Oxoquinoline acyclonucleoside phosphonate analogues as a new class of specific inhibitors of human immunodeficiency virus type 1

The emergence of a multidrug-resistant HIV-1 strain and the toxicity of anti-HIV-1 compounds approved for clinical use are the most significant problems facing antiretroviral therapies. Therefore, it is crucial to find new agents to overcome these issues. In this study, we synthesized a series of new oxoquinoline acyclonucleoside phosphonate analogues (ethyl 1-[(diisopropoxyphosphoryl)methyl]-4-oxo-1,4-dihydroquinoline-3-carboxylates 3a–3k), which contained different substituents at the C6 or C7 positions of the oxoquinoline nucleus and an N1-bonded phosphonate group. We subsequently investigated these compounds’ in vitro inhibitory effects against HIV-1-infected peripheral blood mononuclear cells (PBMCs). The most active compounds were the fluoro-substituted derivatives 3f and 3g, which presented excellent EC50 values of 0.4 ± 0.2 μM (3f) and 0.2 ± 0.005 μM (3g) and selectivity index values (SI) of 6240 and 14675, respectively.

In this work we report the synthesis and in vitro anti-HIV-1 evaluation of a new class of oxoquinoline acyclonucleoside phosphonate analogues ethyl 1-[(diisopropoxyphosphoryl)methyl]-4-oxo-1,4-dihydroquinoline-3-carboxylates 3a–3k.Figure optionsDownload as PowerPoint slide