2-Mercaptobenzenesulphonamides as Novel Inhibitors of Human Immunodeficiency virus Type 1 Integrase and Replication

Abstract

An obligatory requirement in the retroviral life cycle is the integration of the viral dsDNA into the host chromosome, a process performed by viral integrase. The retroviral integrase is able to catalyse at least three discrete enzymatic steps. Two of these steps, 3' processing and DNA strand transfer, can be measured in an in vitro assay in the presence of a duplex oligonucleotide corresponding to the viral long terminal repeat, recombinant integrase and the divalent cations, Mg 2+ or Mn 2+ . This assay provides an efficient means of testing integrase inhibitors. As part of our continuous effort in developing novel inhibitors we examined a series of 2-mercapto-benzenesulphonamides (MBSAs) for their inhibitory activity against human immunodeficiency virus type 1 (HIV-1) integrase. From the list of compounds tested in an assay specific for HIV-1 integrase, 26 compounds inhibited the 3' processing and strand transfer step with 50% inhibitory concentration (IC 50 ) values below 25 μM. All the thioether derivatives were inactive. These results were further compared with the ability of MBSAs to protect HIV-1-injected T4 lymphocyte CEM cells. Among 68 compounds tested, 27 exhibited antiviral activity in cell-based assays with therapeutic indices of 1-16. All the MBSAs with antiviral activity were also effective inhibitors of recombinant HIV-1 integrase. Several aromatic disulphides were also tested and found to exhibit moderate antiviral and anti-integrase activities. These data demonstrate that MBSAs can be developed as inhibitors of HIV-1 integrase with the potential for antiviral activity.