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 journalArticlepeer-review

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

Bibliographical note

Funding Information:
This research was supported in part by the National Institutes of Health (AI100890 to SGS, MAP and ZW), and by the Research Development and Seed Grant Program of the Center for Drug Design, University of Minnesota.

Publisher Copyright:
© 2017 Elsevier Masson SAS

Keywords

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

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