Inhibitors of the NTPase/helicases of hepatitis C and related Flaviviridae viruses.

Abstract: In the search for inhibitors of the non-structural protein 3 (NS3)-associated NTPase/helicase activities of the hepatitis C virus (HCV), and of the related West Nile Virus (WNV), and Japanese Encephalitis Virus (JEV), random screening of a broad range of unrelated low-molecular weight compounds revealed that 4,5,6,7-tetrabromo-1H-benzotriazole (TBBT) is a good inhibitor of the helicase activity of HCV and WNV NTPase/helicases (IC50 >> 20 mM and 1.7 mM with a DNA substrate), but a very weak inhibitor of the JEV enzyme (IC50 >> 200 mM). The synthesis of new TBBT derivatives was undertaken and their inhibitory activities against HCV, WNV, and JEV NTPase/helicases and cytotoxicities were examined. The N-alkyl derivatives showed good activity and lower cytotoxicity than TBBT.