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.
New 1-[(3-aryloxy-3-aryl)propyl]-1 H-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 microg/mL. Against dermatophytes strains, compounds 20, 25, and 33 (MIC <or= 5 microg/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.
Dipartimento di Studi Farmaceutici, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza Università di Roma, Piazzale Aldo Moro 5, I-00185 Roma, Italy.
Giuseppe
G
La Regina
Felicia Diodata
FD
D'Auria
Andrea
A
Tafi
Francesco
F
Piscitelli
Stefania
S
Olla
Fabiana
F
Caporuscio
Lucia
L
Nencioni
Roberto
R
Cirilli
Francesco
F
La Torre
Nadja Rodrigues
NR
De Melo
Steven L
SL
Kelly
David C
DC
Lamb
Marino
M
Artico
Maurizio
M
Botta
Anna Teresa
AT
Palamara
Romano
R
Silvestri
D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D003883:Arthrodermataceae / Q000187:drug effects*; D002176:Candida albicans / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003198:Computer Simulation; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000935:Antifungal Agents; D007093:Imidazoles