacterial strains and C. albicans, A. fumigatus, T. mentagrophytes, and P. marneffei fungal strains. The study results showed no difference in activity between the bioisosteres of oxadiazoles and thiadiazoles. Examination of SAR indicated that the presence of a hydroxyalkyl chain at the fifth position of the oxa-/thiadiazole ring increased the antibacterial activity in compounds 143c, 143d, 145c, and 145d, as they were equally as potent as the reference drug chloramphenicol (MIC = 6.25 μg/mL). Moreover, the compounds with an internal double bond in the long alkenyl substituent of synthesized oxa-/thiadiazoles 143b and 145b were found to be potent antifungal agents (Figure 22 ) [64] . A series of 5-[N-(p-flurobenzyl)indolyl]propyl-1,3,4-(oxa)thiadiazoles were tested in vitro for their antibacterial and antifungal activities. Only the thiadiazole derivatives showed promising results. The 2-phenylamino derivative 75d was more potent than the reference drug Gentamicin against Gram-negative E. coli, with MIC = 0.24 and 3.9 μg/mL, respectively. The 2-ethylamino analog 75b was equipotent to Gentamicin against E. coli (MIC = 3.9 μg/mL), and was four times more potent than Gentamicin against P. aeruginosa (MIC 3.9 μg/mL and 15.6 μg/mL, respectively). The 2-cyclohexyl amino counterpart 75c showed promising results against E. coli (MIC 0.49 μg/mL) compared to Gentamicin and displayed equivalent potency to Amphotericin B against the S. racemosum fungus (MIC = 3.9 μg/mL) (Figure 23 ) [61] . Long-chain 5-alkenyl/hydroxyalkenyl-2-phenylamine-1,3,4-oxadiazoles and thiadiazoles were synthesized and screened as antimicrobial agents against S. pyogenes, S. aureus, P. aeruginosa, K. pneumoniae, and E. coli bacterial strains and C. albicans, A. fumigatus, T. mentagrophytes, and P. marneffei fungal strains. The study results showed no difference in activity between the bioisosteres of oxadiazoles and thiadiazoles. Examination of SAR indicated that the presence of a hydroxyalkyl chain at the fifth position of the oxa-/thiadiazole ring increased the antibacterial activity in compounds 143c, 143d, 145c, and 145d, as they were equally as potent as the reference drug chloramphenicol (MIC = 6.25 µg/mL). Moreover, the compounds with an internal double bond in the long alkenyl substituent of synthesized oxa-/thiadiazoles 143b and 145b were found to be potent antifungal agents ( Figure 22 ) [64] . Long-chain 5-alkenyl/hydroxyalkenyl-2-phenylamine-1,3,4-oxadiazoles and thiadiazoles were synthesized and screened as antimicrobial agents against S. pyogenes, S. aureus, P. aeruginosa, K. pneumoniae, and E. coli bacterial strains and C. albicans, A. fumigatus, T. mentagrophytes, and P. marneffei fungal strains. The study results showed no difference in activity between the bioisosteres of oxadiazoles and thiadiazoles. Examination of SAR indicated that the presence of a hydroxyalkyl chain at the fifth position of the oxa-/thiadiazole ring increased the antibacterial activity in compounds 143c, 143d, 145c, and 145d, as they were equally as potent as the reference drug chloramphenicol (MIC = 6.25 μg/mL). Moreover, the compounds with an internal double bond in the long alkenyl substituent of synthesized oxa-/thiadiazoles 143b and 145b were found to be potent antifungal agents (Figure 22 ) [64] . A series of 5-[N-(p-flurobenzyl)indolyl]propyl-1,3,4-(oxa)thiadiazoles were tested in vitro for their antibacterial and antifungal activities. Only the thiadiazole derivatives showed promising results. The 2-phenylamino derivative 75d was more potent than the reference drug Gentamicin against Gram-negative E. coli, with MIC = 0.24 and 3.9 μg/mL, respectively. The 2-ethylamino analog 75b was equipotent to Gentamicin against E. coli (MIC = 3.9 μg/mL), and was four times more potent than Gentamicin against P. aeruginosa (MIC 3.9 μg/mL and 15.6 μg/mL, respectively). The 2-cyclohexyl amino counterpart 75c showed promising results against E. coli (MIC 0.49 μg/mL) compared to Gentamicin and displayed equivalent potency to Amphotericin B against the S. racemosum fungus (MIC = 3.9 μg/mL) (Figure 23 ) [61] . A series of 5-[N-(p-flurobenzyl)indolyl]propyl-1,3,4-(oxa)thiadiazoles were tested in vitro for their antibacterial and antifungal activities. Only the thiadiazole derivatives showed promising results. The 2-phenylamino derivative 75d was more potent than the reference drug Gentamicin against Gram-negative E. coli, with MIC = 0.24 and 3.9 µg/mL, respectively. The 2-ethylamino analog 75b was equipotent to Gentamicin against E. coli (MIC = 3.9 µg/mL), and was four times more potent than Gentamicin against P. aeruginosa (MIC 3.9 µg/mL and 15.6 µg/mL, respectively). The 2-cyclohexyl amino counterpart 75c showed promising results against E. coli (MIC 0.49 µg/mL) compared to Gentamicin and displayed equivalent potency to Amphotericin B against the S. racemosum fungus (MIC = 3.9 µg/mL) (Figure 23 ) [61] .

The potential antimicrobial effect of 5-(benzimidazol-1-yl methyl)-2-arylamino-1,3,4-(oxa)thiadiazoles was investigated against microorganisms representing Gram-positive bacteria (S. aureus and S. epidermidis), Gram-negative bacteria (E. coli and P. aerugnosa), and fungi (C. albicans). [100] . The designed compounds were tested for antibacterial activity against a selection of 24 bacterial species, using KKL-35 as a reference. 6-Chloro-N-(5-(4-(trifluoromethyl)phenyl)-1,3,4-oxadiazol-2-yl)nicotinamide 153c, and its 3-chlorobenzamide analog 153a exhibited a wide spectrum of action and strong antimicrobial activity. They were active against almost all of the tested Gram-positive strains except C. perfringens and S. pyogenes. However, the only Gram-negative strain affected was B. fragilis (by 153c). They also affected the growth of the mycobacterium, M. fortuitum, and 153c had an effect against M. abscessus. Compared to KKL-35, 153c displayed lower MICs for E. faecalis (MIC 2-4 mg/L), E. faecium (MIC 2 mg/L), and M. fortuitum (MIC 8 mg/L). In addition, 153a showed a superior effect against E. faecalis, E. faecium, and S. epidermidis (MICs = 0.0625-1 mg/L). Furthermore, these compounds show synergistic activity with conventional antibiotics and have low toxicities (Figure 26 ) [87] .

various non-related bacteria [100] . The designed compounds were tested for antibacterial activity against a selection of 24 bacterial species, using KKL-35 as a reference. 6-Chloro-N- (5-(4-(trifluoromethyl)phenyl)-1,3,4-oxadiazol-2-yl) nicotinamide 153c, and its 3chlorobenzamide analog 153a exhibited a wide spectrum of action and strong antimicrobial activity. They were active against almost all of the tested Gram-positive strains except C. perfringens and S. pyogenes. However, the only Gram-negative strain affected was B. fragilis (by 153c). They also affected the growth of the mycobacterium, M. fortuitum, and 153c had an effect against M. abscessus. Compared to KKL-35, 153c displayed lower MICs for E. faecalis (MIC 2-4 mg/L), E. faecium (MIC 2 mg/L), and M. fortuitum (MIC 8 mg/L). In addition, 153a showed a superior effect against E. faecalis, E. faecium, and S. epidermidis (MICs = 0.0625-1 mg/L). Furthermore, these compounds show synergistic activity with conventional antibiotics and have low toxicities (Figure 26 ) [87] . Karabanovich et al., evaluated the activity of a series of substituted benzylsulfanyl-1,3,4-oxadiazoles and 1,3,4-thiadiazoles as antitubercular agents. The majority of these compounds exhibited outstanding in vitro activity against Mycobacterium tuberculosis. The activity results revealed that there was no difference in activity between oxadiazoles and thiadiazole analogs. Most of the compounds bearing the 3,5-dinitrobenzylsulfanyl moiety (233 and 234 series) exhibited excellent activity against drug-susceptible and multidrugresistant M.tb. strains, with no cross-resistance with first-and second-line anti-TB drugs. An SAR study indicated that removal or substitution of one nitro group or changing the positions of both nitro groups resulted in a decrease or loss of activity ( Figure 27 ). The anti-TB effect of the compounds was selectivity with low toxicity, genotoxicity, and mutagenicity [101] . Karabanovich et al., evaluated the activity of a series of substituted benzylsulfanyl-1,3,4-oxadiazoles and 1,3,4-thiadiazoles as antitubercular agents. The majority of these compounds exhibited outstanding in vitro activity against Mycobacterium tuberculosis. The activity results revealed that there was no difference in activity between oxadiazoles and thiadiazole analogs. Most of the compounds bearing the 3,5-dinitrobenzylsulfanyl moiety (233 and 234 series) exhibited excellent activity against drug-susceptible and multidrugresistant M.tb. strains, with no cross-resistance with first-and second-line anti-TB drugs. An SAR study indicated that removal or substitution of one nitro group or changing the positions of both nitro groups resulted in a decrease or loss of activity ( Figure 27 ). The anti-TB effect of the compounds was selectivity with low toxicity, genotoxicity, and mutagenicity [101] . According to the theory that the incorporation of different pharmacophores into a single molecule can change the activity of the newly obtained compound, a series of cyclic imides containing both 1,3,4-oxadiazole and 1,3,4-thiadiazole heterocycles was prepared and tested for their antimicrobial activity against four strains of bacteria (S. aureus, S. pyogenes, E. coli, and P. aeruginosa) and C. albicans fungi. The results indicated that compounds 235 (IZD = 14-20.5 mm), 236 (IZD = 12.6-21 mm), and 237 (IZD = 12.9-20.1 mm) were highly active against all types of tested bacteria compared to Ampicillin (IZD = 12-17 mm). Only compounds 235 (IZD = 18.6 mm) and 237 (IZD = 22.2 mm) were also According to the theory that the incorporation of different pharmacophores into a single molecule can change the activity of the newly obtained compound, a series of cyclic imides containing both 1,3,4-oxadiazole and 1,3,4-thiadiazole heterocycles was prepared and tested for their antimicrobial activity against four strains of bacteria (S. aureus, S. pyogenes, E. coli, and P. aeruginosa) and C. albicans fungi. The results indicated that compounds 235 (IZD = 14-20.5 mm), 236 (IZD = 12.6-21 mm), and 237 (IZD = 12.9-20.1 mm) were highly active against all types of tested bacteria compared to Ampicillin (IZD = 12-17 mm). Only compounds 235 (IZD = 18.6 mm) and 237 (IZD = 22.2 mm) were also highly active against C. albicans fungi (Fluconazole IZD = 18 mm) ( Figure 28 ) [102] . According to the theory that the incorporation of different pharmacophores into a single molecule can change the activity of the newly obtained compound, a series of cyclic imides containing both 1,3,4-oxadiazole and 1,3,4-thiadiazole heterocycles was prepared and tested for their antimicrobial activity against four strains of bacteria (S. aureus, S. pyogenes, E. coli, and P. aeruginosa) and C. albicans fungi. The results indicated that compounds 235 (IZD = 14-20.5 mm), 236 (IZD = 12.6-21 mm), and 237 (IZD = 12.9-20.1 mm) were highly active against all types of tested bacteria compared to Ampicillin (IZD = 12-17 mm). Only compounds 235 (IZD = 18.6 mm) and 237 (IZD = 22.2 mm) were also highly active against C. albicans fungi (Fluconazole IZD = 18 mm) ( Figure 28 ) [102] . This study supports the same theory, whereby the potential antibacterial activity of a series of 1,3,4-thiadiazole derivatives tagged to oxadiazole and thiadiazole units were evaluated against E. coli, S. typhimurium, L. monocytogenes, K. pneumonia, S. typhi, S. aureus, and B. subtilis species. The assay results revealed that compounds 238 and 239, with a strong electron-withdrawing fluorine atom at the para position, were more potent than Ampicillin on all tested strains (MIC = 62.5-100 μg/mL and 100-250 μg/mL, respectively). This study supports the same theory, whereby the potential antibacterial activity of a series of 1,3,4-thiadiazole derivatives tagged to oxadiazole and thiadiazole units were evaluated against E. coli, S. typhimurium, L. monocytogenes, K. pneumonia, S. typhi, S. aureus, and B. subtilis species. The assay results revealed that compounds 238 and 239, with a strong electron-withdrawing fluorine atom at the para position, were more potent than Ampicillin on all tested strains (MIC = 62.5-100 µg/mL and 100-250 µg/mL, respectively). It was also noticed that the 1,3,4-thiadiazoles linked with 1,3,4-thiadiazole units 239 were more active than 1,3,4-thiadiazoles linked with 1,3,4-oxadiazole 238 (Figure 29 ) [103] . A series of 2,5-disubstituted-1,3,4-thiadiazole tethered 1,3,4-(oxa)thiadiazole derivatives were synthesized as antimicrobial agents. Their activities were evaluated against a panel of standard strains of pathogenic microorganisms, including Gram-positive bacteria (S. pneumonia, B. subtilis, and S. aureus), Gram-negative bacteria (P. aeruginosa, E. coli, and K. pneumonia), and fungi (A. fumigatus, C. albicans, and G. candidum), and against reference drugs Ciprofloxacin and Fluconazole. The antimicrobial activity of the thiadiazoles (102a-c) revealed that the tested compounds showed promising activity against all bacterial and fungal strains at 8-31.25 µg/mL. However, the oxadiazole isosteres (101a-c) showed greater antibacterial activity against Gram-positive bacteria, at MIC = 8-16 µg/mL, but they exhibited lower antifungal activity (MIC = 31.25-62.5 µg/mL). Oxadiazole 240 functionalized with a thiol group at position 2 exhibited excellent antibacterial activities against all bacterial strains at MIC = 4-8 µg/mL and good activity towards fungal strains at MIC =16-31.28 µg/mL (Figure 30 ) [76] .

