key: cord-0020890-2fhhbdfa
authors: Nasli Esfahani, Anita; Iraji, Aida; Alamir, Amir; Moradi, Shahram; Asgari, Mohammad Sadegh; Hosseini, Samanesadat; Mojtabavi, Somayeh; Nasli-Esfahani, Ensieh; Faramarzi, Mohammad Ali; Bandarian, Fatemeh; Larijani, Bagher; Hamedifar, Haleh; Hajimiri, Mir Hamed; Mahdavi, Mohammad
title: Design and synthesis of phenoxymethybenzoimidazole incorporating different aryl thiazole-triazole acetamide derivatives as α-glycosidase inhibitors
date: 2021-09-13
journal: Mol Divers
DOI: 10.1007/s11030-021-10310-7
sha: f823e8d132ebf454e3e49a4d1716d4297c97a1be
doc_id: 20890
cord_uid: 2fhhbdfa

A novel series of phenoxymethybenzoimidazole derivatives (9a-n) were rationally designed, synthesized, and evaluated for their α-glycosidase inhibitory activity. All tested compounds displayed promising α-glycosidase inhibitory potential with IC(50) values in the range of 6.31 to 49.89 μM compared to standard drug acarbose (IC(50) = 750.0 ± 10.0 μM). Enzyme kinetic studies on 9c, 9g, and 9m as the most potent compounds revealed that these compounds were uncompetitive inhibitors into α-glycosidase. Docking studies confirmed the important role of benzoimidazole and triazole rings of the synthesized compounds to fit properly into the α-glycosidase active site. This study showed that this scaffold can be considered as a highly potent α-glycosidase inhibitor. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11030-021-10310-7.

Diabetes mellitus (DM) recognizes as one of the most extensive global health emergencies in the twenty-first century affecting more than 400 million people worldwide, and it is estimated that the number will reach around 600 million by 2035 [1].

DM is a chronic metabolic disorder leading to hyperglycemia with the problem in the metabolism of carbohydrates, lipids, and proteins [2] . DM is categorized into two major sub-types type 1 DM and type 2 DM. Type 1 DM is an autoimmune disorder that the immune system mistakenly attacks the β cells of the pancreas which reduces or impairs the production of insulin [3] . Type 2 DM, with more than 90-95% of the cases, characterized by insulin resistance in target tissues, mainly skeletal muscle, adipose tissue, and liver. To fight back against insulin resistance, β-cells overwork to produce more insulin, and gradually the β-cells of the pancreas are destroyed, and insulin secretion is reduced and diminished [4] . DM is associated with a lot of complications including heart disease, stroke, blindness, renal failure, foot amputation, and even death [5] . The main medical approach to control the progress of DM and its complications focuses on the reduction of the postprandial glucose level in blood via regulating and/or inhibiting carbohydrate hydrolytic enzymes [6, 7] . α-Glycosidase (EC.3.2.1. 20) is an important membranebound intestinal hydrolytic enzyme playing a vital role in the digestion of carbohydrates [8] [9] [10] . It hydrolyzes oligosaccharides, trisaccharides, and disaccharides to glucose and other monosaccharides at their non-reducing ends (α-glycosidic bonds) after hydrolysis of polysaccharides to oligosaccharides by α-amylase. As a result, α-glycosidase inhibitors transfer the undigested carbohydrate into the distal part of the small intestine and colon, delay the process of carbohydrate absorption in the gastrointestinal tract, and reduce postprandial hyperglycemia [4, 11, 12] .

Acarbose, miglitol, and voglibose used as α-glycosidase inhibitors, mostly obtained from natural sources due to multiple complicated syntheses steps [13] . Also, administration of these inhibitors can bring undesirable side effects including serious gastrointestinal disorders such as diarrhea and flatulence. For this reason, several research groups have investigated the efficiency of small molecules possessing potent α-glycosidase inhibitory potential including imidazole [14] , pyrazoles [15] , quinazolinone [16] , isatin [17] , pyrimidine [18] , xanthone [19] , azole [20] , and macrocyclic compounds [21, 22] .

Considering the important properties of triazoles such as easy synthetic protocol and promising anti-diabetic properties [23] as well as imidazole and its derivatives as one of the most important nitrogen-containing heterocyclic scaffolds in medicinal chemistry [24, 25] , the current study is conducted to evaluate anti-α-glycosidase properties of newly designed phenoxymethybenzoimidazole coupled different thiazoletriazole acetamide (9a-n) derivatives. Kinetic studies of the most potent compounds were also performed to evaluate their inhibition pattern against α-glycosidase.

