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

  • J Med Chem. 2019 Apr 11;62(7):3367-3380. doi: 10.1021/acs.jmedchem.8b01790.
Thuy G Le  1 ,  Abhijit Kundu  2 ,  Atanu Ghoshal  2 ,  Nghi H Nguyen  1 ,  Sarah Preston  3  4 ,  Yaqing Jiao  3 ,  Banfeng Ruan  1  5 ,  Lian Xue  6 ,  Fei Huang  6 ,  Jennifer Keiser  7  8 ,  Andreas Hofmann  9 ,  Bill C H Chang  3 ,  Jose Garcia-Bustos  3 ,  Timothy N C Wells  10 ,  Michael J Palmer  10 ,  Abdul Jabbar  3 ,  Robin B Gasser  3 ,  Jonathan B Baell  6  1
Affiliations
  • 1. Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences , Monash University , Parkville , Victoria 3052 , Australia.
  • 2. TCG Lifesciences Private Limited , Block BN, Plot 7, Salt-lake Electronics Complex, Sector V , Kolkata 700091 , West Bengal , India.
  • 3. Department of Veterinary Biosciences, Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences , The University of Melbourne , Parkville , Victoria 3010 , Australia.
  • 4. School of Health and Life Sciences , Federation University , Ballarat , Victoria 3353 , Australia.
  • 5. School of Food and Biological Engineering , Hefei University of Technology , Hefei 230009 , P. R. China.
  • 6. School of Pharmaceutical Sciences , Nanjing Tech University , No. 30 South Puzhu Road , Nanjing 211816 , P. R. China.
  • 7. Swiss Tropical and Public Health Institute , 4051 Basel , Switzerland.
  • 8. University of Basel , 4001 Basel , Switzerland.
  • 9. Griffith Institute for Drug Discovery , Griffith University , Nathan , Queensland 4111 , Australia.
  • 10. Medicines for Malaria Venture , 1215 Geneva , Switzerland.
PMID: 30875218 DOI: 10.1021/acs.jmedchem.8b01790
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.

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