Synthesis and biological evaluation of novel 5(H)-phenanthridin-6-ones, 5(H)-phenanthridin-6-one diketo acid, and polycyclic aromatic diketo acid analogs as new HIV-1 integrase inhibitors

A new series of phenanthridinone derivatives, and diketo acid analogs, as well as related phenanthrene and anthracene diketo acids have been synthesized and evaluated as HIV integrase (IN) inhibitors. Several new β-diketo acid analogs with the phenanthridinone scaffold replaced by phenanthrene, anthracene or pyrene exhibited the highest IN inhibitory potency. There is a general selectivity against the integrase strand transfer step. The most potent IN was 2,4-dioxo-4-phenanthren-9-yl-butyric acid (27f) with an IC50 of 0.38 μM against integrase strand transfer. The phenanthrene diketo acids 27d–f were more potent (IC50 = 2.7–0.38 μM) than the corresponding phenanthridinone diketo acid 16 (IC50 = 65 μM), suggesting that the polar amide bridge in the phenanthridinone system decreases inhibitory activity relative to the more lipophilic phenanthrene system. This might have to do with the possible binding of the aryl group of the compounds binding to a lipophilic pocket at the integrase active site as suggested by the docking simulations. Molecular modeling also suggested that effectiveness of chelation of the active site Mg2+ contributes to IN inhibitory potency. Finally, some of the potent compounds inhibited HIV-1 replication in human peripheral blood mononuclear cells (PBMC) with EC50 down to 8 μM for phenanthrene-3-(2,4-dioxo)butyric acid (27d), with a selectivity index of 10 against PBMCs.

Substitution of β-diketo acid moiety onto the phenanthridinone and analogous polycyclic aromatic systems provided new potent HIV integrase (IN) inhibitors. The best IN inhibitor was, phenanthrene diketo acid, 2,4-dioxo-4-phenanthren-9-yl-butyric acid (27f), with an IC50 of 0.38 μM against integrase strand transfer reaction. Compound 27d had the best anti-viral activity against HIV replication in peripheral blood mononuclear cells, with an EC50 of 8.0 μM and selectivity index of 10.Figure optionsDownload as PowerPoint slide