Abstract
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.
Publication types
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Research Support, N.I.H., Intramural
MeSH terms
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Benzamides / chemical synthesis
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Benzamides / chemistry
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Benzamides / pharmacology
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Catalysis
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Cations, Divalent
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Cell Line
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Cell Line, Tumor
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Genetic Vectors
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HIV Integrase Inhibitors / chemical synthesis*
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HIV Integrase Inhibitors / chemistry
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HIV Integrase Inhibitors / pharmacology
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HIV-1 / drug effects*
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HIV-1 / genetics
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Humans
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Hydrazines / chemical synthesis
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Hydrazines / chemistry
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Hydrazines / pharmacology
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Isoindoles / chemical synthesis*
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Isoindoles / chemistry
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Isoindoles / pharmacology
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Magnesium / metabolism
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Molecular Conformation
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Structure-Activity Relationship
Substances
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Benzamides
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Cations, Divalent
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HIV Integrase Inhibitors
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Hydrazines
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Isoindoles
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Magnesium