key: cord-0979492-djmigvd8 authors: Aggarwal, Ranjana; Hooda, Mona; Kumar, Prince; Sumran, Garima title: Vision on Synthetic and Medicinal Facets of 1,2,4-Triazolo[3,4-b][1,3,4]thiadiazine Scaffold date: 2022-02-05 journal: Top Curr Chem (Cham) DOI: 10.1007/s41061-022-00365-x sha: 656cb8d5a03bbb81e19f16e2b8e30c4e30d52ad9 doc_id: 979492 cord_uid: djmigvd8 The present review article strives to compile the latest synthetic approaches for the synthesis of triazolothiadiazine and its derivatives, along with their diverse pharmacological activities, viz. anticancer, antimicrobial, analgesic and anti-inflammatory, antioxidant, antiviral, enzyme inhibitors (carbonic anhydrase inhibitors, cholinesterase inhibitors, alkaline phosphatase inhibitors, anti-lipase activity, and aromatase inhibitors) and antitubercular agents. The review focuses particularly on the structure–activity relationship of biologically important 1,2,4-triazolo[3,4-b][1,3,4]thiadiazines, which have profound importance in drug design, discovery and development. In silico pharmacokinetic and molecular modeling studies have also been summarized. It is hoped that this review article will be of help to researchers engaged in the development of new biologically active entities for the rational design and development of new target-oriented 1,2,4-triazolo[3,4-b][1,3,4]thiadiazine-based drugs for the treatment of multifunctional diseases. GRAPHICAL ABSTRACT: [Image: see text] Heterocyclic compounds are of prime importance due to their extensive therapeutic uses [1] . One of the outstanding structural features innate to heterocycles, which continues to be exploited to great advantage by the drug industry, lies in their ability to manifest substituents around a core scaffold in defined three-dimensional (3D) representations. Among the collection of heterocycles, triazolothiadiazine, a hybrid nucleus made by fusion of two pharmaceutically active moieties, i.e., triazole and thiadiazine, is one of the most essential nuclei owing to their wide range of applications as synthetic intermediates and promising pharmaceuticals. The ability of hydrogen bond accepting and donating characteristics makes this core a much précised pharmacophore with a bioactive profile, as it can make specific interactions with different target receptors. On the basis of fusion permutations of a five-membered triazole ring with a six-membered thiadiazine ring, four isomeric structural variants of triazolothiadiazine, namely 1,2,4-triazolo [3,4-b] [1, 3, 4] thiadiazines (I), 1,2,4-triazolo [5,1-b] [1, 3, 5] thiadiazines (II), 1,2,4-triazolo [1,5-c] [1, 3, 5] thiadiazines (III), and 1,2,3-triazolo [5,1-b] [1, 3, 4] thiadiazines (IV) may exist (Fig. 1) . As a class of privileged pharmacophores, the chemistry and synthesis of compounds possessing a 1,2,4-triazolo [3,4-b] [1, 3, 4] thiadiazine nucleus has attracted enormous attention. This review is focused on the synthetic protocols and biological potential, including structure-activity relationship (SAR), in silico pharmacokinetics, molecular modeling and mechanistic studies of 1,2,4-triazolo [3,4b] [1, 3, 4] thiadiazines since 2010. The literature is enriched with several approaches for synthesis of the 1,2,4-triazolo [3,4b] [1, 3, 4] thiadiazine nucleus. Synthetic design for 1,2,4-triazolo [3,4-b] [1, 3, 4] thiadiazine involves primarily four routes: a, b, c and d (Fig. 2) . Route a involves the acidcatalyzed cyclization of 2-hydrazinyl-6H-1,3,4-thiadiazine with ortho esters, thereby annulation of the triazole ring on thiadiazole [2] . However, this method has limited substrate scope. Route b involves the cyclocondensation of 4-amino-3-mercaptotriazoles with various bielectrophiles such as α-bromopropenone [3] , phenacyl bromides [4] [5] [6] [7] [8] , α-tosyloxy ketones [9] , ethyl bromoacetate [10] , hydrazonoyl halides [11] , α-chloroacetylacetone [12] and propargyl bromide in presence of heteropolyacids [13] under conventional heating conditions to access the triazolothiadiazine scaffold. This can be credited to mercapto and amino groups as easily accessible nucleophilic centers in 4-amino-3-mercaptotriazole for the synthesis of condensed heterocyclic rings. Route b offers vast diversity in terms of substitution at 5-position of 4-amino-3-mercaptotriazole as well as choices of bielectrophiles; therefore, this route is the most common approach for the synthesis of 1,2,4-triazolo [3,4-b] [1, 3, 4] thiadiazines. Route c involves synthesis of triazolothiadiazine derivatives by intermolecular condensation of 3-mercapto-4-arylideneamino-1,2,4-triazoles and α-halo compounds with activated methylene group [14, 15] . Route d involves ring transformation of oxadiazole-3H-thione upon treatment with phenacyl bromide followed by reaction with hydrazine hydrate to furnish triazolothiadiazine ring [16, 17] . The present review encapsulates and highlights the development of synthetic protocols in the last decade (2010-2021) for the synthesis of 1,2,4-triazolo [3,4-b] [1, 3, 4] thiadiazines as illustrated in Schemes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32 , 33 and 34. Foroughifar et al. [14] reported an efficient route for the synthesis of 1,2,4-triazolo [3,4-b] [1, 3, 4] thiadiazine derivatives (5) by treating Schiff's bases (3), Scheme 1 Synthesis of 1,2,4-triazolo [3,4-b] [1, 3, 4] thiadiazine derivatives Scheme 2 Synthesis of 6,7-dihydro-5H- [1, 2, 4] triazolo [3,4- 3, 4] thiadiazine derivatives [1, 3, 4] thiadiazines (8) , which isomerized gradually in CDCl 3 and rapidly in DMSO-d 6 into corresponding cis-stereoisomers (9) (Scheme 2). Motamedi et al. [18] developed a heteropolyacid (HPA)-catalyzed one-pot synthesis of [1, 2, 4] triazolo [3,4-b] [1, 3, 4] thiadiazine derivatives (11) and (13) in excellent yields via cyclocondensation reaction of 5-substituted 4-amino-1,2,4triazole-3-thiols (1) with α-chloroacetone (10) or α-chloroacetonitrile (12) in refluxing acetic acid (Scheme 3). Jakhar and Makrandi [19] described one-pot synthesis of [1, 2, 4] triazolo [3,4b] [1, 3, 4] thiadiazine derivatives (15) by iodine-mediated condensation of 3-alkyl/ aryl-4-amino-5-mercapto-1,2,4-triazoles (1) with 3-acetyl-6-substituted coumarin (14) in dimethylformamide (DMF) under microwave (MW) irradiation (Scheme 4). This protocol avoids the use of highly lachrymatory molecular bromine and its main advantage is good yields (78-92%) in a very short time. A literature survey revealed that manifestation of the coumarin nucleus in heterocycles is found to have broad pharmacological activities [22, 23] . Vaarla et al. [24] designed a series of coumarin substituted 1,2,4-triazolo [3,4b] [1, 3, 4] thiadiazine derivatives (20) via cyclocondensation of 5-substituted Scheme 22 Synthesis of phthalazinedione based 1,2,4-triazolo [3,4-b] [1, 3, 4] thiadiazines Scheme 23. Multicomponent synthesis of [1, 2, 4] triazolo [3,4-b] [1, 3, 4] thiadiazine derivatives Scheme 24 One-pot multicomponent synthesis of substituted [1, 2, 4] triazolo [3,4-b] [1, 3, 4] thiadiazine derivatives 4-amino-1,2,4-triazole-3-thiols (1) with differently substituted 3-(2-bromoacetyl) coumarins (6) in ethanol under reflux (Scheme 7). Substitution of coumarin with electron-withdrawing groups at R 1 and/or R 2 provided higher yields of products than electron rich groups. Utilizing a conventional approach, Lechani et al. [25] synthesized [1, 2, 4] triazolo [3,4-b] [1, 3, 4] thiadiazine hybrids bearing aryl-, pyran-2-one-, or coumarin Scheme 25 Synthesis of 3-ethyl-6-methyl-7-(2-arylhydrazono)-7H- [1, 2, 4] triazolo [3,4-b] [1, 3, 4] thiadiazine derivatives Scheme 26 Synthesis of (7Z)-7-[2-(aryl)hydrazinylidene]-6-methyl-3-(pyridine-4-yl)-7H- [1, 2, 4] triazolo [3,4-b] [1, 3, 4] thiadiazines Scheme 27. Synthesis of pyrimidine clubbed 1,2,4-triazolo [3,4-b] [1, 3, 4] thiadiazine derivatives moieties (21) in moderate to good yields by acetic acid catalyzed cyclocondensation reaction of 2-(4-amino-5-mercapto-4H- [1, 2, 4] triazol-3-yl)phenol (1) with aromatic or heterocyclic α-bromoacetyl derivatives (6) in refluxing EtOH (Scheme 8). Simple reaction conditions, short reaction times, good yields and synthesis of highly Scheme 31 Synthesis of 5-substituted [1, 2, 4] triazolo [3,4-b] [1, 3, 4] thiadiazine) derivatives Scheme 32 One-step synthesis of triazolo [3,4-b] [1, 3, 4] thiadiazines Scheme 33 Synthesis of spirocyclic triazolo [3,4-b] [1, 3, 4] thiadiazine derivatives Scheme 34 Synthesis of 3-alkyl/aryl-7/9-methyl-10,10a-dihydroindeno [1,2-e] [1, 2, 4] triazolo [3,4-b] [1, 3, 4] thiadiazines functionalized hybrids bearing oxygen-, nitrogen-, and sulfur-based heterocycles make this method potentially valuable. Tang et al. [26] synthesized a new series of 1,2,4-triazolo [3,4-b] [1, 3, 4] thiadiazine derivatives (22) via reaction of 4-amino-5-[2-(2-piperazinyl-1-yl)quinolin-3-yl]-4H-1,2,4-triazole-3-thiol (1) with various phenacyl bromides (6) in refluxing ethanol/DMF mixture (10:1) (Scheme 9). Kattimani et al. [27] successfully synthesized 3,6-disubstituted [1, 2, 4] triazolo [3,4b] [1, 3, 4] thiadiazine derivatives (23) via reaction of phenacyl bromide (6) with various 4-(4-amino-5-mercapto-4H-1,2,4-triazol-3-yl)methyl)-2-aryl-2H-1,2,4-triazol-3(4H)-ones (1) in refluxing ethanol (Scheme 10). In recent years, organic reactions under visible-light irradiation are grabbing intense attention as a powerful strategy involving the concept of 'Green Chemistry' to reduce hazardous ecological imprints of organic synthesis. In order to achieve a green protocol, Aggarwal et al. [28] developed first visible-light mediated regioselective synthesis of novel acyl derivatives of 1,2,4-triazolo [3,4-b] [1, 3, 4] thiadiazines 26 involving reaction of binucleophilic 4-amino-3-mercapto-1,2,4-triazoles (1) with in situ generated α-bromodiketones (25) from unsymmetrical β-diketones (24) . In principle, reaction of unsymmetrical α-bromodiketones (25) (having two carbonyl carbon of different electrophilicity) with 4-amino-3-mercapto-1,2,4-triazoles (1) may lead to the formation of two regioisomers-7-aroyl-6-methyl- [1, 2, 4] triazolo [3,4b] [1, 