2D/3D-QSAR-guided design of novel 1,2,4-triazole derivatives with predicted enhanced antimicrobial activity.
- 1Department of Organic Chemistry, Educational and Research Institute of Chemistry and Ecology, Uzhhorod National University Fedyntsa st. 53/1 Uzhhorod 88000 Ukraine [email protected].
- 2Division of Mathematics, Department of Physics, Mathematics and Technologies, Faculty of Humanities and Natural Sciences, University of Presov 17. Novembra st. 1 080 01 Presov Slovakia.
- 3Department of Pharmaceutical Disciplines, Uzhhorod National University Narodna sq. 3 Uzhhorod 88000 Ukraine.
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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BibTeX
@article{korol20262d3dqsarguided,
title = {{2D/3D-QSAR-guided design of novel 1,2,4-triazole derivatives with predicted enhanced antimicrobial activity.}},
author = {Nataliya Korol and Oksana Mulesa and Olesia Symkanych and Mykhailo Slyvka},
journal = {RSC advances},
year = {2026},
month = nov,
doi = {10.1039/d6ra03272a},
url = {https://europepmc.org/article/MED/42997545},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - 2D/3D-QSAR-guided design of novel 1,2,4-triazole derivatives with predicted enhanced antimicrobial activity.
AU - Nataliya Korol
AU - Oksana Mulesa
AU - Olesia Symkanych
AU - Mykhailo Slyvka
PY - 2026
DA - 2026/11/06
JO - RSC advances
DO - 10.1039/d6ra03272a
UR - https://europepmc.org/article/MED/42997545
AB - 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.
SN - 2046-2069
ER -