Antimicrobial activity screening of 2-(bis((1,3,4-oxadiazolyl/1,3,4-thiadiazolyl) methylthio) methylene)malononitrile derivatives (241a-c, 242a-c) against S. aureus, B. subtilis (Grampositive bacteria) and E. coli, K. pneumoniae (Gram-negative bacteria) revealed that compounds having a thiadiazole moiety (242a-c) exhibited high activity against both Gram-positive and Gram-negative bacteria (IZD = 17-35 mm). However, the oxadiazole compounds (241a-c) displayed moderate activity towards Gram-positive bacteria (IZD = 10-20 mm). Similarly, compounds having thiadiazole rings (242a-c, IZD = 18-34 mm) exhibited higher antifungal activity than those with an oxadiazole moiety (241a-c, IZD = 12-22 mm) against C. albicans, A. niger, and F. solani (Figure 31 ) [99] .

A series of 2,5-disubstituted-1,3,4-thiadiazole tethered 1,3,4-(oxa)thiadiazole derivatives were synthesized as antimicrobial agents. Their activities were evaluated against a panel of standard strains of pathogenic microorganisms, including Grampositive bacteria (S. pneumonia, B. subtilis, and S. aureus) , Gram-negative bacteria (P. aeruginosa, E. coli, and K. pneumonia), and fungi (A. fumigatus, C. albicans, and G. candidum) , and against reference drugs Ciprofloxacin and Fluconazole. The antimicrobial activity of the thiadiazoles (102a-c) revealed that the tested compounds showed promising activity against all bacterial and fungal strains at 8-31.25 μg/mL. However, the oxadiazole isosteres (101a-c) showed greater antibacterial activity against Gram-positive bacteria, at MIC = 8-16 μg/mL, but they exhibited lower antifungal activity (MIC = 31.25-62.5 μg/mL). Oxadiazole 240 functionalized with a thiol group at position 2 exhibited excellent antibacterial activities against all bacterial strains at MIC = 4-8 μg/mL and good activity towards fungal strains at MIC =16-31.28 µg/mL (Figure 30 ) [76] . Sekhar et al., prepared new classes of methylthio-linked pyrimidinyl 1,3,4oxadiazoles and 1,3,4-thiadiazoles. Screening the antibacterial activity indicated that the title compounds were more effective against Gram-negative bacteria than Gram-positive ones. The pyrimidinyl bis-thiadiazoles 243 exhibited greater activity than pyrimidinyl bisoxadiazoles. The presence of an electron-withdrawing group on the aromatic ring increased the activity. The p-chlorophenyl 243a and p-nitrophenyl 243b derivatives (MIC 6.25 μg/well) were effective, particularly against P. aeruginosa, and were equipotent to Chloramphenicol (MIC 6.25 μg/well) (Figure 32 ) [104] . In 2019, a new class of aroylethenesulfonylmethyl/arylsulfonylethenesulfonylmethyl styryl 1,3,4-oxadiazoles, 1,3,4-thiadiazoles (Figure 33) , was synthesized and evaluated for antimicrobial activity. It was observed that compounds having thiadiazole (19c, 20c) moiety exhibited higher antimicrobial activity than those with the oxadiazole moiety (17c, Sekhar et al., prepared new classes of methylthio-linked pyrimidinyl 1,3,4-oxadiazoles and 1,3,4-thiadiazoles. Screening the antibacterial activity indicated that the title compounds were more effective against Gram-negative bacteria than Gram-positive ones. The pyrimidinyl bis-thiadiazoles 243 exhibited greater activity than pyrimidinyl bis-oxadiazoles. The presence of an electron-withdrawing group on the aromatic ring increased the activity. The p-chlorophenyl 243a and p-nitrophenyl 243b derivatives (MIC 6.25 µg/well) were effective, particularly against P. aeruginosa, and were equipotent to Chloramphenicol (MIC 6.25 µg/well) (Figure 32 ) [104] . Sekhar et al., prepared new classes of methylthio-linked pyrimidinyl 1,3,4oxadiazoles and 1,3,4-thiadiazoles. Screening the antibacterial activity indicated that the title compounds were more effective against Gram-negative bacteria than Gram-positive ones. The pyrimidinyl bis-thiadiazoles 243 exhibited greater activity than pyrimidinyl bisoxadiazoles. The presence of an electron-withdrawing group on the aromatic ring increased the activity. The p-chlorophenyl 243a and p-nitrophenyl 243b derivatives (MIC 6.25 μg/well) were effective, particularly against P. aeruginosa, and were equipotent to Chloramphenicol (MIC 6.25 μg/well) (Figure 32 ) [104] . In 2019, a new class of aroylethenesulfonylmethyl/arylsulfonylethenesulfonylmethyl styryl 1,3,4-oxadiazoles, 1,3,4-thiadiazoles (Figure 33) , was synthesized and evaluated for antimicrobial activity. It was observed that compounds having thiadiazole (19c, 20c) moiety exhibited higher antimicrobial activity than those with the oxadiazole moiety (17c, In 2019, a new class of aroylethenesulfonylmethyl/arylsulfonylethenesulfonylmethyl styryl 1,3,4-oxadiazoles, 1,3,4-thiadiazoles (Figure 33 ), was synthesized and evaluated for antimicrobial activity. It was observed that compounds having thiadiazole (19c, 20c) moiety exhibited higher antimicrobial activity than those with the oxadiazole moiety (17c, 18c) . Additionally, arylsulfonylethenesulfonylmethyl styryl azoles (18c, 20c) exhibited greater antimicrobial activity than aroylethenesulfonylmethyl styrylazoles (17c, 19c) . Moreover, compounds with an electron-withdrawing chloro substituent on the phenyl ring possessed enhanced activity [6] . In 2019, a new class of aroylethenesulfonylmethyl/arylsulfonylethenesulfonylmethyl styryl 1,3,4-oxadiazoles, 1,3,4-thiadiazoles (Figure 33 ), was synthesized and evaluated for antimicrobial activity. It was observed that compounds having thiadiazole (19c, 20c) moiety exhibited higher antimicrobial activity than those with the oxadiazole moiety (17c,  18c) . Additionally, arylsulfonylethenesulfonylmethyl styryl azoles (18c, 20c) exhibited greater antimicrobial activity than aroylethenesulfonylmethyl styrylazoles (17c, 19c) . Moreover, compounds with an electron-withdrawing chloro substituent on the phenyl ring possessed enhanced activity [6] . The potential activity of 2-(arylaminosulfonyl methyl)-1,3,4-oxa(thia)diazole derivatives (compounds 33a-c to 36a-c) as antimicrobial agents was screened in vitro against a panel of Gram-positive bacteria-S. aureus, B. subtilis-and Gram-negative bacteria-K. pneumoniae and P. vulgaris and fungi F. solani, C. lunata, and A. niger. The results showed that compounds with the thiadiazole moiety (35a-c, 36a-c) exhibited higher antimicrobial activity than those with oxadiazole units (33a-c, 34a-c) . In particular, compounds (7a-c) carrying the thiadiazole moiety displayed potent activity against the tested Grampositive bacteria and fungi (IZD > 26 mm) and good activity against Gram-negative bacteria (IZD > 20 mm). Thiadiazole derivatives featuring the 5-arylsulfonylmethane moiety (36a-c) displayed higher activity than their respective 5-aryl counterparts (35a-c) against all of the tested microorganisms. Additionally, the antimicrobial effect was enhanced upon grafting a Cl-substituent to the phenyl ring ( Figure 34 ) [50] . The results showed that compounds with the thiadiazole moiety (35a-c, 36a-c) exhibited higher antimicrobial activity than those with oxadiazole units (33a-c, 34a-c) . In particular, compounds (7a-c) carrying the thiadiazole moiety displayed potent activity against the tested Gram-positive bacteria and fungi (IZD > 26 mm) and good activity against Gramnegative bacteria (IZD > 20 mm). Thiadiazole derivatives featuring the 5arylsulfonylmethane moiety (36a-c) displayed higher activity than their respective 5-aryl counterparts (35a-c) against all of the tested microorganisms. Additionally, the antimicrobial effect was enhanced upon grafting a Cl-substituent to the phenyl ring ( Figure 34 ) [50] . A series of 5-(styryl/pyrrolyl/pyrazolylsulfonylmethyl)-2-(arylaminosulfonylmethyl) 1,3,4-oxa(thia)diazoles ( Figure 35 ) were prepared and tested for antimicrobial activity against S. aureus, B. subtilis (Gram-positive bacteria), P. aeruginosa and K. pneumoniae (Gram-negative bacteria). The data showed that the presence of a chloro substituent on phenyl rings of thiadiazoles (31c, 245c, 247c) enhanced the activity against the tested bacteria. The corresponding oxadiazole analogs (30a-c, 244a-c, 246a-c) proved to be less potent antimicrobial agents. It was also observed that the styryl derivatives (30a-c, 31a-c) displayed higher potency than their pyrrolyl/pyrazolyl counterparts (244a-c-247a-c) [49] . A series of 5-(styryl/pyrrolyl/pyrazolylsulfonylmethyl)-2-(arylaminosulfonylmethyl) 1,3,4-oxa(thia)diazoles ( Figure 35 ) were prepared and tested for antimicrobial activity against S. aureus, B. subtilis (Gram-positive bacteria), P. aeruginosa and K. pneumoniae (Gramnegative bacteria). The data showed that the presence of a chloro substituent on phenyl rings of thiadiazoles (31c, 245c, 247c) enhanced the activity against the tested bacteria. The corresponding oxadiazole analogs (30a-c, 244a-c, 246a-c) proved to be less potent antimicrobial agents. It was also observed that the styryl derivatives (30a-c, 31a-c) displayed higher potency than their pyrrolyl/pyrazolyl counterparts (244a-c-247a-c) [49] .

