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J Med Chem. 2008 Jan 24;51(2):251-9. Epub 2007 Dec 21.

2,3-dihydro-6,7-dihydroxy-1H-isoindol-1-one-based HIV-1 integrase inhibitors.

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Laboratory of Medicinal Chemistry and HIV Drug Resistance Program, Center for Cancer Research, National Cancer Institute-Frederick, National Institutes of Health, Frederick, Maryland 21702, USA.


The bis-salicylhydrazides class of HIV-1 integrase (IN) inhibitors has been postulated to function by metal chelation. However, members of this series exhibit potent inhibition only when Mn2+ is used as cofactor. The current study found that bis-aroylhydrazides could acquire inhibitory potency in Mg2+ using dihydroxybenzoyl substituents as both the right and left components of the hydrazide moiety. Employing a 2,3-dihydro-6,7-dihydroxy-1 H-isoindol-1-one ring system as a conformationally constrained 2,3-dihydroxybenzoyl equivalent provided good selectivity for IN-catalyzed strand transfer versus the 3'-processing reactions as well as antiviral efficacy in cells using HIV-1 based vectors.

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