Abstract
Human immunodeficiency virus type-1 integrase is an essential enzyme for effective viral replication and hence a valid target for the design of inhibitors. We report here on the design and synthesis of a novel series of phthalimide analogues as integrase inhibitors. The short synthetic pathway enabled us to synthesize a series of analogues with a defined structure diversity. The presence of a single carbonyl-hydroxy-aromatic nitrogen motif was shown to be essential for the enzymatic activity and this was confirmed by molecular docking studies. The enzymatically most active compound from this series is 7-(3,4-dichlorobenzyl)-5,9-dihydroxypyrrolo[3,4-g]quinoxaline-6,8-dione (15l) with an IC(50) value of 112 nM on the HIV-1 integrase enzyme, while ((7-(4-chlorobenzyl)-5,9-dihydroxy-pyrrolo[3,4-g]quinoxaline-6,8-dione (15k)) showed an EC(50) of 270 nM against HIV-1 in a cell-based assay.
MeSH terms
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Anti-HIV Agents / chemical synthesis*
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Anti-HIV Agents / chemistry
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Anti-HIV Agents / pharmacology
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Binding Sites
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Cell Line
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HIV Integrase / chemistry
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HIV Integrase / metabolism*
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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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Heterocyclic Compounds, 3-Ring / chemical synthesis*
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Heterocyclic Compounds, 3-Ring / chemistry
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Heterocyclic Compounds, 3-Ring / pharmacology
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Humans
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Models, Molecular
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Phthalimides / chemical synthesis*
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Phthalimides / chemistry
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Phthalimides / pharmacology
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Protein Binding
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Pyrroles / chemical synthesis*
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Pyrroles / chemistry
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Pyrroles / pharmacology
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Quinoxalines / chemical synthesis*
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Quinoxalines / chemistry
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Quinoxalines / pharmacology
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Structure-Activity Relationship
Substances
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7-(3,4-dichlorobenzyl)-5,9-dihydroxypyrrolo(3,4-g)quinoxaline-6,8-dione
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7-(4-chlorobenzyl)-5,9-dihydroxypyrrolo(3,4-g)quinoxaline-6,8-dione
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Anti-HIV Agents
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HIV Integrase Inhibitors
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Heterocyclic Compounds, 3-Ring
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Phthalimides
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Pyrroles
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Quinoxalines
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HIV Integrase