Synthesis of new benzimidazole–coumarin conjugates as anti-hepatitis C virus agents

Nineteen new conjugated compounds were successfully synthesized by a one-flask method from benzimidazole and coumarin derivatives. A methylenethio linker was used to connect these two kinds of derivatives. In addition, substituted benzimidazol-2-thiones were also coupled with β-d-glucose peracetate; the resultant glucosides were further converted to the corresponding 2-(methylthio)coumarin derivatives. Their activity against the hepatitis C virus was tested; two of the most potent compounds 2-[(6′-bromocoumarin-3′-yl)methylenethio]-5-fluorobenzimidazole (4i) and its derivative 1-[(2″,3″,4″,6″-tetra-O-acetyl)glucopyranos-1″-yl]-2-[(6′-bromocoumarin-3′-yl)methylenethio]benzimidazole (7c) showed EC50 values of 3.4 μM and 4.1 μM, respectively. At a concentration of 5.0 μM, compound 7c inhibited HCV RNA replication by 90% and had no effect on cell proliferation. Given these data, a structure–activity relationship was established.