Chemotherapeutic agents for the treatment of fungal infections. Imidazole derivatives highly active against Candida albicans

Fungi may be classified by the level of tissue affected as superficial, subcutaneous, and systemic. The term "opportunistic mycoses" is used to refer to serious fungal infections occurring in patients with compromised host defenses. The most common opportunistic mycoses include candidiasis, invasive aspergillosis, cryptococcal meningitis, and mucormycosis. During the past two decades, the incidence of these and other unusual opportunistic mycoses has been increasing, related to the use of broad-spectrum antibiotics, immusuppressive agents, anticancer and anti-AIDS drugs. Recently, Lass-Flörl et al. reported the in vitro antifungal properties of selective serotonin reuptake inhibitors (SSRIs) against Aspergillus species and Candida parapsilosis. Fluoxetine (1) and sertraline (2) showed the highest activity against these fungi with differences in susceptibility of the various isolates tested. Starting from this report and pursuing our personal interest on azole antifungal agents, we synthesized novel antimicotic derivatives as econazole (3) isomers (4), replacing the fluoxetine NHCH3 terminus with an imidazole ring.1 All new derivatives, evaluated in vitro activity for their antifungal activity against 20 strains of Candida albicans, showed a very potent anti-Candida activity, higher than miconazole and econazole. 1-(4-Chlorophenyl)-1-(2,4-dichlorophenoxy)-3-(1H-imidazol-1-yl)-propane was about 2-fold more active than econazole. High increase of activity was observed with methyl, nitro, fluorine and chlorine (Cl>F>CH3>NO2>CF3). References (1) Silvestri, R.; Artico, M.; La Regina, G.; Di Pasquali, A.; De Martino, G.; D’Auria, F. D.; Nencioni, L.; Palamara, A. T. Imidazole Analogues of fluoxetine, a novel class of anti-Candida agents. J. Med. Chem. 2004, 47, in press.