3- O-Arylmethylgalangin, a novel isostere for anti-HCV 1,3-diketoacids (DKAs)

• Published in: Bioorganic & medicinal chemistry 2010-11, Vol.18 (21), p.7331-7337
• Main Authors: Lee, Hyo Seon, Park, Kwang-su, Lee, Bokhui, Kim, Dong-Eun, Chong, Youhoon
• Format: Article
• Language: English
• Subjects: 1,3-Diketoacid; 3- O-Arylmethylgalangin; Acids; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Biological and medical sciences; Cell Line, Tumor; Flavonoids - chemical synthesis; Flavonoids - chemistry; Flavonoids - pharmacology; Hepacivirus - drug effects; Hepatitis C virus; Hepatitis C Virus (HCV); Humans; Isostere; Keto Acids - chemical synthesis; Keto Acids - chemistry; Keto Acids - pharmacology; Medical sciences; Pharmacology. Drug treatments; Protease Inhibitors - chemical synthesis; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacology; Structure-Activity Relationship; Viral Nonstructural Proteins - antagonists & inhibitors; Viral Nonstructural Proteins - metabolism
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2010.09.021

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.