A mechanism-driven strategy for in-silico prediction, molecular docking, synthesis, and biological assessment of substituted 1,3,4-oxadiazole derivatives as novel antidiabetic agents

Mohini  Patidar; Raghvendra  Dubey; Sunita Minz; Madhulika  Pradhan; Nitin Deshmukh

doi:10.69857/joapr.v13i2.1031

Authors

Mohini Patidar Department of Pharmaceutical Chemistry, Sage University: Institute of Pharmaceutical Sciences, Indore, 452016, India
Raghvendra Dubey Department of Pharmaceutical Chemistry, Sage University: Institute of Pharmaceutical Sciences, Indore, 452016, India
Sunita Minz Department of Pharmaceutics, Indira Gandhi National Tribal University, Amarkantak, Madhya Pradesh, India
Madhulika Pradhan Gracious College of Pharmacy, Abhanpur, Chhattisgarh, India 493661
Nitin Deshmukh Department of Pharmaceutical Chemistry, Mangaldeep Institute of Pharmacy, Aurangabad, Maharashtra 431001

DOI:

https://doi.org/10.69857/joapr.v13i2.1031

Keywords:

Mannich bases reaction, Anti-diabetic effects, 1,3,4-oxadiazole derivatives

Abstract

Background: Diabetes mellitus is a long-standing and debilitating metabolic condition that imposes a substantial global health burden, leading to severe and widespread complications. Objectives: This study aims to predict physicochemical properties of 1,3,4-oxadiazole derivatives using in-silico methods and molecular docking simulations to explore their potential as α-glucosidase inhibitors for diabetes management. Furthermore, this study aims to experimentally synthesize and characterize these derivatives to validate their inhibitory activity. Methods: In silico drug-likeness, pharmacokinetic, and toxicity profiling of substituted oxadiazole derivatives were performed using the Molinspiration and PreADMET web tools. Molecular docking simulations were conducted with the target protein alpha-glucosidase (PDB ID: 3WY1) to assess its anti-diabetic potential. This study suggests that oxadiazole has the potential to be a novel anti-diabetic agent. Results: Compound 3a1 formed 5 significant hydrogen bonds with Gly228, Thr226, Leu227, Tyr235, Glu271 with docking scores of -156.118 and re-rank scores of -91.600 comparable to the standard drug Miglitol, which formed 6 hydrogen bonds Val380, Asp401, Lys398, Gly399, Glu377, Asp379 but had lower docking and re-rank scores (-69.4415 and -95.887). Based on docking results, five oxadiazole derivatives were synthesized via Mannich base cyclization, yielding 62.2 – 79.9%. They showed moderate to excellent anti-diabetic activity, with compounds 3a1 and 3a3 demonstrating no toxicity or mortality at 40 mg/kg oral dose. Conclusion: Our study highlights that the oxadiazole pharmacophore is a key structural motif for the development of potential anti-diabetic compounds

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