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Available treatments are costly, lengthy and toxic, not to mention the problem of parasite resistance. The development of alternative treatments is warranted and natural products demonstrate promising activity. This study investigated the activity of <jats:italic>Connarus suberosus<\/jats:italic> extracts and compounds against <jats:italic>Leishmania<\/jats:italic> species. Several <jats:italic>C<\/jats:italic>. <jats:italic>suberosus<\/jats:italic> extracts were tested against <jats:italic>L<\/jats:italic>. <jats:italic>amazonensis<\/jats:italic> promastigotes. Active and inactive extracts were analyzed by UHPLC-MS and data evaluated using a metabolomics platform, revealing an unknown neoflavonoid (connarin, <jats:bold>3<\/jats:bold>), isolated together with the pterocarpans: hemileiocarpin (<jats:bold>1<\/jats:bold>) and leiocarpin (<jats:bold>2<\/jats:bold>). The aforementioned compounds (<jats:bold>1<\/jats:bold>\u2013<jats:bold>3<\/jats:bold>), together with the benzoquinones: rapanone (<jats:bold>4<\/jats:bold>), embelin (<jats:bold>5<\/jats:bold>) and suberonone (<jats:bold>6<\/jats:bold>) previously isolated by our group from the same species, were tested against: (i) <jats:italic>L<\/jats:italic>. <jats:italic>amazonensis<\/jats:italic> and <jats:italic>L<\/jats:italic>. <jats:italic>infantum<\/jats:italic> promastigotes, and (ii) <jats:italic>L<\/jats:italic>. <jats:italic>amazonensis<\/jats:italic> intracellular amastigotes, with the most active compound (<jats:bold>3<\/jats:bold>) also tested against <jats:italic>L<\/jats:italic>. <jats:italic>infantum<\/jats:italic> amastigotes. Cytotoxicity against murine peritoneal macrophages was also investigated. Compounds <jats:bold>2<\/jats:bold> and <jats:bold>3<\/jats:bold> presented an IC<jats:sub>50<\/jats:sub> 33.8 \u03bcM and 11.4 \u03bcM for <jats:italic>L<\/jats:italic>. <jats:italic>amazonensis<\/jats:italic> promastigotes; and 44.3 \u03bcM and 13.3 \u03bcM for <jats:italic>L<\/jats:italic>. <jats:italic>infantum<\/jats:italic> promastigotes, respectively. For <jats:italic>L<\/jats:italic>. <jats:italic>amazonensis<\/jats:italic> amastigotes, the IC<jats:sub>50<\/jats:sub> of <jats:bold>2<\/jats:bold> was 20.4 \u03bcM with a selectivity index (SI) of 5.7, while the IC<jats:sub>50<\/jats:sub> of <jats:bold>3<\/jats:bold> was 2.9 \u03bcM with an SI of 6.3. For <jats:italic>L<\/jats:italic>. <jats:italic>infantum<\/jats:italic> amastigotes, the IC<jats:sub>50<\/jats:sub> of <jats:bold>3<\/jats:bold> was 7.7 \u03bcM. Compounds <jats:bold>2<\/jats:bold> and <jats:bold>3<\/jats:bold> presented activity comparable with the miltefosine positive control, with compound <jats:bold>3<\/jats:bold> found to be 2\u20134 times more active than the positive control, depending on the <jats:italic>Leishmania<\/jats:italic> species and form. The extracts and isolated compounds showed moderate toxicity against macrophages. Compounds <jats:bold>2<\/jats:bold> and <jats:bold>3<\/jats:bold> altered the mitochondrial membrane potential (\u0394\u03a8m) and neutral lipid body accumulation, while <jats:bold>2<\/jats:bold> also impacted plasma membrane permeabilization, culminating in cellular disorder and parasite death. Transmission electron microscopy of <jats:italic>L<\/jats:italic>. <jats:italic>amazonensis<\/jats:italic> promastigotes treated with compound <jats:bold>3<\/jats:bold> confirmed the presence of lipid bodies. Leiocarpin (<jats:bold>2<\/jats:bold>) and connarin (<jats:bold>3<\/jats:bold>) demonstrated antileishmanial activity. This study provides knowledge of natural products with antileishmanial activity, paving the way for prototype development to fight this neglected tropical disease.<\/jats:p>","DOI":"10.1371\/journal.pone.0241855","type":"journal-article","created":{"date-parts":[[2020,11,6]],"date-time":"2020-11-06T18:34:36Z","timestamp":1604687676000},"page":"e0241855","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":19,"title":["Antileishmanial compounds from Connarus suberosus: Metabolomics, isolation and mechanism of action"],"prefix":"10.1371","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1340-7681","authenticated-orcid":true,"given":"Lais S.","family":"Morais","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renata G.","family":"Dusi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3576-5148","authenticated-orcid":true,"given":"Daniel P.","family":"Demarque","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raquel L.","family":"Silva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorena C.","family":"Albernaz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00f4nia N.","family":"B\u00e1o","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Merten","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luciana M. 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