BIOLOGICAL AND BIOCHEMICAL ANTI-HIV ACTIVITY OF THE BENZOTHIADIAZINE CLASS OF NONNUCLEOSIDE REVERSE-TRANSCRIPTASE INHIBITORS

A series of benzothiadiazine derivatives were screened against the hum an immunodeficiency virus (HIV) and certain structure-activity relatio nships were defined for anti-HIV activity in this chemical class. The selected representative NSC 287474 was a highly potent inhibitor of HI V-induced cell killing and HIV replication in a variety of human cell lines, as well as in fresh human peripheral blood lymphocytes and macr ophages. The compound was active against a panel of biologically diver se laboratory and clinical strains of HIV-1, including the AZT-resista nt strain G910-6. However, the agent was inactive against HIV-2, and a lso against both nevirapine- and pyridinone-resistant strains (N119 an d A17) of HIV-1, which are cross-resistant to several structurally div erse nonnucleoside reverse transcriptase inhibitors. The compound sele ctively inhibited HIV-1 reverse transcriptase, but not HIV-2 reverse t ranscriptase. Combination of NSC 287474 with AZT synergistically inhib ited HIV-1-induced cell killing in vitro. The compound did not inhibit the replication of the Rauscher murine leukemia retrovirus or the sim ian immunodeficiency virus. The benzothiadiazine class of compounds re presents a new active anti-HIV-1 chemotype within the diverse group of nonnucleoside reverse transcriptase inhibitors.