6-Biphenylmethyl-3-hydroxypyrimidine-2,4-diones potently and selectively inhibited HIV reverse transcriptase-associated RNase H

Lei Wang, Jing Tang, Andrew D. Huber, Mary C. Casey, Karen A. Kirby, Daniel J. Wilson, Jayakanth Kankanala, Michael A. Parniak, Stefan G. Sarafianos, Zhengqiang Wang

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

Human immunodeficiency virus (HIV) reverse transcriptase (RT)-associated ribonuclease H (RNase H) remains an unvalidated drug target. Reported HIV RNase H inhibitors generally lack significant antiviral activity. We report herein the design, synthesis, biochemical and antiviral evaluations of a new 6-biphenylmethyl subtype of the 3-hydroxypyrimidine-2,4-dione (HPD) chemotype. In biochemical assays, analogues of this new subtype potently inhibited RT RNase H in low nanomolar range without inhibiting RT polymerase (pol) or integrase strand transfer (INST) at the highest concentrations tested. In cell-based assays, a few analogues inhibited HIV in low micromolar range without cytotoxicity at concentrations up to 100 μM.

Original languageEnglish (US)
Pages (from-to)680-691
Number of pages12
JournalEuropean Journal of Medicinal Chemistry
Volume156
DOIs
StatePublished - Aug 5 2018

Keywords

  • 3-Hydroxypyrimidine-2,4-dione (HPD)
  • Human immunodeficiency virus (HIV)
  • Inhibitors
  • RNase H
  • Structure-activity-relationship (SAR)

PubMed: MeSH publication types

  • Journal Article

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