Bis-Triazole-Containing Heterocycles: Synthesis, Pharmacokinetic Prediction, Molecular Modeling, and Antimicrobial Activity Evaluation

Abstract

Abstract The 1,2,4-triazole nucleus is a privileged scaffold in medicinal chemistry, as it is present in many clinically approved antifungal, anticancer and antiviral agents. However, the development of new triazole-based derivatives with better potency and safety profiles is demanded due to the emergence of antimicrobial resistance. The present study was designed to synthesize novel bis-triazole derivatives, to evaluate their antimicrobial activity against clinically relevant pathogens and to establish structure-activity relationships for future optimization. A new series of bis-triazole derivatives (2–14) was synthesized starting from isophthalic acid as the key intermediate 1. All compounds were characterized by FT-IR, NMR, mass spectrometry and analysis. The antimicrobial activity was determined by disk diffusion, MIC, MBC and MTT cytotoxicity assays. Molecular docking was done using redocking validation (RMSD = 0.92 Å) against DNA gyrase B (PDB: 1KZN). Compound 13 showed the best antibacterial activity (MIC = 12.5 µg/mL for K. pneumoniae; inhibition zone: 23 mm for E. coli). Compound 9 showed potent antifungal activity (19 mm vs C. albicans; MIC = 12.5 µg/mL vs MRSA). Selectivity indices ranged between 5 and 40 indicating good safety profiles. Docking showed that compound 13 had a binding energy of −8.8 kcal/mol with important interactions with ASP73, ARG136 and CYS393. First report of quantitative MIC, MBC and cytotoxicity data for this class of bis-triazole derivatives with evaluation against MDR clinical isolates (MRSA and K. pneumoniae). The validated docking model (RMSD = 0.92 Å) provides a reliable tool for future structure-based design. Compound 9 was found to be a promising oral antifungal lead (SI = 20) and compound 13 a candidate for topical antibacterial applications (SI = 10). These findings provide a basis for further optimization of triazole-based antimicrobial agents. GRAPHICAL ABSTRACTFlowchart illustrating the synthesis, profiling, docking, and toxicity evaluation of Bis-1,2,4-Triazole Diformimidate derivatives.The diagram presents a circular flowchart centered on "Bis-1,2,4-Triazole Diformimidate Derivatives," labeled '9'. Surrounding this structure are four main sections: "Synthesis & Characterization" with lab equipment and techniques (FT-IR, NMR, MS), "Molecular Docking" showing binding to the 1KZN protein, "Antimicrobial Activity" with illustrations of bacteria and fungi highlighting effectiveness, and "Toxicity Evaluation" featuring a spider web plot indicating low predicted toxicity for several categories. "ADME Profiling" indicates drug-likeness and bioavailability. Arrows represent the processes' interconnected workflow.