HIV-1 integrase (IN) is a validated therapeutic target for the treatment of AIDS. The first FDA-approved HIV-1 integrase (IN) inhibitor, Merck's IsentressTM (MK-0518 or Raltegravir), shares key structural features with other IN inhibitors. These features include a co-planar arrangement of heteroatoms that chelate magnesium ions and halogen-substituted aromatic functionality linked to the chelating portion of the molecule that interacts with a region formed between a viral DNA base and the protein in the IN�DNA complex. The emergence of Raltegravir-resistant IN mutants demonstrates a need to develop new IN inhibitors that can overcome this resistance. A co-crystal of Raltegravir bound to the Prototype Foamy virus (PFV) IN complexed with DNA provides insights into the basis for the resistance caused by mutations in IN. Based on our previously reported 4,5-dihydroxy-1H-isoindole-1,3(2H)-diones, which are structurally simple IN inhibitors that exhibit good potency and strand transfer selectivity in vitro in the presence of Mg2+ cofactor, a series of bicylic and tricylic hydroxy-pyrrolopyridine-trione-containing analogues were prepared by insertion of a nitrogen into the original ring system. This simultaneously combines structural features of our original inhibitors with Merck's pyrimidinone IN inhibitors. The efficient synthesis of these compounds relies on the application of a �Pummerer cyclization deprotonation cycloaddition� cascade of imidosulfoxides as well as [3+2] cycloaddition of isom�nchnones. Nitrogen substituent introducing into the catechol ring to give the 2(1H)-pyridone moiety reduces collateral cytotoxicity and improves potency against IN mutants resistant to Raltegravir.The biological evaluation of these agents, including activity profiles against mutant forms of IN that are resistant to raltegravir will be presented.

Hydroxy-pyrrolopyridine-trione based HIV-1 integrase inhibitors

244th National Meeting (2012)

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