An extract from the antimicrobial structure-activity relationship of substituted 1,3,4oxa-/thiadiazoles is illustrated in (Figure 36a,b.) 1,3,4-oxa(thia)diazoles ( Figure 35 ) were prepared and tested for antimicrobial activity against S. aureus, B. subtilis (Gram-positive bacteria), P. aeruginosa and K. pneumoniae (Gram-negative bacteria). The data showed that the presence of a chloro substituent on phenyl rings of thiadiazoles (31c, 245c, 247c) enhanced the activity against the tested bacteria. The corresponding oxadiazole analogs (30a-c, 244a-c, 246a-c) proved to be less potent antimicrobial agents. It was also observed that the styryl derivatives (30a-c, 31a-c) displayed higher potency than their pyrrolyl/pyrazolyl counterparts (244a-c-247a-c) [49] . An extract from the antimicrobial structure-activity relationship of substituted 1,3,4oxa-/thiadiazoles is illustrated in (Figure 36a 

A series of 4-oxo-4H-pyrido[1,2-a]pyrimidine derivatives containing 1,3,4oxa(thia)diazole rings as a part of the metal chelation motif were screened for their in vitro anti-HIV-1 activity by determining their ability to inhibit the replication of HIV-1 in Hela cell cultures. All of the tested compounds were safe with no cytotoxicity at a concentration 

A series of 4-oxo-4H-pyrido[1,2-a]pyrimidine derivatives containing 1,3,4-oxa(thia) diazole rings as a part of the metal chelation motif were screened for their in vitro anti-HIV-1 activity by determining their ability to inhibit the replication of HIV-1 in Hela cell cultures. All of the tested compounds were safe with no cytotoxicity at a concentration of 100 µM. Compounds containing thiadiazole rings were more potent than the corresponding oxadiazole analogs. The highest degrees of inhibition against HIV-1 (NL4-3) were reported for the thiadiazoles 63b and 63c: 51% and 48%, respectively. The docking study revealed that the anti-HIV activity of these compounds might involve a metal chelating mechanism ( Figure 37 ) [59] . The antiviral activity of a series of thioether/sulfone compounds containing 1,2,3thiadiazole and 1,3,4-oxa(thia)diazole rings was tested against tobacco mosaic virus TMV using Ningnanmycin as a reference drug. The data results revealed that the compounds containing 1,2,3-thiadiazole incorporating 1,3,4-oxadiazole ring 248a, 248b, 248c, and 250a showed equipotent activities to Ningnanmycin with curative effects ranging from 46.8% to 54.1%. However, a slight lowering of activity was noticed with the 1,3,4-thiadiazole isosteres (249,251). Oxidation of thioethers (248,249) to their corresponding sulfones (250,251) slightly reduced the values of antiviral activities ( Figure 38 ) [105] . 

A series of N-(4-substitutedphenyl)-5-(pyridin-4-yl)-1,3,4-oxa(thia)diazol-2-amines were synthesized and evaluated with respect to their in vitro cytotoxicity against six human cancer cell lines, including cells derived from human gastric cancer (NUGC), human colon cancer (DLD1), human liver cancer (HA22T and HEPG2), nasopharyngeal carcinoma (HONE1), human breast cancer (MCF), and normal fibroblast cells (WI38) using CHS 828, a pyridyl cyanoguanidine, as a standard antitumor drug. The overall results revealed superior activity of 1,3,4-thiadiazoles compared to that of their 1,3,4oxadiazoles bioisosteres, where only one oxadiazole compound 80b showed selective moderate activity against NUGC and DLD1 cell lines. Among 1,3,4-thiadiazoles, only the compounds bearing 4-chlorophenyl (81b) and 4-bromophenyl 81c pharmacophores were found to be active, which proves that the electronegativity of substituents plays an essential role in the activity. Compound (81c) showed nearly equipotent activity against the NUGC cell line compared to the standard CHS 828, with IC50 = 0.028 μM, while 81c also showed 4-fold higher activity against HA22T and HEPG2 cell lines compared to its analog 81b (IC50 = 0.180, 0.264 μM and 0.753, 0.970 μM, respectively) ( Figure 39 ) [69] . The antiviral activity of a series of thioether/sulfone compounds containing 1,2,3thiadiazole and 1,3,4-oxa(thia)diazole rings was tested against tobacco mosaic virus TMV using Ningnanmycin as a reference drug. The data results revealed that the compounds containing 1,2,3-thiadiazole incorporating 1,3,4-oxadiazole ring 248a, 248b, 248c, and 250a showed equipotent activities to Ningnanmycin with curative effects ranging from 46.8% to 54.1%. However, a slight lowering of activity was noticed with the 1,3,4-thiadiazole isosteres (249,251). Oxidation of thioethers (248,249) to their corresponding sulfones (250,251) slightly reduced the values of antiviral activities ( Figure 38 ) [105] . The antiviral activity of a series of thioether/sulfone compounds containing 1,2,3thiadiazole and 1,3,4-oxa(thia)diazole rings was tested against tobacco mosaic virus TMV using Ningnanmycin as a reference drug. The data results revealed that the compounds containing 1,2,3-thiadiazole incorporating 1,3,4-oxadiazole ring 248a, 248b, 248c, and 250a showed equipotent activities to Ningnanmycin with curative effects ranging from 46.8% to 54.1%. However, a slight lowering of activity was noticed with the 1,3,4-thiadiazole isosteres (249,251). Oxidation of thioethers (248,249) to their corresponding sulfones (250,251) slightly reduced the values of antiviral activities ( Figure 38 ) [105] . 

A series of N-(4-substitutedphenyl)-5-(pyridin-4-yl)-1,3,4-oxa(thia)diazol-2-amines were synthesized and evaluated with respect to their in vitro cytotoxicity against six human cancer cell lines, including cells derived from human gastric cancer (NUGC), human colon cancer (DLD1), human liver cancer (HA22T and HEPG2), nasopharyngeal carcinoma (HONE1), human breast cancer (MCF), and normal fibroblast cells (WI38) using CHS 828, a pyridyl cyanoguanidine, as a standard antitumor drug. The overall results revealed superior activity of 1,3,4-thiadiazoles compared to that of their 1,3,4oxadiazoles bioisosteres, where only one oxadiazole compound 80b showed selective moderate activity against NUGC and DLD1 cell lines. Among 1,3,4-thiadiazoles, only the compounds bearing 4-chlorophenyl (81b) and 4-bromophenyl 81c pharmacophores were found to be active, which proves that the electronegativity of substituents plays an essential role in the activity. Compound (81c) showed nearly equipotent activity against the NUGC cell line compared to the standard CHS 828, with IC50 = 0.028 μM, while 81c also showed 4-fold higher activity against HA22T and HEPG2 cell lines compared to its analog 81b (IC50 = 0.180, 0.264 μM and 0.753, 0.970 μM, respectively) ( Figure 39 ) [69] . 

A series of N-(4-substitutedphenyl)-5-(pyridin-4-yl)-1,3,4-oxa(thia)diazol-2-amines were synthesized and evaluated with respect to their in vitro cytotoxicity against six human cancer cell lines, including cells derived from human gastric cancer (NUGC), human colon cancer (DLD1), human liver cancer (HA22T and HEPG2), nasopharyngeal carcinoma (HONE1), human breast cancer (MCF), and normal fibroblast cells (WI38) using CHS 828, a pyridyl cyanoguanidine, as a standard antitumor drug. The overall results revealed superior activity of 1,3,4-thiadiazoles compared to that of their 1,3,4-oxadiazoles bioisosteres, where only one oxadiazole compound 80b showed selective moderate activity against NUGC and DLD1 cell lines. Among 1,3,4-thiadiazoles, only the compounds bearing 4-chlorophenyl (81b) and 4-bromophenyl 81c pharmacophores were found to be active, which proves that the electronegativity of substituents plays an essential role in the activity. Compound (81c) showed nearly equipotent activity against the NUGC cell line compared to the standard CHS 828, with IC 50 = 0.028 µM, while 81c also showed 4-fold higher activity against HA22T and HEPG2 cell lines compared to its analog 81b (IC 50 = 0.180, 0.264 µM and 0.753, 0.970 µM, respectively) ( Figure 39 ) [69] .

oxadiazoles bioisosteres, where only one oxadiazole compound 80b showed sel moderate activity against NUGC and DLD1 cell lines. Among 1,3,4-thiadiazoles, on compounds bearing 4-chlorophenyl (81b) and 4-bromophenyl 81c pharmacophores found to be active, which proves that the electronegativity of substituents pla essential role in the activity. Compound (81c) showed nearly equipotent activity a the NUGC cell line compared to the standard CHS 828, with IC50 = 0.028 μM, whi also showed 4-fold higher activity against HA22T and HEPG2 cell lines compared analog 81b (IC50 = 0 Rajak et al., prepared two series of hydroxamic acid-based 1,3,4-oxa-/thiadiazoles as histone deacetylase inhibitors and examined their antiproliferative activities in vitro using histone deacetylase inhibitory assay and MTT assay. They were also tested for antitumor activity against Ehrlich ascites carcinoma cells in Swiss albino mice. The results showed that among the oxadiazole series, compound 252 was the most potent, displaying the maximum HDAC inhibitory activity with an IC 50 = 0.017 µM against HDAC-1 and an IC 50 = 0.28 µM in HCT-116 cell proliferation assay, as well as %TWI = 85.7 and %TCI = 77.7 against Ehrlich ascites carcinoma cells in Swiss albino mice. In the thiadiazole series, compound 253 was the most potent, displaying the maximum HDAC inhibitory activity, with an IC 50 = 0.018 µM against HDAC-1 and an IC 50 = 0.31 µM in HCT-116 cell proliferation assay, and %TWI = 75.0; %TCI = 76.8 against Ehrlich ascites carcinoma cells.

