title: Optically active antifungal azoles. I. Synthesis and antifungal activity of (2R,3R)-2-(2,4-difluorophenyl)-3-mercapto-1-(1H-1,2,4-triazol-1-yl)-2-b utanol and its stereoisomers.
abstract: (2R,3R)-2-(2,4-Difluorophenyl)-3-mercapto-1-(1H-1,2,4-triazol-1-yl )-2-butano l [(2R,3R)-7] and its stereoisomers [(2S,3R)-, (2S,3S)- and (2R,3S)-7] were prepared from the optically active oxiranes 6 by a newly developed ring-opening reaction and evaluated for antifungal activity. The thiol (2R,3R)-7 showed extremely potent antifungal activity in vitro and in vivo. The optically active oxirane (2R,3S)-6, a useful intermediate for the synthesis of sulfur-containing antifungal azoles 5, was synthesized from methyl (R)-lactate [(R)-8] via eight steps in a stereocontrolled manner. The key step in the synthesis is the Grignard reaction of an amide derivative [(R)-12a] of (R)-lactic acid with 2,4-difluorophenyl-magnesium bromide (13).
authors.affiliation: Pharmaceutical Research Laboratories III, Takeda Chemical Industries, Ltd., Osaka, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Tasaka
authors.forename: N
authors.initials: N
authors.lastname: Tamura
authors.forename: Y
authors.initials: Y
authors.lastname: Matsushita
authors.forename: K
authors.initials: K
authors.lastname: Teranishi
authors.forename: R
authors.initials: R
authors.lastname: Hayashi
authors.forename: K
authors.initials: K
authors.lastname: Okonogi
authors.forename: K
authors.initials: K
authors.lastname: Itoh
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001393:Azoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002177:Candidiasis / Q000188:drug therapy*; D002855:Chromatography, Thin Layer; D005658:Fungi / Q000187:drug effects*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008826:Microbial Sensitivity Tests; D013055:Spectrophotometry, Infrared; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000935:Antifungal Agents; D001393:Azoles; D014230:Triazoles; C083107:2-(2,4-difluorophenyl)-3-mercapto-1-(1H-1,2,4-triazol-1-yl)-2-butanol