Abstract
Bifunctional inhibitors were designed and synthesized based on 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT)a1 non-nucleoside reverse transcriptase (RT) inhibitors and diketoacid (DKA) integrase (IN) inhibitors. Biochemical studies revealed activity against RT and IN at low nanomolar and low micromolar concentrations, respectively. Exceptionally low IC50 values from a cell-based assay were achieved along with remarkably high therapeutic indices. Compound 7 was identified as the best compound of the series (IC50: 24 nM against RT, 4.4 microM against IN, and 10 nM against HIV-1).
Publication types
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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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Crystallography, X-Ray
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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 Reverse Transcriptase / antagonists & inhibitors*
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HIV-1 / drug effects
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HIV-1 / enzymology*
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Humans
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In Vitro Techniques
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Ketones / chemical synthesis*
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Ketones / chemistry
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Ketones / pharmacology
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Leukocytes, Mononuclear / drug effects
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Leukocytes, Mononuclear / virology
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Models, Molecular
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Structure-Activity Relationship
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Thymine / analogs & derivatives*
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Thymine / chemical synthesis
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Thymine / chemistry
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Thymine / pharmacology
Substances
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Anti-HIV Agents
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HIV Integrase Inhibitors
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Ketones
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1-((2-hydroxyethoxy)methyl)-6-(phenylthio)thymine
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HIV Reverse Transcriptase
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Thymine