4-Aryl-2,4-dioxobutanoic Acid Inhibitors of HIV-1 Integrase and Viral Replication in Cells

Human immunodeficiency virus type 1 (HIV-1) is the etiological agent of acquired immunedeficiency syndrome (AIDS). The unique nature of the replicative cycle of HIV-1 provides many potential targets for chemotherapeutic intervention. One of these, the viral integrase, catalyzes the insertion of the proviral DNA into the genome of the host cell. Integration is a multistep process which includes three different biochemical processes: assembly of proviral DNA on integrase, endonucleolytic processing of the proviral DNA, and strand transfer of the proviral DNA to host cell DNA. Recently, diketo acid derivative 1 was reported to be a selective inhibitor of the strand-transfer process. This compound effectively prevents proviral DNA integration and inhibits HIV-1 replication in cell culture. In this Communication, we describe the chemistry and structure-activity relationships (SAR) of a series of diketo acids derived from 1.