Study on synthesis and measure biological effects of some fluconazole derivatives

ABSTRACT

Fluconazol has been used as an effective antifungal drug for decades. However, increasing drug resistance make it becoming ineffective against many fungal strains. In search for new antifungal agents we have designed and synthesized eight derivatives of fluconazol, in which the hydroxy group of fluconazol was replaced by different functional groups, including halogens [Br (4a), Cl (4b), F (4c)}, azide (4d), cyanide (4e), carboxyl (4f), thiol (4g), and methanesulfonate (4h). Halogenated fluconazol derivatives (4a-4c) showed considerable antifungal activity against three fungal strains tested (C. albicans, A. niger, A. neoformans) with MIC values ranging from 139 to 552 mg/ml. Replacement of the -OH in fluconazol by bulkier groups like azide, cyanide, carboxyl, or methanesulfonate led to decrease or loss of antifungal activity. Exceptionally, however, a thiol derivative 4g (assigned UR/10289) exhibited very potent activity against all fungi tested, including two fluconazol-resistant strains (C. albicans, A. niger). This compound has been chosen as a candidate for further preclinical development by Parma Co. Ltd. (USA)