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

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Author(s)
Le, Thuy G
Kundu, Abhijit
Ghoshal, Atanu
Nguyen, Nghi H
Preston, Sarah
Jiao, Yaqing
Ruan, Banfeng
Xue, Lian
Huang, Fei
Keiser, Jennifer
Hofmann, Andreas
Chang, Bill CH
Garcia-Bustos, Jose
Wells, Timothy NC
Palmer, Michael J
Jabbar, Abdul
Gasser, Robin B
Baell, Jonathan B
Griffith University Author(s)
Year published
2019
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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 ...
View more >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.
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View more >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.
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Journal Title
JOURNAL OF MEDICINAL CHEMISTRY
Volume
62
Issue
2
Copyright Statement
© 2019 This document is the post-print of a Published Work that appeared in final form in the Journal of Medicinal Chemistry, copyright 2019 American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see 10.1021/acs.jmedchem.8b01789
Subject
Medicinal and biomolecular chemistry
Organic chemistry
Pharmacology and pharmaceutical sciences