Structure–Activity Relationship Studies of Tolfenpyrad Reveal Subnanomolar Inhibitors of Haemonchus contortus Development
| Autor: | Thuy G. Le, Nghi H. Nguyen, Jose F. Garcia-Bustos, Yaqing Jiao, Andreas Hofmann, Banfeng Ruan, Abdul Jabbar, Abhijit Kundu, Robin B. Gasser, Jonathan B. Baell, Sarah Preston, Timothy N. C. Wells, Bill C.H. Chang, Atanu Ghoshal, Fei Huang, Michael J. Palmer, Jennifer Keiser, Lian Xue |
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| Rok vydání: | 2018 |
| Předmět: |
01 natural sciences
Inhibitory Concentration 50 Structure-Activity Relationship 03 medical and health sciences parasitic diseases Drug Discovery Ic50 values medicine Animals Structure–activity relationship Potency Anthelmintic Cytotoxicity IC50 030304 developmental biology Anthelmintics 0303 health sciences biology Chemistry biology.organism_classification 0104 chemical sciences 010404 medicinal & biomolecular chemistry Nematode Biochemistry Larva Pyrazoles Molecular Medicine Haemonchus Haemonchus contortus medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 62:1036-1053 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | Recently, we have discovered that the registered pesticide, tolfenpyrad, unexpectedly and potently inhibits the development of the L4 larval stage of the parasitic nematode Haemonchus contortus with an IC50 value of 0.03 μM while displaying good selectivity, with an IC50 of 37.9 μM for cytotoxicity. As a promising molecular template for medicinal chemistry optimization, we undertook anthelmintic structure–activity relationships for this chemical. Modifications of the left-hand side (LHS), right-hand side (RHS), and middle section of the scaffold were explored to produce a set of 57 analogues. Analogues 25, 29, and 33 were shown to be the most potent compounds of the series, with IC50 values at a subnanomolar level of potency against the chemotherapeutically relevant fourth larval (L4) stage of H. contortus. Selected compounds from the series also showed promising activity against a panel of other different parasitic nematodes, such as hookworms and whipworms. |
| Databáze: | OpenAIRE |
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