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This study reports a hit\u2010to\u2010lead optimization of morpholinephenylbenzamides, starting from hit\n                    <jats:bold>1<\/jats:bold>\n                    , which showed potent activity against\n                    <jats:italic>Trypanosoma cruzi<\/jats:italic>\n                    (IC\n                    <jats:sub>50<\/jats:sub>\n                    0.29\u20130.76\u2009\u03bcM) and\n                    <jats:italic>Leishmania infantum<\/jats:italic>\n                    (IC\n                    <jats:sub>50<\/jats:sub>\n                    10.7\u2009\u03bcM), despite a suboptimal ADME profile. A structure\u2013activity relationship study of twenty\u2010four novel derivatives provided key pharmacophoric insights. While\n                    <jats:italic>Trypanosoma cruzi<\/jats:italic>\n                    was less susceptible to chemical modifications, compound\n                    <jats:bold>20<\/jats:bold>\n                    exhibited potency comparable to benznidazole (IC\n                    <jats:sub>50<\/jats:sub>\n                    3.58\u2009\u03bcM) with significantly improved selectivity, lipophilicity, and solubility relative to compound\n                    <jats:bold>1<\/jats:bold>\n                    . Against\n                    <jats:italic>Leishmania infantum<\/jats:italic>\n                    , six derivatives maintained activity, with compound\n                    <jats:bold>24<\/jats:bold>\n                    showing a 1.5\u2010fold potency increase IC\n                    <jats:sub>50<\/jats:sub>\n                    7.6\u2009\u03bcM). Additionally, compound\n                    <jats:bold>16<\/jats:bold>\n                    stood out for its superior ADME profile, including enhanced permeability and metabolic stability. These findings validate the morpholinephenylbenzamide scaffold as a robust class with dual antiparasitic activity.\n                  <\/jats:p>","DOI":"10.1002\/cmdc.70518","type":"journal-article","created":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T06:00:40Z","timestamp":1791525640000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Synthesis, Antiparasitic Activity, and ADME Profile of Morpholinephenylbenzamides: A Pharmacological Study Against Chagas Disease and Visceral Leishmaniasis"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-1222-3110","authenticated-orcid":false,"given":"Danilo Nascimento","family":"Farago","sequence":"first","affiliation":[{"name":"Laborat\u00f3rio de S\u00edntese de Candidatos a F\u00e1rmacos Instituto de Qu\u00edmica Universidade Federal de Uberl\u00e2ndia (UFU)  Uberl\u00e2ndia Minas Gerais 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