Synthesis and molecular docking studies of 5-acetyl-2-(arylidenehydrazin-1-yl)-4-methyl-1,3-thiazoles as α-amylase inhibitors

Abstract

Alpha (α)amylase inhibition is an important strategy for controlling blood glucose level. Presently more potent and easily accessible inhibitors are required for managing diabetes. A series of 5-acetyl-2-(arylidenehydrazin-1-yl)-4-methyl-1,3-thiazoles (2a-n) were designed and synthesised in two steps from thiosemicarbazide via thiosemicarbazones. The structures of the compounds were confirmed spectroscopically (UV, FT-IR, 1H-, 13C-NMR and HRMS). Molecular docking studies of the enzyme-inhibitor complex revealed that the most active compounds have better binding with the α-amylase active site as compared to standard acarbose. Compounds 2c and 2e exhibited excellent α-amylase inhibition with IC50 values 4.80 ± 0.07 and 4.79 ± 0.08 µM, respectively, far better than standard acarbose (IC50 = 5.62 ± 0.04 µM). Compounds 2c and 2e have strong calculated binding affinity (-8.1 and -7.9 kcal/mol, respectively) to the enzyme active site endorsing the experimentally observed inhibition. All other compounds also exhibited excellent α-amylase inhibition and in good agreement with the docking results. Importantly, most of the compounds screened by us did not exhibit any haemolysis up to their active concentrations. All compounds were also evaluated for their anti-glycation and anti-oxidant activities. Their results revealed that besides being α-amylase inhibitors the compounds can be used to reduce diabetic complications, as is evident from anti-glycation results.