Design, Synthesis, and Biological Evaluations of Hydroxypyridonecarboxylic Acids as Inhibitors of HIV Reverse Transcriptase Associated RNase H

Jayakanth Kankanala, Karen A. Kirby, Feng Liu, Lena Miller, Eva Nagy, Daniel J. Wilson, Michael A. Parniak, Stefan G. Sarafianos, Zhengqiang Wang

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

Targeting the clinically unvalidated reverse transcriptase (RT) associated ribonuclease H (RNase H) for human immunodeficiency virus (HIV) drug discovery generally entails chemotypes capable of chelating two divalent metal ions in the RNase H active site. The hydroxypyridonecarboxylic acid scaffold has been implicated in inhibiting homologous HIV integrase (IN) and influenza endonuclease via metal chelation. We report herein the design, synthesis, and biological evaluations of a novel variant of the hydroxypyridonecarboxylic acid scaffold featuring a crucial N-1 benzyl or biarylmethyl moiety. Biochemical studies show that most analogues consistently inhibited HIV RT-associated RNase H in the low micromolar range in the absence of significant inhibition of RT polymerase or IN. One compound showed reasonable cell-based antiviral activity (EC50 = 10 μ). Docking and crystallographic studies corroborate favorable binding to the active site of HIV RNase H, providing a basis for the design of more potent analogues.

Original languageEnglish (US)
Pages (from-to)5051-5062
Number of pages12
JournalJournal of medicinal chemistry
Volume59
Issue number10
DOIs
StatePublished - May 26 2016

Fingerprint Dive into the research topics of 'Design, Synthesis, and Biological Evaluations of Hydroxypyridonecarboxylic Acids as Inhibitors of HIV Reverse Transcriptase Associated RNase H'. Together they form a unique fingerprint.

  • Cite this