Design, Synthesis, And Biological Evaluation Of Novel Quinolone Derivatives (Ciprofloxacin And Moxifloxacin Analogues) As Dual Inhibitors Of DNA Gyrase And Topoisomerase IV In Multidrug-Resistant Bacterial Strains
Abstract
Background: The emergence of multidrug-resistant (MDR) bacterial strains has led to reduced efficacy of fluoroquinolones, necessitating the development of novel quinolone derivatives. Ciprofloxacin and Moxifloxacin, key fluoroquinolone antibiotics, target DNA Gyrase and Topoisomerase IV; however, bacterial resistance mechanisms, including target site mutations and efflux pumps, have diminished their clinical effectiveness. This study aims to design, synthesize, and evaluate novel Ciprofloxacin and Moxifloxacin analogues with enhanced antibacterial activity and reduced resistance potential.Methods: Cipro-1 (piperazine-modified Ciprofloxacin) and Moxi-2 (aminomethyl-modified Moxifloxacin) were synthesized via nucleophilic substitution at the C-7 position. The derivatives were structurally characterized using ¹H and ¹³C NMR, FT-IR, and ESI-MS. In vitro antibacterial activity was assessed via Minimum Inhibitory Concentration (MIC) assays against MDR Gram-positive (MRSA) and Gram-negative (E. coli, K. pneumoniae) bacterial strains. Enzyme inhibition assays measured the IC₅₀ values for DNA Gyrase and Topoisomerase IV. Time-kill kinetics, resistance development studies, and MTT cytotoxicity assays were performed to determine bactericidal effects, mutation frequency, and safety profiles in mammalian cell lines.Results• Moxi-2 exhibited the lowest MIC values (0.25 µg/mL against MRSA, 0.5 µg/mL against MDR E. coli), outperforming Moxifloxacin.• Cipro-1 showed enhanced bacterial…
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