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Neuroangiostrongyliasis, an eosinophilic meningitis caused by\n                    <jats:styled-content style=\"fixed-case\">\n                      <jats:italic>Angiostrongylus cantonensis<\/jats:italic>\n                    <\/jats:styled-content>\n                    , currently lacks effective treatment, highlighting the need for novel anthelmintics. We previously identified cinnamoyl\u2010benzylpiperazine, a simplified analogue of cinnarizine, as an effective anthelmintic agent against first (L1) and third\u2010stage (L3) larvae of\n                    <jats:styled-content style=\"fixed-case\">\n                      <jats:italic>A. cantonensis<\/jats:italic>\n                    <\/jats:styled-content>\n                    in\u00a0vitro. In the present work, structural modifications on the active prototype cinnamoyl\u2010benzylpiperazine were performed, prioritizing the improvement of solubility and the provision of balanced physicochemical properties compatible with blood\u2013brain barrier permeability, alongside anthelmintic activity. A set of 31 compounds divided into two series (I\u2014cinnamoyl and II\u2014benzoyl) was synthesized and tested against L1 and L3 larvae, yielding EC\n                    <jats:sub>50<\/jats:sub>\n                    values ranging from 4.1 to 27.6\u2009\u03bcM. SAR analyses revealed that the activity of set I is strongly associated with balanced electronic density in both the cinnamamide and amine regions (described by ionization potential descriptors), whereas modifications in the charge distribution of the molecules (indicated by topological charge descriptors) appear to determine the anthelmintic activity of set II. None of the compounds displayed significant toxicity to HaCaT mammalian cells (up to 200\u2009\u03bcM) or\n                    <jats:styled-content style=\"fixed-case\">\n                      <jats:italic>Caenorhabditis elegans<\/jats:italic>\n                    <\/jats:styled-content>\n                    worms (up to 1000\u2009\u03bcM), denoting specific activity against\n                    <jats:styled-content style=\"fixed-case\">\n                      <jats:italic>A. cantonensis<\/jats:italic>\n                    <\/jats:styled-content>\n                    . The balanced polarity of compound\n                    <jats:bold>4a\u2010I<\/jats:bold>\n                    (EC\n                    <jats:sub>50<\/jats:sub>\n                    L1 4.7\u2009\u03bcM; L3 10.2\u2009\u03bcM) and the localized charge density provided by the methoxy group in compounds\n                    <jats:bold>1c\u2010II<\/jats:bold>\n                    (EC\n                    <jats:sub>50<\/jats:sub>\n                    L1 5.5\u2009\u03bcM; L3 10.9\u2009\u03bcM) and\n                    <jats:bold>5c\u2010II<\/jats:bold>\n                    (EC\n                    <jats:sub>50<\/jats:sub>\n                    L1 4.9\u2009\u03bcM; L3 11.9\u2009\u03bcM) seem important for interacting with the putative target in the helminth. Collectively, the substituents in these molecules provided improved drug\u2010likeness over the previous set of compounds, and represent noteworthy derivatives for further investigation against\n                    <jats:styled-content style=\"fixed-case\">\n                      <jats:italic>A. cantonensis<\/jats:italic>\n                    <\/jats:styled-content>\n                    in\u00a0vitro.\n                  <\/jats:p>","DOI":"10.1111\/cbdd.70353","type":"journal-article","created":{"date-parts":[[2026,7,4]],"date-time":"2026-07-04T11:32:17Z","timestamp":1783164737000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Probing Cinnamamides and Benzamides as Anthelmintics: Discovery of Potent Drug\u2010Like Agents Against\n                    <i>Angiostrongylus cantonensis<\/i>"],"prefix":"10.1111","volume":"108","author":[{"given":"Bruna 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