Inhibition of human immunodeficiency virus type I integrase by naphthamidines and 2-aminobenzimidazoles

Retroviral integrases catalyze two of the steps of insertion of proviral DNA into the host genomic DNA. Inhibitors that target the second step, strand transfer into the host DNA, have been demonstrated to have antiviral activity in cell culture. We describe two classes of HIV-1 integrase inhibitors that block strand transfer, one based on a naphthamidine core and one on a benzimidazole core. While the naphthamidine compounds showed some propensity to interact with the DNA substrate, both classes were shown to bind directly to integrase. The naphthamidine compounds showed activity in cell culture, and a direct effect on integrase was indicated by an increase in 2-LTR products in the presence of a naphthamidine compound. These two classes of compounds represent potential starting points for the development of new classes of integrase inhibitors. (C) 2004 Elsevier B.V. All rights reserved.