An overview of the results shows that thiadiazoles were found to be more active than the corresponding oxadiazole ( Figure 40 ) [106] .

Molecules 2022, 27, x FOR PEER REVIEW 46 Rajak et al., prepared two series of hydroxamic acid-based 1,3,4-oxa-/thiadiazo histone deacetylase inhibitors and examined their antiproliferative activities in vitro histone deacetylase inhibitory assay and MTT assay. They were also tested for antit activity against Ehrlich ascites carcinoma cells in Swiss albino mice. The results sh that among the oxadiazole series, compound 252 was the most potent, displayin maximum HDAC inhibitory activity with an IC50 = 0.017 μM against HDAC-1 and a = 0.28 μM in HCT-116 cell proliferation assay, as well as %TWI = 85.7 and %TCI = against Ehrlich ascites carcinoma cells in Swiss albino mice. In the thiadiazole s compound 253 was the most potent, displaying the maximum HDAC inhibitory act with an IC50 = 0.018 μM against HDAC-1 and an IC50 = 0.31 μM in HCT-116 proliferation assay, and %TWI = 75.0; %TCI = 76.8 against Ehrlich ascites carcinoma An overview of the results shows that thiadiazoles were found to be more active tha corresponding oxadiazole ( Figure 40 ) [106] . The in vitro antiproliferative activity of a series of benzosuberones embedded 1,3,4-oxa(thia)diazole moieties was examined against four human cancer cell (cervical He La, breast MDA-MB-231, pancreatic PANC1, and alveolar A549), w Paclitaxel, Nocodazole, Colchicine, Combretostatin, and Doxorubicin were use standard drugs. The reported data showed that compounds 204a, 254, and 255 sh potent activity, with GI50 values ranging from 0.079 µM to 0.957 µM against the human cancer cell lines. However, compound 254 was nearly equipotent to Colch against the HeLa cell line with GI50 = 0.079 µM. Based on the overall results, it concluded that benzosuberones attached to oxadiazoles were more active than corresponding thiadiazoles (Figure 41 ) [98] . The in vitro antiproliferative activity of a series of benzosuberones embedded with 1,3,4-oxa(thia)diazole moieties was examined against four human cancer cell lines (cervical He La, breast MDa-mB-231, pancreatic PANC1, and alveolar A549), where Paclitaxel, Nocodazole, Colchicine, Combretostatin, and Doxorubicin were used as standard drugs. The reported data showed that compounds 204a, 254, and 255 showed potent activity, with GI 50 values ranging from 0.079 µM to 0.957 µM against the four human cancer cell lines. However, compound 254 was nearly equipotent to Colchicine against the HeLa cell line with GI 50 = 0.079 µM. Based on the overall results, it was concluded that benzosuberones attached to oxadiazoles were more active than the corresponding thiadiazoles ( Figure 41 ) [98] .

The cytotoxic activities of a series of 2-(5-methyl-2-nitrophenyl)-5-(substituted)-1,3,4oxa(thia)diazoles were tested using Podophyllotoxin as a standard drug. The unsymmetrical 1,3,4-oxadiazole compounds with thiophene or chloropyridine substitution at the 5th position (56c, 56e) and the 1,3,4-thiadiazole compound with furan substitution at the 5th position 57b showed significant activity (IC 50 = 10-19.45 µg/mL) compared to the standard podophyllotoxin (IC 50 of 3.64 µg/mL), in contrast to the inactive symmetrical oxadiazole 56a ( Figure 42 ) [55] .

