Rational design, synthesis, and antimicrobial evaluation of novel 1,2,3-triazole hybrids: structure-activity relationships, molecular docking, and DFT studies.

A series of novel 2,4-dichlorophenyl-1,2,3-triazole derivatives and their structural hybrids incorporating chalcone, hydrazone, thio/semicarbazide, carbamate, and pyrazole moieties were rationally designed, synthesized, and characterized. The antimicrobial activity of the synthesized compounds was evaluated against Gram-positive and Gram-negative bacteria, as well as Candida albicans, revealing clear structure-dependent activity profiles. Among the tested compounds, the parent triazole-acetyl scaffold (compound 3) exhibited the most consistent broad-spectrum activity, with MIC values of 22.5 mg/mL against E. coli, H. pylori, and C. albicans, and 11.25 mg/mL against B. cereus and S. aureus. Structure-activity relationship (SAR) and ADME analyses indicated that a balance between lipophilicity and polarity plays a critical role in modulating antimicrobial performance and membrane permeability. Molecular docking studies against Staphylococcus aureus topoisomerase IV (PDB: 4URN) revealed favorable binding interactions of the active compounds within the enzyme active site. Complementary density functional theory (DFT) calculations provided insights into electronic properties and reactivity trends, supporting the observed biological behavior. Overall, the results suggest that the 2,4-dichlorophenyl-1,2,3-triazole scaffold represents a promising starting point for further optimization, with antimicrobial activity governed by a balance between electronic properties and physicochemical factors influencing membrane permeability.