Benzimidazole-based compounds possess a wide range of pharmaceutical and biological activities, especially α-glycosidase inhibition [26] . Zawawi et al. screened a novel series of thiourea derivatives bearing benzimidazole with IC 50 values between 35.83 and 297.99 μM which was better than the standard drug acarbose with IC 50 = 774.5 μM. According to molecular docking study of the most potent compound (A, Fig. 1 ), imidazole moiety formed hydrogen bond with Glu 276, and phenyl rings showed arene-arene interaction with residue Phe 157 of the α-glycosidase active site [27] . In 2019, Taha et al. evaluated novel benzimidazole-based oxadiazole derivatives for their in vitro anti-α-glycosidase activity. Among the screened analogs, compound B showed excellent inhibitory potential with an IC 50 value of 2.6 ± 0.1 µM compared with acarbose (IC 50 = 38.45 ± 0.80 µM). According to the structure-activity relationship (SAR), the substitution of methyl and methoxy moiety on phenyl ring recorded hydrophobic interaction and decreased inhibitory potential significantly [28] . In another study, Rahim et al. introduced benzimidazole bearing bis-Schiff bases as α-glycosidase inhibitors. All derivatives displayed moderate to good inhibitory potential with an IC 50 ranging from 2.20 to 88.60 µM compared with standard drug acarbose (IC 50 = 38.45 µM). The great potential of analog C (IC 50 = 2.20 ± 0.1 µM) mainly seems to be due to methoxy and hydroxyl groups presented on two phenyl rings which might be involved in hydrogen bonding with the active site ( Fig. 3 ) [29] .

It was found that the benzimidazole ring as the basic skeleton of compounds was responsible for this promising α-glycosidase inhibition.

Triazole acetamide moiety has been already identified with α-glycosidase inhibitory potential. In this context, Wang et al. reported xanthone-triazole acetamide hybrids D with significant anti-α-glycosidase activities. Analog D showed high activities in promoting glucose uptake and low toxicity to the human normal hepatocyte cell line ( Fig. 1) [30] . Another set of benzimidazole-1,2,3triazole hybrids were screened as α-glycosidase inhibitors. In this respect, compound E depicted an IC 50 value of 25.2 ± 0.9 μM in comparison with standard drug acarbose (IC 50 = 750.0 ± 12.5 μM) [31] . In 2021, another set of indolinone-substituted phenoxy methyltriazole was synthesized and the most potent derivative in this set (Compound F) showed around a 46-fold improvement in the inhibitory activity against α-glycosidase, compared with acarbose [17] .

Another interesting pharmacophore to design potent α-glycosidase inhibitors is aryl thiazole substituent. Compound G (IC 50 = 2.2 μM) with p-methoxy pendant displayed strong α-glycosidase inhibitory activity that fulfilled the conformational requirement to fit well in the active site of the enzyme [32] . A set of arylthiazole-pyridine derivatives were also screened as possible α-glycosidase inhibitors (Compound H). All analogs exhibited potent inhibition in the range of 1.40 to 236.10 μM compared to the standard acarbose (IC 50 = 856.45 ± 5.60 μM) owing to interactions with Pro309, Phe157, and Asn347 residues [33] .

Keeping the above-mentioned importance of benzimidazole, triazole, and aryl thiazole moieties in the design of new α-glycosidase inhibitors, herein, the hybridization strategy of these pharmacophores was applied to deign novel phenoxymethybenzoimidazole bearing different aryl thiazoletriazole acetamide derivatives. Various substituents were performed on benzimidazole, triazole, and aryl thiazole moieties to define beneficial SARs as α-glycosidase inhibitors.

The synthesis of compounds 9a-n is schematically presented in scheme 1. The methyl group of commercially available acetophenone derivatives (1) was reacted with n-bromosuccinimide in the presence of p-toluenesulfonic acid to give α-bromoacetophenone derivatives (2) . Then compound 2 reacted with thiourea in ethanol to give 4-arylthiazol-2-amines (3). The reaction of intermediate 3 with 2-chloroacetyl chloride gave compound 4. On the other hand, different phenylenediamines 6 reacted with 4-(prop-2-ynyloxy)benzaldehyde derivatives 7 in the presence of Na 2 S 2 O 5 in DMF at 100 °C to give the corresponding compound 8. The target compounds 9a-n were synthesized via click reaction of compound 5 and freshly prepared azide derivatives in the presence of the catalytic amount of triethylamine (Et 3 N) in H 2 O and t-BuOH (1:1) at RT [34] [35] [36] .

