Synthesis and antifungal activity of new thienyl and aryl conazoles.
Recent studies reported that an first generation azole (tioconazole) was active against Candida glabrata petite mutants, a fluconazole- and voriconazole- resistant strain of fungi characterized as most azole resistant yeast by an overexpression of the efflux pumps. Therefore, monosubstituted 1-[2-(2,4-dichlorophenyl)ethyl]-1H-imidazoles differing from tioconazole by the nature of the linker and of the aromatic ring in their side-chain were synthesized and evaluated against the mutant and the wild-type strain of C. glabrata. New 2-aryl-1-azolyl-3-thienylbutan-2-ols were then designed and synthesized, and their antifungal activity was evaluated against both strains of C. glabrata and two other major human pathogenic fungi, C. albicans and Aspergillus fumigatus. These new compounds exhibited a broad spectrum activity, as well as good efficiency against the petite mutant, suggesting that they may overcome the increased expression of the efflux pumps usually observed in clinical yeast isolates resistant to current azoles.
Chevreuil
Francis
F
EA 921, Laboratoire SONAS, UFR des Sciences Pharmaceutiques et Ingénierie de la Santi, 16 Bd Daviers, Angers 49100, France.
Landreau
Anne
A
Seraphin
Denis
D
Larcher
Gérald
G
Bouchara
Jean-Philippe
JP
Richomme
Pascal
P
D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001232:Aspergillus fumigatus / Q000187:drug effects; D001393:Azoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects; D041221:Candida glabrata / Q000187:drug effects*; D015195:Drug Design; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D013045:Species Specificity; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000935:Antifungal Agents; D001393:Azoles; D007093:Imidazoles