Fenbendazole-amino acid derivatives as novel anthelmintic candidates: Synthesis, activity against Haemonchus...

We report the synthesis and biological evaluation of fifteen fenbendazole-amino acid derivatives from a δ-valerolactam-based scaffold. These compounds were designed to enhance anthelmintic efficacy while reducing mammalian cytotoxicity. Their activity was assessed against Haemonchus contortus at both the exsheathed third-stage larval (xL3) and adult stages. Several derivatives showed early anthelmintic activity (24 h) and low cytotoxicity towards murine macrophages. In silico analysis indicated a correlation between MLOGP-TPSA profiles and biological performance, suggesting improved cuticular diffusion. Compared with albendazole and fenbendazole, active compounds exhibited lower toxicity and occupied distinct regions in the physicochemical property space. These results support the potential of these new compounds as selective scaffolds for developing next-generation anthelmintics.