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




Novel lead structures with both Plasmodium falciparum gametocytocidal and asexual blood stage activity identified from high throughput compound screening - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Malaria Journal

, 16:147

First Online: 13 April 2017Received: 29 November 2016Accepted: 06 April 2017DOI: 10.1186-s12936-017-1805-0

Cite this article as: Sun, W., Huang, X., Li, H. et al. Malar J 2017 16: 147. doi:10.1186-s12936-017-1805-0

Abstract

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.

KeywordsMalaria Transmission blocking Gametocyte Asexual parasite Blood stage Dual-efficacy High throughput screen Cheminformatics Novel structures Dark chemical matter Electronic supplementary materialThe online version of this article doi:10.1186-s12936-017-1805-0 contains supplementary material, which is available to authorized users.

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Autor: Wei Sun - Xiuli Huang - Hao Li - Gregory Tawa - Ethan Fisher - Takeshi Q. Tanaka - Paul Shinn - Wenwei Huang - Kim C. W

Fuente: https://link.springer.com/







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