3, 4] thiadiazines (26) and 7-acetyl-6-aryl- [1, 2, 4] triazolo [3,4-b] [1, 3, 4] thiadiazines (27) . However, the reaction exhibited high level of regioselectivity yielding only (26) , not the other possible isomer, 7-acetyl-6-aryl- [1, 2, 4] triazolo [3,4-b] [1, 3, 4] thiadiazines (27) . The structure of the regioisomer formed has been established unambiguously by heteronuclear 2D-NMR [( 1 H-13 C) and ( 1 H-15 N) HMBC, ( 1 H-13 C) HMQC] spectroscopic and X-ray crystallographic studies. The substrate scope of the reaction was established by taking differently substituted 4-amino-3-mercapto-1,2,4-triazoles (1) and unsymmetrical diketones (24) under optimized conditions. All combinations resulted in exclusive formation of (26) with high regioselectivity. This rapid and efficient method involves use of simple and readily available starting materials, environment benign conditions, and provided excellent yields of the products (85-97%) in a fairly short time (Scheme 11). A solvent-free protocol using p-TsOH as a catalyst was also investigated to achieve the synthesis of (26); however, yields were comparatively lower (72-85%). Bis-heterocycles with a flexible linker reported to possess a wide array of pharmaceutical and biological activities [29] . In this context, Ginidi et al. [30] introduced a novel series of bis(s-triazolo [3,4-b] [1, 3, 4] thiadiazines) (29) tethered via phenoxymethyl spacers. Piperidine catalyzed cyclocondensation reaction of 4-amino-3-mercapto-1,2,4-triazole derivatives (1) with bis(α-bromoketones) (28) in EtOH-DMF mixture under reflux afforded corresponding bis(s-triazolo [3,4-b] [1, 3, 4] thiadiazines) (29) in good yields (Scheme 12). Synthesis of novel mono-and bis-1,2,4-triazolo [3,4-b] [1, 3, 4] thiadiazines linked with pyrazole moiety (32) and (34) was described by Salem et al. [31] . The reaction of 4-amino-3-mercapto-1,2,4-triazole derivatives (1) with 2-bromo-1-(5-methyl-1phenyl-1H-pyrazol-4-yl)ethanone (30) in refluxing ethanol in the presence of triethylamine as catalyst, afforded an intermediate (31) , which underwent cyclization in refluxing acetic acid to access pyrazolyl(5,6-dihydro-s-triazolo [3,4-b] thiadiazines) (32) in good yields (70-75%) (Scheme 13). Bis(6-pyrazolyl-s-triazolo [3,4-b] [1, 3, 4] thiadiazines) linked to the alkyl spacer (34) were synthesized in one-step by cyclocondensation of bis(4-amino-5-mercapto-1,2,4-triazol-3-yl)alkanes (33) with 2 equivalents of (30) in refluxing EtOH containing a few drops of triethylamine. Alternatively, bis(triazolo [3,4-b] thiadiazine) derivatives (35) linked to arene centres via alkyl/ether/sulfanylmethylene insertions were prepared by treating bis(4amino-5-mercapto-s-triazolo-3-y1) derivatives (33) with two equivalents of phenacyl bromide (6) in DMF/ethanol mixture under reflux (Scheme 14) [32] . Shaaban and Elwahy [33] reported the synthesis of bis(5,6-dihydros-triazolo [3,4-b] thiadiazines) (36) in good-to-excellent yields by the reaction of bis(α-bromoketones) (28) with 4-amino-3-mercapto-1,2,4-triazole derivatives (1) in ethanol under refluxing conditions (Scheme 15), which, upon reduction with sodium borohydride in refluxing methanol, afforded bis 4-(6,7-dihydro-3-substituted-5H-1,2,4-triazolo [3,4-b] [1, 3, 4] thiadiazine derivatives (37) in good yields. Sayed et al. [34] have reported the synthesis of bis(5,6-dihydro-s-triazolo[3,4-b] thiadiazines) (38) in moderate yields (60-66%) via reaction of bis(α-bromoketones) (28) with 4-amino-3-mercapto-1,2,4-triazole derivatives (1) in catalytic amount of triethylamine in refluxing ethanol-DMF mixture (Scheme 16). Recently, the synthesis of mono-and bis(triazolothiadiazine) derivatives coupled with benzofuran or benzo[d]thiazole moieties (39) and (40) in good yields (69-79%) has been achieved by the reaction of bromoacetylbenzothiazole/bromoacetylbenzofuran (6) with each of 4-amino-3-mercapto-1,2,4-triazoles (1) and bis( [1, 2, 4] triazolo [3,4-b] [1, 3, 4] thiadiazin-3-yl)alkanes (33) in catalytic amount of triethylamine in refluxing ethanol (Scheme 17) [35] . In view of the significant biological potential of fused naphthoquinones [36] , Khalafy et al. [37] reported the synthesis of a new series of 10-substituted-5H-naphtho[1,2-e] [1, 2, 4] triazolo [3,4-b] [1, 3, 4] thiadiazin-5-ones (43) from the reaction of 4-amino-5-aryl/alkyl-3-mercapto-1,2,4-triazoles (1) with 2-bromo-1,4-naphthoquinone (41) in ethanol (Scheme 18). This two-step procedure involves the intermediacy of 2-[(4-amino-5-aryl-4H-1,2,4-triazol-3-yl)thio]naphthalene-1,4-diones (42) , which underwent intramolecular cyclization in EtOH-HCl under reflux to afford products (43) in 56-82% yields. Recently, multicomponent reactions (MCRs) due to their high efficiency, atom economy, and reduced time are being explored to access functionalized triazolothiadiazines in a one-pot one-step fashion. In general, construction of triazolothiadiazine scaffold using MCR involves condensation of two components, namely, α-halocarbonyl compounds and 4-amino-5-hydrazinyl-3-mercapto-1,2,4-triazole and the third component is being employed for preparing derivatives or variations at hydrazinyl group. Pavurala and Vedula [38] reported a one-pot multicomponent approach for synthesis of 3-(pyrazolyl)-7H- [1, 2, 4] triazolo [3,4-b] [1, 3, 4] thiadiazin-6-yl)-2H-chromen-2-ones (46) in excellent yields. Reaction of 4-amino-5-hydrazinyl-3-mercapto-1,2,4-triazole (44) , substituted 3-(2-bromo-acetyl)coumarins (6) and acetyl acetone (45) in absolute ethanol under reflux afforded (46) (Scheme 19). The method has the merits of operational simplicity, good yields and accomplished the synthesis of two heterocycles in one stride. Keeping in view the importance of pyrazole-linked heterocyclic compounds, Sujata et al. [39] reported one-pot multicomponent synthesis of 3-aryl-1-(6-aryl-7H- [1, 2, 4] triazolo [3,4-b] [1, 3, 4] thiadiazin-3-yl)-1H-pyrazol-5-amines (48) and 3-(3-(5-amino-3-aryl-1H-pyrazol-1-yl)-7H- [1, 2, 4] triazolo [3,4-b] [1, 3, 4] thiadiazin-6-yl)-8-ethoxy-2H-chromen-2-ones (49) . Acetic acid catalyzed condensation of (44), various phenacyl bromides (6) or 3-(2-bromoacetyl)coumarins (6′) and benzoylacetonitriles (47) in refluxing ethanol yielded 48 and 49 in excellent yields (Scheme 20). Aychiluhim et al. [40] described one-pot multicomponent reaction of 3-(2-bromo acetyl)coumarins (6), (44) and ethyl 2-(2-(aryl)hydrazono)-3-oxobutanoates (50) to produce novel 4-(arylhydrazono)-3-methyl-1-(6-(coumarin-3-yl)-7H- [1, 2, 4] triazolo [3,4-b] [1, 3, 4] thiadiazin-3-yl)-1H-pyrazol-5(4H)-ones (51) (Scheme 21). Short reaction period, higher yields, mild conditions and one-pot synthesis are some of the key features of this methodology. Keeping the importance of triazolo [3,4-b] [1, 3, 4] thiadiazines and phthalazine-1,4-dione, Jilloju et al. [41] explored multicomponent synthesis of 2-(6-phenyl-7H- [1, 2, 4] triazolo [3,4-b] [1, 3, 4] thiadiazin-3-yl)-2,3-dihydrophthalazine-1,4-dione derivatives (53) . Three-component reactions of (44) with phenacyl bromides (6) and phthalic anhydride (52) in acetic acid yielded (53) in good to excellent yields (Scheme 22). A simple, multicomponent efficient synthesis of [1, 2, 4] triazolo[3,4-b]thiadiazines (54) was reported by Sujatha et al. [42] involving pseudo four component condensation of (44) , aromatic aldehydes (2), and various phenacyl bromides (6) in presence of triethyl amine in absolute ethanol to afford novel [1, 2, 4] triazolo [3,4-b] thiadiazine derivatives in excellent yields (Scheme 23). Shorter reaction time, good yields, operational simplicity, mild and clean reaction profiles are some key features of this method. Thirupaiah et al. [43] have described the synthesis of a pyran and phthalazine substituted [1, 2, 4] triazolo [3,4-b] [1, 3, 4] -thiadiazine derivative (55) by multicomponent reaction of equimolar 3-(2-bromoacetyl)-4-hydroxy-6-methyl-2H-pyran-2-one (6), (44) , and phthalic anhydrides (52) in acetic acid under refluxing conditions (Scheme 24). Similarly, the three-component reaction of 44, aldehydes (2) and 3-(2-bromoacetyl)-4-hydroxy-6-methyl-2H-pyran-2-one (6), with few drops of acetic acid in absolute ethanol afforded substituted 3-[3-(N 1 -benzylidene-hydrazino)-7H- [1, 2, 4] triazolo [3,4-b] [1,3,4]thiadiazin-6-yl]-4-hydroxy-6-methyl-pyran-2-ones (56) in good yields. Products of the reactions between 4-amino-3-mercaptotriazoles and hydrazonoyl halides are [1, 2, 4] triazolo [3,4-b] [1, 3, 4] thiadiazines bearing 2-arylhydrazono group at the 7-position. Abdelrazek et al. [44] reported the facile triethylamine-catalyzed synthesis of 3-ethyl-6-methyl-7-(2-arylhydrazono)-7H- [1, 2, 4] triazolo [3,4-b] [1, 3, 4] thiadiazine derivatives (59) from the reaction of 4-amino-5-ethyl-3-mercapto-1,2,4-triazole (1) with variously substituted hydrazonoyl chlorides (57) in refluxing dioxane. S-alkylated intermediates (58) , generated in situ, are cyclized to afford the desired products (59) in good yields (80-88%) (Scheme 25). 