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Most available drugs to treat these diseases possess inadequate properties and candidates to fill the drug pipeline are urgently needed. Paullone\u2010\n                    <jats:italic>N<\/jats:italic>\n                    <jats:sup>5<\/jats:sup>\n                    \u2010acetamides inhibit trypanothione synthetase (TryS), an essential kinetoplastid enzyme, and exhibit antiparasitic activity in the low micromolar range, but lack the desired selectivity against mammalian cells (selectivity index (SI):&lt;10). With the aim to identify the paullones\u2019 moieties responsible for TryS inhibition and bioactivity, we applied molecular simplification and ring disconnection approaches. The new indolylacetamides lost activity against the expected molecular target (TryS) compared to the reference paullone MOL2008 (\n                    <jats:italic>Leishmania infantum<\/jats:italic>\n                    TryS IC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009:\u2009150\u2005nM;\n                    <jats:italic>Trypanosoma brucei<\/jats:italic>\n                    bloodstream form EC\n                    <jats:sub>50<\/jats:sub>\n                    : 4.3\u2005\u03bcM and SI: 2.4). However, several of them retained potency (\n                    <jats:italic>T.\u2005b. brucei<\/jats:italic>\n                    EC\n                    <jats:sub>50<\/jats:sub>\n                    : 2.4\u201312.0\u2005\u03bcM) and improved selectivity (SI: 5 to &gt;25).\n                  <\/jats:p>","DOI":"10.1002\/cmdc.202300036","type":"journal-article","created":{"date-parts":[[2023,2,27]],"date-time":"2023-02-27T10:08:45Z","timestamp":1677492525000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Discovery of Antitrypanosomal Indolylacetamides by a Deconstruction\u2013Optimization Strategy Applied to Paullones"],"prefix":"10.1002","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8892-5790","authenticated-orcid":false,"given":"Jens C.","family":"Lindhof","sequence":"first","affiliation":[{"name":"Institut f\u00fcr Medizinische und Pharmazeutische Chemie Technische Universit\u00e4t Braunschweig  Beethovenstra\u00dfe 55 38106 Braunschweig Germany"},{"name":"Zentrum f\u00fcr Pharmaverfahrenstechnik (PVZ) Technische Universit\u00e4t Braunschweig  Franz-Liszt-Stra\u00dfe 35A 38106 Braunschweig Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9711-640X","authenticated-orcid":false,"given":"Irina","family":"Ihnatenko","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Medizinische und Pharmazeutische Chemie Technische Universit\u00e4t Braunschweig  Beethovenstra\u00dfe 55 38106 Braunschweig Germany"},{"name":"Zentrum f\u00fcr Pharmaverfahrenstechnik (PVZ) Technische Universit\u00e4t Braunschweig  Franz-Liszt-Stra\u00dfe 35A 38106 Braunschweig Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4019-6653","authenticated-orcid":false,"given":"Marco J.","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Medizinische und Pharmazeutische Chemie Technische Universit\u00e4t Braunschweig  Beethovenstra\u00dfe 55 38106 Braunschweig Germany"},{"name":"Zentrum f\u00fcr Pharmaverfahrenstechnik (PVZ) Technische Universit\u00e4t Braunschweig  Franz-Liszt-Stra\u00dfe 35A 38106 Braunschweig Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5506-789X","authenticated-orcid":false,"given":"Oliver C. F.","family":"Orban","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Medizinische und Pharmazeutische Chemie Technische Universit\u00e4t Braunschweig  Beethovenstra\u00dfe 55 38106 Braunschweig Germany"},{"name":"Zentrum f\u00fcr Pharmaverfahrenstechnik (PVZ) Technische Universit\u00e4t Braunschweig  Franz-Liszt-Stra\u00dfe 35A 38106 Braunschweig Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1096-0326","authenticated-orcid":false,"given":"Cecilia","family":"Ort\u00edz","sequence":"additional","affiliation":[{"name":"Laboratorio de Biolog\u00eda Redox de Tripanosomas Institut Pasteur de Montevideo  Mataojo 2020 Montevideo 11400 Uruguay"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4639-8539","authenticated-orcid":false,"given":"Diego","family":"Ben\u00edtez","sequence":"additional","affiliation":[{"name":"Laboratorio de Biolog\u00eda Redox de Tripanosomas 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