The fourteen derivatives prepared herein (9a-n) were subjected to in vitro α-glycosidase inhibition. According to the results reported in Table 1 , all compounds showed exceptionally high potency against α-glycosidase with an IC 50 value ranging from 6.31 to 49.89 μM which is significantly lower than that of acarbose as the positive control (IC 50 = 750.0 ± 10.0 μM). Compound 9g (IC 50 = 6.31 µM; 

According to the obtained results, it can be seen that 9a as an unsubstituted compound (R 1 = H, R 2 = H, R 3 = H) demonstrated an IC 50 value of 19.12 µM with around 39 times improvement in potency compared to that of acarbose as a positive control. Substitution of fluorine as a small electron-withdrawing group at R 1 (9b) decreased the inhibitory potency compared to 9a. However, the replacement of fluorine (9b) with bromine (9c) as more lipophile and bulkier halogen group significantly improved the α-glycosidase inhibition with around twofold increase in the inhibitory potency compared to 9a. Considering the substitution of electron-donating moieties, it can be seen that the presence of a moderate electron-donating group at the para position led to the relatively strong inhibitory activity (9d; R 1 = 4CH 3 , R 2 = H, R 3 = H; IC 50 = 9.53 µM). Replacement of the methyl group with a strong electron-donating group (MeO) on the benzoimidazole ring significantly reduced the α-glycosidase inhibition. This trend can be seen in 9e (R 1 = 4OCH 3 , R 2 = H, R 3 = H; IC 50 = 35.11 µM) and 9f (R 1 = 3OCH 3 , R 2 = H, R 3 = H; IC 50 = 15.01 µM).

In cases of 9g-j, it can be seen that the 9g (R 1 = H, R 2 = H, R 3 = OCH 3 ) recorded the best inhibitory activity among all derivatives with an IC 50 value of 6.31 µM. As can be understood in 9h (R 1 = 4Br, R 2 = H and R 3 = OCH 3 ; IC 50 = 26.97 µM), 9i (R 1 = 4CH 3 , R 2 = H and R 3 = OCH 3 ; IC 50 = 49.89 µM), and 9j (R 1 = 4OCH 3 , R 2 = H and R 3 = OCH 3 ; IC 50 = 11.25 µM), any substitution in this set dramatically reduced the α-glycosidase inhibitory activity. The least potent derivatives in this set were 9i possessing para-CH 3 

In this set of compounds (9k-n), the most active compound was 9m (R 1 = 4CH 3 , R 2 = CH 3 and R 3 = H) with an IC 50 value of 8.30 µM. Disappointingly replacement of 4CH 3 in 9m with 4OCH 3 (9n) moiety significantly lessened the inhibitory activity. Although the substitution of para-bromine as an electron-withdrawing group (9l, IC 50 = 14.2 ± 0.21 μM) led to around twofold improvement of α-glycosidase inhibitory activity compared with 9n, the inhibitory potency did not improve compared with 4CH 3 (9m) counterpart.

Evaluating the inhibitory effect on phenoxymethybenzoimidazole while R 1 = 4CH 3 moiety.

On the other hand, the potency of 9d, 9i, 9m bearing methyl group at R 1 indicated the following order of potency so that 9m (IC 50 = 8.30 µM, R 1 = 4CH 3 , R 2 = CH 3 , R 3 = H) > 9d (IC 50 = 9.53 µM, R 1 = 4CH 3 , R 2 = H, R 3 = H) > > 9i (IC 50 = 49.89 ± 0.09 µM, R 1 = 4CH 3 , R 2 = H, R 3 = 2OCH 3 ). It seems that substitution of OCH 3 at R 3 position in compounds bearing 4CH 3 at R 1 deteriorated the inhibitory potency.

