Synthesis, Characterization, Molecular Docking, and Biological Evaluation of Novel Levofloxacin–Thiourea Derivatives as Potential Antibacterial Agents

Fluoroquinolone resistance is a major challenge in managing bacterial infections and motivates the development of new derivatives with improved activity and pharmacokinetic properties . In this study, a series of levofloxacin–thiourea hybrids (L1–L3) were synthesized via esterification of levofloxacin, conversion to the corresponding hydrazide, and condensation with para‑substituted phenyl isothiocyanates under mild conditions. The structures of the intermediates and final products were confirmed by melting point, ATR‑FTIR, and ¹H NMR spectroscopy, which demonstrated introduction of the hydrazide and thiourea moieties while preserving the levofloxacin core. Antibacterial activity was assessed against Escherichia coli (G–) and Staphylococcus aureus (G+) using the agar well diffusion method, with levofloxacin as reference; the p‑chloro derivative L2 showed inhibition zones comparable to or greater than levofloxacin at higher concentrations, whereas L1 and L3 retained substantial activity. SwissADME predictions indicated that all derivatives display high gastrointestinal absorption, acceptable polarity (TPSA 122.96 Ų), and only one Lipinski rule violation, with moderate decreases in solubility relative to levofloxacin but overall favourable drug‑likeness profiles. Molecular docking into the Streptococcus pneumoniae DNA gyrase–DNA complex (PDB ID: 4Z2D) showed that L1–L3 adopt poses similar to levofloxacin, preserving the key Mg²⁺‑mediated contacts and base stacking while forming additional hydrogen‑bond and π–π interactions through the thiourea–aryl fragment; L2 exhibited the most favourable docking score. Together, the experimental and in silico results identify levofloxacin–thiourea derivatives, particularly the p‑chloro analogue L2, as promising leads for further optimization against resistant bacterial pathogens.