title: Synthesis and in vitro and in vivo antifungal activity of the hydroxy metabolites of saperconazole.
abstract: Herein we describe the scalable diastereoselective and enantioselective syntheses of eight enantiomers of hydroxy metabolites of saperconazole. The in vitro antifungal activity of the eight stereoisomers (compounds 1-8) was compared against a broad panel of Candida spp. (n=93), Aspergillus spp. (n=10), Cryptococcus spp. (n=19), and dermatophytes (n=27). The four 2S isomers 1-4 of the new agent were generally slightly more active than the four 2R isomers 5-8. All eight isomers were tested in a model of experimental A. fumigatus infection in guinea pigs by intravenous inoculation of the fungal conidia. Treatment doses were 1.25 mg kg(-1) and 2.5 mg kg(-1) per day. Infection severity was measured in terms of mean survival time (MST) after infection and mean tissue burdens in brain, liver, spleen, and kidney at postmortem examination. Among the eight isomers, the 2S diastereomers 1-4 showed a generally higher level of activity than the 2R diastereomers 5-8, revealing compounds 1 and 4 as the most potent overall in eradicating tissue burden and MST. Compared with reference compounds itraconazole and saperconazole, the hydroxy isomers 1-8 are less potent inhibitors of the growth of A. fumigatus in vitro and of ergosterol biosynthesis in both A. fumigatus and C. albicans.
authors.affiliation: Johnson & Johnson Pharmaceutical Research & Development, Beerse, Belgium. lmeerpoe@its.jnj.com <lmeerpoe@its.jnj.com>
authors.forename: Lieven
authors.initials: L
authors.lastname: Meerpoel
authors.forename: Jan
authors.initials: J
authors.lastname: Heeres
authors.forename: Leo J J
authors.initials: LJ
authors.lastname: Backx
authors.forename: Louis J E
authors.initials: LJ
authors.lastname: Van der Veken
authors.forename: Rob
authors.initials: R
authors.lastname: Hendrickx
authors.forename: David
authors.initials: D
authors.lastname: Corens
authors.forename: Alex
authors.initials: A
authors.lastname: De Groot
authors.forename: Stef
authors.initials: S
authors.lastname: Leurs
authors.forename: Luc
authors.initials: L
authors.lastname: Van der Eycken
authors.forename: Johan
authors.initials: J
authors.lastname: Weerts
authors.forename: Paul
authors.initials: P
authors.lastname: Luyts
authors.forename: Frans
authors.initials: F
authors.lastname: Van Gerven
authors.forename: Filip A A
authors.initials: FA
authors.lastname: Woestenborghs
authors.forename: Andre
authors.initials: A
authors.lastname: Van Breda
authors.forename: Michel
authors.initials: M
authors.lastname: Oris
authors.forename: Pascal
authors.initials: P
authors.lastname: van Dorsselaer
authors.forename: Gustaaf H M
authors.initials: GH
authors.lastname: Willemsens
authors.forename: Danny
authors.initials: D
authors.lastname: Bellens
authors.forename: Patrick J M G
authors.initials: PJ
authors.lastname: Marichal
authors.forename: Hugo F
authors.initials: HF
authors.lastname: Vanden Bossche
authors.forename: Frank C
authors.initials: FC
authors.lastname: Odds
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001232:Aspergillus fumigatus / Q000187:drug effects; D001393:Azoles / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology; D002176:Candida albicans / Q000187:drug effects; D006168:Guinea Pigs; D008826:Microbial Sensitivity Tests; D013237:Stereoisomerism
chemical_list: D000935:Antifungal Agents; D001393:Azoles; C060571:saperconazole