Molecular Diagnostic Studies and Synthesis of Bis-sulfonamide Triazine Derivatives as Antibacterial Agents: Insights from Molecular Docking: Insights from Molecular Docking

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Objectives: To design and synthesize a novel series of bis-sulfonamide derivatives of 2,4-diamino-6-substituted phenyl-1,3,5-triazines and to evaluate their potential as bacterial DNA topoisomerase inhibitors with potent antibacterial activity. Methods: The target compounds were synthesized and evaluated for their in vitro antibacterial efficacy against selected Gram-positive and Gram-negative bacterial strains using zone-of-inhibition and minimum inhibitory concentration (MIC) assays. Cytotoxicity was determined in CHO cells using dose- and time-dependent assays at 48 and 72 h. In silico molecular docking was executed against DNA topoisomerase IV (PDB ID: 4EMV) and DNA gyrase (PDB ID: 4DUH). Fluorescence quenching experiments were performed to biophysically validate the binding interactions. Results and Discussion: The synthesized compounds exhibited robust antibacterial efficacy and demonstrated non-cytotoxic profiles at concentrations up to 50 μM (48 h) and 25 μM (72 h). Docking simulations revealed tight binding interactions within the active sites of both topoisomerase targets, which were strongly corroborated by steady-state fluorescence quenching data. A high degree of consensus was observed between the in vitro antibacterial metrics and in silico structural predictions. Conclusions: These triazine-based bis-sulfonamide derivatives represent a promising therapeutic scaffold for the development of next-generation bacterial DNA topoisomerase inhibitors. Notably, N,Nʹ-[6-(2-nitrophenyl)-1,3,5-triazine-2,4-diyl]-bis-4-bromobenzenesulfonamide emerged as a highly potent lead candidate targeting DNA gyrase/topoisomerase IV, serving as an optimal baseline for further structural optimization.