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

Abstract

DNA gyrase B is a validated antibacterial target for combating resistance. A new series of 2-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-N-phenylacetamides was synthesized and characterized by spectroscopic techniques. Compounds 6e and 6h displayed potent antibacterial activity, with MIC values of 50 μg/mL against Escherichia coli and Pseudomonas aeruginosa, comparable to chloramphenicol and superior to other analogues. Molecular docking revealed binding affinities of −4.7 and −5.1 kcal/mol for 6e and 6h, similar to chloramphenicol (−5.0 to −5.3 kcal/mol). MM-GBSA analysis indicated stronger binding free energies for 6e (−46.76 kcal/mol) and 6h (−44.59 kcal/mol) than chloramphenicol (−28.19 to −40.03 kcal/mol). A 100 ns MD simulation confirmed stable complex formation, with 6e 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 6e and 6h represent promising scaffolds for further optimization as potent antibacterial agents targeting DNA gyrase B.