Comparison of the bromine derivatives at R 1 (9c, 9h, 9l) highlighted this trend that the presence of OCH 3 pendant with strick hindrance at R 3 had a negative effect on α-glycosidase inhibition compared to the unsubstituted one. Overall, it can be understood that phenoxymethybenzoimidazole bearing thiazole-triazole acetamide as the basic skeleton was responsible for this outstanding α-glycosidase inhibition. 

According to Figs. 2, 3, and S1, the Lineweaver-Burk plot showed that the K m gradually increased and V max remained unchanged with increasing inhibitor concentration indicating an uncompetitive inhibition. The results showed 9c, 9 g, and 9 m bind to ES and had no binding with the free active site. Furthermore, the plots of the 1/V´m ax versus different concentrations of 9c, 9g, and 9m gave an estimate of the inhibition constant, K i of 8.5, 6.3, and 8.3 µM, respectively (Figs. 2b, 3b, and Fig. S1b ).

Docking studies were carried out to understand the interaction modes of the most potent derivatives (9c, 9g, and 9m) in the α-glycosidase active site. First, the validation process was performed and resulted in an RMSD value of 3.41 Å. The top-scoring pose of acarbose as a crystallographic ligand (PDB ID: 5NN8) is shown in Fig. 4 . Acarbose demonstrated seven H-bound interactions with Asp282, Arg600, Asp616, and His674, two Van der Waals with Trp376 and Asp404 plus one pi-alkyl interaction with Trp376.

The gold score value of 9c, 9g, 9m plus their interactions with amino acid residues in the α-glycosidase active site is shown in Table 2 . As can be seen, the order of in vitro inhibitory potency recorded well correlation with gold score values. This trend can easily be seen in 9g as the most potent compound with an IC 50 value of 6.31 µM, generated the highest gold score value (70.16).

3D interaction patterns of compounds 9c, 9g, 9m as the best α-glycosidase inhibitors are shown in Figs. 5, 6, 7.

Overall it can be seen that benzimidazole and triazole rings can be considered as critical moieties to develop anti-α-glycosidase agents. Meanwhile, phenoxymethyl and thiazoleacetamide linkers can provide optimum length and bulkiness to properly occupy the α-glycosidase active site.

To get better inside into the conformation and orientation of each derivative into the active site compared with acarbose, the superimposed structures of all compounds are shown in Fig. 8 . Assessment on superimposed structures exhibited that phenoxymethybenzoimidazole moiety of 9c and 9g had similar orientation in the active site and the difference in their pose came back to the substituted group at R 1 . However, 9m showed different conformation in the active site compared to 9c and 9g which may be due to the presence of the para-methyl group as well as methyl at R 1 and R 2 , respectively.

Interestingly, amino-4-(hydroxymethyl)cyclohexene-triol group of acarbose was well aligned on the benzimidazole moiety of 9c and 9g, while methylphenyl group (R 1 ) of 9m was aligned on glucopyranose of acarbose. According to docking studies, it was clear that substituted moiety at R 1 and R 2 effectively determined the conformation and pose of each ligand in the binding site as well as provided additional interactions with the active site. Although these compounds were unable to exhibit the same binding pose, they were properly fitted into the binding site and demonstrated interactions with the critical resides of the α-glycosidase active site.

A novel series of phenoxymethybenzoimidazole incorporating different aryl thiazole-triazole acetamide derivatives (9a-n) were rationally designed, synthesized, and evaluated for their α-glycosidase inhibitory activity. All tested derivatives demonstrated better α-glucosidase inhibitory potential with an IC 50 value ranging from 6.31 to 49.89 μM compared to standard drug acarbose (IC 50 = 750.0 ± 10.0 μM). Among the series, compound 9g (IC 50 = 6.31 µM; R 1 = H, R 2 = H, R 3 = OCH 3 ), 9m (IC 50 = 8.30 µM; R 1 = 4CH 3 , R 2 = CH 3 , R 3 = H), and 9c (IC 50 = 8.88 µM; R 1 = 4Br, R 2 = H, R 3 = H) were found to be the most potent α-glycosidase inhibitors. According to SAR analysis, it was found that the phenoxymethybenzoimidazole bearing thiazole-triazole acetamide as the basic skeleton of compounds was responsible for this promising α-glycosidase inhibition. The obtained SAR profile found that in the case of benzoimidazole core (9a-j), 2OCH 3 -substituted on phenoxy (R 3 ), while R 1 = H contributed to the improved inhibitory activity. Additionally, in the other set bearing methyl-benzoimidazole (9k-n) small and moderate electron-donating group at R 1 is more favorable. Alkyl-Alkyl Methyl Benzimidazole Ala554

