- Title
- Novel 1-Methyl-1H-pyrazole-5-carboxamide derivatives with potent anthelmintic activity
- Creator
- Le, Thuy; Kundu, Abhijit; Ghoshal, Atanu; Nguyen, Nghi; Preston, Sarah; Jiao, Yaqing; Ruan, Banfeng; Xue, Lian; Huang, Fei; Keiser, Jennifer; Hofmann, Andreas; Chang, Bill; Garcia-Bustos, Jose; Wells, Timothy; Palmer, Michael; Jabbar, Abdul; Gasser, Robin; Baell, Jonathan
- Date
- 2019
- Type
- Text; Journal article
- Identifier
- http://researchonline.federation.edu.au/vital/access/HandleResolver/1959.17/169308
- Identifier
- vital:13982
- Identifier
-
https://doi.org/10.1021/acs.jmedchem.8b01790
- Identifier
- ISBN:0022-2623
- 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-1H-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.
- Publisher
- ACS Publications
- Relation
- Journal of Medicinal Chemistry Vol. 62, no. 7 (2019), p. 3367-3380
- Rights
- Copyright © 2019 American Chemical Society.
- Rights
- This metadata is freely available under a CCO license
- Subject
- 0304 Medicinal and Biomolecular Chemistry; 0305 Organic Chemistry; 1115 Pharmacology and Pharmaceutical Sciences; Anthelmintic; Haemonchus; Benzimidazole resistance
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