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

Abstract：

: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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

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

doi

10.1021/acs.jmedchem.8b01789

subject

Has Abstract

pub_date

2019-01-24 00:00:00

pages

1036-1053

issue

2

eissn

0022-2623

issn

1520-4804

journal_volume

62

pub_type

杂志文章

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