title: 3-O-arylmethylgalangin, a novel isostere for anti-HCV 1,3-diketoacids (DKAs).
abstract: Through chelation of the metal ions at the enzyme active site, 1,3-diketoacids (DKAs) show potent inhibition of viral enzymes such as HIV integrase and HCV NS5B. In order to optimize the antiviral activity of the DKAs, structural modification of their metal-binding units, keto-enol acids or monoketo acids, have been actively performed. In this study, we proposed 3-O-arylmethylgalangin 3 as an alternative to ortho-substituted aromatic DKA, a potent inhibitor of HCV NS5B. As a proof-of-concept study, a series of 3-O-arylmethylgalangin derivatives (3a-3r) were prepared and their inhibitory activity against HCV NS5B was estimated. Structure-activity relationship of the 3-O-arylmethylgalangin derivatives was in good accordance with that of the ortho-substituted aromatic DKA series. In particular, two galangin ethers (3g and 3i) completely superimposable with the most potent ortho-substituted aromatic DKA analogue (2) in atom-by-atom fashion showed equipotent inhibitory activity to that of 2. Taken together, this result provides convincing evidence that the 3-O-arylmethylgalangin can successfully mimic the chelating function of the DKA pharmacophore to show potent inhibitory activity against the target enzyme, HCV NS5B.
authors.affiliation: Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Hwayang-dong, Gwangjin-gu, Seoul 143-701, Republic of Korea.
authors.forename: Hyo Seon
authors.initials: HS
authors.lastname: Lee
authors.forename: Kwang-Su
authors.initials: KS
authors.lastname: Park
authors.forename: Bokhui
authors.initials: B
authors.lastname: Lee
authors.forename: Dong-Eun
authors.initials: DE
authors.lastname: Kim
authors.forename: Youhoon
authors.initials: Y
authors.lastname: Chong
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D005419:Flavonoids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D016174:Hepacivirus / Q000187:drug effects*; D006801:Humans; D007651:Keto Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D005419:Flavonoids; D007651:Keto Acids; D011480:Protease Inhibitors; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase