title: 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.
abstract: 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.
authors.affiliation: Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Studi Farmaceutici, Università di Roma La Sapienza, Piazzale Aldo Moro 5, I-00185 Rome, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Di Santo
authors.forename: Andrea
authors.initials: A
authors.lastname: Tafi
authors.forename: Roberta
authors.initials: R
authors.lastname: Costi
authors.forename: Maurizo
authors.initials: M
authors.lastname: Botta
authors.forename: Marino
authors.initials: M
authors.lastname: Artico
authors.forename: Federico
authors.initials: F
authors.lastname: Corelli
authors.forename: Michela
authors.initials: M
authors.lastname: Forte
authors.forename: Fabiana
authors.initials: F
authors.lastname: Caporuscio
authors.forename: Letizia
authors.initials: L
authors.lastname: Angiolella
authors.forename: Anna Teresa
authors.initials: AT
authors.lastname: Palamara
mesh_terms: 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
chemical_list: C503892:1-((4-(4-chlorophenyl)-1-propyl-1H-pyrrol-3-yl)phenylmethyl)-1H-imidazole; D000935:Antifungal Agents; D007093:Imidazoles; D011758:Pyrroles