Pi-Alkyl Benzimidazole Ala554

Pi-Alkyl Benzimidazole Arg527

Pi-Alkyl Benzimidazole Ala555

Pi-Sigma Benzimidazole Ala555

Pi-Alkyl Phenoxymethyl Ala555

Hydrogen Bond Triazole Arg600

Pi-Alkyl Triazole Met519

Sulfur -Alkyl Triazole Met519

Sulfur -Alkyl Triazole Met519

Pi-Pi T-shaped Triazole Trp481

Pi-Anion Triazole Asp616

Pi-Anion Thiazole Phe649

Pi-Sigma Methylphenyl Leu650

Pi-Alkyl Methylphenyl Tro618

Pi-Alkyl Methylphenyl Leu678 The in vitro kinetic assay of 9g, 9m, and 9c presented the uncompetitive type of inhibition against α-glycosidase. Docking studies showed the critical role of benzoimidazole and triazole moieties of the synthesized compounds to fit properly into the active site and occupy the binding site of α-glycosidase. Even though the inhibitory activities of compounds 9g, 9m, and 9c were considered quite good, due to the presence of benzoimidazole and phenoxymethyltriazole moieties which effectively participated in interactions with the critical residues of the α-glycosidase active site, the important role of aryl-substituted at R 1 should not be neglected. The substituted groups at R 1 rather than providing additional hydrophobic interactions, played the dominant role in the conformation of these derivatives in the α-glycosidase active site.

All reagents of this protocol were purchased from chemical suppliers and used without further purification. The purity of synthesized analogs was checked through TLC (aluminum plates precoated with silica gel, Kieselgel 60, 254, E. Merck, Germany). The melting points of 9a-n were determined on a Kofler hot stage apparatus. Nicolet Magna FTIR 550 spectrophotometer was used to record IR spectra of the synthesized compounds by using KBr disks. 1 H-NMR and 13 C-NMR were carried out on Avance Bruker 500 MHz. 

In a round-bottom flask, 10 mmol benzene-1,2-diamine (6a) and 10 mmol 4-(prop-2-yn-1-yloxy)benzaldehyde (7a) were dissolved in DMF in the presence of Na 2 S 2 O 5 . The reaction mixture was then stirred at 100 °C for 4 h and then the crude product was extracted and recrystallized in EtOH. 1 13 1,2,3-triazol-1-yl}-N-[2-(4-fluorophenyl)-1,3- 2-{4-[4-(1H-1,3-benzodiazol-2-yl)phenoxymethyl]-1H-1,2,3-triazol-1-yl}-N-[2-(4-bromophenyl)-1,3- 1,2,3-triazol-1-yl}-N-[2-(4-methoxyphenyl)-1,3- Fig. 8 Representation of the docking poses of compounds over the active site. Acarbose was presented in yellow in stick mode, while 9c, 9g, and 9m were shown in purple, cyan, and red color in line mode

The mode of inhibition of the most active compound (9c, 9g, and 9m), identified with the lowest IC 50 , was investigated against an α-glycosidase activity with different concentrations of p-nitrophenyl α-D-glucopyranoside (2-10 mM) as substrate in the absence and presence of sample (9c, 9g, and 9m) at different concentrations (0, 1.25, 2.5, 5, and 10 µM). A Lineweaver-Burk plot was generated to identify the type of inhibition, and the Michaelis-Menten constant (1/V´m ax ) value was determined from the plot between reciprocal of the substrate concentration (1/[S]) and reciprocal of enzyme rate (1/V) over various inhibitor concentrations. The experimental inhibitor constant (K i ) value was constructed by secondary plots of the inhibitor concentration [I] versus 1/Viʹ max [15, 42, 43] .

The 3D structure of α-glycosidase (PDB entry code: 5NN8) in complex with acarbose was obtained from the protein data bank. After editing the crystallographic structure which contains removing ligand and water molecules and adding hydrogen atoms, the prepared ligands (the ligands were sketched in HyperChem software and energy minimized by the MM1 force field) were docked into the active site of the enzyme. The binding site of the enzyme for the docking was defined automatically using the coordinates of the native ligand acarbose in such a way that 10 Å around the ligand was defined as the binding site. Gold docking program with ChemScore function was used for docking analyses and redock acarbose inside the 5NN8. The top-score binding poses were used for further analysis. Protein-ligand interactions were analyzed with Discovery Studio Visualizer [17] .

