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 language | English (US) |
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Article number | 127162 |
Journal | Bioorganic and Medicinal Chemistry Letters |
Volume | 30 |
Issue number | 11 |
DOIs | |
State | Published - 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