HYDRAZIDE INHIBITORS OF HIV-1 INTEGRASE

WIPO Patent Application WO2000053577

A9

The design, synthesis and antiviral activity of novel mercaptosalicylhydrazides are disclosed, which inhibit human immunodeficiency virus type-1 integrase (HIV-1 IN), an essential enzyme for effective viral replication. Examples of the compounds are N,N'-bis(2-mercaptobenzoyl)hydrazide, N,N'-bis(2,2'-dithiosalicyl)hydrazide, and N,N'-bis(2-mercaptobenzyl)-2,2'-dithiosalicylhydrazide. These compounds are effective against the integrase catalytic core domain, inhibit integrase binding to HIV LTR DNA, and inhibit integrase in preassmbled integrase-DNA complexes. The disclosed mercaptosalicylhydrazides are 300 fold less cytotoxic than other known salicylhydrazides, and exhibit antiviral activity. They are also active in Mg<+2>-based assays, while integrase inhibition by salicylhydrazides is strictly Mn<+2>-dependent. The mercaptosalicylhydrazides have no detectable effect on other retroviral targets, including reverse transcriptase, protease, and virus attachment, and exhibit no detectable activity against human topoisomerase I at concentrations that effectively inhibited integrase. The mercaptosalicylhydrazides of the invention are therefore selective inhibitors of HIV-1 integrase, are useful in therapeutic compositions for the treatment of HIV disease, and can also be used to find related antiviral drugs.

NEAMATI NOURI (US)
POMMIER YVES (US)
LIN ZHAIWEI (US)
BURKE TERRENCE (US)

PCT/US2000/006361

September 20, 2001

March 10, 2000

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US GOV HEALTH & HUMAN SERV (US)
NEAMATI NOURI (US)
POMMIER YVES (US)
LIN ZHAIWEI (US)
BURKE TERRENCE (US)

A61P31/18; C07C323/62; C07D215/48; C07D285/00; (IPC1-7): C07C323/62; A61K31/167; A61P31/18; C07D285/00

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