title: Structure-activity relationships of a new antifungal imidazole, AFK-108, and related compounds.
abstract: Fungicidal activity of widely used imidazole antifungal drugs in topical applications is not so strong in spite of their fungistatic activities against dermatophytes and pathogenic yeasts. In order to improve fungicidal activity of imidazole antifungal agents, a series of novel imidazole derivatives having a hydrophobic substituent derived from isoprenoid were synthesized. The efficacy of these compounds was evaluated with respect to direct cell-membrane damaging activity, ergosterol biosynthesis inhibition, minimum growth-inhibitory concentration (MIC) and therapeutic effect for experimental dermatophytosis of guinea pigs. Among the newly synthesized compounds, the geranyl derivative named AFK-108 (2a) showed the highest in vivo fungicidal activity with both cell membrane damaging activity and ergosterol biosynthesis inhibition in vitro.
authors.affiliation: Biological Science Laboratories, KAO Co., Ltd., Tochigi, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Hori
authors.forename: A
authors.initials: A
authors.lastname: Sakaguchi
authors.forename: M
authors.initials: M
authors.lastname: Kudoh
authors.forename: K
authors.initials: K
authors.lastname: Ishida
authors.forename: Y
authors.initials: Y
authors.lastname: Aoyama
authors.forename: Y
authors.initials: Y
authors.lastname: Yoshida
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D002176:Candida albicans / Q000187:drug effects / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects; D002855:Chromatography, Thin Layer; D003881:Dermatomycoses / Q000188:drug therapy; D004875:Ergosterol / Q000096:biosynthesis; D006168:Guinea Pigs; D007093:Imidazoles / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D050356:Lipid Metabolism; D008826:Microbial Sensitivity Tests; D013329:Structure-Activity Relationship; D014249:Trichophyton / Q000187:drug effects / Q000378:metabolism
chemical_list: D000935:Antifungal Agents; D007093:Imidazoles; C078434:AFK 108; D004875:Ergosterol