Molecular modelling and structure-activity relationship of pyrrolo[2,3- <i>d</i> ]pyrimidine derivatives as potent DNA gyrase B inhibitors

DNA gyrase B is a validated antibacterial target for combating resistance. A new series of 2-(4-chloro-7<i>H</i>-pyrrolo[2,3-<i>d</i>]pyrimidin-7-yl)-N-phenylacetamides was synthesized and characterized by spectroscopic techniques. Compounds <b>6e</b> and <b>6h</b> displayed potent antibacterial activity, with MIC values of 50 μg/mL against <i>Escherichia coli</i> and <i>Pseudomonas aeruginosa</i>, comparable to chloramphenicol and superior to other analogues. Molecular docking revealed binding affinities of -4.7 and -5.1 kcal/mol for <b>6e</b> and <b>6h</b>, similar to chloramphenicol (-5.0 to -5.3 kcal/mol). MM-GBSA analysis indicated stronger binding free energies for <b>6e</b> (-46.76 kcal/mol) and <b>6h</b> (-44.59 kcal/mol) than chloramphenicol (-28.19 to -40.03 kcal/mol). A 100 ns MD simulation confirmed stable complex formation, with <b>6e</b> showing minimal RMSD fluctuations and reduced RMSF values for key binding site residues, consistent with strong hydrogen bonding, hydrophobic, and ionic interactions. ADME profiling predicted favorable oral bioavailability. Overall, compounds <b>6e</b> and <b>6h</b> represent promising scaffolds for further optimization as potent antibacterial agents targeting DNA gyrase B.