Chem Biol Drug Des 2026 Jul 01;1081:e70353. doi: 10.1111/cbdd.70353.

Probing Cinnamamides and Benzamides as Anthelmintics: Discovery of Potent Drug-Like Agents Against Angiostrongylus cantonensis.

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Emergent helminthiases are increasingly impacting global health in both humans and animals, especially given the limited efficacy of existing drugs against these infections. Neuroangiostrongyliasis, an eosinophilic meningitis caused by Angiostrongylus cantonensis, currently lacks effective treatment, highlighting the need for novel anthelmintics. We previously identified cinnamoyl-benzylpiperazine, a simplified analogue of cinnarizine, as an effective anthelmintic agent against first (L1) and third-stage (L3) larvae of A. cantonensis in vitro. In the present work, structural modifications on the active prototype cinnamoyl-benzylpiperazine were performed, prioritizing the improvement of solubility and the provision of balanced physicochemical properties compatible with blood-brain barrier permeability, alongside anthelmintic activity. A set of 31 compounds divided into two series (I-cinnamoyl and II-benzoyl) was synthesized and tested against L1 and L3 larvae, yielding EC50 values ranging from 4.1 to 27.6 μM. 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 μM) or Caenorhabditis elegans worms (up to 1000 μM), denoting specific activity against A. cantonensis. The balanced polarity of compound 4a-I (EC50 L1 4.7 μM; L3 10.2 μM) and the localized charge density provided by the methoxy group in compounds 1c-II (EC50 L1 5.5 μM; L3 10.9 μM) and 5c-II (EC50 L1 4.9 μM; L3 11.9 μM) seem important for interacting with the putative target in the helminth. Collectively, the substituents in these molecules provided improved drug-likeness over the previous set of compounds, and represent noteworthy derivatives for further investigation against A. cantonensis in vitro.

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