New cycloalkyl[b]thiophenylnicotinamide-based -glucosidase inhibitors as promising anti-diabetic agents: Synthesis, in silico study, in vitro and in vivo evaluations

In the present study, a series of cycloalkyl[b]thiophenylnicotinamide derivatives against alpha-glucosidase were synthesized, and evaluated for their in vitro and in vivo anti-diabetic potential. Most of the synthetic analogues exhibited superior alpha-glucosidase inhibitory effects than the standard drug acarbose (IC50 = 258.5 mu M), in which compound 11b with cyclohexyl[b]thiophene core demonstrated the highest activity with an IC50 value of 9.9 mu M and showed higher selectivity towards alpha-glucosidase over alpha-amylase by 7.4-fold. Fluorescence quenching experiment confirmed the direct binding of 11b with alpha-glucosidase, kinetics study revealed that 11b was a mixed-type inhibitor, and its binding mode was analyzed using molecular docking. Moreover, analogs com-pounds 6a-9b, 11b, 12b did not show in vitro cytotoxicity against LO2 and HepG2 cells. Finally, compound 11b exhibited in vivo hypoglycemic activity by reducing the blood glucose levels in sucrose-loaded rats.