In Vitro Antifungal Activities of a Series of Dication-Substituted Carbazoles,Furans, and Benzimidazoles

Aromatic dicationic compounds possess antimicrobial activity against a wide range of eucaryotic pathogens, and in the present study an examination of the structures-functions of a series of compounds against fungi was performed. Sixty-seven dicationic molecules were screened for their inhibitory and fungicidal activities against Candida albicans and Cryptococcus neoformans. The MICs of a large number of compounds were comparable to those of the standard antifungal drugs amphotericin B and fluconazole. Unlike fluconazole, potent inhibitory compounds in this series were found to have excellent fungicidal activities. The MIC of one of the most potent compounds against C. albicans was 0.39 μg/ml, and it was the most potent compound against C. neoformans (MIC, ≤0.09 μg/ml). Selected compounds were also found to be active against Aspergillus fumigatus, Fusarium solani, Candida species other than C. albicans, and fluconazole-resistant strains of C. albicans and C. neoformans. Since some of these compounds have been safely given to animals, these classes of molecules have the potential to be developed as antifungal agents.The incidence of fungal infections in the immunocompromised population has significantly increased over the past two decades. Frequent infections caused by molds which may be primarily resistant to azoles and azole-resistant isolates of Candida albicans and Cryptococcus neoformans, which have developed recently, have increasingly been reported (7, 13, 23, 30). In light of these developments, new antifungal agents with various mechanisms of action and fungicidal activities are needed for the effective management of these clinically important infections.Recently, we reported on the antifungal activities of analogues and metabolites of pentamidine and a series of dicationic substituted bis-benzimidazoles (11). Those in vitro studies uncovered a number of compounds with potent activity against C. albicans and C. neoformans. Several compounds were found to have inhibitory activity against these two fungi more potent than that of either fluconazole or amphotericin B. In addition, the dicationic molecules, unlike fluconazole, proved to have potent fungicidal activity, with the most potent compounds having minimum fungicidal concentrations (MFCs) below 1.0 μg/ml. These initial studies also found that dicationic molecules were effective against Aspergillus fumigatus, Fusarium solani, several Candida species other than C. albicans, and fluconazole-resistant strains of C. albicans and C. neoformans.On the basis of the initial promising results reported above, the current work expands our studies on the antifungal activities of dication-substituted molecules by screening 67 additional compounds against C. albicans and C. neoformans. The criteria used to choose the structures for the current studies were based on years of testing dicationic molecules against the fungus Pneumocystis carinii in a rat model of disease (5, 14, 17, 18, 24, 26–28). Compounds in the current studies include molecules with the cationic moieties linked by carbazole, furan, and benzimidazole bridges. In addition to screening all compounds against C. albicans and C. neoformans, selected compounds were tested against other yeasts, molds, and azole-resistant strains of C. albicans and C. neoformans.