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Optimization of novel 1-methyl-1 h-pyrazole-5-carboxamides leads to high potency larval development inhibitors of the barber's pole worm

Le, Thuy G. and Kundu, Abhijit and Ghoshal, Atanu and Nguyen, Nghi H. and Preston, Sarah and Jiao, Yaqing and Ruan, Banfeng and Xue, Lian and Huang, Fei and Keiser, Jennifer and Hofmann, Andreas and Chang, Bill C. H. and Garcia-Bustos, Jose and Jabbar, Abdul and Wells, Timothy N. C. and Palmer, Michael J. and Gasser, Robin B. and Baell, Jonathan B.. (2018) Optimization of novel 1-methyl-1 h-pyrazole-5-carboxamides leads to high potency larval development inhibitors of the barber's pole worm. Journal of medicinal chemistry, 61 (23). pp. 10875-10894.

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Official URL: https://edoc.unibas.ch/68247/

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Abstract

A phenotypic screen of a diverse library of small molecules for inhibition of the development of larvae of the parasitic nematode Haemonchus contortus led to the identification of a 1-methyl-1 H-pyrazole-5-carboxamide derivative with an IC; 50; of 0.29 μM. Medicinal chemistry optimization targeted modifications on the left-hand side (LHS), middle section, and right-hand side (RHS) of the scaffold in order to elucidate the structure-activity relationship (SAR). Strong SAR allowed for the iterative and directed assembly of a focus set of 64 analogues, from which compound 60 was identified as the most potent compound, inhibiting the development of the fourth larval (L4) stage with an IC; 50; of 0.01 μM. In contrast, only 18% inhibition of the mammary epithelial cell line MCF10A viability was observed, even at concentrations as high as 50 μM.
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:31 Jan 2019 14:12
Deposited On:31 Jan 2019 14:12

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