Development of tricyclic hydroxy-1H-pyrrolopyridine-trione containing HIV-1 integrase inhibitors

Abstract

New tricyclic HIV-1 integrase (IN) inhibitors were prepared that combined structural features of bicyclic pyrimidinones with recently disclosed 4,5-dihydroxy-1H-isoindole-1,3(2H)-diones. This combination resulted in the introduction of a nitrogen into the aryl ring and the addition of a fused third ring to our previously described inhibitors. The resulting analogues showed low micromolar inhibitory potency in in vitro HIV-1 integrase assays, with good selectivity for strand transfer relative to 3′-processing.

Activities, Crystal Structures, and Molecular Dynamics of Dihydro-1H-isoindole Derivatives, Inhibitors of HIV-1 Integrase

“…The 50% cytotoxicity concentrations (CC 50 ) were determined as previously described (21). HOS cells were seeded in a 96-well luminescence cell culture plate at a density of 4000 cells in 100 μL per well.…”

Bicyclic Hydroxy‐1H‐pyrrolopyridine‐trione Containing HIV‐1 Integrase Inhibitors

“…To a refluxing solution of acetic anhydride (15 mmol), and N ‐(3‐chloro‐4‐flourobenzyl)maleimide 9 (1.5 mmol) (17) and p ‐toluenesulfonic acid (2 mg) in toluene (20 mL), a solution of ethanesulfinylacetyl‐containing substrate 8 (1.5 mmol) in toluene (2 mL) was added dropwise and the mixture was stirred at reflux (1 h). The mixture was then concentrated and purified by silica gel column chromatography.…”

“…Reaction of N ‐Icetyl‐2‐ethanesulfinyl‐ N ‐phenylacetamide [prepared from N ‐phenylacetamide ( 6b )] (18) and N ‐(3‐chloro‐4‐flourobenzyl)maleimide ( 9 ) (17), according to General Procedure C, provided 10b in 41% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 7.43–7.30 (m, 5H), 7.20–7.17 (m, 1H), 7.14–7.11 (m, 1H), 7.06–7.01 (m, 1H), 4.59 (q, J = 14.5 Hz, 2H), 3.56 (d, J = 6.7 Hz, 1H), 3.39 (d, J = 6.7 Hz, 1H), 2.85 (q, J = 7.5 Hz, 2H), 1.76 (s, 3H), 1.29 (t, J = 7.5 Hz, 3H).…”

“…More recently, we prepared and tested tricyclic hydroxy‐1 H ‐pyrrolopyridine‐triones ( 4 ) as IN inhibitors. These compounds remove the catechol functionality by combining 3 with features of 2 (Figure 1) (17). However, although these compounds had the desired reduction in cytotoxicity, they suffered from a loss of IN inhibitory potency.…”

Pyrroloaryls and pyrroloheteroaryls: Inhibitors of the HIV fusion/attachment, reverse transcriptase and integrase

“…Tricyclic hydroxy-1H-pyrrolopyridine-triones (38a, 38b) were furnished recently and tested for their HIV-1 integrase inhibitory potential against 3'-processing and strand transfer, in which all 28a and 38b were having moderate potential against 3'-processing with >111 µM of IC 50 level, while against strand transfer, compounds 38i, 38ii, 38iii, 38iv, 38bi, 38bii, 38biii and 38biv indicated 6.0±0.7 µM, 10.4±1.0 µM, 6.01 µM, 9.2±1.4 µM, 10.9±1.4 µM, 9.1±1.1 µM, 6.0±0.7 µM and 5.4±0.8 µM of IC 50 s, respectively. In addition, these analogues were less sensitive than raltegravir towards its resistant HIV mutant strains, G140S/Q148H, Y143R and N155H[77].Furthermore, bicyclic hydroxy-1H-pyrrolopyridine-triones(39) were explored by the same group of researchers targeting 3'-processing as HIV integrase inhibitors synthesized via Pumerer cyclization deprotonation cycloaddition. Anti-HIV evaluation against raltegravir-resistant integrase enzyme mutants revealed IC 50 s, 6.7±0.7 µM, 6.4±0.6 µM, 15.6±3.7 µM, 7.1±0.6 µM, 12.3±0.8 µM, 6.5±0.6 µM for analogues 39i, 39ii and 39iv-39vii, respectively[78].…”