4-Amino-3-(4-pyridyl)-5-mercapto-1,2,4-triazole (1) couples with substituted aryl hydrazonoyl chlorides (57) in a similar manner to yield 7-(2-arylhydrazono) [1, 2, 4] triazolo [3,4-b] [1, 3, 4] thiadiazine derivatives (60) (Scheme 26) [45] . Ebrahimpour et al. [46] synthesized pyrimido [4,5- ]thiadiazine derivatives (64) in good yields via S/N type Smiles rearrangement. Initially, the reaction of 5-bromo-2,6-dichloropyrimidine (61) with 4-amino-5-methyl-3-mercapto-1,2,4-triazole 1 in CH 3 CN afforded intermediate 3-((5-bromo-6-chloropyrimidin-4-yl)thio)-5-methyl-4H-1,2,4-triazol-4-amine (62) and subsequently nucleophilic substitution with secondary amines gave corresponding heteroaryl thioethers (63) . Treatment of (63) in refluxing CH 3 CN in the presence of NaNH 2 afforded the regioisomer 64 instead of expected regioisomer 65 by an intramolecular S N Ar type reaction (Scheme 27). X-ray structural analysis of the product having NR 2 = morpholine group demonstrated the formation of 64 through Smiles rearrangement. A series of pyrimido [5,4- [47] through the condensation reaction of 5-bromo-4-[1-(5-bromo-2,6-dichloropyrimidin-4-yl)ethyl]-2-chloro-6-methylpyrimidine (66) with 4-amino-5-methyl-3-mercapto-1,2,4-triazole (1) (Scheme 28). This three-step reaction involves the formation of intermediate (67) , which underwent nucleophilic substitution with secondary amine to give corresponding diheteroaryl sulfide intermediates (68) . Intramolecular S N Ar reaction of compounds 68 in the presence of NaNH 2 afforded the desired products (69) . Interestingly, nucleophilic substitution with piperidine provided the desired products in good yields (73-75%) whereas substitution with piperazines resulted in lower yields of products (62-68%). Skryl'nikova et al. [48] reported the synthesis of 7-benzylidene-3-methyl-6,7-dihydro-5H- [1, 2, 4] triazolo [3,4-b] [1, 3, 4] thiadiazine (74) by intramolecular cyclization of 5-methyl-4-(3-phenylprop-2-yn-1-yl)amino-4H-1,2,4-triazole-3-thiol (72) in DMF at 100 °C in the presence of catalytic amounts of a 40% aqueous solution of KOH (Scheme 29). Compound 72, in turn, was formed by p-toluenesulfonic acid (p-TsOH)-catalyzed reaction of 4-amino-3-mercapto-1,2,4-triazole (1) with phenylpropiolaldehyde (70), involving synthesis of 5-methyl-4-[(3-phenylprop-2-yn-1-ylidene)amino]-4H-1,2,4-triazole-3-thiol intermediate (71) , followed by hydrogenation with NaBH 4 . The hydrogenation with NaBH 4 excluded the possibility of formation of side product, 3-methyl-8-phenyl-5,6-dihydro [1, 2, 4] triazolo [3,4-b] [1, 3, 4] thiadiazepine (73) . An efficient synthesis of 1,2,4-triazolo [3,4-b] [1, 3, 4] thiadiazines (76) in excellent yields (> 90%) has been presented via a one-pot metal-free protocol by nucleophilic addition of 4-amino-3-mercapto-1,2,4-triazole derivatives (1) to dibenzoylacetylene (DBA) (75) under stirring in acetonitrile at room temperature (Scheme 30) by Shah et al. [49] . The structure of product 76 having R = Ph was unambiguously confirmed by X-ray crystallographic data. Pandey et al. [50] have synthesized a series of novel 5-[(3-aralkyl amido/imidoalkyl) phenyl]-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazine derivatives (78) in good yields by condensation reaction of 4-amino-5-mercapto-3-[(3-aralkyl amido/imidoalkyl)phenyl]-1,2,4-triazoles (1) with benzoin (77) in polyphosphoric acid under reflux (Scheme 31). The reaction of 4-amino-3-mercapto-5-phenyl-s-triazole (1) with aromatic/aliphatic/cyclic ketones 79 and 81 in refluxing acetic acid afforded the corresponding triazolo [3,4-b] [1, 3, 4] thiadiazines 80 and 82 in a single step (Scheme 32) [51] . This method is better than classical methods in terms of synthesis of 6-and 7-substituted derivatives (rare), and avoidance of use of highly toxic and irritating halo compounds. A base catalyzed condensation reaction of 4-amino-3-[(4-nitrobenzyl) thio]-4H-1,2,4-triazoles (1) with alkylisatins (83) in ethanol was described by Gaponenko et al. [52] . Spirocyclic triazolo [3,4-b] [1, 3, 4] thiadiazine derivatives (85) were obtained by the formation of new C-C bond in the final step of diastereospecific heterocyclization of intermediate 84 (Scheme 33). Prakash et al. [53] synthesized a series of 3-alkyl/aryl-7/9-methyl-10,10adihydroindeno[1,2-e] [1, 2, 4] triazolo [3,4-b] [1, 3, 4] thiadiazines (87) (67-93% yields) by the cycloconsensation of 4/6-methyl-2-tosyloxy-1-indanones (86) , generated by oxidation of 4/6-methyl-1-indanones with [(hydroxy)tosyloxyiodo]benzene (HTIB) in acetonitrile, and 3-alkyl/aryl-4-amino-5-mercapto-1,2,4-s-triazoles (1) in refluxing ethanol (Scheme 34). Reported literature protocols have provoked researchers to discover new biological active compounds consisting of triazolothiadiazine as a core motif. 1,2,4-Triazolo[3,4-b] [1, 3, 4] thiadiazine derivatives have been reported to possess significant pharmacological activity as anticancer, antimicrobial, analgesic and antiinflammatory, antioxidant, antiviral, enzyme inhibitors and antitubercular agents through different mechanisms of action, such as enzyme inhibition, interaction with intracellular targets, etc. Triazolothiadiazines also find applications in other fields, such as intermediates for photographical couplers [54, 55] , PDE4 inhibitors [56] , and corrosion inhibitors [57, 58] . Aytaç et al. [59] designed and synthesized a series of 1,2,4-triazolo[3,4-b] [1, 3, 4] thiadiazines (88) linked with structural motifs of nonsteroidal analgesic antiinflammatory drugs (ibuprofen, naproxen and flurbiprofen) at the 3-position. All synthesized derivatives were screened for their in vitro cytotoxic potential against liver (Huh7), breast (MCF-7) and colon (HCT116) cancer cell lines. Preliminary results indicated that all triazolothiadiazine derivatives exhibited significant cytotoxic potential (IC 50 = 1.1-18.8 µM) than synthon, 4-amino-1,2,4-triazole-5-thiones (IC 50 = 20.2-67.9 µM), thereby implying that fusion of triazole with thiadiazine is crucial for cytotoxic potential. Among triazolothiadiazines, compounds 88a-j with lower IC 50 values were further evaluated against hepatocellular carcinoma cell lines (HepG2, Hep-3B, Mahlavu, FOCUS and Snu475) and were found to display substantial cytotoxic activities (IC 50 = 1.5-10.1 µM) (Fig. 3 ). According to fluorescent microscopy and flow cytometry analysis, the compounds 88a-c, 88f and 88j were found to induce apoptosis and SubG1 arrest in Huh7 cells. Mechanistic study revealed that compounds 88b and 88c initiated oxidative stress induced apoptosis through ASK-1 protein activation and Akt protein inhibition. Ahmad et al. [60] synthesized a series of 1,2,4-triazolo[3,4-b][1,3,4]thiadiazines (89) having an alkenyl/hydroxyalkenyl fatty acid chain and evaluated them for their in vitro anticancer activity against three different human cancer cell lines, namely Hep3 B, MCF-7, HeLa (human cervical carcinoma) and toxicity against PBMCs (peripheral blood mononuclear cells). All the synthesized compounds were found to be non-toxic against PBMCs. SAR studies revealed that compounds 89c and 89d containing a hydroxyl group on a fatty acid chain exhibited maximum cytotoxic potential (IC 50 = 6.0-8.8 µM) against all the three tested cancer cells, as depicted in Among the tested series, compound 91c showed the highest potency, with 78.6% inhibition (100 µM) against H157 cells, which was better than the standard drug vincristine (74.5%). Compounds 91a and 91d exhibited excellent cytotoxicity against BHK-21 cells with 73.3% and 72.6% inhibition (100 µM). SAR studies presented the significance of aryl substituents at position-6 of triazolothiadiazine for anticancer activity and substitution of C6 by biphenyl group significantly decreased anticancer activity (Fig. 6 ). In another work, Khan et al. [63] synthesized 6-aryl-3-(pyridin-3-yl)-7H-[1,2,4] triazolo [3,4-b] [1, 3, 4] thiadiazine derivatives (92) and screened their cytotoxic potential against lung carcinoma (H157) and vero cell lines. Compound 92 h (R = pyridin-3-yl, Ar = 3,4-diClPh) presented excellent antiproliferative activity against H157 cell lines with an IC 50 value of 0.96 ± 0.43 µM at 1 µM concentration as compared with the standard drug vincristine (IC 50 = 1.03 ± 0.04 µM) (Fig. 6 ). Farghaly et al. [66] carried out the synthesis and anticancer evaluation of 3,6,7-trisubstituted-1,2,4-triazolo [3,4-b] [1, 3, 4] thiadiazines (95) . Among them, compound 95a exhibited potential activity against both HEPG-2 and HCT cell lines, with IC 50 values of 8.63 and 8.33 µg ml −1 , respectively, whereas compound 95h presented excellent activity against HEPG-2 cell line with an IC 50 value of 5.63 µg ml −1 (Fig. 9 ). Through an HTS process, LaPorte et al. [67] identified a series of pyrazole-linked 1,2,4-triazolo [3,4-b] [1, 3, 4] thiadiazines (96) as potent and selective STAT3 inhibitors. STAT3 is an attractive target for anticancer agents. Among the tested series, compounds 96a and 96b displayed significant antiproliferative activity against several head and neck squamous cell carcinoma (HNSCC) cell lines, namely 686LN, Cal33, FaDu, and OSC19 (GI 50 = 14-44 µM) by reduction of phosphorylated STAT3 levels and downstream effects on STAT3 gene expression targets. Compounds 96a and 96b proved to be selective inhibitors STAT3 with IC 50 values of 6.8 and 9.6 µM, respectively, over STAT1 (IC 50 : > 50 µM for each). SAR studies revealed the significance of pyrazole group and specific aryl substitution on the thiadiazine for inhibition of STAT3 pathway as shown in Fig. 10 . Further, improvements in potency and metabolic stability were accomplished by the introduction of α-methyl group on the thiadiazine (96c, GI 50 SAR studies indicated that the presence of an electron-rich group on the coumarin ring was responsible for better activity, as shown in Fig. 15 . Iqbal et al. [73] reported the synthesis of coumarin-triazolothiadiazine conjugates (102) and explored them for their cytotoxic potential against three different cancer cell lines: breast cancer cells (MCF-7), bone-marrow cancer cells (K-562), and Moreover, compound 102a with an IC 50 value of 2.21 µM was found to be more potent than the standard drug carboplatin (IC 50 = 3.91 µM) against MCF-7 cell lines, and this compound induced 50.1% apoptosis in via G 2 /M phase arrest in MCF-7 cells. A SAR study was carried out to correlate the importance of substituents with the observed activity (Fig. 16 ). Arandkar and Vedula [74] introduced a series of 1,2,4-triazolo[3,4-b][1,3,4]thiadiazine derivatives (103) and screened them for anticancer activity at a concentration 10 -5 M against 60 cancer cell lines comprising leukemia, non-small cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian, renal, prostate cancer and breast cancer lines. A SAR study revealed that compounds containing halo groups exhibited higher potency than other groups (Fig. 17) . From the tested compounds 103d, 103e, 103f and 103l exhibited significant activity against renal cancer OU-31 cell line with 47.42%, 54.64%, 46.76 and 48.14% growth, respectively. Compound 103f also exhibited significant activity on leukemia MOLT-4 cell line with 49.82% growth. Mohamady et