Design, synthesis and biological evaluation of theophylline containing variant acetylene derivatives as α-amylase inhibitors

Abstract A novel pharmacophore with theophylline and acetylene moieties was constructed by using a fragment-based drug design and a series of twenty theophylline containing acetylene conjugates were designed and synthesized, and all the compounds were evaluated by enzyme-based in vitro α-amylase inhibition activity. The in vitro evaluation revealed that most of the compounds displayed good inhibitory activities, and among them nine analogs 13–15 , 20 , 21 and 24–27 were exhibited more or nearly as equipotent inhibitory activity with IC 50 values 1.11±0.07, 1.14±0.17, 1.07±0.01 and 1.21±0.03, 1.33±0.09, 1.17±0.01, 1.05±0.02, 1.61±0.04, 1.02±0.03 μM respectively, as compared with standard, acarbose 1.37±0.26 μM. Further, molecular docking simulation studies were done to identify the interactions and binding mode of synthesized analogs at binding site of α-amylase enzyme (PBD ID: 4GQR). Among the synthesized analogs, two compounds 25 and 27 were selected on the basis of α-amylase inhibition activity and evaluated for in vivo anti-diabetic activity by High Fat Diet-Streptozotocin (HFD-STZ) model in normal rats. At the dose of 10 mg/kg, bw, po these compounds have significantly reduced Plasma Glucose level in rats as compared to pioglitazone. The anti-diabetic activity results showed that the animal treated with the compounds 25 and 27 could better reverse and control the progression of the disease compared to the standard.