Human immunodeficiency virus type 1 (HIV-1) integrase, which catalyzes the insertion of proviral DNA into the host cell genome, is a key target for AIDS chemotherapy. Diketo acid derivative 1 was previously reported as a selective inhibitor of the strand-transfer process of integrase. In this study, we modified the structure of 1 to explore the chemistry and structure-activity relationships (SAR) of a series of diketo acid analogs. Replacing the central pyrrole ring of 1 with various aromatic systems and optimizing substituents on the distal benzene ring led to the development of potent 3-benzylphenyl diketo acid inhibitors. The most active compounds, such as 19, inhibit HIV-1 replication in cell culture with CIC95 values ranging from 0.10 to 0.62 µM, which is a 100-fold improvement in potency compared to the lead compound 1. Compound 19 is only 2-fold less potent than the protease inhibitor indinavir (CIC95 0.055 ± 0.019 µM) in the same assay. No cytotoxicity was observed at concentrations up to 50 µM. These results indicate that these diketo acid derivatives are promising candidates for the development of new antiviral agents to treat HIV infection.