Synthesis, Characterisation and In silico Evaluation of Novel 2-Methyl-Pyridin-3(2H)-one Derivatives

Abstract

A novel series of 2-methyl-pyridin-3(2H)-one derivatives (S₁-S₄) was synthesised and evaluated for their physico-chemical, pharmaco-kinetic and biological potential using combined experimental and in silico approaches. The target compounds were obtained via a two-step synthetic route involving Claisen-Schmidt condensation to form chalcone intermediates, followed by alanine-mediated cyclisation to generate the pyridinone scaffold. The structural confirmation was achieved through elemental analysis, FTIR, ¹H NMR, ¹³C NMR, and mass spectrometry. Computational studies revealed that all compounds possess favourable drug-like characteristics, complying with Lipinski’s criteria and exhibiting suitable lipophilicity, polarity and molecular size. ADMET predictions suggested acceptable absorption, distribution, and excretion profiles, although metabolic studies highlighted cytochrome P450 inhibition, particularly CYP2C19 and CYP2C8, as a potential limitation. Toxicity assessment indicated variable safety profiles, with some compounds showing predicted risks of genotoxicity and hepatotoxicity. Molecular docking studies against microbial targets (1KZN and 6Q9N) demonstrated stable binding interactions, with compound S₂ exhibiting the most favourable interaction pattern and binding affinity. PASS analysis further supported the potential biological activity of the series, particularly for enzyme inhibition.