Identification of compounds with anti-West Nile virus activity

John R. Goodell, Francesc Puig-Basagoiti, Brett M. Forshey, Pei-Yong Shi, David M. Ferguson

Research output: Contribution to journalArticle

116 Citations (Scopus)

Abstract

The lack of antiviral compounds targeting flaviviruses represents a significant problem in the development of strategies for treating West Nile Virus (WNV), Dengue, and Yellow Fever infections. Using WNV high-throughput screening techniques developed in our laboratories, we report the identification of several small molecule anti-WNV compounds belonging to four different structural classes including pyrazolines, xanthanes, acridines, and quinolines. The initial set of "hits" was further refined using cell viability-cytotoxicity assays to two 1,3,5-triaryl pyrazoline compounds: 1-(4-chlorophenylacetyl)-5-(4-nitrophenyl)-3-(thiophen-2-yl)-4, 5-dihydro-1H-pyrazole and 1-benzoyl-5-(4-chlorophenyl)-3-(thiophen-2-yl)-4,5- dihydro-1H-pyrazole. On the basis of their activity and favorable therapeutic indexes, these compounds were identified as viable leads and subjected to additional evaluation using an authentic viral titer reduction assay employing an epidemic strain of WNV. The compounds were further evaluated in a transient replicon reporting system to gain insight into the mechanism of action by identifying the step at which inhibition takes place during viral replication. The results indicate the pyrazolines inhibit RNA synthesis, pointing to viral RNA polymerase, RNA helicase, or other viral replication enzymes as potential targets. Progress was also made in understanding the structural requirements for activity by synthesizing a focused chemical library of substituted pyrazolines. Preliminary SAR data are presented that show the aryl-rings are required for activity against WNV. More importantly, the results indicate WNV activity is tolerant to aryl-substitutions paving the way for the design and development of much larger combinatorial libraries with varied physicochemical properties.

Original languageEnglish (US)
Pages (from-to)2127-2137
Number of pages11
JournalJournal of Medicinal Chemistry
Volume49
Issue number6
DOIs
StatePublished - Mar 23 2006
Externally publishedYes

Fingerprint

West Nile virus
Viruses
Assays
West Nile Fever
Quinolines
RNA Helicases
Small Molecule Libraries
Acridines
Yellow Fever
Flavivirus
Replicon
Dengue
Viral RNA
DNA-Directed RNA Polymerases
Cytotoxicity
Antiviral Agents
Cell Survival
Screening
Substitution reactions
Cells

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Goodell, J. R., Puig-Basagoiti, F., Forshey, B. M., Shi, P-Y., & Ferguson, D. M. (2006). Identification of compounds with anti-West Nile virus activity. Journal of Medicinal Chemistry, 49(6), 2127-2137. https://doi.org/10.1021/jm051229y

Identification of compounds with anti-West Nile virus activity. / Goodell, John R.; Puig-Basagoiti, Francesc; Forshey, Brett M.; Shi, Pei-Yong; Ferguson, David M.

In: Journal of Medicinal Chemistry, Vol. 49, No. 6, 23.03.2006, p. 2127-2137.

Research output: Contribution to journalArticle

Goodell, JR, Puig-Basagoiti, F, Forshey, BM, Shi, P-Y & Ferguson, DM 2006, 'Identification of compounds with anti-West Nile virus activity', Journal of Medicinal Chemistry, vol. 49, no. 6, pp. 2127-2137. https://doi.org/10.1021/jm051229y
Goodell, John R. ; Puig-Basagoiti, Francesc ; Forshey, Brett M. ; Shi, Pei-Yong ; Ferguson, David M. / Identification of compounds with anti-West Nile virus activity. In: Journal of Medicinal Chemistry. 2006 ; Vol. 49, No. 6. pp. 2127-2137.
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