Screening a Natural Product-Based Library against Kinetoplastid Parasites

Abstract

Kinetoplastid parasites cause vector-borne parasitic diseases including leishmaniasis, human African trypanosomiasis (HAT) and Chagas disease. These Neglected Tropical Diseases (NTDs) impact on some of the world's lowest socioeconomic communities. Current treatments for these diseases cause severe toxicity and have limited efficacy, highlighting the need to identify new treatments. In this study, the Davis open access natural product-based library was screened against kinetoplastids (<i>Leishmania donovani</i> DD8, <i>Trypanosoma brucei brucei</i> and <i>Trypanosoma cruzi</i>) using phenotypic assays. The aim of this study was to identify hit compounds, with a focus on improved efficacy, selectivity and potential to target several kinetoplastid parasites. The IC₅₀ values of the natural products were obtained for <i>L. donovani</i> DD8, <i>T. b. brucei</i> and <i>T. cruzi</i> in addition to cytotoxicity against the mammalian cell lines, HEK-293, 3T3 and THP-1 cell lines were determined to ascertain parasite selectivity. Thirty-one compounds were identified with IC₅₀ values of ≤ 10 µM against the kinetoplastid parasites tested. Lissoclinotoxin E (<b>1</b>) was the only compound identified with activity across all three investigated parasites, exhibiting IC₅₀ values < 5 µM. In this study, natural products with the potential to be new chemical starting points for drug discovery efforts for kinetoplastid diseases were identified.