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

Abstract

We report herein the synthesis of a series of 19 2-hydroxyisoquinoline-1,3(2H,4H)-dione derivatives variously substituted at position 7 aimed at inhibiting selectively two-metal ion catalytic active sites. The compounds were tested against HIV-1 reverse transcriptase (RT) polymerase, HIV-1 RT ribonuclease H (RNase H), and HIV-1 integrase (IN). Most compounds displayed poor inhibition of RT polymerase even at 50 microM. The majority of the synthesized compounds inhibited RNase H and IN at micromolar concentrations, 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 enzymatic inhibitory properties may be related to the metal binding abilities of the compounds. Physicochemical studies were consistent with a 1/1 stoichiometry of the magnesium complexes in solution, and the metal complexation was strictly dependent on the enolization abilities of the compounds. Unfortunately, all tested compounds exhibited high cellular cytotoxicity in cell culture which limits their applications as antiviral agents.

Structural and Inhibition Studies of the RNase H Function of Xenotropic Murine Leukemia Virus-Related Virus Reverse Transcriptase

“…Some of these inhibitors were initially discovered as HIV-1 integrase inhibitors (85,89) and were designed as active-site-directed compounds that would bind divalent metals at the integrase or RNase H active site (2,8,9,21,42,87,88). Acylhydrazone-based (11,30,35,80), hydroxyisoquinolinedione-based (8,9), and naphthyridinonebased (84,95) compounds are three classes of HIV-1 RNHIs. Like most RNHIs, these compounds are based on metal-chelating pharmacophore scaffolds that have been optimized for potent inhibition of HIV-1 RNase H. Our data are consistent with previous results suggesting that naphthyridinone NAPHRHI binds to the RNase H active site of HIV-1 RT and extend these findings for XMRV RNase H (95).…”

“…Such drugs would likely be active against all current drug-resistant viral strains, because the RNase H active site is located at the opposite end of the enzyme from the polymerase domain (ϳ50 Å away) that is currently targeted by nucleoside and nonnucleoside RT inhibitors (79). Several compounds have been found in recent years to effectively inhibit the RNase H activity of HIV-1 RT, including ␣,␥-diketo acids and derivatives (27,77,78,91), pyrimidinol carboxylic acids (43,47), hydroxytropolones (including ␤-thujaplicinol) (6,12,15,21,34), dimeric lactones (19), 1,3,4,5-tetragalloylapiitol (86), phenolic glycosides (10), vinylogous ureas (16,94), N-hydroxyimides (33,44), 2-hydroxyisoquinoline-1,3(2H,4H)-diones (8,9), acylhydrazones (11,30,35,80), and naphthyridinones (84,95). Although these inhibitors have been studied for the ability to inhibit HIV-1 RT, little is known about their effectiveness against other retroviral RTs, such as the gammaretroviral Moloney murine leukemia virus (MoMLV) and xenotropic murine leukemia virus-related virus (XMRV) RTs.…”

2-Hydroxyisoquinoline-1,3(2H,4H)-dione

“…For the biological properties of the title compound, see: Parkes et al (2003); Hang et al (2004); Billamboz et al (2008). For a related structure, see: Miao et al (1995).…”

“…The title compound is known to inhibit metalloenzymes such as influenza endonuclease (Parkes et al, 2003), HIV-1 reverse transcriptase RNase H (Hang et al, 2004), and HIV-1 integrase (Billamboz et al, 2008). Here we report the crystal structure of the title compound, which was obtained from the deprotection of 2-benzyloxyisoquinoline-1,3(2H,4H)-dione by the use of boron tribromide.…”

“…The title compound was synthesized according to the literature (Billamboz et al, 2008). Single crystals suitable for X-ray diffraction were obtained by slow evaporation of an acetone solution of the compound at room temperature.…”