【文章名】Design, Synthesis, and Biological Evaluation of a Series of 2-Hydroxyisoquinoline-1,3(2H,4H)-diones as Dual Inhibitors of Human Immunodeficiency Virus Type 1 Integrase and the Reverse Transcriptase RNase H Domain.
Design, Synthesis, and Biological Evaluation of a Series of 2-Hydroxyisoquinoline-1,3(2H,4H)-diones as Dual Inhibitors of Human Immunodeficiency Virus Type 1 Integrase and the Reverse Transcriptase RNase H Domain.
[摘要]：The synthesis of a series of 2-hydroxyisoquinoline-1,3(2H,4H)-diones I (R = H, NO2, Cl, Br, I, OH, NHCOMe, 4-HCC6h4, etc.) variously substituted at the position 7 aimed at inhibiting selectively two-metal ion catalytic active sites is reported. The compds. I were tested against HIV-1 reverse transcriptase (RT) polymerase, HIV-1 RT RNase H (RNase H), and HIV-1 integrase (IN). Most compds. displayed poor inhibition of RT polymerase even at 50 mM. The majority of the synthesized compds. inhibited RNase H and IN at micromolar concns., and some of them were weakly selective for IN. Surprisingly, two new hits were discovered, which displayed a high selectivity for IN with submicromolar IC50 values. These enzymic inhibitory properties may be related to the metal binding abilities of the compds. Physicochem. studies were consistent with a 1:1 stoichiometry of the magnesium complexes in soln., and the metal complexation was strictly dependent on the enolization abilities of the compds. Unfortunately, all tested compds. exhibited high cellular cytotoxicity in cell culture which limits their applications as antiviral agents.
