Design, Synthesis, and Integrated Computational Evaluation of Novel Quinoline Hydrazones as Dual-Action Anti-Inflammatory and Antibacterial Agents.

Addressing both bacterial infections and inflammation necessitates the development of innovative therapeutic strategies that mitigate the risks associated with polypharmacy. The targeted quinoline hydrazone derivatives (6a-j) were synthesized via a two-step process, beginning with the preparation of the essential quinoline hydrazide intermediate 5, followed by its condensation with substituted aromatic aldehydes. Advanced spectroscopic techniques, including 1H NMR, 13C NMR, and HRMS, confirmed their structures. Comprehensive computational studies, comprising DFT, molecular docking, and molecular dynamics, were performed to establish structure-activity relationships and substantiate the biological results. The derivatives exhibited notable dual activity; specifically, 6a (p-OH) displayed the highest antibacterial efficacy against Escherichia coli (MIC = 31.25 µg/mL). Compound 6d (p-Cl) demonstrated the fastest onset of in vivo anti-inflammatory activity, exceeding diclofenac. Most compounds demonstrated comparable or slightly reduced in vitro anti-inflammatory activity (81.25%-94.59% hemolysis inhibition). Molecular dynamics simulations confirmed the stability and robust binding interactions at the active sites of COX-2 and bacterial DNA gyrase B. ADMET predictions indicated favorable bioavailability and drug likeness. This study underscores the potential of the nonacidic quinoline hydrazone scaffold as a versatile platform for the development of multi-target therapeutics and offers valuable SAR insights to guide the design of safer, more efficacious agents.