Derivatives of imidazotriazine and pyrrolotriazine C-nucleosides as potential new anti-HCV agents

Previous investigations identified 2′-C-Me-branched ribo-C-nucleoside adenosine analogues, 1, which contains a pyrrolo[2,1-f][1,2,4]triazin-4-amine heterocyclic base, and 2, which contains an imidazo[2,1-f][1,2,4]triazin-4-amine heterocyclic base as two compounds with promising anti-HCV in vitro activity. This Letter describes the synthesis and evaluation of a series of novel analogues of these compounds substituted at the 2-, 7-, and 8-positions of the heterocyclic bases. A number of active new HCV inhibitors were identified but most compounds also demonstrated unacceptable cytotoxicity. However, the 7-fluoro analogue of 1 displayed good potency with a promising cytotherapeutic margin. © 2014 Elsevier Ltd.

Keywords

Viral diseases, Hepatitis, Infectious hepatitis, RNA, Therapy, Viruses

Citation

Draffan, A. G., Frey, B., Fraser, B. H., Pool, B., Gannon, C., Tyndall, E. M., Cianci, J., Harding, M., Lilly, M., Hufton, R., Halim, R., Jahangiri, S., Bond., Jeynes, T. P., Nguyen V. T. T., Wirth, V., Luttick, A., Tilmanis, D., Pryor, M., Porter, K., Morton, C. J., Lin, B., Duan, J., Bethell, R. C., Kukolj, G., Sinoneau, B., & Tucker, S. P. (2014). Derivatives of imidazotriazine and pyrrolotriazine C-nucleosides as potential new anti-HCV agents. Bioorganic & Medicinal Chemistry Letters, 24(21), 4984-4988. doi:10.1016/j.bmcl.2014.09.030