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Malar J. 2017 Apr 13;16(1):147. doi: 10.1186/s12936-017-1805-0.

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

Author information

1
National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Bethesda, MD, 20892, USA.
2
Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.
3
Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD, 20814, USA. kim.williamson@usuhs.edu.
4
National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Bethesda, MD, 20892, USA. wzheng@mail.nih.gov.

Abstract

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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

KEYWORDS:

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

PMID:
28407766
PMCID:
PMC5390467
DOI:
10.1186/s12936-017-1805-0
[Indexed for MEDLINE]
Free PMC Article

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