QSAR-Based Hansch Modelling and Molecular Docking Studies of 1,2,4-Triazole Derivatives Against Microbial Targets

Triazole scaffolds represent a versatile class of heterocyclic pharmacophores that have attracted considerable attention in medicinal chemistry due to their broad spectrum of biological activities, including antimicrobial, antifungal, antiviral, anticancer, and anti-inflammatory properties. The unique electronic configuration, aromatic stability, and hydrogen-bonding potential of the 1,2,4-triazole nucleus make it an ideal framework for drug design, particularly in the context of antimicrobial resistance (AMR), which remains a pressing global health challenge. In the present study, twenty novel 1,2,4-triazole derivatives were synthesised and systematically evaluated using 2D Quantitative Structure–Activity Relationship (QSAR) modelling and molecular docking approaches to establish structure–activity relationships and predict antimicrobial potential. QSAR equations were developed against Bacillus subtilis, Pseudomonas aeruginosa, and Escherichia coli, revealing that antimicrobial activity was significantly influenced by thermodynamic descriptors such as molar refractivity and total energy, as well as steric and topological parameters including the Wiener index, Balaban index, and number of rotatable bonds. The statistical robustness of the models was confirmed by high correlation coefficients (r² values ranging from 0.712 to 0.823) and satisfactory predictive validation (q² values between 0.683 and 0.798), underscoring the reliability of the models in forecasting biological activity. Molecular docking studies were performed against microbial protein targets (PDB IDs: 1AJO and 7P2M) to complement QSAR findings. Among the synthesised derivatives, Compound 10 (−2.814 kcal/mol) and Compound 16 (−4.272 kcal/mol) exhibited the most favourable binding affinities, forming stable interactions with active site residues through hydrogen bonding and hydrophobic contacts. Although reference antibiotics such as amoxicillin and ciprofloxacin demonstrated superior docking scores, several triazole derivatives displayed comparable binding interactions, suggesting their potential as lead candidates for further biological evaluation. The integration of QSAR and docking analyses highlights the utility of computational drug design as a cost-effective and time-saving strategy in modern drug discovery. By predicting biological activity prior to synthesis and guiding structural optimisation, this approach accelerates the identification of promising antimicrobial agents. The findings of this study not only reinforce the pharmacological relevance of the triazole scaffold but also provide a rational framework for the design of next-generation antimicrobial drugs capable of addressing the escalating threat of AMR.