Synthesis, antidiabetic activity and in silico studies of benzo[b]thiophene based small molecule α-amylase inhibitors

Abstract

Benzo[ b ]thiophene has been implicated as molecular framework in the drug discovery against broadspectrum of biological targets. In the antidiabetic drug regime, benzo[ b ]thiophene based SGLT2 andALR2 inhibitors have been recently developed but their potential towards α-amylase inhibitionremained unexplored to date. In this context, a series of novel small molecule benzo[ b ]thiophene-2- carboxylic acid derivatives (3a-p) was synthesized, characterized, and evaluated for antidiabeticactivity as α-amylase inhibitors. We found that, all benzo[ b ]thiophene derivatives exhibitedsignificant α-amylase inhibition with IC value ranging from 5.37 ± 0.25 μM to 29.89 ± 0.68 μM. TheSAR studies showed benzo[ b ]thiophene carboxylate bearing bis(2-hydroxyethyl)amino group ( 3b )was most potent with IC of 5.37 ± 0.25 μM compared to standard drug Acarbose (IC = 6.40 ± 0.14μM). Further, the enzyme inhibition mechanism study regarded 3b as competitive inhibitor of α-amylase with Ki value of 1.76 μM. A detailed in silico study was also performed in order to estimatebinding properties, drug likeness and predict toxicity profile of these agents. It was demonstratedthat novel small molecule benzo[ b ]thiophene derivative ( 3b ) can effectively bind through H-bonding,hydrophobic and π-stacking interactions within α-amylase active site. Moreover, drug likeness andtoxicity prediction studies suggested compound 3b as potential & safter α-amylase inhibitor. Overall,our present study disclosed a novel class of benzo[ b ]thiophene based α-amylase inhibitors andopened a template for further lead optimization and development.