White solid; isolated yield: 95%; mp 182-184 °C; IR (KBr, υ): 3357, 2924, 1670 cm −1 ; 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.03-12.70 (m, 2H, 2 × NH), 8.41 (s, 1H), 8.20 (d

thiazol-5-yl)acetamide (9g) White solid; isolated yield: 91%; mp 238-240 °C; IR (KBr, υ): 3357, 2926, 1683 cm −1 ; 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.31-12.51 (m, 2H, 2 × NH), 8.39 (s, 1H)

White solid; isolated yield: 84%; mp 200-202 °C; IR (KBr, υ): 3359, 2926, 1675 cm −1 ; 1 H NMR (400 MHz, DMSO-d 6 ) δ 13

3-triazol-1-yl}-N-[2-(4-methylphenyl)-1,3-thiazol-5-yl]acetamide (9i) White solid; isolated yield: 94%; mp 227-229 °C; IR (KBr, υ): 3355, 2930, 1691 cm −1 ; 1 H NMR (400 MHz, DMSO-d 6 ) δ 13

White solid; isolated yield: 95%; mp 196-198 °C; IR (KBr, υ): 3352, 2926, 1673 cm −1 ; 1 H NMR (400 MHz, DMSO-d 6 ) δ 12

3-triazol-1-yl}-N-(2-phenyl-1,3-thiazol-5-yl)acetamide (9k) White solid; isolated yield: 87%; mp 172-174 °C; IR (KBr, υ): 3355, 2928, 1695 cm −1 ; 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.93 (s, 1H, NH)

H -1 , 3 -b e n z o d i a z o l -2 -y l ) phenoxymethyl]-1H-1,2,3-triazol-1-yl}acetamide (9l) White solid; isolated yield: 89%; mp 194-196 °C; IR (KBr, υ): 3351, 2917, 1688 cm −1 ; 1 H NMR (400 MHz, DMSO-d 6 ) δ 13

3-triazol-1-yl}-N-[2-(4-methylphenyl)-1,3-thiazol-5-yl]acetamide (9m) White solid; isolated yield: 90%; mp 208-210 °C; IR (KBr, υ): 3351, 2924, 1693 cm −1 ; 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.87 (s, 1H, NH), 12.68 (s, 1H), 8.40 (s, 1H), 8.16 (d, J = 8.5 Hz, 3H), 7.89 (d, J = 8

3-triazol-1-yl}acetamide (9n) White solid; isolated yield: 87%; mp 197-199 °C; IR (KBr, υ): 3352, 2928, 1683 cm −1 ; 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.87 (s, 1H, NH)

Glycosidase inhibition assay The anti-α-glycosidase effects of synthesized compound 9a-n were screened according to the previously reported method. Briefly, 135 µL of potassium phosphate buffer, 20 µL of target compounds 9a-n with various concentrations, and 20 µL of α-glycosidase solution were added to each well in the 96-well plate and incubated for 10 min at 37 °C. Then, p-nitrophenyl glucopyranoside as substrate (25 µL, 4 mM) was added and incubation was continued at 37 °C for 20 min. Finally

Potential effect of hydroxychloroquine in diabetes mellitus: a systematic review on preclinical and clinical trial studies

Treatments for diabetes mellitus type II: new perspectives regarding the possible role of calcium and cAMP interaction

Type 1 diabetes mellitus

Treatment strategies against diabetes: Success so far and challenges ahead

Health promotion and health education about diabetes mellitus

Stabilization of postprandial blood glucose fluctuations by addition of glucagon like polypeptide-analog administration to intensive insulin therapy

Dietary polyphenols and type 2 diabetes: current insights and future perspectives

Natural products as α-amylase and α-glucosidase inhibitors and their hypoglycaemic potential in the treatment of diabetes: an update

Design, synthesis, characterization, enzymatic inhibition evaluations, and docking study of novel quinazolinone derivatives

Antidiabetic and antiparasitic potentials: inhibition effects of some natural antioxidant compounds on α-glycosidase, α-amylase and human glutathione S-transferase enzymes

Design and screening strategies for α-glucosidase inhibitors based on enzymological information

