Novel 4,5-dibromo-N-phenyl-1H-pyrrole-2-carboxamide Hybrids as Promising DNA Gyrase Inhibitors: Design, Synthesis and Antimicrobial Evaluation

Bacterial DNA gyrase remains a prominent and vital target in discovering new antibacterial drugs. In the present research work, we designed and synthesized a series of novel 4,5-dibromo-N-phenyl-1H-pyrrole-2-carboxamide hybrids containing substituted 1,2,3-triazole and isoxazole moieties which could serve as potential E. coli DNA gyrase inhibitors. The title compounds were synthesized with a good to excellent yield, and all the newly synthesized compounds were characterized by physicochemical and spectral analysis (FTIR, 1H NMR, and 13C NMR). The DNA gyrase (E. coli) inhibitory assay was performed for all synthesized compounds. Results showed that four compounds, 11a (IC50 = 0.90 µM), 11b (IC50 = 0.28 µM), 17a (IC50 = 0.72 µM) and 17b (IC50 = 0.43 µM), exhibited good DNA gyrase inhibitory activity. In-silico molecular docking study was performed to understand the mode of interaction of compounds with the target enzyme. A docking study on the E. coli DNA gyrase protein revealed that compounds 11b (-7.011 kcal/mol) and 17b (-6.60 kcal/mol) interact with ARG136 and ASP73, two key amino acid residues, with docking scores of −7.01 and −6.60, respectively. The MD simulation was further employed to elucidate the thermodynamic binding energy, RMSD, and RMSF of compounds 11b and 17b. They exhibited binding energies of -47.598 kcal/mol and -41.682 kcal/mol, respectively. This provides valuable information on the binding mode and structure-activity relationship of these new hybrids of 4,5-dibromo-N-phenyl-1H-pyrrole-2-carboxamides as promising E. coli DNA gyrase B inhibitors. In addition, these hybrid derivatives showed more prominent antibacterial action on Gram-negative rather than Gram-positive organisms. Surprisingly, compounds 11b (MIC = 1.56 µg/mL) and 17b (MIC = 3.125 µg/mL) also displayed promising anti-mycobacterial activity.