Synthesis, biological evaluation and molecular modeling of 2-Hydroxyisoquinoline-1,3-dione analogues as inhibitors of HIV reverse transcriptase associated ribonuclease H and polymerase

Jing Tang, Sanjeev Kumar V. Vernekar, Yue Lei Chen, Lena Miller, Andrew D. Huber, Nataliya Myshakina, Stefan G. Sarafianos, Michael A. Parniak, Zhengqiang Wang

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Human immunodeficiency virus (HIV) reverse transcriptase (RT) associated ribonuclease H (RNase H) remains the only virally encoded enzymatic function not clinically validated as an antiviral target. 2-Hydroxyisoquinoline-1,3-dione (HID) is known to confer active site directed inhibition of divalent metal-dependent enzymatic functions, such as HIV RNase H, integrase (IN) and hepatitis C virus (HCV) NS5B polymerase. We report herein the synthesis and biochemical evaluation of a few C-5, C-6 or C-7 substituted HID subtypes as HIV RNase H inhibitors. Our data indicate that while some of these subtypes inhibited both the RNase H and polymerase (pol) functions of RT, potent and selective RNase H inhibition was achieved with subtypes 8–9 as exemplified with compounds 8c and 9c.

Original languageEnglish (US)
Pages (from-to)85-96
Number of pages12
JournalEuropean Journal of Medicinal Chemistry
Volume133
DOIs
StatePublished - 2017

Keywords

  • 2-hydroxyisoquinoline-1,3-diones
  • HIV
  • Inhibitor
  • RNase H
  • Reverse transcriptase

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