Design and synthesis of novel benzofurans as a new class of antifungal agents targeting fungal N-myristoyltransferase. Part 3.
A new series of acid-stable antifungal agents having strong inhibitory activity against Candida albicans N-myristoyltransferase (CaNmt) has been developed starting from acid-unstable benzofuranylmethyl aryl ether 2. The inhibitor design is based on X-ray crystallographic analysis of a CaNmt complex with aryl ether 3. Among the new inhibitors, pyridine derivative 8b and benzimidazole derivative 8k showed clear antifungal activity in a murine systemic candidiasis model.
Kawasaki
Ken-ichi
K
Department of Chemistry, Nippon Roche Research Center, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
Masubuchi
Miyako
M
Morikami
Kenji
K
Sogabe
Satoshi
S
Aoyama
Tsunehisa
T
Ebiike
Hirosato
H
Niizuma
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; D001572:Benzofurans / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D002176:Candida albicans / Q000187:drug effects / Q000201:enzymology; D004195:Disease Models, Animal; D015195:Drug Design; D004355:Drug Stability; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D005656:Fungal Proteins / Q000037:antagonists & inhibitors*; D020128:Inhibitory Concentration 50; D051379:Mice; D008958:Models, Molecular; D013329:Structure-Activity Relationship
D000935:Antifungal Agents; D001572:Benzofurans; D004791:Enzyme Inhibitors; D005656:Fungal Proteins; D000217:Acyltransferases; C050480:glycylpeptide N-tetradecanoyltransferase