Optimization of Novel 1-Methyl-1 H-Pyrazole-5-carboxamides Leads to High Potency Larval Development Inhibitors of the Barber's Pole Worm
| Autor: | Yaqing Jiao, Banfeng Ruan, Jonathan B. Baell, Sarah Preston, Jose F. Garcia-Bustos, Fei Huang, Michael J. Palmer, Thuy G. Le, Bill C.H. Chang, Abhijit Kundu, Atanu Ghoshal, Jennifer Keiser, Robin B. Gasser, Abdul Jabbar, Andreas Hofmann, Timothy N. C. Wells, Nghi H. Nguyen, Lian Xue |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Stereochemistry Phenotypic screening Drug Evaluation Preclinical Pyrazole 01 natural sciences 03 medical and health sciences chemistry.chemical_compound Inhibitory Concentration 50 Structure-Activity Relationship Cell Line Tumor Drug Discovery Structure–activity relationship Potency Animals Humans IC50 biology 010405 organic chemistry Antinematodal Agents biology.organism_classification Small molecule 0104 chemical sciences 030104 developmental biology Phenotype chemistry Cell culture Larva Molecular Medicine Pyrazoles Haemonchus Haemonchus contortus |
| Zdroj: | Journal of medicinal chemistry. 61(23) |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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