Title
Unsaturated Mannich bases active against multidrug-resistant **Trypanosoma brucei brucei** strains
Author
Faculty/Department
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences. Pharmacy
Publication type
article
Publication
,
Subject
Biology
Pharmacology. Therapy
Source (journal)
ChemMedChem. - Place of publication unknown
Volume/pages
4(2009) :3 , p. 339-351
ISSN
1860-7179
1860-7187
ISI
000264832000005
Carrier
E
Target language
English (eng)
Full text (Publishers DOI)
Affiliation
University of Antwerp
Abstract
Unsaturated Mannich bases with potent antitrypanosomal action against multidrug-resistant strains of T. brucei brucei were identified. Their observed activities correlated well with their high Michael acceptor properties but not with their affinities to the P2 purine transporter. A series of unsaturated Mannich bases possessing two electrophilic sites was recently identified as irreversible inhibitors of trypanothione reductase from Trypanosoma cruzi. New derivatives were synthesized by modifying the substitution pattern on the aromatic ring and by incorporating the melamine motif of melarsoprol. Their affinity to P2 transporter and their trypanocidal properties have been studied using three strains expressing various purine transporters. While the melamine derivatives showed some affinity to the P2 transporter, unsaturated Mannich bases without the melamine motif showed excellent potencies against pentamidine-resistant strains of T. brucei brucei suggesting alternative drug uptake routes. The Michael acceptor properties of the three most active compounds towards glutathione correlated with the observed trypanocidal activities.
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