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Aiming for the establishment of SAR, five different compounds (<jats:bold>1a \u2013 1e<\/jats:bold>) were prepared and tested against <jats:italic>T. cruzi<\/jats:italic>. The 2-allyl derivative of licarin A (<jats:bold>1d<\/jats:bold>) exhibited higher activity against trypomastigotes of <jats:italic>T. cruzi<\/jats:italic> (IC<jats:sub>50<\/jats:sub>\u2009=\u20095.0\u2009\u03bcM and SI\u2009=\u20099.0), while its heterocyclic derivative <jats:bold>1e<\/jats:bold> displayed IC<jats:sub>50<\/jats:sub> of 10.5\u2009\u03bcM and reduced toxicity against NCTC cells (SI\u2009&gt;\u200919.0). However, these compounds presented limited oral bioavailability estimation (&lt;85%, Papp &lt;1.0\u2009\u00d7\u200910<jats:sup>\u22126<\/jats:sup>\u2009cm\/s) in parallel artificial membrane permeability assays (PAMPA) due to excessive lipophilicity. Based on these results, different simplified structures of licarin A were designed: vanillin (<jats:bold>2<\/jats:bold>), vanillyl alcohol (<jats:bold>3<\/jats:bold>), isoeugenol (<jats:bold>4<\/jats:bold>), and eugenol (<jats:bold>5<\/jats:bold>), as well as its corresponding methyl (<jats:bold>a<\/jats:bold>), acetyl (<jats:bold>b<\/jats:bold>), O-allyl (<jats:bold>c<\/jats:bold>), and C-allyl (<jats:bold>d<\/jats:bold>) analogues. Vanillin (<jats:bold>2<\/jats:bold>) and its acetyl derivative (<jats:bold>2b<\/jats:bold>) displayed expressive activity against intracellular amastigotes of <jats:italic>T. cruzi<\/jats:italic> with IC<jats:sub>50<\/jats:sub> values of 5.5 and 5.6\u2009\u03bcM, respectively, and reduced toxicity against NCTC cells (CC<jats:sub>50<\/jats:sub>\u2009&gt;\u2009200\u2009\u03bcM). In addition, these simplified analogues showed a better permeability profile (Papp\u2009&gt;\u20091.0\u2009\u00d7\u200910<jats:sup>\u22126<\/jats:sup>\u2009cm\/s) on PAMPA models, resulting in improved drug-likeness. Vanillyl alcohol acetyl derivative (<jats:bold>3b<\/jats:bold>) and isoeugenol methyl derivative (<jats:bold>4a<\/jats:bold>) displayed activity against the extracellular forms of <jats:italic>T. cruzi<\/jats:italic> (trypomastigotes) with IC<jats:sub>50<\/jats:sub> values of 5.1 and 8.8\u2009\u03bcM respectively. Based on these results, compounds with higher selectivity index against extracellular forms of the parasite (<jats:bold>1d<\/jats:bold>, <jats:bold>1e<\/jats:bold>, <jats:bold>3d<\/jats:bold>, and <jats:bold>4a<\/jats:bold>) were selected for a mechanism of action study. After a short incubation period (1\u2009h) all compounds increased the reactive oxygen species (ROS) levels of trypomastigotes, suggesting cellular oxidative stress. The ATP levels were increased after two hours of incubation, possibly involving a high energy expenditure of the parasite to control the homeostasis. Except for compound <jats:bold>4a<\/jats:bold>, all compounds induced hyperpolarization of mitochondrial membrane potential, demonstrating a mitochondrial imbalance. Considering the unique mitochondria apparatus of <jats:italic>T. cruzi<\/jats:italic> and the lethal alterations induced by structurally based on licarin A, these compounds are interesting hits for future drug discovery studies in Chagas disease.<\/jats:p>","DOI":"10.1038\/s41598-020-62352-w","type":"journal-article","created":{"date-parts":[[2020,3,25]],"date-time":"2020-03-25T11:03:32Z","timestamp":1585134212000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Improving the drug-likeness of inspiring natural products - evaluation of the antiparasitic activity against Trypanosoma cruzi through semi-synthetic and simplified analogues of licarin A"],"prefix":"10.1038","volume":"10","author":[{"given":"Thiago R.","family":"Morais","sequence":"first","affiliation":[]},{"given":"Geanne A. 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