Pyridine-linked 1,3,4-oxadiazoles decorated with secondary amines as α-amylase inhibitors: Synthesis, crystal structure, enzyme kinetics and computational studies

Chandan, M. and Udaya Kumar, A. H. and Karthik Kumara and Rekha, N. D. and Dinesh Kumar, G. and Lokanath, N. R. and Ajay Kumar, K. (2026) Pyridine-linked 1,3,4-oxadiazoles decorated with secondary amines as α-amylase inhibitors: Synthesis, crystal structure, enzyme kinetics and computational studies. Journal of Molecular Structure, 1353. p. 144655. ISSN 1872-8014

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Abstract

A new series of pyridine-linked 1,3,4-oxadiazole derivatives (5a–5j) incorporating different secondary amines were synthesized in good yields (80–92 ) and their structures confirmed by 1H and 13C NMR spectroscopy and mass spectrometry. Biological screening revealed that compound 5c displayed the strongest α-amylase inhibition with an IC₅₀ of 106.1 ± 1.21 µM, compared with the standard drug acarbose (35.8 ± 1.25 µM). Enzyme kinetic studies (Lineweaver-Burk analysis) demonstrated that 5c acts through a non-competitive inhibition mechanism, increasing Km from 27.36 µM (control) to 135.77 µM, while reducing Vmax from 1.55 µM min−1 to 0.135 µM min−1. The structure of 5c was further validated by single-crystal X-ray diffraction, and Hirshfeld surface analysis highlighted key intermolecular interactions, predominantly H···H (45.1 ), H···N (18.4 ), and H···C (12.6 ). Density Functional Theory calculations at the B3LYP/6–311+G(d,p) level reproduced the crystal geometry and indicated a HOMO-LUMO gap of 3.898 eV, consistent with moderate electronic reactivity. Molecular docking revealed that Compound 5c showed strong α-amylase binding with docking energies of -7.7 to -8.0 kcal mol−1 outperforming reference inhibitor acarbose and indicating superior inhibitory efficacy. ADME profiling supported the drug-like nature of 5c (MW = 323.35 g·mol−1, logP = 0.42, TPSA = 84.07 Ų, zero Lipinski violations), suggesting good oral bioavailability. Collectively, these experimental and computational findings identify 5c as a promising lead scaffold for the design of new antidiabetic agents.

Item Type:	Article
Uncontrolled Keywords:	Pyridine-linked 1,3,4-oxadiazole, Secondary amine decoration, α-Amylase inhibition, Enzyme kinetics, X-ray diffraction, DFT calculations
Subjects:	C Chemical Science > Chemistry
Divisions:	Yuvaraj college > Chemistry
Depositing User:	C Swapna Library Assistant
Date Deposited:	17 Dec 2025 05:16
Last Modified:	17 Dec 2025 05:16
URI:	http://eprints.uni-mysore.ac.in/id/eprint/18214

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