Abstract
The impact of helminthiases on global health for both humans and animals and the limited efficacy of existing drugs against these infections reinforces the urgent need for novel anthelmintic agents. On this background, in previous work we identified cinnarizine, a first-generation antihistamine, as effective anthelmintic agent against Angiostrongylus cantonensis first-stage larvae (L1) in vitro. A. cantonensis worm is the causative agent of neuroangiostrongyliasis, a condition that leads to eosinophilic meningitis with no effective treatment to date. In the present work, modifications on cinnarizine structure were designed to improve its efficacy against the larvae but keeping its ability to cross the blood brain barrier allied to improvement in the drug-like and solubility profile. A set of 11 compounds were synthesized and tested against L1 larvae, showing EC(50) values ranging from 9.3 to 4.2 μM. The most effective were also tested against infective third-stage larvae (L3), with EC(50) 18.1-8.6 μM. None of the compounds showed toxicity to both HaCat mammalian cells (at 500 μM) and Caenorhabditis elegans (at 1000 μM), indicating their high selective toxicity toward A. cantonensis. Structure-activity relationship analysis using molecular descriptors indicated that presence of two basic nitrogen atoms and balanced lipophilicity of compound 2b (EC(50) L1 9.3 μM; L3 8.8 μM) played the role in the anthelmintic activity, and simplified compound 3a (EC(50) L1 8.7 μM; L3 18.1 μM) represent a novel prototype for further modifications.