Synthesis and in vitro antifungal activities of novel triazole antifungal agent CS-758.
Synthesis and in vitro antifungal activities of a novel triazole antifungal agent CS-758 (former name, R-120758) are described. The minimum inhibitory concentrations (MICs) of a series of dioxane-triazole compounds related to R-102557 were examined. Variation of the length of the chain between the dioxane ring and the phenyl ring revealed that the linkage with two double bonds is the most preferable. When a cyano group was introduced to the C4 position on the benzene ring, MICs improved further. A fluorine atom was introduced to obtain CS-758. The MICs of CS-758 surpassed those of fluconazole and itraconazole against Candida, Aspergillus and Cryptococcus species. The precursor (E,E)-aldehyde was synthesized stereoselectively from 3-fluoro-4-methylbenzonitrile using the Horner-Wadsworth-Emmons reaction.
Konosu
T
T
Medicinal Chemistry Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan. kohnos@shina.sankyo.co.jp
Oida
S
S
Nakamura
Y
Y
Seki
S
S
Uchida
T
T
Somada
A
A
Mori
M
M
Harada
Y
Y
Kamai
Y
Y
Harasaki
T
T
Fukuoka
T
T
Ohya
S
S
Yasuda
H
H
Shibayama
T
T
Inoue
S
S
Nakagawa
A
A
Seta
Y
Y
D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D015725:Fluconazole / Q000494:pharmacology; D005658:Fungi / Q000187:drug effects*; D007202:Indicators and Reagents; D017964:Itraconazole / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D014230:Triazoles / Q000138:chemical synthesis* / Q000494:pharmacology*
D000935:Antifungal Agents; D007202:Indicators and Reagents; D014230:Triazoles; C453343:R-120758; D017964:Itraconazole; D015725:Fluconazole