Title |
Novel lead structures with both Plasmodium falciparum gametocytocidal and asexual blood stage activity identified from high throughput compound screening
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Published in |
Malaria Journal, April 2017
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DOI | 10.1186/s12936-017-1805-0 |
Pubmed ID | |
Authors |
Wei Sun, Xiuli Huang, Hao Li, Gregory Tawa, Ethan Fisher, Takeshi Q. Tanaka, Paul Shinn, Wenwei Huang, Kim C. Williamson, Wei Zheng |
Abstract |
Blocking malaria transmission is an important step in eradicating malaria. In the field, transmission requires the production of sexual stage Plasmodium parasites, called gametocytes, which are not effectively killed by the commonly used anti-malarials allowing individuals to remain infectious after clearance of asexual parasites. To identify new gametocytocidal compounds, a library of 45,056 compounds with diverse structures was screened using a high throughput gametocyte viability assay. The characteristics of active hits were further evaluated against asexual stage parasites in a growth inhibition assay. Their cytotoxicity were tested against mammalian cells in a cytotoxicity assay. The chemical scaffold similarity of active hits were studied using scaffold cluster analysis. A set of 23 compounds were identified and further confirmed for their activity against gametocytes. All the 23 confirmed compounds possess dual-activities against both gametocytes responsible for human to mosquito transmission and asexual parasites that cause the clinical symptoms. Three of these compounds were fourfold more active against gametocytes than asexual parasites. Further cheminformatic analysis revealed three sets of novel scaffolds, including highly selective 4-1H-pyrazol-5-yl piperidine analogs. This study revealed important new structural scaffolds that can be used as starting points for dual activity anti-malarial drug development. |
X Demographics
Geographical breakdown
Country | Count | As % |
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Unknown | 4 | 100% |
Demographic breakdown
Type | Count | As % |
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Members of the public | 2 | 50% |
Science communicators (journalists, bloggers, editors) | 2 | 50% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
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Unknown | 42 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
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Researcher | 11 | 26% |
Student > Ph. D. Student | 7 | 17% |
Student > Master | 5 | 12% |
Student > Postgraduate | 2 | 5% |
Student > Bachelor | 2 | 5% |
Other | 1 | 2% |
Unknown | 14 | 33% |
Readers by discipline | Count | As % |
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Biochemistry, Genetics and Molecular Biology | 10 | 24% |
Pharmacology, Toxicology and Pharmaceutical Science | 4 | 10% |
Agricultural and Biological Sciences | 4 | 10% |
Immunology and Microbiology | 2 | 5% |
Chemistry | 2 | 5% |
Other | 1 | 2% |
Unknown | 19 | 45% |