al. [75] designed a series of naphthoquinone-hydrazino[1,2,4] triazolo[3,4-b]-1,3,4-thiadiazine derivatives (104) and screened their cytotoxicity against breast cancer cell lines (MCF-7) and hepatocellular carcinoma cell lines (HepG2) via MTT assay. Among the tested compounds, compound 104a (Fig. 18 ) (105) and tested them for their in vitro anticancer activity against MCF-7 cancer cell lines, among which compounds 105c, 105e, and 105k-l exhibited significant anticancer activity (IC 50 = 0.016-0.119 µM). Moreover, compounds 105e and 105l were found to be more active (IC 50 = 0.016 and 0.018 µM, respectively) than the standard drug cisplatin (IC 50 = 0.020 µM). A SAR study explained the effect of substituents (Fig. 19) . Puthiyapurayil et al. [77] synthesized several 6-arylsubstituted-3-[2-(4-substitutedphenyl)propan-2-yl]-7H- [1, 2, 4] triazolo [3,4-b] [1, 3, 4] thiadiazines (106) and evaluated them for their in vitro cytotoxicity against MCF-7 and A549. Among the screened series, compound 106h and 106i showed most promising cytotoxicity, with an IC 50 value 10.54 and 14.28 µM, respectively, against the MCF-7 cell line. A SAR study showed the significance of substituents for favorable activity (Fig. 20) . (113) and studied their anticancer potential against full NCI-60 cancer cell lines. Compound 113h was found to show the highest percent inhibition over the 60 cell lines, with mean growth inhibition percentage of 45.44%. SAR studies revealed that compounds with p-cholorophenyl substitution at C-6 postion of triazolothiadiazine nucleus had better activity than analogs with an unsubstituted phenyl ring (Fig. 27 ). Mechanistic having cyclopropyl substituted fluoroquinolones displayed better activity against L1210 cell lines, with an IC 50 value of 0.14 µmol/L (Fig. 28) . Gomha et al. [86] explored bis-triazolothiadiazines (115) as potent anticancer agents against human hepatocellular carcinoma (HepG-2) cell lines using harmine as a reference. Bioassay results showed that compounds 115i-k exhibited promising potency with IC 50 value of 24.8, 28.3, and 31 μM, respectively. SAR studies demonstrated that compound substituted with naphthocoumarin (IC 50 = 24.8) showed higher activity than a coumarin (IC 50 = 28.3 μM), pyridine (IC 50 = 31 μM) and pyrazole (IC 50 = 59.0 μM) substituted analog (Fig. 29) . Substitution of the phenyl ring with electron-donating (CH 3 or OCH 3 ) as well as electron-withdrawing groups (Cl, F or NO 2 ) diminished the cytotoxic activity compared with the unsubstituted phenyl group. In docking studies, potential interactions of 115i and 115j within the active site of DYRK1A are observed. Deohate et al. [87] accomplished the synthesis of 6,7-disubstituted phenyl-3-pyridin-4-yl-5H- [1, 2, 4] triazolo [3,4-b] [1, 3, 4] thiadiazines (116) and screened them for antimicrobial activity. Screening results indicated that compounds 116b, 116e, f showed highest inhibition against bacterial strains Escherichia coli, Staphylococcus aureus, and Salmonella typhi (zone of inhibition = > 21 mm) and moderate activity against Aerobacter aerogenes (zone of inhibition = 17-20 mm). Most of the tested compounds were found inactive against Bacillus subtilis (zone of inhibition = 13-16 mm). A SAR study showed that compounds containing electron donating substituents on the phenyl ring at position-6 and -7 of triazolothiadiazine enhanced the biological response markedly in comparison with electronwithdrawing groups, as depicted in Fig. 30 . Penta et al. [88] synthesized pyrazolyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-6-yl)-2H-pyran-2-one derivatives (117) and evaluated their in vitro antibacterial activity against S. aureus, B. subtilis, E. coli and Klebsiella pneumonia and antifungal activity against Candida albicans. Among the tested compounds, compound 117e showed better inhibition (zone of inhibition = 27-35 mm) than standard drugs (zone of inhibition = 25-32 mm). SAR study revealed that derivative containing electron-withdrawing group on phenyl ring exhibited most potent antimicrobial activity (Fig. 31) . Mekala et al. [89] reported indole-based 1,2,4-triazolo[3,4-b][1,3,4]thiadiazine derivatives (118) and screened them for antifungal activity against Aspergillus fumigatus, C. albicans,Trichophyton rubrum and Trichophyton mentagrophytes. Amongst the tested compounds, compound 118c was highly potent against T. rubrum and T. mentagrophytes (MIC = 3.12 µg ml −1 ) while compound 118e showed high activity against C. albicans (MIC = 3.12 µg ml −1 ) even better than standard amphotericin-B (MIC = 6.25 µg ml −1 ). SAR studies revealed that the electron-withdrawing group enhanced the biological impact (Fig. 32) . Jadhav et al. [90] synthesized a series of 1,2,4-triazolo[3,4-b][1,3,4]thiadiazine derivatives (119) linked with chromeno[4,3-b]pyridin-5-one moiety and screened for antibacterial potency against S. aureus, E. coli, B. cereus and antifungal activity against C. albicans and Aspergillus clavatus. Compound 119c showed significant antifungal effect against C. albicans (MIC = 5 µg ml −1 ), comparable to that of standard ciprofloxacin (MIC = 5 µg ml −1 ). Compound 119d showed good inhibitory activity against the bacteria B. cereus (MIC = 5 µg ml −1 ) and fungus A. clavatus (MIC = 5 µg ml −1 which was nearly the same as the standard ciprofloxacin and ketokonazole (MIC = 5 µg ml −1 . SAR studies revealed that compounds containing chloro or methoxy substituent displayed high potency (Fig. 33) . SAR studies showed that propoxy group at ortho-position of the phenyl ring was accountable for promoting the activity (Fig. 34) . Ghosh et al. [92] introduced a series of triazolothiadiazines (121) bearing substituted phenylquinolin-2-one moiety and evaluated them for their antibacterial pyridin-5-one moiety activity against Pseudomonas aeruginosa, E. coli, S. aureus, and antifungal activity against A. fumigatus, A. niger and C. albicans. SAR study revealed that triazolothiadiazine derivatives bearing phenyl quinoline moiety possessed moderate to good antimicrobial activities and halogen substituted compounds 121d, 121g and 121h showed the promising antifunfal activity against C. albicans with zones of inhibition of 20 mm, 23 mm and 19 mm, respectively (Fig. 35) . El-Sayed et al. [93] reported synthesis of 1,2,4-triazolo[3,4-b][1,3,4]thiadiazines (122) bearing a 1,2,3-triazole moiety and screened them for antimicrobial activity against bacterial and fungal strains. Out of the tested series, the most potent compound 122b exhibited moderate activity against bacterial strains of E. coli, P. aeruginosa, S. aureus, and B. subtilis (zone of inhibition = 14-18 mm) and fungal strains of C. albicans, and Aspergillus flavus (zone of inhibition = 17 and 19 mm) as compared with standard drugs. SAR study revealed the effect of different substituents on 1,2,4-triazolo [3,4- . Among the screened derivatives, compounds 123a, 123c, 123e and 123g exhibited higher antifungal activity against some Candida species (MIC = 6.25-12.5 µg ml −1 ) than the standard drug ketoconazole (MIC = 7-30 µg ml −1 ). SAR studies indicated that p-chlorophenyl substitution on triazolothiadiazine ring positively influenced the anti-Candidal activity (Fig. 37) . . SAR studies revealed the significance of cyclohexyl group and p-chlorophenyl substituent on triazolothiadiazine ring for anti-Candidal activity (Fig. 38) . Prakash et al. [95] synthesized two series of dihydroindeno (125) and indenoclubbed 1,2,4-triazolo [3,4-b] [1, 3, 4] thiadiazine derivatives (126) and evaluated their antimicrobial effects against S. aureus, B. subtilis, E. coli, P. aeruginosa, A. niger, A. flavus and Penicillium species. Bioassay results showed that dihydroindeno derivatives are more potent than indeno derivatives in terms of antimicrobial activity, and the tested compounds showed more potency towards Gram positive bacteria than towards Gram negative bacteria. Dihydroindeno compounds 125d-e, 125g-i and indeno compounds 126d, 126g, 126j exhibited noticeable antibacterial activities (zone of inhibition = 14.3-28.6 mm). In antifungal screening, compounds 125h, 126g and 126j exhibited highest potential (mycelial growth inhibition = 51.1-68.8%) compared with standard drug fluconazole. A brief SAR study is presented in Fig. 39 . Badr et al. [96] accomplished the synthesis of 6-(4-substituted phenyl)-3-(5-nitrofuran-2-yl)-7H- [1, 2, 4] triazolo [3,4-b] [1, 3, 4] thiadiazine analogs (127) and screened their antibacterial potential against S. aureus and E. coli. Results Pundeer et al. [98] synthesized 7H-7-alkoxy-3-alkyl/phenyl-6-aryl-s-triazolo [3,4b] [1, 3, 4] thiadiazine derivatives (129) and tested for antimicrobial potency against S. aureus, B. subtilis, E. coli, P. aeruginosa, Saccharomyces cerevisiae and C. albicans. Compounds 129f and 129l exhibited maximum inhibition against S. aureus, with MIC = 16 and 16 µg ml −1 , respectively, while compound 129i generated good inhibition against B. subtilis with MIC = 32 µg ml −1 . In antifungal screening, compounds 129c, 129f and 129i exhibited potent activity (MIC = 32-64 µg ml −1 ) in comparison with the standard drug amphotericin-B (MIC = 100 µg ml −1 ). A SAR study revealed the effect of substitution on the scaffold (Fig. 42) . Puthiyapurayil et al. [77] developed a novel 6-arylsubstituted-3-[2-(4-substituted phenyl)propan-2-yl]-7H- [1, 2, 4] triazolo [3,4-b] [1, 3, 4] thiadiazines (130) and evaluated antimicrobial potential against E. coli, S. aureus, P. aeruginosa, B. subtilis, Rhizopus oryzae, A. fumigatus, A. niger and T. mentagrophytes. Bioassay results revealed that, out of the evaluated derivatives, compounds 130e, 130j and 130m showed equipotent antibacterial and antifungal activity to the standard streptomycin [3,4-b] [1, 3, 4] thiadiazines and amphotericin-B (MIC = 6.25 µg ml −1 ). SAR studies explained that, due to their increased lipophilicity, highly electronegative substituents (F and Cl) facilitate hydrophobic interactions of the compounds with specific binding sites on either receptor or enzymes (Fig. 43) . Purohit et al. [99] reported a new