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J Med Chem. 2018 Nov 29. doi: 10.1021/acs.jmedchem.8b01544. [Epub ahead of print]

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

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Medicinal Chemistry , Monash Institute of Pharmaceutical Sciences, Monash University , Parkville , Victoria 3052 , Australia.
TCG Lifesciences Private Limited , Block BN, Plot 7, Salt-lake Electronics Complex, Sector V , Kolkata 700091 , West Bengal , India.
Department of Veterinary Biosciences, Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences , The University of Melbourne , Parkville , Victoria 3010 , Australia.
School of Health and Life Sciences , Federation University , Ballarat , Victoria 3353 , Australia.
School of Food and Biological Engineering , Hefei University of Technology , Hefei 230009 , People's Republic of China.
School of Pharmaceutical Sciences , Nanjing Tech University , No. 30 South Puzhu Road , Nanjing 211816 , People's Republic of China.
Swiss Tropical and Public Health Institute , 4051 Basel , Switzerland.
University of Basel , 4001 Basel , Switzerland.
Griffith Institute for Drug Discovery , Griffith University , Nathan , Queensland 4111 , Australia.
Medicines for Malaria Venture , 1215 Geneva , Switzerland.


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 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.

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