1. Bistacrines as potential antitrypanosomal agents
- Author
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August Stich, Ines Schmidt, Elena Katzowitsch, Heike Bruhn, Antje Fuß, Alexandra Miliu, Sarah Göllner, Tanja Schirmeister, Anna Kucharski, R. Luise Krauth-Siegel, and Ulrike Holzgrabe
- Subjects
0301 basic medicine ,medicine.drug_class ,Trypanosoma brucei brucei ,Clinical Biochemistry ,Pharmaceutical Science ,Flavoprotein ,Biochemistry ,Cell Line ,Mice ,Structure-Activity Relationship ,03 medical and health sciences ,Parasitic Sensitivity Tests ,Oxidoreductase ,parasitic diseases ,Drug Discovery ,medicine ,Animals ,African trypanosomiasis ,Molecular Biology ,Cell Proliferation ,chemistry.chemical_classification ,Dose-Response Relationship, Drug ,Molecular Structure ,biology ,Chemistry ,Organic Chemistry ,Trypanosoma brucei rhodesiense ,medicine.disease ,biology.organism_classification ,Trypanocidal Agents ,Cysteine protease ,Trypanosomiasis, African ,030104 developmental biology ,Tacrine ,Antiprotozoal ,biology.protein ,Molecular Medicine ,Protozoa ,medicine.drug - Abstract
Human African Trypanosomiasis (HAT) is caused by two subspecies of the genus Trypanosoma, namely Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense. The disease is fatal if left untreated and therapy is limited due to only five non-adequate drugs currently available. In preliminary studies, dimeric tacrine derivatives were found to inhibit parasite growth with IC50-values in the nanomolar concentration range. This prompted the synthesis of a small, but smart library of monomeric and dimeric tacrine-type compounds and their evaluation of antiprotozoal activity. Rhodesain, a lysosomal cathepsin-L like cysteine protease of T. brucei rhodesiense is essential for parasite survival and likely target of the tacrine derivatives. In addition, the inhibition of trypanothione reductase by bistacrines was found. This flavoprotein oxidoreductase is the main defense against oxidative stress in the thiol redox system unique for protozoa.
- Published
- 2017
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