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Widespread drug (anthelmintic) resistance in livestock parasites, the absence of vaccines against most of these nematodes, and a lack of new and effective chemical entities on the commercial market demands the discovery of new anthelmintics. In the present study, we searched the Global Health Priority Box (Medicines for Malaria Venture) for new candidates for anthelmintic development.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We employed a whole-organism, motility-based phenotypic screening assay to identify compounds from the Global Health Priority Box with activity against larvae of the model parasite\n                      <jats:italic>H. contortus<\/jats:italic>\n                      , and the free-living comparator nematode\n                      <jats:italic>Caenorhabditis elegans<\/jats:italic>\n                      . Hit compounds were further validated via dose\u2013response assays, with lead candidates then assessed for nematocidal activity against\n                      <jats:italic>H. contortus<\/jats:italic>\n                      adult worms, and additionally, for cytotoxic and mitotoxic effects on human hepatoma (HepG2) cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The primary screen against\n                      <jats:italic>H. contortus<\/jats:italic>\n                      and\n                      <jats:italic>C. elegans<\/jats:italic>\n                      revealed or reidentified 16 hit compounds; further validation established MMV1794206, otherwise known as \u2018flufenerim\u2019, as a significant inhibitor of\n                      <jats:italic>H. contortus<\/jats:italic>\n                      larval motility (half-maximal inhibitory concentration [IC\n                      <jats:sub>50<\/jats:sub>\n                      ]\u2009=\u200918\u00a0\u03bcM) and development (IC\n                      <jats:sub>50<\/jats:sub>\n                      \u2009=\u20091.2\u00a0\u03bcM),\n                      <jats:italic>H. contortus<\/jats:italic>\n                      adult female motility (100% after 12\u00a0h of incubation) and\n                      <jats:italic>C. elegans<\/jats:italic>\n                      larval motility (IC\n                      <jats:sub>50<\/jats:sub>\n                      \u2009=\u20090.22\u00a0\u03bcM). Further testing on a mammalian cell line (human hepatoma HepG2 cells), however, identified flufenerim to be both cytotoxic (half-maximal cytotoxic concentration [CC\n                      <jats:sub>50<\/jats:sub>\n                      ]\u2009&lt;\u20090.7\u00a0\u03bcM) and mitotoxic (half-maximal mitotoxic concentration [MC\n                      <jats:sub>50<\/jats:sub>\n                      ]\u2009&lt;\u20090.7\u00a0\u03bcM).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      The in vitro efficacy of MMV1794206 against the most pathogenic stages of\n                      <jats:italic>H. contortus<\/jats:italic>\n                      , as well as the free-living\n                      <jats:italic>C. elegans<\/jats:italic>\n                      , suggests the potential for development as a broad-spectrum anthelmintic compound; however, the high toxicity towards mammalian cells presents a significant hindrance. Further work should seek to establish the protein\u2013drug interactions of MMV1794206 in a nematode model, to unravel the mechanism of action, in addition to an advanced structure\u2013activity relationship investigation to optimise anthelmintic activity and eliminate mammalian cell toxicity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical Abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1186\/s13071-024-06183-y","type":"journal-article","created":{"date-parts":[[2024,3,14]],"date-time":"2024-03-14T08:02:30Z","timestamp":1710403350000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["A phenotypic screen of the Global Health Priority Box identifies an insecticide with anthelmintic activity"],"prefix":"10.1186","volume":"17","author":[{"given":"Harrison T.","family":"Shanley","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aya C.","family":"Taki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph J.","family":"Byrne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nghi","family":"Nguyen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim N. 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