Increased activity of CF3-derivatized levamisole at the ACC-2 receptor from the parasitic nematode Haemonchus contortus

The acetylcholine-gated chloride channel (ACC) family in parasitic nematodes represents a promising target for anthelmintic drug development. Levamisole, a widely known and utilized cholinergic agonist, has been used for decades to address many types of parasitic infections by targeting nematode nicotinic acetylcholine receptors (nAChRs) in nematodes. In this study, we report the synthesis and pharmacological evaluation of eight levamisole derivatives, five of which are novel, on the H. contortus ACC-2 receptor. This includes a CF₃-derivatized compound we have identified as compound 6 whose structure contains levamisole as a backbone with the addition of a 2-trifluoromethyl benzyl group. Electrophysiological assays revealed that compound 6 exhibited a five-fold increase in sensitivity (EC₅₀ 20 μM) compared to levamisole (EC₅₀ 100 μM), our parent compound, with an EC₅₀ comparable to that of acetylcholine (20 μM). Investigation of the in silico docking of compound 6 with H. contortus ACC-2 suggest that it interacts uniquely within the H. contortus ACC-2 binding pocket, which may contribute to its increased receptor sensitivity. These findings highlight the potential of structural modifications containing an electron-withdrawing group at the 2-position which can significantly enhance activity at the H. contortus ACC-2 receptor. This opens many avenues for the development of more effective treatments against parasitic nematodes, in an environment with increasing resistance.