Design, synthesis and anti-HIV-1 evaluation of a series of 5-hydroxypyridine-4-one derivatives as possible integrase inhibitors

Abstract

A series of 5-hydroxypyridine-4-one derivatives were synthesized and subjected to HIV-1 replication inhibition assay. Docking studies provide a detailed molecular binding model for this class of compounds interacting with integrase enzyme. All of the derivatives were recognized potent in the docking studies in terms of both the estimated free energy change of binding and interactions with integrase key elements. 5a, 5c, 5d, 5h and 5n exhibited good anti-HIV-1 activities in cell-based assay. Compound 5d was the most potent derivative not only in vitro but also in silico. 5c and 5h offered the highest therapeutic indices. Suboptimal lipophilicity of 6b, 6g, 6i, 6j, 6l and 5m made them inactive in assays, despite the high activity in the docking studies.