Antileishmanial High-Throughput Drug Screening Reveals Drug Candidates with New Scaffolds
- Department for International Development
- 1 January 2010
- Document Type:
- Journal Article
- Nam, J., Chatelain, E., Freitas-Junior, L.H., Yang, G., Siqueira Neto, J.L. Song, O.R., Oh, H., Sohn, J.H., Jang, J., Cechetto, J., Lee, C.B., Moon, S., Genovesio, A., and Christophe, T.
Drugs currently available for leishmaniasis treatment often show parasite resistance, highly toxic side effects and costs that are prohibitive commonly for patients from the tropical endemic countries. There is an urgent need for new drugs as a treatment solution for this neglected disease. Here the authors describe the development and implementation of an automated high-throughput viability screening assay for the discovery of new drugs against Leishmania. Assay validation was done with Leishmania promastigote forms, and included the screening of 4000 compounds with known pharmacological properties. In an attempt to find new compounds with leishmanicidal properties, 26,500 structurally diverse chemical compounds were screened. A cut-off of 70% growth inhibition in the primary screening led to the identification of 567 active compounds. Cellular toxicity and selectivity were responsible for the exclusion of 78% of the pre-selected compounds. The activity of the remaining 124 compounds was confirmed against the intramacrophagic amastigote form of the parasite. In vitro microsomal stability and cytochrome P450 (CYP) inhibition of the two most active compounds from this screening effort were assessed to obtain preliminary information on their metabolism in the host. The HTS approach employed here resulted in the discovery of two new antileishmanial compounds (a hydrazine and a quinoline), bringing promising candidates to the leishmaniasis drug discovery pipeline.
PLoS Neglected Tropical Diseases 4 (5) e675 [doi:10.1371/journal.pntd.0000675]
Published: 1 January 2010