Paclitaxel, Nocodazole, Colchicine, Combretostatin, and Doxorubicin were used as standard drugs. The reported data showed that compounds 204a, 254, and 255 showed potent activity, with GI50 values ranging from 0.079 µM to 0.957 µM against the four human cancer cell lines. However, compound 254 was nearly equipotent to Colchicine against the HeLa cell line with GI50 = 0.079 µM. Based on the overall results, it was concluded that benzosuberones attached to oxadiazoles were more active than the corresponding thiadiazoles ( Figure 41 ) [98] . In the same year, two series of novel diosgenin derivatives bearing 1,3,4-ox or 1,3,4-thiadiazole moieties were evaluated for their cytotoxicity in four huma cell lines (HepG2, A549, MCF-7, and HCT-116) and normal human gastric epithe (GES-1) using the MTT assay in vitro. The data revealed that the 1,3,4-thiadiazo were more active than the 1,3,4-oxadiazole series against HepG2 and A549 cells. the 1,3,4-thiadiazoles, compound 60d ( Figure 43 ) with a 3-pyridyl group at the C5 was the most potent. It was 6.7-fold more potent than the parent drug diosgen against the A549 cell line (IC50 = 3.93 µM and 26.41 µM, respectively, as well as b fold more potent than DG against the HepG2 cell line (MIC = 11.73 μM and 33 respectively). Moreover, compound 60d displayed low toxicity against non-can GES-1 cells (IC50 = 420.4 µM), showing high selectivity [58] . On the basis that combining different heterocyclic nuclei may show syn effects, Kamal and Sobhy decided to merge the two bioisosteres, 1,3,4-oxadiaz 1,3,4-thiadiazole, in one system to enhance the biological activity of the syn In the same year, two series of novel diosgenin derivatives bearing 1,3,4-oxadiazole or 1,3,4-thiadiazole moieties were evaluated for their cytotoxicity in four human cancer cell lines (HepG2, A549, MCF-7, and HCT-116) and normal human gastric epithelial cells (GES-1) using the MTT assay in vitro. The data revealed that the 1,3,4-thiadiazole series were more active than the 1,3,4-oxadiazole series against HepG2 and A549 cells. Among the 1,3,4-thiadiazoles, compound 60d ( Figure 43 ) with a 3-pyridyl group at the C5 position was the most potent. It was 6.7-fold more potent than the parent drug diosgenin (DG) against the A549 cell line (IC 50 = 3.93 µM and 26.41 µM, respectively, as well as being 2.9-fold more potent than DG against the HepG2 cell line (MIC = 11.73 µM and 33.87 µM, respectively). Moreover, compound 60d displayed low toxicity against non-cancer cells GES-1 cells (IC 50 = 420.4 µM), showing high selectivity [58] . In the same year, two series of novel diosgenin derivatives bearing 1,3,4-oxa or 1,3,4-thiadiazole moieties were evaluated for their cytotoxicity in four human cell lines (HepG2, A549, MCF-7, and HCT-116) and normal human gastric epithe (GES-1) using the MTT assay in vitro. The data revealed that the 1,3,4-thiadiazo were more active than the 1,3,4-oxadiazole series against HepG2 and A549 cells. the 1,3,4-thiadiazoles, compound 60d ( Figure 43 ) with a 3-pyridyl group at the C5 was the most potent. It was 6.7-fold more potent than the parent drug diosgen against the A549 cell line (IC50 = 3.93 µM and 26.41 µM, respectively, as well as be fold more potent than DG against the HepG2 cell line (MIC = 11.73 μM and 33 respectively). Moreover, compound 60d displayed low toxicity against non-can GES-1 cells (IC50 = 420.4 µM), showing high selectivity [58] . On the basis that combining different heterocyclic nuclei may show syn effects, Kamal and Sobhy decided to merge the two bioisosteres, 1,3,4-oxadiaz 1,3,4-thiadiazole, in one system to enhance the biological activity of the synt compounds and evaluated their cytotoxicity against a human colon carcinoma (HCT-116) using Doxorubicin as a reference drug. Among all the tested compou On the basis that combining different heterocyclic nuclei may show synergistic effects, Kamal and Sobhy decided to merge the two bioisosteres, 1,3,4-oxadiazole and 1,3,4thiadiazole, in one system to enhance the biological activity of the synthesized compounds and evaluated their cytotoxicity against a human colon carcinoma cell line (HCT-116) using Doxorubicin as a reference drug. Among all the tested compounds, the most active derivatives were 257d and 258c (IC 50 = 0.73 and 0.86 µg/mL, respectively), while the other compounds showed moderate to poor activity compared to Doxorubicin IC 50 = 0.42 µg/mL. The assay results and an examination of the structure-activity relationship revealed that, as a substituent at position 2 of 1,3,4-thiadiazole, the acetyl group (COCH 3 ) (257a-f) resulted in higher activity than the anilide group (CONHPh) (258a-c), which was better than the phenyl moiety (Ph) 256. Additionally, for substituents at position 4 of 1,3,4thiadiazole, 4-ClC 6 H 4 > 4-NO 2 C6H 4 > 4-OCH 3 C 6 H 4 > 4-CH 3 C 6 H 4 > 4-BrC 6 H 4 > C 6 H 5 ( Figure 44 ) [107] . Based on the same idea, a series of novel hybrid molecules containing 1,3,4oxadiazole and 1,3,4-thiadiazole bearing the Schiff base moiety were designed and evaluated with respect to their in vitro antitumor activities against SMMC7721, MCF-7, and A549 human tumor cell lines by CCK-8 assay. The data revealed that some compounds were more potent than the positive control, 5-Fluorouracil (5-FU), against various cell lines. Among these compounds, compound 259b (4-chloro) was the most potent against SMMC-7721 cells, with IC50 =2.84 μM. Compounds 259c (4-methoxy) and 259d (4-nitro) displayed highly effective antitumor activities against MCF-7 cells, with IC50 = 4.56 and 4.25 μM, respectively. The unsubstituted phenyl derivative 259a and the 4nitro-substituted derivative 259d showed significant activity against A549 cells, with IC50 = 4.11 and 4.13 μM, respectively. The pharmacological results suggest that the substituents of the phenyl ring on the 1,3,4-oxadiazole are important for modulating antiproliferative activities against various tumor cell lines ( Figure 45 ) [108] . In 2015, a series of 2,5-Bis[(2-substituted-1,3,4-oxa(thia)diazol-5-yl)propylthio]-1,3,4thiadiazoles were tested for their in vitro antiproliferative activities in four different human cancer cell lines (human breast adenocarcinoma, MCF7, human ductal breast epithelial tumor, T47D, human epithelial colorectal adenocarcinoma, Caco-2, and human epithelial carcinoma, He La). All compounds demonstrated relatively high activities against the examined cell lines. There was no difference in activity related to the replacement of oxadiazole with a thiadiazole ring, while changing methyl and phenyl groups in (101a,c) and (102a,c) into ethyl groups 101b and 102b significantly enhanced the cytotoxic activity, with LD50 values ranging from 376 ng/µL to 438 ng/µL, which suggests a steric factor mediating either transport or molecular interaction of these compounds with cellular targets. Furthermore, the addition of one more Cl atom into the structure of compound 260a (LD50 = 648-690 ng/µL) gave compound 260b, with double the activity Based on the same idea, a series of novel hybrid molecules containing 1,3,4-oxadiazole and 1,3,4-thiadiazole bearing the Schiff base moiety were designed and evaluated with respect to their in vitro antitumor activities against SMMC7721, MCF-7, and A549 human tumor cell lines by CCK-8 assay. The data revealed that some compounds were more potent than the positive control, 5-Fluorouracil (5-FU), against various cell lines. Among these compounds, compound 259b (4-chloro) was the most potent against SMMC-7721 cells, with IC 50 = 2.84 µM. Compounds 259c (4-methoxy) and 259d (4-nitro) displayed highly effective antitumor activities against MCF-7 cells, with IC 50 = 4.56 and 4.25 µM, respectively. The unsubstituted phenyl derivative 259a and the 4-nitro-substituted derivative 259d showed significant activity against A549 cells, with IC 50 = 4.11 and 4.13 µM, respectively. The pharmacological results suggest that the substituents of the phenyl ring on the 1,3,4oxadiazole are important for modulating antiproliferative activities against various tumor cell lines ( Figure 45 ) [108] . Based on the same idea, a series of novel hybrid molecules containing 1,3,4oxadiazole and 1,3,4-thiadiazole bearing the Schiff base moiety were designed and evaluated with respect to their in vitro antitumor activities against SMMC7721, MCF-7, and A549 human tumor cell lines by CCK-8 assay. The data revealed that some compounds were more potent than the positive control, 5-Fluorouracil (5-FU), against various cell lines. Among these compounds, compound 259b (4-chloro) was the most potent against SMMC-7721 cells, with IC50 =2.84 μM. Compounds 259c (4-methoxy) and 259d (4-nitro) displayed highly effective antitumor activities against MCF-7 cells, with IC50 = 4.56 and 4.25 μM, respectively. The unsubstituted phenyl derivative 259a and the 4nitro-substituted derivative 259d showed significant activity against A549 cells, with IC50 = 4.11 and 4.13 μM, respectively. The pharmacological results suggest that the substituents of the phenyl ring on the 1,3,4-oxadiazole are important for modulating antiproliferative activities against various tumor cell lines ( Figure 45 ) [108] . In 2015, a series of 2,5-Bis[(2-substituted-1,3,4-oxa(thia)diazol-5-yl)propylthio]-1,3,4thiadiazoles were tested for their in vitro antiproliferative activities in four different human cancer cell lines (human breast adenocarcinoma, MCF7, human ductal breast epithelial tumor, T47D, human epithelial colorectal adenocarcinoma, Caco-2, and human epithelial carcinoma, He La). All compounds demonstrated relatively high activities against the examined cell lines. There was no difference in activity related to the replacement of oxadiazole with a thiadiazole ring, while changing methyl and phenyl groups in (101a,c) and (102a,c) into ethyl groups 101b and 102b significantly enhanced the cytotoxic activity, with LD50 values ranging from 376 ng/µL to 438 ng/µL, which suggests a steric factor mediating either transport or molecular interaction of these compounds with cellular targets. Furthermore, the addition of one more Cl atom into the structure of compound 260a (LD50 = 648-690 ng/µL) gave compound 260b, with double the activity In 2015, a series of 2,5-Bis[(2-substituted-1,3,4-oxa(thia)diazol-5-yl)propylthio]-1,3,4thiadiazoles were tested for their in vitro antiproliferative activities in four different human cancer cell lines (human breast adenocarcinoma, MCF7, human ductal breast epithelial tumor, T47D, human epithelial colorectal adenocarcinoma, Caco-2, and human epithelial carcinoma, He La). All compounds demonstrated relatively high activities against the examined cell lines. There was no difference in activity related to the replacement of oxadiazole with a thiadiazole ring, while changing methyl and phenyl groups in (101a,c) and (102a,c) into ethyl groups 101b and 102b significantly enhanced the cytotoxic activity, with LD 50 values ranging from 376 ng/µL to 438 ng/µL, which suggests a steric factor mediating either transport or molecular interaction of these compounds with cellular targets. Furthermore, the addition of one more Cl atom into the structure of compound 260a (LD 50 = 648-690 ng/µL) gave compound 260b, with double the activity (LD 50 = 356-398 ng/µL) ( Figure 46 ) [76] . Ozdemir et al. designed and evaluated several oxadiazole and thiadiazole derivatives with respect to their anticancer effects on A549 human lung adenocarcinoma and C6 rat glioma cell lines and evaluated their inhibitory effects on matrix metalloproteinases (MMPs). Compounds 261, 263, and 264 showed high cytotoxic activity against the C6 cell line, with IC50 ranging from 0.0128 mM to 0.157 mM, compared to Cisplatin, with IC50 = 0.103 mM. Only the benzodioxole-substituted oxadiazoles 263 and 264 had a cytotoxic effect on the A549 cell line, with IC50 values of 0.125 and 0.349 mM, without causing any toxicity towards the NIH/3T3 mouse embryonic fibroblast cell line, which suggests that the (1,3-benzodioxol-5-ylmethyl) amino group enhances the antitumor activity against A549 cells. At the same time, the benzodioxole-substituted thiadiazole analog 262 was inactive against A549 cell lines, which proves that the oxadiazole scaffold is essential for activity against A549 cells. Compounds 263 and 264 were also the most effective MMP-9 inhibitors in this series. Moreover, docking studies pointed out that compounds 263 and 264 had a good affinity for the active site of the MMP-9 enzyme ( Figure 47 ) [109] . The structure-activity relationship of the anticancer activity of substituted 1,3,4-oxa-/thiadiazoles is summarized in Figure 48 . Ozdemir et al. designed and evaluated several oxadiazole and thiadiazole derivatives with respect to their anticancer effects on A549 human lung adenocarcinoma and C6 rat glioma cell lines and evaluated their inhibitory effects on matrix metalloproteinases (MMPs). Compounds 261, 263, and 264 showed high cytotoxic activity against the C6 cell line, with IC 50 ranging from 0.0128 mM to 0.157 mM, compared to Cisplatin, with IC 50 = 0.103 mM. Only the benzodioxole-substituted oxadiazoles 263 and 264 had a cytotoxic effect on the A549 cell line, with IC 50 values of 0.125 and 0.349 mM, without causing any toxicity towards the NIH/3T3 mouse embryonic fibroblast cell line, which suggests that the (1,3benzodioxol-5-ylmethyl) amino group enhances the antitumor activity against A549 cells. At the same time, the benzodioxole-substituted thiadiazole analog 262 was inactive against A549 cell lines, which proves that the oxadiazole scaffold is essential for activity against A549 cells. Compounds 263 and 264 were also the most effective MMP-9 inhibitors in this series. Moreover, docking studies pointed out that compounds 263 and 264 had a good affinity for the active site of the MMP-9 enzyme ( Figure 47 ) [109] . Ozdemir et al. designed and evaluated several oxadiazole and thiadiazole derivatives with respect to their anticancer effects on A549 human lung adenocarcinoma and C6 rat glioma cell lines and evaluated their inhibitory effects on matrix metalloproteinases (MMPs). Compounds 261, 263, and 264 showed high cytotoxic activity against the C6 cell line, with IC50 ranging from 0.0128 mM to 0.157 mM, compared to Cisplatin, with IC50 = 0.103 mM. Only the benzodioxole-substituted oxadiazoles 263 and 264 had a cytotoxic effect on the A549 cell line, with IC50 values of 0.125 and 0.349 mM, without causing any toxicity towards the NIH/3T3 mouse embryonic fibroblast cell line, which suggests that the (1,3-benzodioxol-5-ylmethyl) amino group enhances the antitumor activity against A549 cells. At the same time, the benzodioxole-substituted thiadiazole analog 262 was inactive against A549 cell lines, which proves that the oxadiazole scaffold is essential for activity against A549 cells. Compounds 263 and 264 were also the most effective MMP-9 inhibitors in this series. Moreover, docking studies pointed out that compounds 263 and 264 had a good affinity for the active site of the MMP-9 enzyme ( Figure 47 ) [109] . The structure-activity relationship of the anticancer activity of substituted 1,3,4-oxa-/thiadiazoles is summarized in Figure 48 . The structure-activity relationship of the anticancer activity of substituted 1,3,4-oxa-/thiadiazoles is summarized in Figure 48 . 

In 2019, Taha et al., reported a series of 5-(4-hydroxy-2-methoxyphenyl)-1,3,4oxadiazoles coupled to 5-aryl-1,3,4-thiadiazole motifs through a phenyl ring as potent βglucuronidase inhibitors. Several analogs were more potent enzyme inhibitors (IC50 = 0.96-28.10 μM) than the standard D-saccharic acid 1,4-lactone (IC50 = 48.40 μM). Study of the structure-activity relationships indicated that the nature and relative position of substituents on the phenyl ring attached to thiadiazole greatly affected the inhibitory potency. The 2,4,6-trichlorophenyl derivative 265 displayed superior activity (IC50 = 0.96 μM) compared to monochloro-substituted analogs, regardless of the position (o,m or p-). Moreover, compound 266a with the 3,4-dihydroxyphenyl moiety (IC50 = 1.40 μM) was four times more potent than the 2,5-dihydroxyphenyl analog 267a (IC50 = 6.20 μM). A docking study revealed that the hydroxyl groups in 6 had higher potential to be engaged in proper hydrogen bonding interaction with the enzyme active site than in 7. In contrast, compound 267b having 2-hydroxy-5-methoxy groups on the phenyl ring was much more potent than the 3-hydroxy-4-methoxy phenyl derivative 266b, with IC50 = 12.30 and 28.10 μM, respectively. The steric effect of the methoxy group next to the hydroxy function in 266b decreased the ability of the hydroxyl group to be involved in H-bonding with the enzyme and reduced the activity (Figure 49 ) [109] . 

