Design, synthesis and biological evaluation of spiropyrazolopyridone derivatives as potent dengue virus inhibitors

Jimin Xu, Xuping Xie, Haiying Chen, Jing Zou, Yu Xue, Na Ye, Pei Yong Shi, Jia Zhou

Research output: Contribution to journalArticle

Abstract

The effective treatment for dengue virus infection continues to be a challenge. We herein reported our continued SAR exploration on the spiropyrazolopyridone scaffold. Introducing different substituents at the 3́- or 5́-site of the pyrazolopyridone core or moving the benzyl chain to the adjacent nitrogen led to a significant loss of potency on DENV-2. While a narrow range of substitutions were tolerated at the para-position of the phenyl ring, di-substitution on the phenyl ring is beneficial for DENV-2 potency and has variable influences on DENV-3 potency depending on the exact compound. Among these molecules, compounds 22 (JMX0376) with 4-chloro-3-fluorobenzyl and 24 (JMX0395) with 2,4-bis(trifluoromethyl)benzyl showed the most potent and broadest inhibitory activities against DENV-1 to −3 with nanomolar to low micromolar EC50 values.

Original languageEnglish (US)
Article number127162
JournalBioorganic and Medicinal Chemistry Letters
Volume30
Issue number11
DOIs
StatePublished - Jun 1 2020

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Keywords

  • Antiviral agents
  • Dengue virus
  • NS4B inhibitors
  • Spiropyrazolopyridone
  • Structure-activity relationship (SAR)

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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