Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 4, Issue 6, Pages 547-550Publisher
AMER CHEMICAL SOC
DOI: 10.1021/ml4001112
Keywords
antiviral; influenza A; quinolinones; 3-hydroxyquinolin-2-ones; endonuclease
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Funding
- NCRR [1S10RR23698-1A1]
- NIH National Center for Research Resources [P41RR0954]
- NSF & NIH/NIGMS via NSF [DMR-0225180]
- NIH/NCRR [RR-01646]
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Several 3-hydroxyquinolin-2(1H)-ones. derivatives were synthesized and evaluated as inhibitors of 2009 pandemic H1N1 influenza A endonuclease. All five of the monobrominated 3-hydroxyquinolin (1H)-2-ones derivatives were synthesized. Suzuki-coupling of p-fluorophenylboronic acid with each of these brominated derivatives provided the respective p-fluorophenyl hydroxyquinolin (1H)-2-ones. In addition to 3-hydroxyquinolin-2 (1H)-one, its 4-methyl, 4-phenyl, 4-methyl-7-(p-fluorophenyl), and 4-phenyl-7-(p-fluorophenyl) derivatives were also synthesized. Comparative studies on their relative activity revealed that both 6- and 7-(p-fluorophenyl)-3- hydroxyquinolin-2(1H)-one are among the more potent inhibitors of H1N1 influenza A endonuclease. An X-ray crystal structure of 7-(p-fluorophenyl)-3-hydroxyquinolin-2(1H)-one complexed to the influenza endonuclease revealed that this molecule chelates to two metal ions at the active site of the enzyme.
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