Abstract
The increasing efficiency of HAART has helped to transform HIV/AIDS into a chronic disease. Still, resistance and drug-drug interactions warrant the development of new anti-HIV agents. We previously discovered hit 6, active against HIV-1 replication and targeting RNase H in vitro. Because of its diketo-acid moiety, we speculated that this chemotype could serve to develop dual inhibitors of both RNase H and integrase. Here, we describe a new series of 1-benzyl-pyrrolyl diketohexenoic derivatives, 7a-y and 8a-y, synthesized following a parallel solution-phase approach. Those 50 analogues have been tested on recombinant enzymes (RNase H and integrase) and in cell-based assays. Approximately half (22) exibited inhibition of HIV replication. Compounds 7b, 7u, and 8g were the most active against the RNase H activity of reverse-transcriptase, with IC50 values of 3, 3, and 2.5 μM, respectively. Compound 8g was also the most potent integrase inhibitor with an IC50 value of 26 nM.
Publication types
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
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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Cell Line, Tumor
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Cell Survival / drug effects
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Dose-Response Relationship, Drug
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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HIV Integrase / metabolism*
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HIV-1 / drug effects*
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HeLa Cells
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Humans
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Keto Acids / chemical synthesis
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Keto Acids / chemistry
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Keto Acids / pharmacology*
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Molecular Structure
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Pyrroles / chemical synthesis
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Pyrroles / chemistry
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Pyrroles / pharmacology*
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Ribonuclease H / antagonists & inhibitors*
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Ribonuclease H / metabolism
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Structure-Activity Relationship
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Virus Replication / drug effects
Substances
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6-(1-(4-fluorophenyl)methyl-1H-pyrrol-2-yl)-2,4-dioxo-5-hexenoic acid
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Anti-HIV Agents
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Enzyme Inhibitors
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Keto Acids
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Pyrroles
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HIV Integrase
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Ribonuclease H
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p31 integrase protein, Human immunodeficiency virus 1