Structure–Activity Relationship Studies of Tolfenpyrad Reveal Subnanomolar Inhibitors of Haemonchus contortus Development

Recently, we have
discovered that the registered pesticide, tolfenpyrad,
unexpectedly and potently inhibits the development of the L4 larval
stage 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
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 subnanomolar level of
potency against the chemotherapeutically relevant fourth larval (L4)
stage 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.