Indolocarbazoles: potent, selective inhibitors of human cytomegalovirus replication

Abstract

In our search for new, safer anti-HCMV agents, we discovered that the natural product Arcyriaflavin A ( 1a) was a potent inhibitor of HCMV replication in cell culture. A series of analogues (symmetrical indolocarbazoles) was synthesised to investigate structure–activity relationships in this series against a range of herpes viruses (HCMV, VZV, HSV1, and 2). This identified a number of novel, selective and potent inhibitors of HCMV, 12,13-dihydro-2,10-difluoro-5 H-indolo[2,3- a]pyrrolo[3,4- c]carbazole-5,7-(6 H)-dione ( 1d) being the best example (IC 50=40 nM, therapeutic index >1450). Compounds described in this series were generally poor inhibitors of protein kinase C βII, and no correlation was found between the ability to inhibit HCMV and the enzyme PKC.