| Autor: |
Le, Thuy G., Kundu, Abhijit, Ghoshal, Atanu, Nguyen, Nghi H., Preston, Sarah, Jiao, Yaqing, Ruan, Banfeng, Xue, Lian, Huang, Fei, Keiser, Jennifer, Hofmann, Andreas, Chang, Bill C. H., Garcia-Bustos, Jose, Wells, Timothy N. C., Palmer, Michael J., Jabbar, Abdul, Gasser, Robin B., Baell, Jonathan B. |
| Zdroj: |
Journal of Medicinal Chemistry; December 2018, Vol. 62 Issue: 2 p1036-1053, 18p |
| Abstrakt: |
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 contortuswith an IC50value of 0.03 μM while displaying good selectivity, with an IC50of 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 33were shown to be the most potent compounds of the series, with IC50values 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: |
Supplemental Index |
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