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

• Published in: Journal of medicinal chemistry Vol. 51; no. 13; pp. 3841 - 3855
• Main Authors: La Regina, Giuseppe, D’Auria, Felicia Diodata, Tafi, Andrea, Piscitelli, Francesco, Olla, Stefania, Caporuscio, Fabiana, Nencioni, Lucia, Cirilli, Roberto, La Torre, Francesco, De Melo, Nadja Rodrigues, Kelly, Steven L, Lamb, David C, Artico, Marino, Botta, Maurizio, Palamara, Anna Teresa, Silvestri, Romano
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 10.07.2008; Amer Chemical Soc
• Subjects: Antibiotics. Antiinfectious agents. Antiparasitic agents; Antifungal agents; Antifungal Agents - chemical synthesis; Antifungal Agents - chemistry; Antifungal Agents - pharmacology; Arthrodermataceae - drug effects; Biological and medical sciences; Candida albicans - drug effects; Cell Line, Tumor; Cell Survival - drug effects; Chemistry, Medicinal; Computer Simulation; Humans; Imidazoles - chemical synthesis; Imidazoles - chemistry; Imidazoles - pharmacology; Life Sciences & Biomedicine; Medical sciences; Models, Molecular; Molecular Structure; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Science & Technology; Stereoisomerism; Structure-Activity Relationship; ANALOGS; ANTIFUNGAL AGENTS; RESISTANCE; BINDING; DERIVATIVES; FLUOXETINE; ANTICANDIDA ACTIVITY; CYP51; Candida albicans; Imidazole derivatives; Ether; Azole derivatives; Benzene derivatives; Prediction; In vitro; Modeling; Fungi; Antifungal agent; Structure activity relation; Chlorine Organic compounds; Molecular model; Fluorine Organic compounds; Fungi Imperfecti; Chemical synthesis; Dermatophyte
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm800009r

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.