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Novel 1-methyl-1 H-pyrazole-5-carboxamide derivatives with potent anthelmintic activity

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 Wells, Timothy N. C. and Palmer, Michael J. and Jabbar, Abdul and Gasser, Robin B. and Baell, Jonathan B.. (2019) Novel 1-methyl-1 H-pyrazole-5-carboxamide derivatives with potent anthelmintic activity. Journal of medicinal chemistry, 62 (7). pp. 3367-3380.

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Official URL: https://edoc.unibas.ch/70357/

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Abstract

A phenotypic screen of two different libraries of small molecules against the motility and development of the parasitic nematode Haemonchus contortus led to the identification of two 1-methyl-1 H-pyrazole-5-carboxamide derivatives. Medicinal chemistry optimization targeted modifications of the left-hand side, middle section, and right-hand side of the hybrid structure of these two hits to elucidate the structure-activity relationship (SAR). Initial SAR around these hits allowed for the iterative and directed assembly of a focused set of 30 analogues of their hybrid structure. Compounds 10, 17, 20, and 22 were identified as the most potent compounds, inhibiting the development of the fourth larval (L4) stage of H. contortus at sub-nanomolar potencies while displaying strong selectivity toward the parasite when tested in vitro against the human MCF10A cell line. In addition, compounds 9 and 27 showed promising activity against a panel of other parasitic nematodes, including 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:07 May 2019 07:14
Deposited On:07 May 2019 07:14

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