Design, Synthesis and Evaluation of 1, 3, 4-Oxadiazole Derivatives for Antidiabetic Activity

Abstract

Introduction: Diabetes mellitus is a chronic metabolic disorder that leads to severe complications worldwide. 1,3,4-oxadiazole is one of the potent bioactive heterocyclic agent.

Objectives: The objective of the study is the in-silico prediction of physicochemical properties, molecular docking studies and synthesis of 1, 3, 4, oxadiazole derivatives as α-glucosidase enzyme inhibition for diabetes mellitus.

Methods: In- silico design of proposed derivatives were conducted by Molegro Virtual Docker software. The docking interaction of derivatives A4, A11, A12, and A15 has four hydrogen bonds with Arg 315, Thr310, Ser 241, Lys 156 amino acids, hydrophobic interaction with ASP242, hydrophobic interaction with Pro 312, Glu411 His280, and pi-pi stacking with Tyr 158 amino acids of receptor 3A4A. Compound A12 had the highest affinity for protein 3A4A and the highest binding energy, measuring -12.8327 kcal/mol with the highest affinity among the entire compound compared with the standard Metformin of -9.01594 kcal/mol.

Results: The synthesis of target compounds was performed by cyclization reaction using aromatic amines and carbon disulphide to get mannich bases. Yield of all compounds was in the range of 62.2-79.9 %. The anti-diabetic effects of all compounds were moderate to excellent. The acute toxicity study indicates that A12 and A15 when administered orally at the dose of 4000 mg/kg did not produce any sign of toxicity or death in treated animals. Our study reveals that oxadiazole pharmacophore are one of the important pharmacophores to develop antidiabetic potential compounds.