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

•Benzo[b]thiophene based small molecule α-amylase inhibitors.•Significant antidiabetic activity with IC50 ranging from 5.37 to 29.89 μM.•Compound 3b more potent than acarbose with IC50 of 5.37 μM.•Competitive inhibitor of α-amylase having Ki of 1.76 µM.•Safer antidiabetic agent endowed with drug-likeness properties. Benzo[b]thiophene has been implicated as molecular framework in the drug discovery against broad spectrum of biological targets. In the antidiabetic drug regime, benzo[b]thiophene based SGLT2 and ALR2 inhibitors have been recently developed but their potential towards α-amylase inhibition remained 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 antidiabetic activity as α-amylase inhibitors. We found that, all benzo[b]thiophene derivatives exhibited significant α-amylase inhibition with IC50 value ranging from 5.37 ± 0.25 μM to 29.89 ± 0.68 μM. The SAR studies showed benzo[b]thiophene carboxylate bearing bis(2-hydroxyethyl)amino group (3b) was most potent with IC50 of 5.37 ± 0.25 μM compared to standard drug Acarbose (IC50 = 6.40 ± 0.14 μM). 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 estimate binding properties, drug likeness and predict toxicity profile of these agents. It was demonstrated that 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 and toxicity 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 and opened a template for further lead optimization and development. [Display omitted]