3-Hydroxypyrimidine-2,4-diones as Selective Active Site Inhibitors of HIV Reverse Transcriptase-Associated RNase H: Design, Synthesis, and Biochemical Evaluations

Jing Tang, Feng Liu, Eva Nagy, Lena Miller, Karen A. Kirby, Daniel J. Wilson, Bulan Wu, Stefan G. Sarafianos, Michael A. Parniak, Zhengqiang Wang

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

Human immunodeficiency virus (HIV) reverse transcriptase (RT) associated ribonuclease H (RNase H) remains an unvalidated antiviral target. A major challenge of specifically targeting HIV RNase H arises from the general lack of selectivity over RT polymerase (pol) and integrase (IN) strand transfer (ST) inhibitions. We report herein the synthesis and biochemical evaluations of three novel 3-hydroxypyrimidine-2,4-dione (HPD) subtypes carefully designed to achieve selective RNase H inhibition. Biochemical studies showed the two subtypes with an N-1 methyl group (9 and 10) inhibited RNase H in low micromolar range without siginificantly inhibiting RT polymerase, whereas the N-1 unsubstituted subtype 11 inhibited RNase H in submicromolar range and RT polymerase in low micromolar range. Subtype 11 also exhibited substantially reduced inhibition in the HIV-1 INST assay and no significant cytotoxicity in the cell viability assay, suggesting that it may be amenable to further structure-activity relationship (SAR) for identifying RNase H inhibitors with antiviral activity.

Original languageEnglish (US)
Pages (from-to)2648-2659
Number of pages12
JournalJournal of medicinal chemistry
Volume59
Issue number6
DOIs
StatePublished - Mar 24 2016

Bibliographical note

Funding Information:
ACKNOWLEDGMENTS: This research was supported by the National Institutes of Health (AI100890 to S.G.S., M.A.P. and Z.W.) and partially by the Center for Drug Design, University of Minnesota.

Publisher Copyright:
© 2016 American Chemical Society.

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