Studies On Synthesis And Evaluation Of Biological Activity Of C-3Isonicotinoylhydrazone Substituted Fluoroquinolone Derivatives

Since the mid-1980s, with the on-going rising incidence of drug-resistant tuberculosis and the increasein AIDS associated infections, the prevalence of tuberculosis (TB) has been increasing, and thattuberculosis becomes a leading infectious cause of death worldwide. Unfortunately, because of thehigh-difficulty of developing anti-tuberculosis drugs, the current anti-TB treatment program is far fromsatisfaction, as well as the emergency of drug-resistant strains, especially, multi-drug resistant strains, thereis not a new anti-tuberculosis drug since the advent of rifampicin during the past30years. Therefore, thereis an urgent need to develop new drugs or new target for anti-TB drugs. Fluoroquinolones is a kind ofsynthetic antibiotics which have a good inhibitory against Mycobacterium tuberculosis, their mainbiological targets are the DNA gyrase (Gyr) and topoisomerase IV (Top4). At present, There are no reportsof cross-resistance with other classes of anti-tuberculosis drugs. Fluoroquinolones can be administeredorally with good absorption and favorable pharmacokinetics, as well as low incidence of severity ofadverse effects. With above advantages, some species (Ciprofloxacin, Gatifloxacin, Ofloxacin, etc.) havebeen used as second-line anti-tuberculosis drugs in combination with other anti-tuberculosis drugs for thetreatment of multiple drug-resistant TB (MDR-TB), and the intolerable patients to the first-lineanti-tuberculosis drugs. Isoniazid derivatives (isonicotinoylhydrazone analogs) were reported to exhibit thesame levels of the in vitro anti-MTB activity as that of Isoniazid. However, these Isoniazid analogs areappreciably improved in pharmacological attributes, in terms of adverse effects or pharmacokinetics.Consequently, we alternate the C-3carboxyl of fluoroquinolones with formyl, and then condensed withisoniazid, in this way, it is expected to get new anti-tuberculosis drugs with a complementarity betweenfluoroquinolones and Isoniazid, and lower toxicity, as well as low incidence of cross-resistance.1. Design and synthesis of target compoundsIn this paper,10new compounds have been designed and synthesized with fluoroquinolones and itsderivatives in the principles of bioisosterism and combination of activity group. Through a series ofreactions, the C-3carboxyl of fluoroquinolones was substituted by Isonicotinoyl hydrazone, and thecorrespondingly target compounds were obtained. The structures of new compounds synthesized had beencharacterized by MS、1H-NMR and IR. 2. Evaluation of biological activity2.1Evaluation of anti-tuberculosis activity in vitroMIC of target compounds was determined against M. tuberculosis H37Rv strain and H37Ra strain byusing broth dilution assay method. All the tested compounds exhibited good activity against both of the twoM. tuberculosis strains which showed the similar levels of the in vitro anti-MTB activity as that ofIsoniazid.2.2Cytotoxicity for VERO cells in vitroCell cytotoxicity of isonicotinoylhydrazones was tested by MTT assay respectively towards VEROcells. The result shows that most of the compounds were with wealy cytoxcicity which are better thanofloxacin.3. Conclusion10target compounds were synthesized and their structures confirmed by spectral data, the result ofanti-tuberculosis activity in vitro shows that: all the tested compounds exhibited good activity, the MIC ofthem are next to the level of Isoniazid; The cytotoxicity result showed that most of the compounds werewith wealy cytoxcicity which were better than ofloxacin. Therefore, the substatution of quinolone C-3carboxylic with isonicotinoylhydrazone is worthy to be developed into anti-tuberculosis agents.