Synthesis, Characterization, Density Functional Theory Calculation, <i>In Silico</i> and <i>In Vitro</i> Antimicrobial Evaluation of New 1,2,4‐Triazole‐Amide Conjugates

Abstract

ABSTRACT The present work describes the synthesis of new 1,2,4‐triazole derivatives incorporating an amide moiety, obtained through a reaction sequence involving amidation, cyclization, and alkylation steps. Structural characterization of the synthesized 1,2,4‐triazole–amide conjugates was confirmed by nuclear magnetic resonance ( 1 H, 1 3 C) and high‐resolution mass spectrometry analyses. The antimicrobial evaluation revealed significant activity, particularly against fungal strains such as Candida albicans, Aspergillus flavus, and Fusarium oxysporum, with minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) values ranging from 5 to 20 µg/mL, and the most active compounds, 3d and 3c, showed MIC = 5 µg/mL and MFC = 10 µg/mL. Docking analysis further demonstrated favorable interactions of all derivatives with lanosterol 14‐α‐demethylase (CYP51), with compound 3d exhibiting the highest binding affinity (−9.6 kcal/mol). Molecular dynamics simulations confirmed the stability of the 3d ‐CYP51 complex (root mean square deviation &lt; 2.5 Å over 100 ns). Absorption, Distribution, Metabolism, Excretion, and Toxicity predictions and drug‐likeness assessments additionally indicated that the synthesized molecules possess acceptable pharmacokinetic properties, supporting their potential as antimicrobial agents.