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

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.