Indolocarbazoles: Potent, selective inhibitors of human cytomegalovirus replication

In our search for new, safer anti-HCMV agents, we discovered that the natur al product Arcyriaflavin A (la) was a potent inhibitor of HCMV replication in cell culture. A series of analogues (symmetrical indolocarbazoles) was s ynthesised to investigate structure-activity relationships in this series a gainst 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-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7-(6H)-dione (Id) be ing the best example (IC50 = 40 nM, therapeutic index > 1450). Compounds de scribed in this series were generally poor inhibitors of protein kinase C b eta II, and no correlation was found between the ability to inhibit HCMV an d the enzyme PKC. (C) 1999 Elsevier Science Ltd. All rights reserved.