Enhanced of norfloxacin bioavailability using conjugation of isosorbide via enzymatic catalysis

Norfloxacin is a broad-spectrum synthetic antibacterial agent that has been used to treat complicated urinary tract infections. However, the poor water-solubility of norfloxacin limits its bioavailability. The aim of the present study was to synthesize water-soluble norfloxacin derivate through adding isosorbide via enzymatic catalyst (Green chemistry) and to evaluate its physiological and biological properties. Isosorbide-dinorfloxacin (ISDNf) was synthesized by enzymatic esterification between the carboxyl group of norfloxacin and two hydroxyl groups of isosorbide. Chemical structure and water-solubility of ISDNf purified by HPLC was investigated by using 1H NMR and MALDITOF, and optical spectrometry, respectively. Antibacterial effects of ISDNf were evaluated against 7 drug-susceptible and 7 drug-resistant bacteria. ISDNf, which was successfully synthesized, was water-soluble at 10,000 mg/L, compared that free norfloxacin was water-insoluble at 100 mg/L. The antibacterial efficiency of ISDNf was maintained in drugsusceptible bacteria, while that was enhanced in drugresistant bacteria. Additionally, its cytotoxicity in mammalian cells was remarkably reduced and its solid diffusion capacity was increased. The increased water-solubility, antibacterial efficacy, and diffusion capacity and reduced cytotoxicity of ISDNf suggests that it could potentially be developed as a novel prodrug.