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Article

1-[(3-Aryloxy-3-aryl)propyl]-1H-imidazoles, New Imidazoles with Potent Activity against Candida albicans and Dermatophytes. Synthesis, Structure−Activity Relationship, and Molecular Modeling Studies

Supporting Info

Giuseppe La Regina^†, Felicia Diodata D’Auria^§, Andrea Tafi*^‡, Francesco Piscitelli^†, Stefania Olla^‡, Fabiana Caporuscio^‡, Lucia Nencioni^§, Roberto Cirilli^#, Francesco La Torre^#, Nadja Rodrigues De Melo, Steven L. Kelly, David C. Lamb, Marino Artico^†, Maurizio Botta^‡, Anna Teresa Palamara^§ and Romano Silvestri*^†

Dipartimento di Studi Farmaceutici, Istituto Pasteur

Fondazione Cenci Bolognetti, Sapienza Universit

di Roma, Piazzale Aldo Moro 5, I-00185 Roma, Italy, Dipartimento di Scienze di Sanit

Pubblica, Sezione di Microbiologia Farmaceutica, Sapienza Universit

di Roma, Piazzale Aldo Moro 5, I-00185 Roma, Italy, Dipartimento Farmaco Chimico Tecnologico, Universit

di Siena, Polo Scientifico Universitario San Miniato, Via Aldo Moro 2, I-53100 Siena, Italy, Dipartimento del Farmaco, Istituto Superiore di Sanit

, Viale Regina Elena 299, I-00161 Roma, Italy, and Institute of Life Science, Swansea Medical School, Grove Building, Swansea University, Swansea SA2 8PP, Wales, U.K.

J. Med. Chem., 2008, 51 (13), pp 3841–3855

DOI: 10.1021/jm800009r

Publication Date (Web): June 5, 2008

†

Istituto PasteurFondazione Cenci Bolognetti, Sapienza Universit di Roma.

Sezione di Microbiologia Farmaceutica, Sapienza Universit di Roma.

* To whom correspondence should be addressed. For A.T. (on molecular modeling): phone, +39 0577 23 43 13; fax, +39 0577 23 43 33; e-mail, tafi@unisi.it.. For R.S.: phone, +39 06 4991 3800; fax, +39 06 491 491; e-mail, romano.silvestri@uniroma1.it.

‡

Universit di Siena.

Istituto Superiore di Sanit.

Swansea University.

Abstract

New 1-[(3-aryloxy-3-aryl)propyl]-1H-imidazoles were synthesized and evaluated against Candida albicans and dermatophytes in order to develop structure−activity relationships (SARs). Against C. albicans the new imidazoles showed minimal inhibitory concentrations (MICs) comparable to those of ketoconazole, miconazole, and econazole, and were more potent than fluconazole. Several derivatives (10, 12, 14, 18−20, 24, 28, 29, 30, and 34) turned out to be potent inhibitors of C. albicans strains resistant to fluconazole, with MIC values less than 10 µg/mL. Against dermatophytes strains, compounds 20, 25, and 33 (MIC ≤ 5 µg/mL) were equipotent to ketoconazole, econazole, and miconazole. SARs of imidazoles 10−44 were rationalized with reasonable accuracy by a previously developed quantitative pharmacophore for antifungal agents.