Design and synthesis of novel benzofurans as a new class of antifungal agents targeting fungal N-myristoyltransferase. Part 1.
Potent and selective Candida albicans N-myristoyltransferase (CaNmt) inhibitors have been identified through optimization of a lead compound 1 discovered by random screening. The inhibitor design is based on the crystal structure of the CaNmt complex with compound (S)-3 and structure-activity relationships (SARs) have been clarified. Modification of the C-4 side chain of 1 has led to the discovery of a potent and selective CaNmt inhibitor 11 (RO-09-4609), which exhibits antifungal activity against C. albicans in vitro.
Masubuchi
M
M
Nippon Roche Research Center, 200 Kajiwara, Kamakura, 247-8530, Kanagawa, Japan.
Kawasaki
K
K
Ebiike
H
H
Ikeda
Y
Y
Tsujii
S
S
Sogabe
S
S
Fujii
T
T
Sakata
K
K
Shiratori
Y
Y
Aoki
Y
Y
Ohtsuka
T
T
Shimma
N
N
D000217:Acyltransferases / Q000187:drug effects*; D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D001572:Benzofurans / Q000138:chemical synthesis* / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects / Q000201:enzymology*; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D011943:Receptors, Adrenergic, beta / Q000187:drug effects; D013045:Species Specificity; D013329:Structure-Activity Relationship
D000935:Antifungal Agents; D001572:Benzofurans; D011943:Receptors, Adrenergic, beta; D000217:Acyltransferases; C050480:glycylpeptide N-tetradecanoyltransferase