Synthesis of Sordaricin analogues as potent antifungal agents against Candida albicans.
Sordaricin derivatives possessing a cyclohexane ring appendage attached via an ether, thioether, amine, oxime, ester or amide linkage were synthesized and their antifungal activity was evaluated in vitro. Compounds containing a thioether bond or an oxime bond as a linkage exhibited potent MICs (< or = 0.125 microg/mL) against four Candida albicans strains including azole-low-susceptible strains. They were also active (MIC < or = 0.125 microg/mL) against Candida glabrata. Their in vivo efficacy was confirmed in a murine intravenous infection model with Candida albicans.
Kaneko
Satoru
S
Medicinal Chemistry Research Laboratories, Sankyo Co., Ltd., 2-58, Hiromachi 1-chome, Shinagawa-ku, 140-8710, Tokyo, Japan. skanek@shina.sankyo.co.jp
Uchida
Takuya
T
Shibuya
Satoshi
S
Honda
Takeshi
T
Kawamoto
Isao
I
Harasaki
Tamako
T
Fukuoka
Takashi
T
Konosu
Toshiyuki
T
D000818:Animals; D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001424:Bacterial Infections / Q000188:drug therapy; D001952:Bridged-Ring Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002176:Candida albicans / Q000187:drug effects* / Q000254:growth & development; D004224:Diterpenes; D051379:Mice; D008826:Microbial Sensitivity Tests
D000935:Antifungal Agents; D001952:Bridged-Ring Compounds; D004224:Diterpenes; C116705:sordaricin