Inhibition of HIV Replication and Integrase Activity by 4-[(1,2-dihydro-2-oxo-3H-indol-3-ylidene)amino]- N-(4,6-dimethyl-2-pyrimidinyl)-Benzenesulphonamide and Derivatives

We evaluated the broadspectrum antiretroviral activity of 4-[(1,2-dihydro-2-oxo-3H-indol-3-ylidene)amino]N-(4,6-dimethyl-2-pyrimidinyl)-benzene sulphonamide and its derivatives using different strains of HIV-1, HIV-2 and SIV. Several SPIII derivatives were found to inhibit HIV-1 (IIIB and NL4.3) replication in MT-4 cells at EC50 values ranging from 3.6 to 49.6 μg/ml. No cytotoxicity was observed at concentrations up to 125 μg/ml in mock-infected MT-4 cells. The compounds were evaluated for their inhibitory effects against a variety of mutant HIV strains. The SPIII derivatives showed low level resistance (up to 11-fold) to NL4.3 virus strains resistant to agents that block virus entry, i.e. NL4.3 strains resistant to the binding inhibitor dextran sulphate or the CXCR4 antagonist AMD3100. Moreover, the SPIII-5Br and 5Cl derivatives showed some low level cross-resistance to an integrase inhibitorresistant virus. We observed no crossresistance against the fusion inhibitor, nucleoside reverse transcriptase, nonnucleoside reverse transcriptase or protease inhibitor resistant HIV strains. The SPIII compounds were found to inhibit the human immunodeficiency virus type 1 integrase enzymatic activity, HIV-1 integrase binding to target DNA and adsorption of HIV-1 to MT-4 cells, all at IC50 values in the μg/ml range. We conclude that it would be interesting to synthesize and evaluate more derivatives of SPIII to identify more selective congeners. These compounds would enable us to determine the structural requirements for inhibition of entry or integration steps in the replication cycle of HIV.