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

Details

• Alternative Title:
  Bioorg Med Chem Lett
• Personal Author:
  Xu, Jimin ; Xie, Xuping ; Chen, Haiying ; Zou, Jing ; Xue, Yu ; Ye, Na ; Shi, Pei-Yong ; Zhou, Jia
• Description:
  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 EC| values.
• Subjects:
  Antiviral Agents Article Cell Line Cell Survival Dengue Virus Drug Design Humans Membrane Proteins NS4B Inhibitors Pyridones Spiro Compounds Spiropyrazolopyridone Structure-Activity Relationship Structure-activity Relationship (SAR) Viral Nonstructural Proteins

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• Source:
  Bioorg Med Chem Lett. 30(11):127162
• Pubmed ID:
  32247736
• Pubmed Central ID:
  PMC8848308
• Document Type:
  Journal Article
• Funding:
  R01 AI127744/AI/NIAID NIH HHSUnited States/ ; U01CK000512/ACL/ACL HHSUnited States/ ; R41 AI136126/AI/NIAID NIH HHSUnited States/ ; U19 AI142759/AI/NIAID NIH HHSUnited States/ ; U01 CK000512/CK/NCEZID CDC HHSUnited States/
• Volume:
  30
• Issue:
  11
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:adc621654aa6a2e82e0e3e2d0e691158100da52cc5a95e763de318b4e0a16ce4
• Download URL:
  https://stacks.cdc.gov/view/cdc/114570/cdc_114570_DS1.pdf
• File Type:
  [PDF - 773.49 KB ]