Abstract
Analogues or isosteres of α,γ-diketoacid (DKA) 1a show potent inhibition of hepatitis C virus (HCV) NS5B polymerase through chelation of the two magnesium ions at the active site. The anti-HCV activity of the flavonoid quercetin (2) could partly be attributed to it being a structural mimic of DKAs. In order to delineate the structural features required for the inhibitory effect and improve the anti-HCV potency, two novel types of quercetin analogues, 7-O-arylmethylquercetins and quercetin-3-O-benzoic acid esters, were designed, synthesized and evaluated for their anti-HCV properties in cell-based assays. Among the 38 newly synthesized compounds, 7-O-substituted derivative 3i and 3-O-substituted derivative 4f were found to be the most active in the corresponding series (EC50 = 3.8 μM and 9.0 μΜ, respectively). Docking studies suggested that the quercetin analogues are capable of establishing key coordination with the two magnesium ions as well as interactions with residues at the active site of HCV NS5B.
Highlights
It was estimated that about 170 million people worldwide were chronically infected by hepatitis C virus (HCV) and were at risk of developing liver cirrhosis and/or hepatocellular carcinoma [1]
DKA analogues or isosteres show potent inhibition of HCV NS5B through chelation of the two magnesium ions at the active site
Experimental and modeling results highlighted the importance of introducing an aromatic group at 7-O position, which is exemplified by compound 3i, where a 3-chlorobenzyl substitution at quercetin 7-O position confers low micromolar inhibitory activity (EC50 = 3.8 μM) and a decent selectivity ratio (SI = 7.2)
Summary
It was estimated that about 170 million people worldwide were chronically infected by hepatitis C virus (HCV) and were at risk of developing liver cirrhosis and/or hepatocellular carcinoma [1]. Recent advances in the development of direct acting antivirals (DAAs) have significantly improved SVR in patients, providing a new hope for cure in infected patients. Three NS3/4A protease inhibitors were approved by FDA for the treatment of genotype 1 hepatitis C, and in late 2013, sofosbuvir, a first-in-class NS5B polymerase inhibitor, was launched and became a cornerstone of recommended HCV therapy against almost all HCV genotypes [4,5,6,7]. The pivotal role of the divalent cations in the active site of the HCV polymerase supports the rational basis of the inhibition of this enzyme by metal chelating motifs
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