Therapeutic Potential of Disubstituted [{[5-(2-Chloro phenyl)-1,3,4-thiadiazole-2-yl]imino}-methyl]phenyl Derivatives as α-Amylase Antagonists: Synthesis, In silico and In vitro Screening

Abstract

During the last few decades medicinal chemist focus turns to the novel heterocyclic moiety thiadiazole having similar stereotype with thiazole ring with hypoglycemic activity. Henceforth, this study aims to synthesise the designed novel 2,5-diarylsubstituted 1,3,4 thiadiazole derivatives (TDZ) by two step process using microwave irradiation method. The title compounds with electron withdrawing groups (nitro), electron donating groups (hydroxy, dimethyl amine) were synthesized from condensation of thiosemicarbazide with o-chlorobenzoic acid in presence of acidic catalyst followed by the condensation of the intermediate with substituted benzaldehydes under microwave irradiation. Molecular docking studies against α-amylase using Autodock and Schrödinger, molecular dynamic simulation studies using Growmacs and in vitro antidiabetic activity by α-amylase inhibition assay was performed to all the 2,5-diarylsubstituted 1,3,4-thiadiazole derivatives. There is a correlation of in silico and in vitro results, derivatives TDZ7 and TDZ2 (61% and 59%) showed significant α-amylase inhibition than the miglitol (81%) at 1000 µg/mL concentration. Molecular modelling studies demonstrates that derivatives TDZ2 and TDZ7 against 7taa (-8.67 and -7.82 kcal/mol), 1b2y (-4.8 and -4.5 kcal/mol), respectively, possess least binding energies than that of the standard drugs miglitol (-5.05 kcal/mol) and metformin (-8.19 kcal/mol) against 7taa with enzyme inhibition constant 442.33 nM, 1.85, 197.74 µM and 998 nM, respectively. All the ligands and standard drugs showed hydrophilic interactions with active site amino acids, with varying distances. Further research is needed to get the active derivatives with hypoglycemic potential.