Optimization of Novel 1-Methyl-1 H-Pyrazole-5-carboxamides Leads to High Potency Larval Development Inhibitors of the Barber's Pole Worm

Thuy 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, Abdul Jabbar, Timothy N.C. Wells, Michael J. Palmer, Robin B. Gasser, Jonathan B. Baell

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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-1H-pyrazole-5-carboxamide derivative with an IC50 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 IC50 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.

Original languageEnglish
Pages (from-to)10875-10894
Number of pages20
JournalJournal of Medicinal Chemistry
Issue number23
Publication statusPublished - 13 Dec 2018

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