Discovery of naphtho[1,2-d]oxazole derivatives as potential anti-HCV agents through inducing heme oxygenase-1 expression.

A number of naphtho[1,2-d]oxazole derivatives were synthesized and evaluated for their anti-HCV virus activity. Among them, compound 18 was the most active, exhibited approximately 21-folds more active anti-HCV activity (IC50 of 0.63 μM) than that of ribavirin (IC50  = 13.16 μM). Compound 18 was less cytotoxic than ribavirin, and the selective index (SI) of 18 is approximately 28-folds higher than that of ribavirin (229.10 v.s. 8.08). By using heme oxygenase-1 (HO-1) promoter-based assay and western blotting, compound 18 could induce HO-1 promoter activity, and protein expression. The antiviral effect of compound 18 was attenuated by HO-1 specific inhibitor SnPP treatment, which indicated that compound 18 suppressed HCV replication through inducing HO-1 expression. We further found that compound 18 reduced bach1 expression resulting in increasing the activity of Nrf-2 binding element. Moreover, the induction of HO-1 by compound 18 reduced HCV NS3/4A protease activity and induced the antiviral interferon responses. Therefore, compound 18 can be considered as a supplemental antiviral agent or a lead compound for further developing more effective agents against HCV replication.