Synthesis and Anti-HCV Activity of 2,6-Bisarylmethyloxy-5-hydroxy-7-phenylchromones

Abstract

Hepatitis C virus (HCV) was identified to be the causative agent of non-A-non-B viral hepatitis in the late 1989. Approximately 80% of the acute infections become chronic, leading to liver cirrhosis and hepatic cellular carcinoma, but a protective vaccine does not exist yet and the current therapeutic options are very limited. Previously, we reported potent anti-HCV activity of the 5hydroxychromone derivatives, 6-arylmethyl-5-hydroxy-7phenylchromone (1, Fig. 1) and 2-arylmethyloxy-6-(3chlorobenzyloxy)-5-hydroxychromome (2, Fig. 1), of which aromatic substituents (R, Fig. 1) were found to play the critical role for antiviral activity. In both cases, electron withdrawing substituents on the aromatic C-3 or C-3' position provided the resulting 5-hydroxychromone derivative with significantly enhanced antiviral activity against HCV. In addition, compound 2 having 3'-substituted arylmethoxy group showed higher anti-HCV activity than the corresponding analogue of 1. This result suggests that the HCV RdRp might have a binding site specific for the 5-hydroxychromone scaffold around which two hydrophobic pockets are located. In this study, as a part of our ongoing efforts to discover a potent anti-HCV compound, we designed a novel 5-hydroxychromone derivative with a combination of structures 1 and 2. Herein, we report synthesis of 2,6-bis(arylmethyloxy)-5-hydroxy-7-phenylchromone derivatives (3) with various metaor paraelectron withdrawing aromatic substituents (R = F, Cl, Br, I, CN, NO2, CF3) and evaluation of their anti-HCV activities. The synthetic route to the title compounds, 2,6-bis(arylmethyloxy)-5-hydroxy-7-phenylchromes (3a-3k) is outlined in Scheme 1. Following our previous protocols, 1-[5-hydroxy-2,3-dimethoxy-(1,1'-biphenyl)-4-yl]ethanone (4) was prepared from commercially available 5-bromovanilline. Treatment of 4 with a mixture of LiHMDS, CS2, and MeI in THF provided the corresponding ketene dithioacetal, which was then cyclized under basic conditions to give 5 in 41% yield. Oxidation of 5 was accomplished by mCPBA to 6 (83% yield), of which methanesulfonyl group was displaced with benzyloxy moiety upon treatment with benzyl alcohol and NaH in THF to furnish 7 in 49% yield. Lewis acid-catalyzed cleavage of methyl and benzyl ether linkages of 7 provided the free chromone 8 in 90% yield. Due to the intramolecular hydrogen bonding between 4-keto and 5-OH