title: Design and synthesis of novel benzofurans as a new class of antifungal agents targeting fungal N-myristoyltransferase. Part 2.
abstract: 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.
authors.affiliation: Department of Chemistry, Nippon Roche Research Center, 200 Kajiwara, Kamakura, 247-8530, Kanagawa, Japan.
authors.forename: Hirosato
authors.initials: H
authors.lastname: Ebiike
authors.forename: Miyako
authors.initials: M
authors.lastname: Masubuchi
authors.forename: Pingli
authors.initials: P
authors.lastname: Liu
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Kawasaki
authors.forename: Kenji
authors.initials: K
authors.lastname: Morikami
authors.forename: Satoshi
authors.initials: S
authors.lastname: Sogabe
authors.forename: Michiko
authors.initials: M
authors.lastname: Hayase
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Fujii
authors.forename: Kiyoaki
authors.initials: K
authors.lastname: Sakata
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Shindoh
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Shiratori
authors.forename: Yuko
authors.initials: Y
authors.lastname: Aoki
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Ohtsuka
authors.forename: Nobuo
authors.initials: N
authors.lastname: Shimma
mesh_terms: 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
chemical_list: D000935:Antifungal Agents; D001572:Benzofurans; D000217:Acyltransferases; C050480:glycylpeptide N-tetradecanoyltransferase