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Antifungal Agents. 11. N -Substituted Derivatives of 1-[(Aryl)(4-aryl-1 H -pyrrol-3-yl)methyl]-1 H -imidazole: Synthesis, Anti- Candida Activity, and QSAR Studies

2005; American Chemical Society; Volume: 48; Issue: 16 Linguagem: Inglês

10.1021/jm048997u

1520-4804

Roberto Di Santo, Andrea Tafi, Roberta Costi, Maurizo Botta, Marino Artico, Federico Corelli, Michela Forte, Fabiana Caporuscio, Letizia Angiolella, Anna Teresa Palamara,

Cancer therapeutics and mechanisms

1-[(Aryl)(4-aryl-1H-pyrrol-3-yl)methyl]-1H-imidazoles were recently reported by our group as potent anti-Candida agents belonging to the antifungal azole class. In the present paper the synthesis, anti-Candida activities, and QSAR studies on a novel series of N-substituted 1-[(aryl)(4-aryl-1H-pyrrol-3-yl)methyl]-1H-imidazole derivatives are reported. The newly synthesized azoles were tested against 12 strains of Candida albicans together with bifonazole, miconazole, itraconazole, fluconazole, and compounds 1a, 1b, 3a, 3b, and 3c used as reference drugs. In general, tested derivatives showed good antifungal activities, and the most potent compound was 1d (MIC90 = 0.032 μg/mL), which was from 4- to 250-fold more potent than reference drugs. Catalyst software was applied to develop a quantitative pharmacophore model to be used for the rational design of new antifungal azoles. Some key interactions, as well as excluded volumes, further to the coordination bond of azole antifungals with the demethylase enzyme, are highlighted.