Design and synthesis of novel benzofurans as a new class of antifungal agents targeting fungal N-myristoyltransferase. Part 2.
Modification of the C-2 position of a benzofuran derivative 6 (RO-09-4609), an N-myristoyltransferase (Nmt) inhibitor, has led us to discover antifungal agents that are active in a murine systemic candidiasis model. The drug design is based on the analysis of a crystal structure of a Candida Nmt complex with 2. The optimization has been guided by various biological evaluations including a quasi in vivo assay and pharmacokinetic analysis.
Ebiike
Hirosato
H
Department of Chemistry, Nippon Roche Research Center, 200 Kajiwara, Kamakura, 247-8530, Kanagawa, Japan.
Masubuchi
Miyako
M
Liu
Pingli
P
Kawasaki
Ken-ichi
K
Morikami
Kenji
K
Sogabe
Satoshi
S
Hayase
Michiko
M
Fujii
Toshihiko
T
Sakata
Kiyoaki
K
Shindoh
Hidetoshi
H
Shiratori
Yasuhiko
Y
Aoki
Yuko
Y
Ohtsuka
Tatsuo
T
Shimma
Nobuo
N
D000217:Acyltransferases / Q000037:antagonists & inhibitors*; D000818:Animals; D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D019540:Area Under Curve; D001572:Benzofurans / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology; D002176:Candida albicans / Q000187:drug effects / Q000201:enzymology; D002177:Candidiasis / Q000188:drug therapy; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D015195:Drug Design; D006801:Humans; D051379:Mice; D011485:Protein Binding; D051381:Rats; D011916:Rats, Inbred F344; D013329:Structure-Activity Relationship
D000935:Antifungal Agents; D001572:Benzofurans; D000217:Acyltransferases; C050480:glycylpeptide N-tetradecanoyltransferase