Linked Life Data

16539402

Source:http://linkedlifedata.com/resource/pubmed/id/16539402

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
6
pubmed:dateCreated
2006-3-16
pubmed:abstractText
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.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
23
pubmed:volume
49
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
2127-37
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed:year
2006
pubmed:articleTitle
Identification of compounds with anti-West Nile Virus activity.
pubmed:affiliation
Department of Medicinal Chemistry and Center for Drug Design, University of Minnesota, Minneapolis, Minnesota 55455, USA.
pubmed:publicationType
Journal Article, Research Support, N.I.H., Extramural