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N-3 Hydroxylation of Pyrimidine-2,4-diones Yields Dual Inhibitors of HIV Reverse Transcriptase and Integrase

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Center for Drug Design, Academic Health Center, University of Minnesota, 516 Delaware Street SE, Minneapolis, Minnesota 55455, United States
Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, United States
*E-mail: [email protected]. Phone: +1 (612) 626-7025. Fax: +1 (612) 625-8154.
Cite this: ACS Med. Chem. Lett. 2011, 2, 1, 63–67
Publication Date (Web):October 22, 2010
Copyright © 2010 American Chemical Society

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    Abstract Image

    A new molecular scaffold featuring an N-hydroxyimide functionality and capable of inhibiting both reverse transcriptase (RT) and integrase (IN) of human immunodeficiency virus (HIV) was rationally designed based on 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) non-nucleoside RT inhibitors (NNRTIs). The design involves a minimal 3-N hydroxylation of the pyrimidine ring of HEPT compound to yield a chelating triad which, along with the existing benzyl group, appeared to satisfy major structural requirements for IN binding. In the mean time, this chemical modification did not severely compromise the compound’s ability to inhibit RT. A preliminary structure−activity relationship (SAR) study reveals that this N-3 OH is essential for IN inhibition and that the benzyl group on N-1 side chain is more important for IN binding than the one on C-6.

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    Synthesis of 1118, experimental details, compound characterization (1H, 13C NMR, HRMS), HPLC analysis for final products and assay methods. This material is available free of charge via the Internet at

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