Novel lead structures with both Plasmodium falciparum gametocytocidal and asexual blood stage activity identified from high throughput compound screening

Malaria Journal

Research

Kim C. Williamson¹  Takeshi Q. Tanaka²  Wei Sun³  Wenwei Huang³  Wei Zheng³  Xiuli Huang³  Hao Li³  Ethan Fisher³  Paul Shinn³  Gregory Tawa³ 

[1]Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, 20814, Bethesda, MD, USA

[2]Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA

[3]National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, 20892, Bethesda, MD, USA

关键词: Malaria;    Transmission blocking;    Gametocyte;    Asexual parasite;    Blood stage;    Dual-efficacy;    High throughput screen;    Cheminformatics;    Novel structures;    Dark chemical matter;   

DOI  :  10.1186/s12936-017-1805-0

 received in 2016-11-29, accepted in 2017-04-06,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundBlocking 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.MethodsTo 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.ResultsA 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.ConclusionsThis study revealed important new structural scaffolds that can be used as starting points for dual activity anti-malarial drug development.

【 授权许可】

CC BY   
© The Author(s) 2017