期刊
CHEMMEDCHEM
卷 13, 期 9, 页码 957-967出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.201800067
关键词
antiprotozoal agents; molecular recognition; neglected diseases; trypanothione reductase; X-ray co-crystal structures
资金
- ETH Research Council [ETH-01 13-2]
- Deutsche Forschungsgemeinschaft [DFG KR 1242/8-1]
- National Science and Engineering Research Council of Canada [RGPIN-2015-04877]
- Canadian Research Chairs Program
- DOE Office of Science by Argonne National Laboratory [DE-AC02-06CH11357]
- National Cancer Institute [ACB-12002]
- National Institute of General Medical Sciences [AGM-12006]
The tropical diseases human African trypanosomiasis, Chagas disease, and the various forms of leishmaniasis are caused by parasites of the family of trypanosomatids. These protozoa possess a unique redox metabolism based on trypanothione and trypanothione reductase (TR), making TR a promising drug target. We report the optimization of properties and potency of cyclohexylpyrrolidine inhibitors of TR by structure-based design. The best inhibitors were freely soluble and showed competitive inhibition constants (K-i) against Trypanosoma (T.) brucei TR and T.cruzi TR and invitro activities (half-maximal inhibitory concentration, IC50) against these parasites in the low micromolar range, with high selectivity against human glutathione reductase. X-ray co-crystal structures confirmed the binding of the ligands to the hydrophobic wall of the mepacrine binding site with the new, solubility-providing vectors oriented toward the surface of the large active site.
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