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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Design, synthesis, and biological activities of closantel analogues: Structural promiscuity and its impact on onchocerca volvulus
Journal of Medicinal Chemistry, Volume 54, No. 11, Year 2011
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Description
Onchocerciasis, or river blindness, is a neglected tropical disease that affects more than 37 million people worldwide, primarily in Africa and Central and South America. We have disclosed evidence that the larval-stage-specific chitinase, OvCHT1, may be a potential biological target for affecting nematode development. On the basis of screening efforts, closantel, a known anthelmintic drug, was discovered as a potent and highly specific OvCHT1 inhibitor. Originally, closantel's anthelmintic mode of action was believed to rely solely on its role as a proton ionophore; thus, the impact of each of its biological activities on O. volvulus L3moltingwas investigated. Structure-activity relationship studies on an active closantel fragment are detailed, and remarkably, by use of a simple salicylanilide scaffold, compounds acting only as protonophores or chitinase inhibitors were identified. From these data, unexpected synergistic protonophore and chitinase inhibition activities have also been found to be critical for molting in O. volvulus L3 larvae. © 2011 American Chemical Society.
Authors & Co-Authors
Garner, Amanda L.
United States, San Diego
Scripps Research Institute
Gloeckner, Christian Johannes
United States, San Diego
Scripps Research Institute
Tricoche, Nancy
United States, New York
New York Blood Center
Zakhari, Joseph S.
United States, San Diego
Scripps Research Institute
Samje, Moses
Cameroon, Buea
University of Buea
Cho-Ngwa, Fidelis
Cameroon, Buea
University of Buea
Lustigman, Sara
United States, New York
New York Blood Center
Janda, Kim D.
United States, San Diego
Scripps Research Institute
Statistics
Citations: 27
Authors: 8
Affiliations: 3
Identifiers
Doi:
10.1021/jm200364n
ISSN:
00222623
e-ISSN:
15204804
Research Areas
Infectious Diseases