Structure-activity relationship studies of tolfenpyrad reveal sub-nanomolar inhibitors of Haemonchus contortus development

Recently, we discovered that the registered pesticide, tolfenpyrad (TFP), unexpectedly and potently inhibits the development of L4 larval stages of the parasitic nematode Haemonchus contortus with an IC50 value of 0.03 µM while displaying good selectivity, with an IC50 of 37.9 µM for cytotoxicity. As a promising molecular template for medicinal chemistry optimization, we undertook anthelmintic structure-activity relationships (SAR) for this chemical. Modifications of the left hand side (LHS), right hand side (RHS), and middle section of the scaffold were explored to produce a set of 57 analogues. Analogues 25, 29 and 33 were shown to be the most potent compounds of the series, with IC50 values at a sub-nanomolar levels of potency against the chemotherapeutically-relevant fourth larval (L4) stages of H. contortus. Selected compounds from the series also showed promising activity against a panel of other different parasitic nematodes such as hookworms and whipworms.