In silico Design of N-Substituted Quinoline-Isatin Hybrids for Multiple Targeted enzymes for Anti-Microbial Activity

Abstract

The World Health Organization reports that approximately 700,000 people are affected by Antimicrobial Resistance (AMR) each year. This growing concern has accelerated the search for new antibacterial agents. Fluoroquinolones are key broad-spectrum antibiotics and recent interest in Isatin derivatives has revealed promising antimicrobial activity. Combining quinoline and Isatin pharmacophores offers a strategy to develop novel agents with unique mechanisms to overcome resistance. Based on SAR and literature data, a series of N-substituted quinoline-isatin conjugates were designed to target bacterial enzymes such as Enoyl-ACP reductase, BioA, and DNA gyrase. Docking studies identified QI7f as a lead compound with superior binding scores (-10.35, -12.38, -8.93 kcal/mol) compared to Standards. In silico ADMET analysis predicted favorable pharmacokinetic and toxicity profiles. The compounds were synthesized and structurally confirmed via FTIR, NMR, and mass spectrometry. Q17f showed notable in-vitro antimicrobial activity (2-10 mg/mL) comparable to gentamicin, likely due to electron-withdrawing groups enhancing target interactions.