Carbonyl J derivatives: A new class of HIV-1 integrase inhibitors

Integration of a DNA copy of the HIV-1 genome is required for viral replica tion and pathogenicity, and this highly specific molecular process is media ted by the virus-encoded integrase protein. The requirement for integration , combined with the lack of a known analogous process in mammalian cells, m akes integrase an attractive target for therapeutic inhibitors of HIV-1 rep lication. While many reports of HIV-1 IN inhibitors exist, no such compound s have yet emerged to treat HIV-1 infection. As such, new classes of integr ase inhibitors are needed. We have combined molecular modeling and combinat orial chemistry to identify and develop a new class of HIV-1 integrase inhi bitors, the Carbonyl J [N, N'-bis(2-(5-hydroxy-7-naphthalenesulfonic acid)u rea] derivatives. This new class includes a number of compounds with sub-mi cromolar IC50 values for inhibiting purl fled HIV-1 integrase in vitro. Her ein we describe the chemical characteristics that are important for integra se inhibition and cell toxicity within the Carbonyl J derivatives, (C) 2000 Academic Press.