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Rationally Designed Dual Inhibitors of HIV Reverse Transcriptase and Integrase

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Download Hi-Res ImageDownload to MS-PowerPointCite This:J. Med. Chem. 2007, 50, 15, 3416-3419
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    Rationally Designed Dual Inhibitors of HIV Reverse Transcriptase and Integrase
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    Center for Drug Design, Academic Health Center, University of Minnesota, 308 Harvard Street SE, Minneapolis, Minnesota 55455
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2007, 50, 15, 3416–3419
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    https://doi.org/10.1021/jm070512p
    Published July 4, 2007
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    Abstract

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    Bifunctional inhibitors were designed and synthesized based on 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT)a 1 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 μM against IN, and 10 nM against HIV-1).

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     To whom correspondence should be addressed. Phone:  612-624-9911. Fax:  612-626-6891. E-mail:  [email protected].

    Abbreviations:  HIV, human immunodeficiency virus; AIDS, acquired immunodeficiency syndrome; HEPT, 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine; RT, reverse transcriptase; IN, integrase; PR, protease; NNRTIs, non-nucleoside reverse transcriptase inhibitors; NRTIs, nucleoside reverse transcriptase inhibitors; DKA, diketoacid; FDA, Food and Drug Administration; TI, therapeutic index.

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    Synthesis of 6−9, experimental details (1H and 13C NMR, HRMS, HPLC) for intermediates and final products, assay and molecular modeling methods. This material is available free of charge via the Internet at http://pubs.acs.org.

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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2007, 50, 15, 3416–3419
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    https://doi.org/10.1021/jm070512p
    Published July 4, 2007
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