Novel 1-Methyl-1 H-pyrazole-5-carboxamide Derivatives with Potent Anthelmintic Activity

Thuy G. Le, Abhijit Kundu, Atanu Ghoshal, Nghi H. Nguyen, Sarah Preston, Yaqing Jiao, Banfeng Ruan, Lian Xue, Fei Huang, Jennifer Keiser, Andreas Hofmann, Bill C.H. Chang, Jose Garcia-Bustos, Timothy N.C. Wells, Michael J. Palmer, Abdul Jabbar, Robin B. Gasser, Jonathan B. Baell

Research output: Contribution to journalArticleResearchpeer-review

4 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)3367-3380
Number of pages14
JournalJournal of Medicinal Chemistry
Volume62
Issue number7
DOIs
Publication statusPublished - 11 Apr 2019

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