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

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.