Synthesis and kinetics studies of N′-(2-(3,5-disubstituted-4H-1,2,4-triazol-4-yl) acetyl)-6/7/8-substituted-2-oxo-2H-chromen-3-carbohydrazide derivatives as potent antidiabetic agents

) α-Glucosidase inhibitors isolated from medicinal plants

Synthesis of imidazole-pyrazole conjugates bearing aryl spacer and exploring their enzyme inhibition potentials

Design and synthesis of novel pyrazole-phenyl semicarbazone derivatives as potential α-glucosidase inhibitor: kinetics and molecular dynamics simulation study

Hamed Hajimiri M (2021) Quinazolinonedihydropyrano[3,2-b]pyran hybrids as new α-glucosidase inhibitors: design, synthesis, enzymatic inhibition, docking study and prediction of pharmacokinetic

Synthesis, in vitro evaluation, and molecular docking studies of novel hydrazineylideneindolinone linked to phenoxymethyl-1,2,3-triazole derivatives as potential α-glucosidase inhibitors

Synthesis and biological activity of pyrimidines-containing hybrids: focusing on pharmacological application

A comprehensive review on xanthone derivatives as α-glucosidase inhibitors

Discovery of potent α-glucosidase inhibitors through structure-based virtual screening of an in-house azole collection

Pharmacology of α-glucosidase inhibition

Recent accomplishments on the synthetic/biological facets of pharmacologically active 1H-1,2,3-triazoles

Imidazole and its biological activities: a review

Insights into the current status of privileged N-heterocycles as antileishmanial agents

Synthesis and antidiabetic evaluation of benzimidazole-tethered 1,2,3-triazoles

Synthesis, molecular docking studies of hybrid benzimidazole as α-glucosidase inhibitor

Synthesis, α-glycosidase inhibitory potential and molecular docking study of benzimidazole derivatives

Synthesis, in vitro alpha-glucosidase inhibitory potential of benzimidazole bearing bis-Schiff bases and their molecular docking study

Design and synthesis of novel xanthonetriazole derivatives as potential antidiabetic agents: α-Glucosidase inhibition and glucose uptake promotion

Synthesis and biological evaluation of new benzimidazole-1,2,3-triazole hybrids as potential α-glucosidase inhibitors

Synthesis, in vitro $$lpha $$-glucosidase inhibitory activity, and in silico study of (E)-thiosemicarbazones and (E)-2-(2-(arylmethylene) hydrazinyl)-4-arylthiazole derivatives

Hydrazinyl arylthiazole based pyridine scaffolds: synthesis, structural characterization, in vitro α-glucosidase inhibitory activity, and in silico studies

Design and synthesis of benzodiazepine-1, 2, 3-triazole hybrid derivatives as selective butyrylcholinesterase inhibitors

Unravelling the anticancer potency of 1,2,4-triazole-Narylamide hybrids through inhibition of STAT3: synthesis and in silico mechanistic studies

2020) 5, 6-Diphenyl triazine-thio methyl triazole hybrid as a new Alzheimer's disease modifying agents

Design and synthesis of 4,5-diphenyl-imidazol-1,2,3-triazole hybrids as new anti-diabetic agents: in vitro α-glucosidase inhibition, kinetic and docking studies

A new series of Schiff base derivatives bearing 1,2,3-triazole: design, synthesis, molecular docking, and α-glucosidase inhibition

Cholinesterases, α-glycosidase, and carbonic anhydrase inhibition properties of 1H-pyrazolo [1, 2-b] phthalazine-5, 10-dione derivatives: Synthetic analogues for the treatment of Alzheimer's disease and diabetes mellitus

Synthesis, characterization, inhibition effects, and molecular docking studies as acetylcholinesterase, α-glycosidase, and carbonic anhydrase inhibitors of novel benzenesulfonamides incorporating 1, 3, 5-triazine structural motifs

Probing 4-(diethylamino)-salicylaldehyde-based thiosemicarbazones as multi-target directed ligands against cholinesterases, carbonic anhydrases and α-glycosidase enzymes

Design, synthesis and biological evaluation of novel phthalimide-Schiff basecoumarin hybrids as potent α-glucosidase inhibitors

A novel fivestep synthetic route to 1,3,4-oxadiazole derivatives with potent α-glucosidase inhibitory potential and their in silico studies

Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations