6533b856fe1ef96bd12b1ef1

RESEARCH PRODUCT

Bistacrines as potential antitrypanosomal agents

August StichInes SchmidtElena KatzowitschHeike BruhnAntje FußAlexandra MiliuSarah GöllnerTanja SchirmeisterAnna KucharskiR. Luise Krauth-siegelUlrike Holzgrabe

subject

0301 basic medicinemedicine.drug_classTrypanosoma brucei bruceiClinical BiochemistryPharmaceutical ScienceFlavoproteinBiochemistryCell LineMiceStructure-Activity Relationship03 medical and health sciencesParasitic Sensitivity TestsOxidoreductaseparasitic diseasesDrug DiscoverymedicineAnimalsAfrican trypanosomiasisMolecular BiologyCell Proliferationchemistry.chemical_classificationDose-Response Relationship DrugMolecular StructurebiologyChemistryOrganic ChemistryTrypanosoma brucei rhodesiensemedicine.diseasebiology.organism_classificationTrypanocidal AgentsCysteine proteaseTrypanosomiasis African030104 developmental biologyBiochemistryTacrineTacrineAntiprotozoalbiology.proteinMolecular MedicineProtozoamedicine.drug

description

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.

yearjournalcountryeditionlanguage
2017-02-15Bioorganic & Medicinal Chemistry
https://doi.org/10.1016/j.bmc.2017.06.051