In 2019, Taha et al., reported a series of 5-(4-hydroxy-2-methoxyphenyl)-1,3,4-oxadiazoles coupled to 5-aryl-1,3,4-thiadiazole motifs through a phenyl ring as potent β-glucuronidase inhibitors. Several analogs were more potent enzyme inhibitors (IC 50 = 0.96-28.10 µM) than the standard D-saccharic acid 1,4-lactone (IC 50 = 48.40 µM). Study of the structureactivity relationships indicated that the nature and relative position of substituents on the phenyl ring attached to thiadiazole greatly affected the inhibitory potency. The 2,4,6trichlorophenyl derivative 265 displayed superior activity (IC 50 = 0.96 µM) compared to monochloro-substituted analogs, regardless of the position (o,m or p-). Moreover, compound 266a with the 3,4-dihydroxyphenyl moiety (IC 50 = 1.40 µM) was four times more potent than the 2,5-dihydroxyphenyl analog 267a (IC 50 = 6.20 µM). A docking study revealed that the hydroxyl groups in 6 had higher potential to be engaged in proper hydrogen bonding interaction with the enzyme active site than in 7. In contrast, compound 267b having 2-hydroxy-5-methoxy groups on the phenyl ring was much more potent than the 3-hydroxy-4-methoxy phenyl derivative 266b, with IC 50 = 12.30 and 28.10 µM, respectively. The steric effect of the methoxy group next to the hydroxy function in 266b decreased the ability of the hydroxyl group to be involved in H-bonding with the enzyme and reduced the activity (Figure 49 ) [109] . 

A series of nuclear factor erythroid 2-related factor 2 (Nrf2) activators with 1,3,4-(oxa)thiadiazole cores were designed as neuroprotective agents against oxidative stress. 2-(1H-benzo[d]imidazol-5-yl)-5-(4-butylphenyl)-1,3,4-oxadiazole 226c (Figure 50 ) exhibited the highest cytoprotective and Nrf2 activation effects in a neuron-like PC-12 cells. It also showed good potential to penetrate the BBB and reach the CNS as a neuroprotective agent. Thus, compound 226c represents a new chemotype against oxidative stress and provides a new therapeutic strategy for different neurodegenerative diseases, including Alzheimer's disease. An SAR study on this series of Nrf2 activators revealed that the 1,3,4-oxadiazole derivatives showed higher Nrf2 inductivity than the 1,3,4-thiadiazole analogs as a result of their improved water solubility and lower lipophilicity [92] . In addition to the reported [99] antimicrobial activity of 2-(bis((1,3,4oxadiazolyl/1,3,4-thiadiazolyl) methylthio)methylene)malononitrile derivatives (241a-c, 242a-c) (Figure 51 ), the compounds were tested for the antioxidant property by NO and DPPH methods. The results revealed that only the compounds with an oxadiazole unit (241a-c) showed high antioxidant activity in both methods. 

A series of nuclear factor erythroid 2-related factor 2 (Nrf2) activators with 1,3,4-(oxa)thiadiazole cores were designed as neuroprotective agents against oxidative stress. 2-(1H-benzo[d]imidazol-5-yl)-5-(4-butylphenyl)-1,3,4-oxadiazole 226c (Figure 50 ) exhibited the highest cytoprotective and Nrf2 activation effects in a neuron-like PC-12 cells. It also showed good potential to penetrate the BBB and reach the CNS as a neuroprotective agent. Thus, compound 226c represents a new chemotype against oxidative stress and provides a new therapeutic strategy for different neurodegenerative diseases, including Alzheimer's disease. An SAR study on this series of Nrf2 activators revealed that the 1,3,4-oxadiazole derivatives showed higher Nrf2 inductivity than the 1,3,4-thiadiazole analogs as a result of their improved water solubility and lower lipophilicity [92] . 

A series of nuclear factor erythroid 2-related factor 2 (Nrf2) activators with 1,3,4-(oxa)thiadiazole cores were designed as neuroprotective agents against oxidative stress. 2-(1H-benzo[d]imidazol-5-yl)-5-(4-butylphenyl)-1,3,4-oxadiazole 226c (Figure 50 ) exhibited the highest cytoprotective and Nrf2 activation effects in a neuron-like PC-12 cells. It also showed good potential to penetrate the BBB and reach the CNS as a neuroprotective agent. Thus, compound 226c represents a new chemotype against oxidative stress and provides a new therapeutic strategy for different neurodegenerative diseases, including Alzheimer's disease. An SAR study on this series of Nrf2 activators revealed that the 1,3,4-oxadiazole derivatives showed higher Nrf2 inductivity than the 1,3,4-thiadiazole analogs as a result of their improved water solubility and lower lipophilicity [92] . In addition to the reported [99] antimicrobial activity of 2-(bis((1,3,4oxadiazolyl/1,3,4-thiadiazolyl) methylthio)methylene)malononitrile derivatives (241a-c, 242a-c) (Figure 51 ), the compounds were tested for the antioxidant property by NO and DPPH methods. The results revealed that only the compounds with an oxadiazole unit (241a-c) showed high antioxidant activity in both methods. In addition to the reported [99] antimicrobial activity of 2-(bis((1,3,4-oxadiazolyl/1,3,4thiadiazolyl) methylthio)methylene)malononitrile derivatives (241a-c, 242a-c) (Figure 31 ), the compounds were tested for the antioxidant property by NO and DPPH methods. The results revealed that only the compounds with an oxadiazole unit (241a-c) showed high antioxidant activity in both methods.

Nabhubygari et al. tested the antioxidant activity of a variety of symmetrical 2,4-bisoxazolyl/thiazolyl/imidazolylacetamido-sulfonylmethyl 1,3,4-oxadiazoles (43a-c, 44a-c, 45a-c) and 1,3,4-thiadiazoles (49a-c, 50a-c, 51a-c) ( Figure 51 ) using 2,2,-diphenyl-1-picrylhydrazyl (DPPH) and nitric oxide (NO) methods. The results showed that oxadiazole derivatives (43a-c, 44a-c, 45a-c) exhibited higher activity than the corresponding thiadiazoles (49a-c, 50a-c, 51a-c) . Among the tested compounds, the bis-(4-methylphenyl oxazolyl)oxadiazole 43b and bis-(4-methylphenyl oxazolyl) thiadiazole 49b were the most potent antioxidants, and they demonstrated higher activity than the standard ascorbic acid in both methods. These results suggest that the presence of an electron-donating methyl substituent on the aromatic ring enhanced the antioxidant activity [51] . picrylhydrazyl (DPPH) and nitric oxide (NO) methods. The results showed that oxadiazole derivatives (43a-c, 44a-c, 45a-c) exhibited higher activity than the corresponding thiadiazoles (49a-c, 50a-c, 51a-c) . Among the tested compounds, the bis-(4methylphenyl oxazolyl)oxadiazole 43b and bis-(4-methylphenyl oxazolyl) thiadiazole 49b were the most potent antioxidants, and they demonstrated higher activity than the standard ascorbic acid in both methods. These results suggest that the presence of an electron-donating methyl substituent on the aromatic ring enhanced the antioxidant activity [51] . Similar results were observed upon evaluating the antioxidant potential of sulfone-/sulfonamide-linked bis(oxadiazoles) and bis(thiadiazoles) using the DPPH and NO methods. The 4-methylphenyl sulfone/sulfonamide-linked bis(oxadiazoles) 24b and 25b presented higher antioxidant activity than Ascorbic acid. The SAR of the tested compounds revealed that compounds with oxadiazole rings (24a-c and 25a-c) showed higher radical scavenging activity than the corresponding thiadiazoles (26a-c and 27a-c). It was also observed that sulfonamide-linked bis(oxadiazoles) and bis(thiadiazoles) (25ac and 27a-c) showed comparatively higher antioxidant activity than sulfone-linked bis(oxadiazoles) and bis(thiadiazoles) (24a-c and 26a-c) ( Figure 53 ) [2] . Similar results were observed upon evaluating the antioxidant potential of sulfone-/ sulfonamide-linked bis(oxadiazoles) and bis(thiadiazoles) using the DPPH and NO methods. The 4-methylphenyl sulfone/sulfonamide-linked bis(oxadiazoles) 24b and 25b presented higher antioxidant activity than Ascorbic acid. The SAR of the tested compounds revealed that compounds with oxadiazole rings (24a-c and 25a-c) showed higher radical scavenging activity than the corresponding thiadiazoles (26a-c and 27a-c). It was also observed that sulfonamide-linked bis(oxadiazoles) and bis(thiadiazoles) (25a-c and 27a-c) showed comparatively higher antioxidant activity than sulfone-linked bis(oxadiazoles) and bis(thiadiazoles) (24a-c and 26a-c) ( Figure 52 ) [2] . NO and DPPH scavenging activities were assayed for a series of 2-(arylaminosulfonyl methyl)-1,3,4-oxa(thia)diazole derivatives (33) (34) (35) (36) (Figure 54 ). The results highlighted that the compounds with an oxadiazole unit (33a-c, 34a-c) exhibited better antioxidant activity than did those with a thiadiazole unit (35a-c, 36a-c), where compounds 33a, 33c, 34a and 34c showed high potency in both methods at a concentration of 100 μM [50] . A summary of the antioxidant structure-activity relationship for substituted 1,3,4oxa-/thiadiazoles is shown in Figure 55 . NO and DPPH scavenging activities were assayed for a series of 2-(arylaminosulfonyl methyl)-1,3,4-oxa(thia)diazole derivatives (33) (34) (35) (36) (Figure 34 ). The results highlighted that the compounds with an oxadiazole unit (33a-c, 34a-c) exhibited better antioxidant activity than did those with a thiadiazole unit (35a-c, 36a-c), where compounds 33a, 33c, 34a and 34c showed high potency in both methods at a concentration of 100 µM [50] .

A summary of the antioxidant structure-activity relationship for substituted 1,3,4oxa-/thiadiazoles is shown in Figure 53 . NO and DPPH scavenging activities were assayed for a series of 2-(arylaminosulfonyl methyl)-1,3,4-oxa(thia)diazole derivatives (33) (34) (35) (36) (Figure 54 ). The results highlighted that the compounds with an oxadiazole unit (33a-c, 34a-c) exhibited better antioxidant activity than did those with a thiadiazole unit (35a-c, 36a-c), where compounds 33a, 33c, 34a and 34c showed high potency in both methods at a concentration of 100 μM [50] . A summary of the antioxidant structure-activity relationship for substituted 1,3,4oxa-/thiadiazoles is shown in Figure 55 . 

In 2013, some N-(tetrazol-1H-5-yl)-6,14-endoethenotetrahydrothebaine 7αsubstituted 1,3,4-(oxa)thiadiazoles were prepared and screened for analgesic activity in 

In 2013, some N-(tetrazol-1H-5-yl)-6,14-endoethenotetrahydrothebaine 7α-substituted 1,3,4-(oxa)thiadiazoles were prepared and screened for analgesic activity in rats, applying hot-plate and tail-flick tests and employing Morphine as a reference drug. At 0.5 and 1 h after administration, the phenylamino-oxadiazole derivative 268 (reaction time in hot plate test = 9.78 s, tail-flick test = 21.45 s) was found to be more potent than Morphine (reaction time in hot plate test = 6.28 s, tail-flick test = 15.90 s). Conversely, the thiadiazole analog 269 was moderately active. The results demonstrated that the oxadiazole group on the 7α position of thebaine increased the analgesic activity ( Figure 54 ) [60] .

Molecules 2022, 27, x FOR PEER REVIEW 54 of 59 rats, applying hot-plate and tail-flick tests and employing Morphine as a reference drug. At 0.5 and 1 h after administration, the phenylamino-oxadiazole derivative 268 (reaction time in hot plate test = 9.78 s, tail-flick test = 21.45 s) was found to be more potent than Morphine (reaction time in hot plate test = 6.28 s, tail-flick test = 15.90 s). Conversely, the thiadiazole analog 269 was moderately active. The results demonstrated that the oxadiazole group on the 7α position of thebaine increased the analgesic activity ( Figure  56 ) [60] . A series of polyheterocyclic thioethers containing 1,3,4-(oxa)thiadiazoles were examined for anti-inflammatory activity using carrageenan-induced rat paw edema assay and Diclofenac as a reference drug. Compounds 270, 271a, and 271b were more effective than Diclofenac in alleviating carrageenan-induced edema after 2, 3, and 4 h of treatment, with inhibition percentages of 37.5-55%, 30-35%, and 38-48%, respectively. In this study, oxadiazole and thiadiazole isosteres were presented as potent anti-inflammatory agents with no difference in their activities ( Figure 57 ) [110] . 

This study is a review article summarizing most of the published work about the medicinally important pharmacophores 1,3,4-oxadiazoles and 1,3,4-thiadiazoles throughout the past 10 years. The review presents different synthetic approaches to the two bioisosteres using different starting compounds, comparing the differences in the reagents used, the conditions, and the yields of the two classes. This comparative study also identified their pharmacological activities, as well as introducing deduced collective structure-activity relationship charts for antimicrobial, anticancer, and antioxidant activities. In most cases, it was concluded that 1,3,4-thiadiazoles are more active antimicrobial agents than 1,3,4oxadiazoles, in contrast to antioxidant activity, where 1,3,4-oxadiazoles are more active agents than 1,3,4-thiadiazoles. Concerning anticancer activity, it was noticed that combining the 1,3,4oxadiazole ring with the 1,3,4-thiadiazole ring enhanced the activity. A series of polyheterocyclic thioethers containing 1,3,4-(oxa)thiadiazoles were examined for anti-inflammatory activity using carrageenan-induced rat paw edema assay and Diclofenac as a reference drug. Compounds 270, 271a, and 271b were more effective than Diclofenac in alleviating carrageenan-induced edema after 2, 3, and 4 h of treatment, with inhibition percentages of 37.5-55%, 30-35%, and 38-48%, respectively. In this study, oxadiazole and thiadiazole isosteres were presented as potent anti-inflammatory agents with no difference in their activities ( Figure 55 ) [110] . ) . Conversely, the thiadiazole analog 269 was moderately active. The results demonstrated that the oxadiazole group on the 7α position of thebaine increased the analgesic activity ( Figure  56 ) [60] . A series of polyheterocyclic thioethers containing 1,3,4-(oxa)thiadiazoles were examined for anti-inflammatory activity using carrageenan-induced rat paw edema assay and Diclofenac as a reference drug. Compounds 270, 271a, and 271b were more effective than Diclofenac in alleviating carrageenan-induced edema after 2, 3, and 4 h of treatment, with inhibition percentages of 37.5-55%, 30-35%, and 38-48%, respectively. In this study, oxadiazole and thiadiazole isosteres were presented as potent anti-inflammatory agents with no difference in their activities ( Figure 57 ) [110] . 

This study is a review article summarizing most of the published work about the medicinally important pharmacophores 1,3,4-oxadiazoles and 1,3,4-thiadiazoles throughout the past 10 years. The review presents different synthetic approaches to the two bioisosteres using different starting compounds, comparing the differences in the reagents used, the conditions, and the yields of the two classes. This comparative study also identified their pharmacological activities, as well as introducing deduced collective structure-activity relationship charts for antimicrobial, anticancer, and antioxidant activities. In most cases, it was concluded that 1,3,4-thiadiazoles are more active antimicrobial agents than 1,3,4oxadiazoles, in contrast to antioxidant activity, where 1,3,4-oxadiazoles are more active agents than 1,3,4-thiadiazoles. Concerning anticancer activity, it was noticed that combining the 1,3,4oxadiazole ring with the 1,3,4-thiadiazole ring enhanced the activity. 

This study is a review article summarizing most of the published work about the medicinally important pharmacophores 1,3,4-oxadiazoles and 1,3,4-thiadiazoles throughout the past 10 years. The review presents different synthetic approaches to the two bioisosteres using different starting compounds, comparing the differences in the reagents used, the conditions, and the yields of the two classes. This comparative study also identified their pharmacological activities, as well as introducing deduced collective structure-activity relationship charts for antimicrobial, anticancer, and antioxidant activities. In most cases, it was concluded that 1,3,4-thiadiazoles are more active antimicrobial agents than 1,3,4oxadiazoles, in contrast to antioxidant activity, where 1,3,4-oxadiazoles are more active agents than 1,3,4-thiadiazoles. Concerning anticancer activity, it was noticed that combining the 1,3,4-oxadiazole ring with the 1,3,4-thiadiazole ring enhanced the activity. 

Synthesis and antioxidant activity of a variety of sulfonamidomethane linked 1,3,4-oxadiazoles and thiadiazoles

Synthesis and antioxidant activity of a new class of sulfone/sulfonamide-linked Bis(Oxadiazoles), Bis(Thiadiazoles), and Bis(Triazoles)

Synopsis of some recent tactical application of bioisosteres in drug design

Synthesis of some 1,3,4-thiadiazole derivatives as inhibitors of entamoeba histolytica

Oxadiazoles in medicinal chemistry

Synthesis and bioassay of a new class of disubstituted 1,3,4-oxadiazoles, 1,3,4-thiadiazoles and 1,2,4-triazoles

Synthesis and antibacterial activity of pyridinium-tailored 2,5-substituted-1,3,4-oxadiazole thioether/sulfoxide/sulfone derivatives

Synthesis and antibacterial evaluation of a novel library of 2-(Thiazol-5-Yl)-1,3,4-oxadiazole derivatives against Methicillin-Resistant Staphylococcus Aureus (MRSA)

5-dinitrophenyl 1,3,4-oxadiazole-2-thiols and tetrazole-5-thiols as highly efficient antitubercular agents

Synthesis of pyrazole acrylic acid based oxadiazole and amide derivatives as antimalarial and anticancer agents

Synthesis and analgesic activity of new 1,3,4-oxadiazoles and 1,2,4-triazoles

Recent progress of 1,3,4-oxadiazoles as anticonvulsants: Future horizons

Synthesis, characterization and anti-inflammatory activity of various isatin derivatives

Anti-hepatitis B virus activity of new 1,2,4-triazol-2-Yl-and 1,3,4-oxadiazol-2-Yl-2-pyridinone derivatives

Newly synthesized series of oxoindole-oxadiazole conjugates as potential anti-SARS-CoV-2 agents: In silico and in vitro studies

Rationale design, synthesis, cytotoxicity evaluation, and molecular docking studies of 1,3,4-oxadiazole analogues

Synthesis, spectroscopy and electrochemistry of new 4-(4-acetyl-5-substituted-4,5-dihydro-1,3,4-oxodiazol-2-yl)methoxy)-2H-chromen-2-ones as a novel class of potential antibacterial and antioxidant derivatives

Therapeutic potential of oxadiazole or furadiazole containing compounds

1,3,4-Oxadiazole and its derivatives: A review on recent progress in anticancer activities

Synthesis of 1,3,4-oxadiazoles from 1,2-diacylhydrazines using [Et2NSF2]BF4 as a practical cyclodehydration agent

In vitro sensitivity of mycoplasmas isolated from various animals and sewage to antibiotics and nitrofurans

The synthesis of antihypertensive 3-(1,3,4-oxadiazol-2-Yl)phenoxypropanolahines

The birth of "Me-Too" HIV-1 integrase inhibitors

1,3,4-Oxadiazole Amide

Effects of tiodazosin, a new antihypertensive, hemodynamics and clinical variables

Analytical toxicity for clinical, forensic and pharmaceutical chemists

Ultrasound-assisted, low-solvent and acid/base-free synthesis of 5-substituted 1,3,4-oxadiazole-2-thiols as potent antimicrobial and antioxidant agents

Efficacy of the specific endothelin a receptor antagonist Zibotentan (ZD4054) in colorectal cancer: A preclinical study

Anti-cancer activity of derivatives of 1,3,4-oxadiazole

-Oxa-6-Azaspiro[3.3]Heptan-6-Ylmethyl)Phenoxy)Azetidin-1-Yl)(5-(4-Methoxyphenyl)-1,3,4-Oxadiazol-2-Yl)Methanone (AZD1979), a melanin concentrating hormone receptor 1 (MCHr1) antagonist with favourable physicochemical properties

Thiadiazole-a promising structure in medicinal chemistry

oxadiazol-2-amines and 1,3,4-thiadiazol-2-amines via Pd-catalyzed heteroarylamination

One pot single step synthesis and biological evaluation of some novel Bis(1,3,4-Thiadiazole) derivatives as potential cytotoxic agents

Synthesis, antioxidant, and antitumor evaluation of certain new n-substituted-2-amino-1,3,4-thiadiazoles

Synthesis and biological evaluation of novel substituted 1,3,4-thiadiazole and 2,6-di aryl substituted imidazo

Synthesis of benzimidazole based thiadiazole and carbohydrazide conjugates as glycogen synthase kinase-3β inhibitors with anti-depressant activity

Design of benzothiazole-1,3,4-thiadiazole conjugates: Synthesis and anticonvulsant evaluation

Molecular modeling, synthesis and pharmacological evaluation of 1,3,4-thiadiazoles as anti-inflammatory and analgesic agents

23-1,3,4-oxadiazoles

Application of self-consistent HMO theory to heteroconjugated molecules

A Theoretical study of the electronic structure and properties of some five-membered heterocyclic compounds: Pyrazole, imidazole, furan, isoxazole, 1,2,5-oxadiazole and 1,3,4-oxadiazole

Amide-imidol tautomerism in aromatic polyamides

Synthesis and electronic structure of new aryl-and alkyl-substituted 1,3,4-oxadiazole-2-thione derivatives

Synthesis and antibacterial activity of 1,3,4-oxadiazole and 1,2,4-triazole derivatives of salicylic acid and its synthetic intermediates

