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 journalArticlepeer-review

1 Scopus citations

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

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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