Antifungal agents. 11. N-substituted derivatives of 1-[(aryl)(4-aryl-1H-pyrrol-3-yl)methyl]-1H-imidazole: synthesis, anti-Candida activity, and QSAR studies.
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 (MIC(90) = 0.032 microg/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.
Di Santo
Roberto
R
Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Studi Farmaceutici, Università di Roma La Sapienza, Piazzale Aldo Moro 5, I-00185 Rome, Italy.
Tafi
Andrea
A
Costi
Roberta
R
Botta
Maurizo
M
Artico
Marino
M
Corelli
Federico
F
Forte
Michela
M
Caporuscio
Fabiana
F
Angiolella
Letizia
L
Palamara
Anna Teresa
AT
D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002176:Candida albicans / Q000187:drug effects*; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship
C503892:1-((4-(4-chlorophenyl)-1-propyl-1H-pyrrol-3-yl)phenylmethyl)-1H-imidazole; D000935:Antifungal Agents; D007093:Imidazoles; D011758:Pyrroles