Menthol- and thymol-based ciprofloxacin derivatives against Mycobacterium tuberculosis: in vitro activity, lipophilicity, and computational studies

In this work, we investigated the antitubercular properties of Ciprofoxacin derivatives conjugated with menthol and thymol moieties. For the sixteen derivatives, we established minimal inhibitory concentrations (MIC) using isolates of ycobacterium tuberculosis that were resistant or susceptible to other antibiotics. For the most potent compound 1‐cyclopropyl‐6‐fuoro‐7‐{4‐[6‐((1R,2S,5R)‐2‐ isopropyl‐5‐methylcyclohexyloxy)‐6‐oxohexyl]piperazin‐1‐yl}‐4‐oxo‐1,4‐dihydroquinoline‐3‐carboxylic acid (6), we determined fractional inhibitory concentration index (FICI) values to confrm antibacterial susceptibility and synergistic efects with other reference drugs. In addition, chromatographic studies of all the derivatives demonstrated a signifcant three to four-fold increase in lipophilicity and afnity to phospholipids compared to Ciprofoxacin. Finally, we conducted structurebased studies of the investigated compounds using molecular docking and taking into account protein target mutations associated with fuoroquinolone resistance. In summary, our fndings indicate that the investigated compounds possess tuberculostatic properties, with some showing similar or even better activity against resistant strains compared to reference drugs. Increased lipophilicity and afnity to phospholipids of the new derivatives can ofer several advantages for new drug candidates, beyond just improved cell membrane penetration. However, further studies are needed to fully understand their safety, efcacy, and mechanism of action.