2D/3D-QSAR-guided design of novel 1,2,4-triazole derivatives with predicted enhanced antimicrobial activity.

Abstract

The present study demonstrates that the integration of structural descriptors, quantum-chemical parameters, regression modelling, and 3D contour map analysis within a hybrid QSAR framework represents an effective strategy for the rational design of bioactive 1,2,4-triazole derivatives with improved predicted antimicrobial properties. The work may also be regarded as a practical roadmap for further research on 1,2,4-triazole-3-thiols. Our dataset comprised previously synthesised 1,2,4-triazoles that had already shown broad-spectrum antimicrobial activity, thereby ensuring a consistent structural core and reliable biological annotations. Structural, quantum-chemical, hybrid, and 3D-QSAR models were developed using structural and DFT-derived descriptors and were assessed by cross-validation, external validation, Y-randomization, and applicability-domain analysis. The best-performing model (hybrid QSAR; n = 28) achieved R2 = 0.731, adjusted R2 = 0.669, Q2 = 0.621 (internal, PRESS-based), and mean Qext2 = 0.43 (100-repeat random-subsampling external validation). Despite its compact size and structural homogeneity, the dataset enabled transparent mechanistic interpretation and identified the difluoromethyl substituent at the C-5 position of the triazole ring, together with avoidance of naphthalimide-type fragments, as the statistically robust structural determinants of activity (p = 0.001 and p = 0.022 respectively). A library of 20 CHF2-bearing candidates (D1-D20) was designed on this basis; fine-grained ranking among them is presented as an exploratory tiebreaker only, since it rests on electronic descriptors that were not statistically significant. These predictions remain to be validated experimentally and are intended to guide future synthesis and biological testing.

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