title: Studies on antifungal agents. 23. Novel substituted 3,5-diphenyl-3-(1H-imidazol-1-ylmethyl)- 2-alkylisoxazolidine derivatives.
abstract: The synthesis and antifungal activity of a novel series of substituted 3,5-diphenyl-3-(1H-imidazol-1-ylmethyl)-2-alkylisoxazolidine derivatives (15-30) are described. The synthesis of the title compounds was accomplished via a 1,3-dipolar cycloaddition reaction of alpha-substituted ketonitrones with appropriate styrene precursors. The compounds when tested in vitro in solid agar cultures exerted a very potent antifungal activity against a wide variety of yeast and systemic mycoses and dermatophytes, especially Trichophyton and Microsporum sp., Epidermophyton floccosum and Candida stellatoidea. The in vitro activity against Aspergillus fumigatus and Candida albicans was moderate to potent. Overall, the two bis(4-chlorophenyl) analogues 18 and 19 were the most potent in vitro compounds, showing MIC values ranging between 0.2 and 7.0 microgram/mL, as compared to 0.2-20.0 micrograms/mL for ketoconazole, which was used as the positive standard in all assays. When tested in vivo in the rat vaginal candidiasis model, derivative 18, although showing significant antifungal activity when compared to controls, was less effective than ketoconazole. The title 3,5-substituted isoxazolidine compounds represent a novel class of potent antifungal agents.
authors.affiliation: Department of Organic Chemistry, Pennwalt Corporation, Rochester, New York 14623.
authors.forename: G B
authors.initials: GB
authors.lastname: Mullen
authors.forename: T R
authors.initials: TR
authors.lastname: DeCory
authors.forename: J T
authors.initials: JT
authors.lastname: Mitchell
authors.forename: S D
authors.initials: SD
authors.lastname: Allen
authors.forename: C R
authors.initials: CR
authors.lastname: Kinsolving
authors.forename: V S
authors.initials: VS
authors.lastname: Georgiev
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D002177:Candidiasis / Q000188:drug therapy; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D007654:Ketoconazole / Q000627:therapeutic use; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D003904:Mitosporic Fungi / Q000187:drug effects*; D010080:Oxazoles / Q000138:chemical synthesis*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000935:Antifungal Agents; D007093:Imidazoles; D007555:Isoxazoles; D010080:Oxazoles; D007654:Ketoconazole