1,3-dihydroxyacridone derivatives as inhibitors of herpes virus replication

The nuclear enzyme DNA topoisomerase II is a candidate pharmacological target for treating herpes virus infections and the novel catalytic inhibitors, 7-chloro-1,3-dihydroxyacridone (compound 1), and 1,3,7-trihydroxyacridone (2) are potential lead compounds [Bastow, K.F., Itoigawa, M., Furukawa, H., Kashiwada, Y., Bori, I.D., Ballas, L.M., Lee, K.-H., 1994. Antiproliferative actions of 7-substituted 1,3-dihydroxyacridones; possible involvement of DNA topoisomerase II and protein kinase C as biochemical targets. Bioorg. Med. Chem. 2, 1403-1411; Vance, J.R., Bastow, K.F., 1999. Inhibition of DNA topoisomerase II catalytic activity by the antiviral agents 7-chloro,1,3-dihydroxyacridone and 1,3,7-trihydroxyacridone. Biochem. Pharmacol. 58, 703-708]. In this report, four new 1,3-dihydroxyacridone analogs with functional groups at either the 5-, 6- or 8-positions (compounds 3-6) were synthesized. Target compounds, three other analogs including compounds 1 and 2 and three anticancer drugs that inhibit DNA topoisomerase II (etoposide, amsacrine and aclarubicin) were then evaluated as selective inhibitors of herpes simplex virus (HSV) replication in cell culture and as enzyme inhibitors in vitro. Etoposide and amsacrine inhibited HSV but acted non-selectively. In general, the activities of 1,3-dihydroxyacridone derivatives as selective anti-HSV agents and as enzyme inhibitors varied inversely suggesting that DNA topoisomerase II probably is not the critical antiviral target. The 5-Cl congener (compound 3) was the most selective agent (about 26-fold under a stringent assay condition) but was not an enzyme inhibitor. Results of exploratory mechanistic studies with compounds 1 and 3 show that HSV replication was blocked at a stage after DNA and late protein synthesis. The acridone derivatives were also tested against human cytomegalovirus (HCMV) replication but none of them were active. (C) 2000 Elsevier Science B.V. All rights reserved.