4-Phenylthiazol-1,2,3-triazole derivatives as new potential α-glucosidase and α-amylase inhibitors

Abstract

Type-2 diabetes mellitus (T2DM) can be managed by targeting carbohydrate hydrolases such as α-glucosidase and α-amylase. In this regard, a new 4-phenylthiazol-benzamide-1,2,3-triazole-N-phenylacetamide scaffold was designed via molecular hybridization (MH), and 15 derivatives (9a-o) were synthesized by changing the substituents on the phenyl ring of the N-phenylacetamide moiety. These compounds were evaluated as potent α-glucosidase and α-amylase inhibitors. The in vitro results indicated that the half maximal inhibitory concentration (IC₅₀) of compounds 9a-o ranged from 10.71 to 42.35 nM against α-glucosidase and 49.17–81.94 nM against α-amylase while the IC₅₀ values of the positive control acarbose against α-glucosidase and α-amylase were 62.03 and 105.44 nM, respectively. The most potent compound against both digestive enzymes was compound 9g with two methyl groups on positions 2 and 3 of the phenyl ring of the N-phenylacetamide moiety. Compound 9g was 5.79 and 2.14 times more potent than acarbose against α-glucosidase and α-amylase, respectively. The docking study showed that all the synthesized compounds (9a-o) attached to the active sites of α-glucosidase and α-amylase with lower binding energies in comparison to acarbose. Furthermore, according to the dynamics simulation, compound 9g established a stable complex with the active site of α-glucosidase.