series of 3-(3-chlorophenyl)-6-aryl-7H- [1, 2, 4] triazolo [3,4-b] [1, 3, 4] thiadiazines (131) and evaluated their antimicrobial effects against B. megaterium, S. aureus, E. coli, P. aeruginosa, and A. niger. Among the tested series, compounds 131g and 131i showed significant activity against bacterial and fungal strains (zone of inhibition = 18-24 mm) while 131c and 131f exhibited promising antibacterial activity against B. megaterium, P. aeruginosa and E. coli (zone of inhibition = 16-20 mm). The pharmacological assessment and SAR of active compounds are given in Fig. 44 . Sim et al. [100] synthesized and screened pyrimidine linked 1,2,4-triazolo [3,4b] [1, 3, 4] thiadiazines (132) for their antibacterial potential against B. subtilis, B. cereus, S. aureus, P. aeruginosa, S. typhimurium, and E. coli. Screening results indicated that compound having 4-flurophenyl ring 132f demonstrated moderate activity against P. aeruginosa with MIC = 62.5 μg ml −1 (Fig. 45) . Almajan et al. [101] accomplished the synthesis of phenylsulfonylphenyl containing 1,2,4-triazolo [3,4-b] [1, 3, 4] thiadiazine derivatives (133) and assessed their in vitro antibacterial potential against the Gram-positive (E. faecalis, S. aureus, S. epidermidis, B. cereus) and Gram-negative (A. baumanii, C. freundii, E. clocae, E. coli, P. aeruginosa) bacterial strains through the broth dilution method. Compound 133a was found to be most potent derivative against S. epidermidis with MIC = 32 µg ml −1 (Fig. 46) . Bioassay results demonstrated that screened derivatives exerted better inhibition against Gram-positive bacterial strains than Gram-negative bacterial strains. Reddy et al. [102] synthesized 1,2,4-triazolo [3,4-b] [1, 3, 4] thiadiazine derivatives (134) and evaluated their in vitro antibacterial activity. Among them, compound 134c exhibited promising antibacterial activity against E. coli, K. pneumoniae, S. dysentriae, and S. flexnei with zone of inhibition value of 30 mm, 29 mm, 29 mm, and 27 mm, respectively, which was more active than standard neomysin (inhibition zone = 20 mm) and equipotent to streptomycin (inhibition zone = 30 mm) (Fig. 47) . Kumar et al. [103] prepared a series of 3-(4-isopropylthiazol-2-yl)-6-substituted phenyl-7H- [1, 2, 4] triazolo [3,4- (Fig. 48) . Indole clubbed derivatives of triazolothiadiazine (136) were evaluated for their antibacterial potential against B. subtilis, B. cereus, S. aureus, M. luteus, E. coli, P. aeruginosa, S. typhimurium and P. vulgaris by Sim et al. [104] . Compound 136d was found to show significant inhibition against B. subtilis, B. cereus and S. aureus with MIC = 3.91 μg ml −1 . SAR studies revealed the importance of chlorine on indole moiety and p-methylphenyl group at C-6 position of triazolothiadiazine ring (Fig. 49) . Puthiyapurayil et al. [105] introduced amide linked 3,6-disubstituted-7H-1,2,4triazolo [3,4-b] [1, 3, 4] thiadiazine derivatives (137) and screened them for their in vivo analgesic and anti-inflammatory potential using acetic acid-induced writhing test and carregeenan-induced rat hind paw edema, respectively. From the tested series, compounds 137a, 137b and 137c exhibited potent and consistent analgesic activity in both 100 and 200 mg kg −1 po −1 doses with less ulcerogenic risk (inhibition = 28-43%) as well as excellent anti-inflammatory activity (at a dose of 50 mg kg −1 ) (edema inhibition = 38-61%). SAR studies demonstrated that derivatives with N-methyl- [4-(trifluoromethyl) phenyl]pyrazole moiety at the position-3 of the fused ring are more potent than the other derivatives bearing [1-(4-chlorophenyl)-1-methylethyl] as shown in Fig. 50 . Compound 137b also displayed promising cytotoxic effect against human breast cancer (MCF-7) cell line with IC 50 value 14.24 µM. Shehry et al. [106] reported synthesis and anti-inflammatory activity of 3-(2,4-dichlorophenoxy)methyl)-1,2,4-triazolo [3,4-b] [1, 3, 4] thiadiazines (138). Compounds 138a and 138b exhibited potent anti-inflammatory activity (edema inhibition = 59-60% at 3 h). The percent change in paw volume compared with base line measurement was recorded after interval of 1 h. SAR studies demonstrated that 2,4-dichlorophenoxy at the 3-position of triazolothidiazine ring was found crucial for biological effect (Fig. 51 ). Hussein et al. [107] synthesized and evaluated 4-substituted phenyl-3-(pyridin-4-yl)-7H-(1,2,4)triazolo [3,4-b] - [1, 3, 4] thiadiazine derivatives (139) for their analgesic and anti-inflammatory effects. Among them, compounds 139d, 139e and 139f (0.03 mmol kg −1 ) displayed maximum anti-inflammatory effect at 5 h, with inflammatory inhibition rates of 75% and 84.85 and 75.31%, respectively. Moreover, compounds 139d-f (0.02 mmol kg −1 ) exhibited potent analgesic effects with 79-145% activity compared to indomethacinin at the 5 h interval. Figure 52 illustrates a brief SAR and activity profile of most active compounds. Koksal et al. [17] reported a series of 3,6-diaryl-1,2,4-triazolo[3,4-b][1,3,4]thiadiazines (140) for their anti-inflammatory activity. The outcome showed that compounds 140c-h and 140j were found to have better inhibitory potency (50.2-62.8%) at different time interval with less ulcerogenic risk than the standard indomethacin (49.2% in 120 min, 54.9% in 240 min). SAR studies were carried out to determine the active functional groups at position-6 of triazolthiadiazine ring in order to enhance potency (Fig. 53) . Naveena et al. [108] reported the synthesis and anti-inflammatory activity evaluation of novel 6-substituted-3-(2-(aryloxymethyl)phenyl) [1, 2, 4] triazolo [3,4-b] [1, 3, 4] thiadiazine derivatives (141). Bioassay results showed that the tested compounds A SAR study demonstrated that substitution with 5-chloro-2-sulfanamido-3-thienyl and 4-nitrophenyl groups at position-6 of triazolothiadiazine scaffold enhanced the anti-inflammatory activity (Fig. 54 ). Ranganatha et al. [109] synthesized diarylmethanone linked 1,2,4-triazolo[3,4-b] [1, 3, 4] thiadiazine derivatives (142) and evaluated their in vitro antioxidant potential by DPPH, nitric oxide and hydrogen peroxide scavenging assay. Among the tested series, compounds 142b, 142c and 142d exhibited significant antioxidant effect in DPPH (2,2-diphenyl-1-picryl-hydrazyl-hydrate) test with the IC 50 values of 18.33, . SAR studies were carried out to determine the active functional groups in order to enhance the potency (Fig. 55) . Patrao et al. [110] synthesized and screened antioxidant activity of a cluster of α and β-naphthoxy methyl linked 1,2,4-triazolo [3,4-b] [1, 3, 4] thiadiazine derivatives (143) using the DPPH assay. The results indicated that, among the tested derivatives, compound 143b exhibited highest antioxidant potential, with inhibition of 60% at a concentration of 100 μg ml −1 . SAR studies demonstrated that derivatives linked with α-naphthoxy group exhibited enhanced activity in comparison with β-naphthoxy derivatives (Fig. 56) . Kaushik et al. [111] prepared 3-substituted phenyl-6-phenyl-7H-[1,2,4] triazolo [3,4-b] [1, 3, 4] thiadiazine derivatives (144) and screened their antioxidant activity on the basis of the scavenging activity of the stable DPPH free radical. Compounds 144a and 144e possess significant antioxidant potential with IC 50 values of 17.27 and 17.05 µg ml −1 , respectively. SAR studies revealed that antioxidant activity of compounds may depend on the basic skeleton of the molecule as well as on the nature of substituents (Fig. 57) . Shakir et al. [112] reported synthesis and antioxidant activity evaluation of 6-amino-7H- [1, 2, 4] triazolo [3,4-b] [1, 3, 4] thiadiazin-3-yl derivatives (145) bearing 2,6-dimethoxy-4-(methoxymethyl)phenol moiety by DPPH and ferric reducing antioxidant power (FRAP) assays. Among the screened compounds, compound 145b exhibited remarkable antioxidant ability in both assays (DPPH inhibition = 92%; IC 50 = 56 µg ml −1 which is higher than standard butylated hydroxytoluene (BHT) (DPPH inhibition = 66%; IC 50 = 78 µg ml −1 ). SAR studies revealed that compounds 145a-c exhibited higher antioxidant potential with inhibition in the range 79-83% due to presence of thiourea moiety than compounds 145d-f containing amide group with 68-75% inhibition (Fig. 58) . Sathyanarayana et al. [113] designed and synthesized benzimidazole linked 1,2,4-triazolo [3,4-b] [1, 3, 4] thiadiazine derivatives (146) and assessed their in vitro antioxidant potential using DPPH, nitric oxide and superoxide radical scavenging methods. Among them, compound 146c showed more activity in both DPPH and nitric oxide radical assay, with IC 50 values of 13.57 and 18.55 μg ml −1 compared with standard (IC 50 = 23.75 and 23.14 μg ml −1 , respectively). SAR studies demonstrated that derivatives substituted with electron-donating groups exhibited enhanced activity in comparison with electron-withdrawing groups (Fig. 59 ). Pavurala et al. [114] synthesized a series of bis coumarinyl bis triazolothiadiazinyl ethane derivatives (147) and screened their antiviral activity against a broad spectrum of RNA and DNA viruses (herpes simplex virus-1 (KOS), herpes simplex virus-2 (G), vaccinia virus, vesicular stomatitis virus, herpes simplex virus-1TKKOSACV r , adenovirus-2, vesicular stomatitis virus, coxsackie virus (Fig. 60) . SAR studies revealed that compounds having an aromatic ring on a coumarin nucleus exhibit better antiviral activity than other substituents such as chloro, bromo or methoxy substituents. Pandey et al. [50] introduced a series of 5-[(3′-aralkyl amido/imidoalkyl) phenyl]-1,2,4-triazolo [3,4-b] [1, 3, 4] thiadiazines (148) and screened their in vitro antiviral potential against two animal viruses, namely Japanese encephalitis virus (JEV) strain P20778 and Herpes simplex virus-1 (HSV-1) strain 753,166. Screening results revealed that compound 148c, with a 2-phenyl-3-methyl-quinazolin-(3H)-4-one group, is mainly responsible for exerting antiviral activity against JEV (EC 50 = 7.8 µg ml −1 inhibition = 50%; therapeutic index = 32) while compounds 148a, 148b and 148d containing phthalimido, phthalimidomethyl, and nicotinamido substituents, respectively, exhibited weak activity (10-20%) against JEV and HSV-I (Fig. 61) . SitaRam et al. [116] synthesized 1,2,4-triazolo [3,4-b] [1, 3, 4] thiadiazine derivatives (150) containing benzenesulfonamide moieties and screened their inhibitory potential against four isomers of the α-carbonic anhydrases (CAs) comprising hCAs I and II (cytosolic, ubiquitous isozymes) and hCAs IX and XII (transmembrane, tumor-associated isozymes). Bioassay results revealed that compound 150a exhibited excellent inhibitory potential against all four isozymes (K i = 3.0-89 nM), 150b inhibited isozymes hCA I, IX and XII (K i = 84, 6.5 and 3.8 nM, respectively) while 150c inhibited isozymes hCA IX and XII (K i = 25 and 18 nM, respectively). Compounds 150d-e selectively inhibited hCA IX (K i = 21-25 nM) even better than the standard drug acetazolamide (K i = 25 nM). SAR revealed the effect of different substituents on 1,2,4-triazolo [3,4-b] [1, 3, 4] thiadiazine for hCA inhibition (Fig. 63) . Alafeefy et al. [117] introduced a series of benzenesulfonamides incorporating aroylhydrazone- [1, 2, 4] triazolo [3,4-b] [1, 3, 4] thiadiazinyl group (151) and examined their inhibitory potential against four CAs, the human (h) isoforms hCA I, II, IX and XII. Bioassay results revealed that compound 151a presented significant inhibitory effects against hCA I (K i = 86.4 nM) (threefold more effective than the standard acetazolamide; K i = 250 nM)) and hCA XII (K i = 4.3 nM) while 151b exhibited inhibition against hCA II and hCA XII (K i = 0.93 and 0.85 nM, respectively) (Fig. 64) . Khan et al. [62] screened 3-(pyridin-4-yl)-7H- [1, 2, 4] triazolo [3,4-b] [1,3,4] thiadiazine derivatives (152) for cholinesterase inhibition against electric eel acetylcholinesterase (EeAChE) and horse serum butyrylcholinesterase (hBChE) as well as for alkaline phosphatase inhibition. Results indicated that compound 152f (IC 50 = 13.66 ± 0.31 µM) exhibited remarkable inhibition against EeAChE, while compounds 152g (IC 50 = 16.6 ± 2.72 µM) and 152h (IC 50 = 12.2 ± 1.67 µM) showed greater inhibitory potential against BChE more than the standard drug neostigmine. Compound 152h also exhibited significant inhibitory effect on alkaline phosphatase with IC 50 = 1.32 ± 0.20 µM. SAR studies revealed the role of different functional groups on the triazolothiadiazine nucleus as shown in Fig. 65 . In another work, evaluation of 3-(pyridin-3-yl)-7H- [1, 2, 4] triazolo [3,4-b] [1, 3, 4] thiadiazines (Fig. 65 ) for cholinesterase inhibitory activity by Khan et al. [63] revealed that compound 153g Ozil et al. [118] synthesized triazole-linked bis( [1, 2, 4] triazolo [3,4-b] [1, 3, 4] thiadiazine) derivatives (154) and assessed anti-lipase activity with regard to pancreatic lipase inhibition. Among them, compounds 154a-c showed considerable anti-lipase activity at various concentrations (inhibition = 90-94%; IC 50 = 0.11-0.42 µg ml −1 ). SAR studies identified the significance of R groups on triazolothiadiazine ring for inhibition of pancreatic lipase (Fig. 66) . Recently, Çevik et al. [119] introduced benzimidazole-triazolothiadiazine derivatives (155) as aromatase inhibitors (IC 50 = 0.037 ± 0.001 μM to 1.345 ± 0.061) using fluorimetric assay kit with letrozole as the reference drug. Among tested compounds, compound 155g was found to be most promising inhibitor against aromatase enzyme (IC 50 = 0.037 μM), which was slightly less potent than standard drug letrozole (IC 50 = 0.024 μM) (Fig. 67) . A series of 1,2,4-triazolo [3,4-b] [1, 3, 4] thiadiazines (156) was explored as dual inhibitors of cholinesterase (ChE) and monoamine oxidase (MAO) by Khan et al. [120] . Bioassay results revealed that compounds 156e and 156h exhibited high selectivity towards EeAChE, with IC 50 values of 0.065 and 0.075 μM, respectively, which is around 250-and 218-fold stronger inhibition than the standard drug neostigmine (IC 50 = 16.3 μM). Compound 156c showed ~330-fold more inhibition [1, 3, 4] thiadiazine on ChE inhibition and AChE/ BChE selectivity (Fig. 68) . Baeeri et al. [121] synthesized 3,6-diaryl-7H- [1, 2, 4] triazolo [3,4-b] [1, 3, 4] thiadiazines (157) as potential phosphodiesterase-4 inhibitors. Among the tested derivatives, compound 157d exerted remarkable specificity for PDE-4 by enhancing the concentration of cAMP (ED 50 = 13 µM), however the level of cGMP remains unaffected (ED 50 = 49.8 µM) (Fig. 69) . Docking studies also validated the selective binding of these compounds in cAMP-specific PDE enzymes binding site. Li et al. [122] reported new analogs of 3,6-disubstituted 1,2,4-triazolo [3,4- and RDRTB (rifampin-resistant strains) by the BacT/ALERT 3D liquid culture technology using rifampin and isoniazid as the standard drugs. According to the results of antitubercular determination, compounds 158a, 158i, 158k, 158r, 158t and 158o exhibited most potent activity (MIC = 0.25-4 µg ml −1 ; IC 50 = 28-252 µg ml −1 ). A SAR study was carried out to correlate the effect on activity of aromatic or hetero-aromatic substituents at the 3-and 6-position of triazolothiadiazine, which is presented in Fig. 70 . Kincaid et al. [123] identified 1,2,4-triazolo[3,4-b][1,3,4]thiadiazine derivatives (159) as antimycobacterial agents via inhibition of uridine 5′-diphosphategalactopyranose mutase (UGM) by means of virtual screening (docking and X-ray crystallography studies). Bioassay outcomes showed that compounds 159g-j (K d = 5-15 µM; inhibition = 97-100%) possessed the most promising activity a,nd compound 159j fully blocked the K. pneumoniae UGM activity at 50 μM. These derivatives also contributed antimicrobial potency against Mtb and Mycobacterium smegmatis. SAR studies of the derivatives revealed that compounds with larger or more polarizable phenyl ring on the position-6 and larger side-chains at position-3 of triazolothiadiazine ring exhibited effective inhibition (Fig. 71 ). Docking and X-ray structure showed consistency with the observed SAR. The present review captures the diverse biological activities exhibited by triazolothiadiazines reported in the literature. After careful analysis, general structural features have been identified that can be used in the design and development of novel triazolothiadiazine deivatives having clinical efficiency. Unfused 5-membered triazole ring systems were found to be biologically inactive; however, fusion of the 5-membered triazole ring with 6-membered thiadiazine ring is important for bioactivity [59, 84] . Unsaturation in the 6-membered thiadiazine ring fueled bioactivity, in comparison with saturated derivatives [84] . At position-3 of the triazole ring, aromatic substitution connected through a spacer (0-3 atoms) exhibited better activity. Aromatic substituents at position-6 of the triazolothiadiazine ring displayed improved potency over the aliphatic analogs. Halogen-substituted aryl groups, specifically chloro-substituted aryl results in better activity than electron-donating groups, as aliphatic substitution bring down the activity. Substitution at position-7 of the triazolothiadiazine ring can be important for activity, but is not essential. Figure 72 summarizes the structural modifications in terms of different substituents at position-3, 6 and 7 (R 1 , R 2 and R 3 ) with respect to various biological activities, namely anticancer, antiviral, antimicrobial, antioxidant, antitubercular, enzyme inhibitiors, analgesic and anti-inflammatory activities. Pharmacokinetics is the study of processes by which drugs are absorbed, distributed, metabolized and eliminated from the body. Performing standard experimental procedures for absorption, distribution, metabolism and excretion (ADME) profiling for a vast number of compounds would have been time-consuming and economically unfeasible. Most drug molecules fail to enter the market due to their adverse pharmacokinetic properties. Recently, computer simulation platforms are gradually becoming popular as they can accelerate the pharmacokinetic development of the drug molecule [124, 125] . In the primary phase of drug discovery, in silico approaches for the prediction of pharmacokinetics of drug candidates play an essential role in terms of cost effectiveness, time factors and avoidance of the ethical problems that arise from a large number of animals required for experiments. A successful lead should obey Lipinski's rule of five, which states that the drug should be easily absorbed, distributed to its target site, not easily metabolized, and excreted easily. The drug-likeness of a compound was assessed according to Jorgensen's rule of three [126] and Lipinski's rule of five [127] , which indicates that a chemical substance can be orally active in humans by estimating structural or physiochemical properties (descriptors) which are important for drug pharmacokinetics. Jorgensen's rule of three states that Caco-2 cell permeability (P Caco ) > 22 nm/s, predicted aqueous solubility (PlogS) > − 5.7 and number of primary metabolites < 7. Lipinski's rule of five states that orally active drug has no more than one violation of the following criteria: molecular weight < 500 Da; hydrogen bond donors ≤ 5; hydrogen bond acceptors ≤ 10; and octanol/water partition coefficient (log P) ≤ 5 (or MlogP not greater than 4.15) [128, 129] . Topological polar surface area (TPSA) ≤ 140 Å 2 and the number of rotatable bonds ≤ 10 are also considered additional criteria used to determine oral bioavailability [130] . Triazolo [3,4-b] [1, 3, 4] thiadiazine derivatives have been identified as compounds with broad-spectrum activity, high safety, and excellent pharmacokinetic properties in a variety of studies. Therefore, analysis of arrangement of substituents around triazolothiadiazine scaffold (Fig. 73 ) might provide useful information to construct novel triazolothiadiazine derivatives with better biological proficiency. Çevik et al. [76] calculated ADME parameters of benzimidazole-triazolothiadiazine derivatives 105 by QikProp 4.8 software for comparing with those of 95% of known drugs. All compounds 105 were found in accordance with the Jorgensen's rule of three and Lipinski's rule of five for drug-likeness properties by causing no more than one violation. According to predictions of ADME properties for compounds 105e and 105l, including molecular weight 433.489 and 467.934, respectively, the number of rotatable bond values (1), only one hydrogen bond donor group, hydrogen bond acceptors 6 and logP 4.468 and 4.96, respectively, it can be suggested that the active compounds 105e and 105l have desirable pharmacokinetic properties. Sathyanarayana et al. [113] reported that novel [1, 2, 4] triazolo [3,4- In silico ADME properties of the most selective triazolothiadiazine derivatives 160a and 160b as a new oral anti-inflammatory agent were accessed using the Swis-sADME web tool by Abdellatif et al. [132] , which revealed that both compounds violated Lipinski's rule of five by two represented by molecular weight (589.94 and 663.61 Da, respectively) and MlogP values (6.46 and 4.55, respectively). Consequently, these triazolothiadiazine derivatives have lower bioavailability scores (0.17) compared with that of the reference drug celecoxib (0.55). Alsaedi et al. [133] synthesized triazolo [3,4-b] [1, 3, 4] thiadiazine derivative 161 as potent VEGFR2 inhibitor with anti-hepatocellular carcinoma activity and predicted pharmacokinetic properties using SwissADME tool. Compound 161 showed good gastrointestinal (GI) absorption, high oral bioavailability, and fitted well in the Lipiniski's rule. ADME prediction revealed that compound 161 has a desirable pharmacokinetic profile and can be considered as a hopeful drug candidate. Sever et al. [134] predicted pharmacokinetic profiles of triazolothiadiazine derivatives using QikProp program of Schrodinger's Maestro molecular modelling package. Compounds exhibited human oral absorption percentages ranging from 91.010% to 100.000%. All compounds comply with Lipinski's rule of five and Jorgensen's rule of three. On the basis of these findings, they are expected to possess favorable oral bioavailability and drug-like properties. According to in silico ADME studies for triazolothiadiazine 162, the total solvent accessible surface area (SASA) was 622.356 Å 2 , the predicted octanol/water partition coefficient (logPo/w) was 5.224, logarithm of predicted binding constant to human serum albumin, logK HSA value was 0.957 and the predicted apparent Caco-2 cell permeability P Caco-2 was 1763.718. These results were in agreement with recommended range, thus indicating compound 162 to possess a favorable ADME profile. In receptor-based drug design, the 3D structure of the binding site is modelled on the target with the aid of molecular simulations. Docking experiments are carried out to identify the binding sites through computationally model ligand-receptor interactions as well as lead candidates from the binding energy scores [135] . A literature survey reflected the prominence of the 1,2,4-triazolo [3,4-b] [1, 3, 4] thiadiazine structural motif in the drug designing aimed at diverse pharmacological activities by its robust interactions with various receptors. Extensive research has focused on structural attributes of 1,2,4-triazolo [3,4-b] [1, 3, 4] thiadiazines responsible for its bioactivity on particular targets via computational studies (docking and molecular dynamics). Structural variations on triazolothiadiazine scaffold and their interactions with different biological receptors are shown in Fig. 74 . 1,2,4-Triazolo[3,4-b] [1, 3, 4] thiadiazine derivative 111j exhibited promising anticancer potential, which is supported by several interactions of its core nucleus with amino acids Lys 352 , Ala 250 , Lys 254 , Leu 248 , Asn 258 and the H-bond between oxygen atom of its trimethoxyphenyl ring and the thiol group of Cys 241 in the colchicine binding site of tubulin polymerase [82] . The methylpropylphenyl moiety of triazolothiadiazines 88b-d inserted into a hydrophobic basin formed by Val 349 , Leu 352 , Phe 518 and Ile 523 amino acids of the COX-1 protein to form a hydrophobic interaction [59] . In compound 113h, the N2 of the triazole ring and NH at position-3 interacted with Val 135 via two H-bonds inside the ATP binding pocket of GSK-3β, one of the targets of anticancer activity of this compound [84] . Compound 104a displayed H-bond interactions with Asp 479 and Lys 456 present at ATP catalytic binding domain of Topo-Iiβ [75] . Docking studies displayed that compound 102a formed strong H-bond interactions with Ser 93 , His 321 and His 154 in active site of tissue-nonspecific alkaline phosphatase (h-TNAP), while compound 102d formed important interactions with the active site of intestinal alkaline phosphatase (h-IAP), which included two H-bonds between two nitrogen atoms of triazole ring and Arg 166 and metal interaction of carbonyl group of coumarin core with Zn 2+ [73] . Docking studies indicated that compound 105e could inhibit aromatase enzyme through an H-bond interaction of CN group at the paraposition of the phenyl ring with Ser 314 . Besides, benzimidazole ring formed two π-π interactions with Arg 115 and Phe 134 and the triazolothiadiazine ring could interact by a salt bridge with the Hem 600 molecule and Cys 437 [76] . Further modifications and changes in substitution patterns at the C-3 and C-6 positions could result in higher affinity towards different receptors with additional interactions. This wide statistics will impart directions to researchers in innovating target selective, optimized and diverse 1,2,4-triazolo [3,4-b] [1, 3, 4] thiadiazine analogs for the treatment of multifactorial diseases. In conclusion, the present review article deliberated the various synthetic protocols engaged for synthesis of diverse array of triazolothiadiazine analogs via multicomponent reactions (MCRs), conventional heating and visible-light-mediated organic reactions. Moreover, the triazolothiadiazine scaffold is an important structural motif in biologically active compounds, exhibiting more potency than standard marketed drugs. This review presented an in-depth analysis of medicinal aspects of 1,2,4-triazolo [3,4-b] [1, 3, 4] thiadiazines for different biological activities such as anticancer, antimicrobial, analgesic and anti-inflammatory, antioxidant, antiviral, enzyme inhibitors and antitubercular activities. The activity profile of this scaffold particularly offers structural modifications at the C3 and C6 positions of the triazolothiadiazine ring to achieve new analogues. This study also revealed the structural diversity, biological importance and SAR examination of heterocyclic compounds containing a triazolothiadiazine nucleus, which will help the practitioners in further exploration of biological efficacy. An insight on medicinal attributes of 1,2,4-triazoles Effective synthesis of 7H-1 Synthesis, structural characterization, crystallographic analysis and antibacterial properties of some nitrofuryl triazolo[3,4-b]-1,3,4-thiadiazines Synthesis and antimicrobial properties of new 4-(alkylidene/arylidene)-amino-5-(2-furanyl)-2,4-dihydro-3H-1,2,4-triazole-3-thiones and 6-aryl-3-(2-furanyl)-7H-1 ]thiadiazines by a C-C ring cyclization under mild conditions ,3,4-thiadiazines carrying thioalkyl and sulphonyl phenoxy moieties Synthesis and antibacterial activity of s-triazoles, s-triazolo Syntheses and biological activities of 6-aryl-3-(3-hydroxy-propyl)-7H-1,2,4-triazolo A facile [hydroxy(tosyloxy)iodo]benzene mediated synthesis of symmetrical triazolo Stereospecific synthesis of 6,7-dihydro-5H-1 4] thiadiazines in ground and excited states Synthesis of 6-aryl-3-(d-gluco-pentitol-1-yl)-7H-1, 2, 4-triazolo Facile routes to 1 Efficient and convenient protocol for the synthesis of novel 1 Stereoselective synthesis of dihydrothiadiazinoazines and dihydrothiadiazinoazoles and their pyrolytic desulfurization ring contraction Synthesis of coumarin substituted triazolothiadiazine derivatives via ring transformation reaction Studies on synthesis and antiinflammatory activities of novel 1 ]thiadiazin-6-one using heteropolyacid catalysts Molecular iodine mediated one step synthesis of 3-substituted-6-(6-substituted-2-oxochromen-3-yl)-7H Synthesis of imidazo ] thiadiazine derivatives as potential bioactive molecules Synthesis and pharmacological evaluation of some novel 2-(5-hydroxy-5-trifluoromethyl-4, 5-dihydropyrazol-1-yl)-4-(coumarin-3-yl) thiazoles Recent advances and perspectives in the synthesis of bioactive coumarins Synthesis of novel 3-(3-(5-methylisoxazol-3-yl)-7H Synthetic approach toward heterocyclic hybrids of Design and synthesis of novel quinoline derivatives bearing oxadiazole, isoxazoline, triazolothiadiazole, triazolothiadiazine, and piperazine moieties C 5 -Alkyl-1,3,4-oxadiazol-2-ones undergo dealkylation upon nitrogen insertion to form 2H-1,2,4-triazol-3-ones: Synthesis of 1,2,4-triazol-3-one hybrids with triazolothiadiazoles and triazolothiadiazines Visiblelight mediated regioselective approach towards synthesis of 7-aroyl-6-methyl Synthesis of sequence-selective C8-linked pyrrolo [2,1-c][1,4]benzodiazepine DNA interstrand cross-linking agents Bis(α-bromo ketones): Versatile precursors for novel bis(s-triazolo 2-Bromo-1-(1H-pyrazol-4-yl) ethanone: versatile precursors for novel mono-, bis-and poly 6-(1H-pyrazol-4-yl Efficient routes for the synthesis of novel bis(striazolo Bis(α-bromo ketones): versatile precursors for novel bis(striazolo bromomethyl)thieno[2,3-b]thiophene: versatile precursors for novel bis(triazolothiadiazines), bis(quinoxalines), bis(dihydrooxadiazoles), and bis(dihydrothiadiazoles Synthesis of novel scaffolds based on thiazole or triazolothiadiazine linked to benzofuran or benzo[d]thiazole moieties as new hybrid molecules The chemical biology of naphthoquinones and its environmental implications Facile synthesis of new 10-substituted-5H-naphtho An efficient, multicomponent synthesis of pyrazolyl triazolo thiadiazinyl chromen-2-ones An efficient one-pot expeditious synthesis of 3-phenyl-1-(6-phenyl-7H Efficient, one-pot synthesis of triazolothiadiazinyl-pyrazolone and pyrazolyl-triazolothiadiazine derivatives via multicomponent reaction One-Pot, multi-component synthesis of substituted 2-(6-phenyl-7H Multicomponent efficient synthesis of new Novel one-pot multicomponent synthesis of substituted 2,3-dihydro-2-(6-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-7H Facile synthesis of some novel triazolo ] thiadiazines and study of their anti-candidal and cytotoxic activities ]thiadiazine derivatives via S/N smiles rearrangement Synthesis and characterisation of new 3-methyl-6-[1-(pyrimidin-4-yl)ethyl]-5H-pyrimido One step synthesis of highly functionalized thiazolo[3,2-b Synthesis and biological evaluation of some novel 5-[(3-aralkyl amido/imidoalkyl)phenyl Novel method for the synthesis of s-triazolo Synthesis of spiro A facile synthesis of novel dihydroindeno Substituent and solvent effects on the thermal isomerisation of 7H-pyrazolo[5,1-c]-1,2,4-triazole azomethine dyes Desulfurization of triazolothiadiazines Exploration and optimization of substituted triazolothiadiazines and triazolopyridazines as PDE4 inhibitors Furan and phenyl substituted triazolothiadiazine derivatives as copper corrosion inhibitors: electrochemical and DFT studies Triazolothiadiazine derivatives as corrosion inhibitors for copper, mild steel and aluminum surfaces: electrochemical and quantum investigations Novel triazolothiadiazines act as potent anticancer agents in liver cancer cells through Akt and ASK-1 proteins Synthesis and anticancer activity of long chain substituted 1,3,4-oxadiazol-2-thione, 1,2,4-triazol-3-thione and 1 Synthesis, crystal structure and biological evaluation of some novel 1 Active compounds from a diverse library of triazolothiadiazole and triazolothiadiazine scaffolds: synthesis, crystal structure determination, cytotoxicity, cholinesterase inhibitory activity, and binding mode analysis Synthesis of novel 1,2,4-triazoles, triazolothiadiazines and triazolothiadiazoles as potential anticancer agents Design, synthesis and biological evaluation of novel 1 Synthesis of novel 1,2,4-triazoles and triazolo-thiadiazines as anticancer agents Optimization of pyrazole-containing 1,2,4-triazolo-[3,4-b]thiadiazines, a new class of STAT3 pathway inhibitors Indomethacin based new triazolothiadiazine derivatives: synthesis, evaluation of their anticancer effects on T98 human glioma cell line related to COX-2 inhibition and docking studies Synthesis, anticancer and antibacterial activities of triazolothiadiazines containing 2,4-dichloro-5-fluorophenyl moiety Studies of in vitro anti-prostate cancer potential of newer 1,2,4-triazolo-1,3,4-thiadiazines with different heteroaromatics Unraveling the alkaline phosphatase inhibition, anticancer, and antileishmanial potential of coumarin-triazolothiadiazine hybrids: design, synthesis, and molecular docking analysis Synthesis and cytotoxicity activity of novel benzotrizolyl methyl Expanding the alkaline phosphatase inhibition, cytotoxic and proapoptotic profile of biscoumarin-iminothiazole and coumarin-triazolothiadiazine conjugates A facile one-pot expeditious synthesis of triazolothiadiazines and anticancer activity Design and novel synthetic approach supported with molecular docking and biological evidence for naphthoquinone-hydrazinotriazolothiadiazine analogs as potential anticancer inhibiting topoisomerase-IIB Synthesis, docking studies and biological activity of new benzimidazole-triazolothiadiazine derivatives as aromatase inhibitor Synthesis, spectral characterization and biological evaluation of a novel series of 6-arylsubstituted-3 Conjugation of substituted ferrocenyl to thiadiazine as apoptosis-inducing agents targeting the Bax/Bcl-2 pathway Design, synthesis and biological evaluation of flexible and rigid analogs of 4H-1,2,4-triazoles bearing 3,4,5-trimethoxyphenyl moiety as new antiproliferative agents Novel 1,2,4-triazole derivatives as antitumor agents against hepatocellular carcinoma ]thiadiazine, a novel tubulin inhibitor, evokes G2/M cell cycle arrest and apoptosis in SGC-7901 and HeLa cells Development of triazolothiadiazine derivatives as highly potent tubulin polymerization inhibitors: structureactivity relationship, in vitro and in vivo study Synthesis and anticancer activity of new spirooxindoles incorporating Design, synthesis, and biological evaluation of novel 7H Synthesis and antitumor evaluation of fluoroquinolone C3 fused heterocycles (II): from triazolothiadiazines to pyrazolotriazoles Design, synthesis, molecular docking study and anti-hepatocellular carcinoma evaluation of new bis-triazolothiadiazines Synthesis, structural study and biological activity of bridgehead nitrogen containing triazolo-thiadiazine derivatives ]thiadiazin-6-yl)-2H-pyran-2-one derivatives via multicomponent approach and their potential antimicrobial and nematicidal activities Synthesis, characterization and biological screening of some novel indole based 1,2,4-triazolo 1,3,4-thiadiazines Synthesis and antimicrobial study of triazolo Synthesis and antibacterial activity of 3,6-diaryl-7H Synthesis, characterization and antimicrobial evaluation of some novel 1 Mohamed AS (2020) An efficient synthesis and antimicrobial activity of N-bridged triazolo[3,4-b]thiadiazine and triazolo[3,4-b]thiadiazole derivatives under microwave irradiation Synthesis and anticandidal activity of new triazolothiadiazine derivatives Synthesis and biological evaluation of dihydroindeno and indeno ]thiadiazoles starting from 5-nitro-2-furoic acid and evaluation of their antimicrobial activity Facile synthesis, cytotoxic and antimicrobial activity studies of a new group of 6-aryl-3 ) α, α-Dibromoacetophenones mediated synthesis of some new 7H-7-alkoxy-3-alkyl/phenyl-6-aryl-s-triazolo Synthesis and antimicrobial activity of some new 1,3,4-thiadiazoles and 1,3,4-thiadiazines containing 1,2,4-triazolo nucleus Synthesis, characterization and antibacterial activity of some new 1,2,4-triazole Schiff bases and 1 ]thiadiazin-6-ones: synthesis, characterization and antibacterial activity evaluation Synthesis and antibacterial activity of N-substituted Synthesis and pharmacological evaluation of clubbed isopropylthiazole derived triazolothiadiazoles, triazolothiadiazines and mannich bases as potential antimicrobial and antitubercular agents Synthesis, characterization and antibacterial evaluation of some new 1 Synthesis, characterization and biological evaluation of a novel series of 1,2,4-triazolo 4-dichlorophenoxy) methyl)-1,2,4-triazolo(thiadiazoles and thiadiazines) as anti-inflammatory and molluscicidal agents Synthesis, anti-inflammatory, analgesic, and antibacterial activities of some triazole, triazolothiadiazole, and triazolothiadiazine derivatives Synthesis and biological evaluation of some Evaluation of antioxidant activity of diarylmethanone integrated thaiadiazine analogues ]thiadiazines and their antimicrobial and antioxidant properties Synthesis of triazolothiadiazine derivatives as antioxidant agents ]thiadiazin-3-yl) derivatives bearing 2,6-dimethoxy-4-(methoxymethyl) phenol moiety ]thiadiazine derivatives embedded with benzimidazole moiety as potent antioxidants Bis coumarinyl bis triazolothiadiazinyl ethane derivatives: synthesis, antiviral activity evaluation, and molecular docking studies New triazolothiadiazole and triazolothiadiazine derivatives as kinesin Eg5 and HIV inhibitors: synthesis, QSAR and modeling studies Benzenesulfonamide bearing 1,2,4-triazole scaffolds as potent inhibitors of tumor associated carbonic anhydrase isoforms hCA IX and hCA XII Inhibition of human carbonic anhydrase isozymes I, II, IX and XII with a new series of sulfonamides incorporating aroylhydrazone Microwave-promoted synthesis and biological activity of some 2-hetarylmethyl-4-(4-hetarylphenyl)-5-methyl-2, 4-dihydro-3H-1,2,4-triazol-3-one derivatives Synthesis and docking study of benzimidazole-triazolothiadiazine hybrids as aromatase inhibitors Exploration of a library of triazolothiadiazole and triazolothiadiazine compounds as a highly potent and selective family of cholinesterase and monoamine oxidase inhibitors: design, synthesis, X-ray diffraction analysis and molecular docking studies ]thiadiazine analogs as potential phosphodiesterase-4 inhibitors in NIH-3T3 mouse fibroblastic cells Preliminary SAR and biological evaluation of antitubercular triazolothiadiazine derivatives against drug-susceptible and drug-resistant Mtb strains Virtual screening for UDP-galactopyranose mutase ligands identifies a new class of antimycobacterial agents Computational methods in drug discovery SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules Prediction of drug solubility from structure Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings Design, synthesis and biological evaluation of 1,3,4-oxadiazoles as promising anti-inflammatory agents Synthesis, anti-inflammatory activity, and COX-1/2 inhibition profile of some novel non-acidic polysubstituted pyrazoles and pyrano[2,3-c]pyrazoles Molecular properties that influence the oral bioavailability of drug candidates Synthesis, biological evaluation and molecular modeling study of pyrazole and pyrazoline derivatives as selective COX-2 inhibitors and anti-inflammatory agents Optimization of pyrazole-based compounds with 1,2,4-triazole-3-thiol moiety as selective COX-2 inhibitors cardioprotective drug candidates: design, synthesis, cyclooxygenase inhibition, antiinflammatory, ulcerogenicity, cardiovascular evaluation, and molecular modeling studies 2022) VEGFR2 and hepatocellular carcinoma inhibitory activities of trisubstituted triazole derivatives A new series of triazolothiadiazines as potential anticancer agents for targeted therapy of non-small cell lung and colorectal cancers: design, synthesis, in silico and in vitro studies providing mechanistic insight into their anticancer potencies Prospects of multitarget drug designing strategies by linking molecular docking and molecular dynamics to explore the protein-ligand recognition process Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations On behalf of all authors, the corresponding author states that there is no conflict of interest.