Design, synthesis and biological evaluation of spiropyrazolopyridone derivatives as potent dengue virus inhibitors. Issue 11 (1st June 2020)

• Record Type: Journal Article
• Authors: Xu, Jimin; Xie, Xuping; Chen, Haiying; Zou, Jing; Xue, Yu; Ye, Na; Shi, Pei-Yong; Zhou, Jia
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 30:Issue 11(2020)
• Publication Date: 2020-06-01
• Subjects: Dengue virus -- Spiropyrazolopyridone -- NS4B inhibitors -- Antiviral agents -- Structure-activity relationship (SAR); Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2020.127162
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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.