Synthesis and In-Vitro Pharmacological Assessment of Fluoroquinolone Derivatives as Effective Antibacterial and Anti-TB Agents: An Experimental Study

The alarming rise of multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis has created an urgent need for new chemotypes capable of overcoming current fluoroquinolone (FQ) resistance. To address this challenge, the present study focuses on the design, synthesis, and biological profiling of novel oxime and thiosemicarbazone quinolone hybrids, developed to enhance DNA gyrase inhibition, circumvent efflux-mediated resistance, and improve antimycobacterial efficacy. The target hybrids were synthesized through a two-step modular route, beginning with derivatization of the FQ core at the C-7 piperazine nitrogen, followed by condensation with appropriately substituted ketone derivatives to yield the corresponding oxime and thiosemicarbazone linkages. All compounds were structurally confirmed using FT-IR, 1H NMR, 13C NMR, and MASS analyses, demonstrating successful formation of oxime (C = N–OH) and thiosemicarbazone (C = N–NH–CSNH2) functionalities without degradation of the quinolone scaffold. The synthesized molecules were evaluated for antibacterial activity against Gram-positive and Gram-negative pathogens using disc diffusion method, while antimycobacterial activity was assessed against Mtb H37RV using Microplate Alamar Blue Assay (MABA). Several hybrids exhibited markedly enhanced antibacterial zones of inhibition and low minimum inhibitory concentration (MIC) values compared with the parent FQ, indicating improved potency. Notably, selected thiosemicarbazone derivatives demonstrated the highest activity, with MICs approaching the low-micromolar range against Mtb, suggesting a favourable interaction with the target enzyme. Overall, the study presents novel quinolone hybrids with promising lead-like characteristics, offering a rational platform for further optimization toward next-generation anti-TB agents capable of addressing current resistance barriers.