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

24 Jan 2019

Le TG, Kundu A, Ghoshal A, Nguyen NH, Preston S, Jiao Y, Ruan B, Xue L, Huang F, Keiser J, Hofmann A, Chang BCH, Garcia-Bustos J, Wells TNC, Palmer MJ, Jabbar A, Gasser RB, Baell JB

Journal of Medicinal Chemistry
PMID: 30571110

Doi: 10.1021/acs.jmedchem.8b01789


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 IC value of 0.03 μM while displaying good selectivity, with an IC 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 IC 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.

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