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

Le, Thuy and Kundu, Abhijit and Ghoshal, Atanu and Nguyen, Nghi and Preston, Sarah and Jiao, Yaqing and Ruan, Banfeng and Xue, Lian and Huang, Fei and Keiser, Jennifer and Hofmann, Andreas and Chang, Bill and Garcia-Bustos, Jose and Wells, Timothy N. C. and Palmer, Michael J. and Jabbar, Abdul and Gasser, Robin B. and Baell, Jonathan B.. (2019) Structure-activity relationship studies of tolfenpyrad reveal sub-nanomolar inhibitors of Haemonchus contortus development. Journal of medicinal chemistry, 62 (2). pp. 1036-1053.

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Official URL: https://edoc.unibas.ch/69811/

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Abstract

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.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology > Helminth Drug Development (Keiser)
UniBasel Contributors:Keiser, Jennifer
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Chemical Society
ISSN:0022-2623
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:18 Mar 2019 12:49
Deposited On:18 Mar 2019 12:49

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