Pyridyl Benzamides as a Novel Class of Potent Inhibitors for the Kinetoplastid Trypanosoma brucei
| Autor: | Michelle Gazdik, Jonathan B. Baell, Marcel Kaiser, Amy J. Jones, Christel A. S. Bergström, Raphaël Rahmani, Susan A. Charman, Lori Ferrins, Karen L. White, Melissa Sykes, Eileen Ryan, Swapna Varghese, Vicky M. Avery |
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| Rok vydání: | 2014 |
| Předmět: |
Trypanosoma brucei rhodesiense
Pyridines Stereochemistry Trypanosoma brucei brucei Trypanosoma brucei Cell Line Myoblasts Structure-Activity Relationship parasitic diseases Drug Discovery Animals Humans Structure–activity relationship biology Chemistry HEK 293 cells biology.organism_classification Trypanocidal Agents Rats HEK293 Cells Liver metabolism Biochemistry Active compound Benzamides Microsomes Liver Molecular Medicine |
| Zdroj: | Journal of Medicinal Chemistry. 57:6393-6402 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | A whole-organism screen of approximately 87000 compounds against Trypanosoma brucei brucei identified a number of promising compounds for medicinal chemistry optimization. One of these classes of compounds we termed the pyridyl benzamides. While the initial hit had an IC50 of 12 μM, it was small enough to be attractive for further optimization, and we utilized three parallel approaches to develop the structure-activity relationships. We determined that the physicochemical properties for this class are generally favorable with particular positions identified that appear to block metabolism when substituted and others that modulate solubility. Our most active compound is 79, which has an IC50 of 0.045 μM against the human pathogenic strain Trypanosoma brucei rhodesiense and is more than 4000 times less active against the mammalian L6 cell line. |
| Databáze: | OpenAIRE |
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