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Article

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

Supporting Info

Roberto Di Santo,*^†^‡ Andrea Tafi,^‡^§ Roberta Costi,^† Maurizo Botta,*^§ Marino Artico,^† Federico Corelli,^§ Michela Forte,^† Fabiana Caporuscio, Letizia Angiolella, and Anna Teresa Palamara

Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Studi Farmaceutici, Universit di Roma La Sapienza, P.le Aldo Moro 5, I-00185 Roma, Italy; Dipartimento Farmaco Chimico Tecnologico, Universit di Siena, Via Aldo Moro, S. Miniato, I-53100 Siena, Italy; and Dipartimento di Studi di Chimica e Tecnologia delle Sostanze Biologicamente Attive, and Istituto di Microbiologia, Universit di Roma La Sapienza, P.le Aldo Moro 5, I-00185 Roma, Italy

J. Med. Chem., 2005, 48 (16), pp 5140–5153

DOI: 10.1021/jm048997u

Publication Date (Web): July 7, 2005

To whom correspondence should be addressed. R.D.S.: phone and fax, +39-6-49913150; e-mail: roberto.disanto@uniroma1.it. M.B.: phone, +39-577-234306; fax, +39-577-234333; e-mail, botta@unisi.it.

†

Dipartimento di Studi Farmaceutici, Università di Roma “La Sapienza”.

‡

These authors contributed equally to this work.

Dipartimento Farmaco Chimico Tecnologico, Università di Siena.

Dipartimento SCTSBA, Università di Roma.

Istituto di Microbiologia, Università di Roma.

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 (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.