Synthetic methods, chemistry, and the anticonvulsant activity of thiadiazoles

Darstellung und eigenschaften des 1.2.4-und des 1.3.4-thiodiazols

1,3,4-oxadiazole, 1,3,4-thiadiazole and 1,2,4-triazole derivatives as potential antibacterial agents

The structure of N-allyl derivatives of (5-(2 -pyridyl)-[1,3,4]thiadiazol-2-yl) amine in solution and the solid state studied by the 1H, 13C, 15N NMR spectroscopy, X-ray crystallography and DFT computations

Synthesis and antimicrobial activity of pyrrolyl/pyrazolyl arylaminosulfonylmethyl 1,3,4-oxadiazoles, 1,3,4-thiadiazoles and 1,2,4-triazoles

Synthesis and bioassay of aminosulfonyl-1,3,4-oxadiazoles and their interconversion to 1,3,4-thiadiazoles

Synthesis and antioxidant activity of bis-oxazolyl/thiazolyl/imidazolyl 1,3,4-oxadiazoles and 1,3,4-thiadiazoles

One pot solvent-free solid state synthesis, photophysical properties and crystal structure of substituted azole derivatives

Microwave-promoted synthesis of highly luminescent s-tetrazine-1,3,4-oxadiazole and s-tetrazine-1,3,4-thiadiazole hybrids

A Convenient synthesis of 1,3,4-thiadiazole and 1,3,4-oxadiazole based peptidomimetics employing diacylhydrazines derived from amino acids

Synthesis, cytotoxicity and antimicrobial evaluation of some new 2-aryl,5-substituted 1,3,4-oxadiazoles and 1,3,4-thiadiazoles

Mesogenic bent-shaped nitrooxadiazoles and thiadiazoles

A New Late-Stage Lawesson's Cyclization Strategy Towards the Synthesis of Aryl 1,3,4-Thiadiazole-2-Carboxylate Esters

Novel diosgenin derivatives containing 1,3,4-oxadiazole/ thiadiazole moieties as potential antitumor agents: Design, synthesis and cytotoxic evaluation

Synthesis, biological evaluation, and molecular modeling studies of new 1,3,4-oxadiazole-and 1,3,4-thiadiazole-substituted 4-oxo-4h-pyrido[1,2-a]pyrimidines as anti-HIV-1 agents

Synthesis and pharmacological evaluation of some novel thebaine derivatives: N-(tetrazol-1H-5-yl)-6,14-endoethenotetrahydrothebaine incorporating the 1,3,4-oxadiazole or the 1,3,4-thiadiazole moiety

Synthesis, characterization, and antimicrobial screening of novel 1,2,4-triazoles, 1,3,4-thiadiazoles, and 1,3,4-oxadiazoles bearing the indole moiety

Synthesis and antimicrobial activity of new 1,2,4-triazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, thiopyrane, thiazolidinone, and azepine derivatives

A Highly efficient diversification of 2-amino/amido-1,3,4-oxadiazole and 1,3,4-thiadiazole derivatives via reagent-based cyclization of thiosemicarbazide intermediate on solid-phase

Synthesis, characterization, and in vitro antimicrobial activities of 5-alkenyl/hydroxyalkenyl-2-phenylamine-1,3,4-oxadiazoles and thiadiazoles

Synthesis and evaluation of cytotoxic activities of some 1,4-disubstituted thiosemicarbazides, 2,5-disubstituted-1,3,4-thiadiazoles and 1,2,4-triazole-5-thiones derived from benzilic acid hydrazide

Synthesis of new pyrimidinylthio-substituted 1,3,4-oxa(thia)diazoles and 1,2,4-triazoles

Synthesis and biological activities of ethyl 2-(2-pyridylacetate) derivatives containing thiourea, 1,2,4-triazole, thiadiazole and oxadiazole moieties

Synthesis and antibacterial screening of 1,3,4-thiadiazoles, 1,2,4-triazoles, and 1,3,4-oxadiazoles containing piperazine nucleus

Synthesis and anticancer evaluation of 1,3,4-oxadiazoles, 1,3,4-thiadiazoles, 1,2,4-triazoles and mannich bases

Synthesis and antimicrobial activities of some triazole, thiadiazole, and oxadiazole substituted coumarins

Synthesis and biological evaluation of some new 1,3,4-oxa, thiadiazole and 1,2,4-triazole derivatives attached to benzimidazole

Synthesis of new 1,3,4-oxadiazol, thiadiazole, 1,2,4-triazole, and arylidene hydrazide derivatives of 4-oxo-1,4-dihydroquinoline with antimicrobial evaluation

Novel synthesis and characterization of some pyrimidine derivatives of oxadiazoles, triazole and 1,3,4-thiadiazoles

Synthesis, characterization, and herbicidal activities of new 1,3,4-oxadiazoles, 1,3,4-thiadiazoles, and 1,2,4-triazoles derivatives bearing (r)-5-chloro-3-fluoro-2-phenoxypyridin

Synthesis of novel sulfonamide-1,2,4-triazoles, 1,3,4-thiadiazoles and 1,3,4-oxadiazoles, as potential antibacterial and antifungal agents. Biological evaluation and conformational analysis studies

3,4-oxadiazole and/or schiff base as potential antimicrobial and antiproliferative agents

Design, synthesis and antifungal evaluation of novel substituted 1,3,4-oxadiazoles, and 1,3,4-thiadiazoles

Synthesis, Characterization and antioxidant activity evaluation of some 1,3,4-thiadiazole and 1,3,4-oxadiazole compounds

Hydrazinecarbothioamides and 1,3,4-thia/oxadiazoles derivatives with potential biological activity synthesis and spectral characterization

Synthesis of some N-alkylated 1,2,4-triazoles, 1,3,4-oxadiazoles, and 1,3,4-thiadiazoles based on n-(furann-2-yl-methylidene)-4,6-dimethyl-1h-pyrazolo-[3,4-b]pyridine-3-amine

Synthesis of some pyridyl and cyclohexyl substituted 1,2,4 triazole, 1,3,4-thiadiazole and 1,3,4-oxadiazole derivatives

Regioselective synthesis of 2-amino-substituted 1,3,4-oxadiazole and 1,3,4-thiadiazole derivatives via reagent-based cyclization of thiosemicarbazide intermediate

Synthesis of 2-amino-1,3,4-oxadiazoles and 2-amino-1,3,4-thiadiazoles via sequential condensation and i2-mediated oxidative c-o/c-s bond formation

Synthesis of coumarin appended pyrazolyl-1,3,4-oxadiazoles and pyrazolyl-1,3,4-thiadiazoles: Evaluation of their in vitro antimicrobial and antioxidant activities and molecular docking studies

Preparation of 1,3,4-oxadiazoles and 1,3,4-thiadiazoles via chemoselective cyclocondensation of electrophilically activated nitroalkanes to (thio)semicarbazides or thiohydrazides

Efficient electrochemical synthesis, antimicrobial and antiinflammatory activity of 2-amino-5-substituted-1,3,4-oxadiazole derivatives

Synthesis and evaluation of 1,3,4-oxadiazole derivatives for development as broad-spectrum antibiotics

Utilization of ultrasonic irradiation as green and effective one-pot protocol to prepare a novel series of bis-2-amino-1,3,4-oxa(thia)diazoles and bis-tetrazoles

Design, synthesis and biological evaluation of 1,3,4-oxadiazoles/thiadiazoles bearing pyrazole scaffold as antimicrobial and antioxidant candidates

Synthesis of 2-(β-d-glucopyranosyl)-5-(substituted-amino)-1,3,4-oxa-and -thiadiazoles for the inhibition of glycogen phosphorylase

Synthesis and evaluation of biological activity of homodrimane sesquiterpenoids bearing 1,3,4-oxadiazole or 1,3,4-thiadiazole units

Design and evaluation of Nrf2 activators with 1,3,4-oxa/thiadiazole core as neuro-protective agents against oxidative stress in PC-12 cells

Synthesis of novel nalidixic acid-based 1,3,4-thiadiazole and 1,3,4-oxadiazole derivatives as potent antibacterial agents

TiCl4 mediated facile synthesis of 1,3,4-oxadiazoles and 1,3,4-thiadiazoles

Palladium-catalyzed one-pot synthesis of diazoles via tert-butyl isocyanide insertion

Synthesis and anti-inflammatory activity of some new 4,5-dihydro-1,5-diaryl-1h-pyrazole-3-substituted-heteroazole derivatives

Synthesis and growth regulatory activity of novel 5-(3-alkyl-4-methyl-2-thioxo-2,3-dihydro-thiazol-5-Yl)-3H-[1,3,4] thiadiazole(oxadiazole)-2-thiones and their derivatives

Synthesis and evaluation of benzosuberone embedded with 1,3,4-oxadiazole, 1,3,4-thiadiazole and 1,2,4-triazole moieties as new potential anti proliferative agents

Synthesis and biological activity of 2-(bis((1,3,4-oxadiazolyl/1,3,4-thiadiazolyl) methylthio)methylene)malononitriles

Small molecule inhibitors of trans-translation have broad-spectrum antibiotic activity

Development of 3,5-dinitrobenzylsulfanyl-1,3,4-oxadiazoles and thiadiazoles as selective antitubercular agents active against replicating and nonreplicating mycobacterium tuberculosis

Synthesis, characterization and antimicrobial activity evaluation of new cyclic iimides containing 1,3,4-thiadiazole and 1,3,4-oxadiazole moieties

Synthesis and antimicrobial activity of new 1,3,4-thiadiazoles containing oxadiazole, thiadiazole and triazole nuclei

Synthesis and antimicrobial activity of pyrimidinyl 1,3,4-oxadiazoles, 1,3,4-thiadiazoles and 1,2,4-triazoles

Synthesis and bioactivities of novel thioether/sulfone derivatives containing 1,2,3-thiadiazole and 1,3,4-oxadiazole/thiadiazole moiety

5-disubstituted-1,3,4-oxadiazoles/thiadiazole as surface recognition moiety: Design and synthesis of novel hydroxamic acid based histone deacetylase inhibitors

Synthesis and anti-cancer activity of 1,3,4-thiadiazole and 1,3-thiazole derivatives having 1,3,4-oxadiazole moiety

Synthesis and antitumor activities of novel hybrid molecules containing 1,3,4-oxadiazole and 1,3,4-thiadiazole bearing schiff base moiety

Synthesis and evaluation of new oxadiazole, thiadiazole, and triazole derivatives as potential anticancer agents targeting MMP-9

Synthesis and anti-inflammatory activity of 5-(pyridin-4-yl)-1,3,4-oxadiazole-2-thiol, 5-(pyridin-4-yl)-1,3,4-thiadiazole-2-thiol and 5-(pyridin-4-yl)-1,2,4-triazole-3-thiol derivatives

Funding: This research received no external funding.

Data Availability Statement: Not applicable.

The authors declare no conflict of interest.