title: Unsaturated Mannich bases active against multidrug-resistant Trypanosoma brucei brucei strains.
abstract: 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.
authors.affiliation: Biochemie-Zentrum der Universität Heidelberg, Im Neuenheimer Feld 504, 69120 Heidelberg, Germany.
authors.forename: I Nicole
authors.initials: IN
authors.lastname: Wenzel
authors.forename: Pui E
authors.initials: PE
authors.lastname: Wong
authors.forename: Louis
authors.initials: L
authors.lastname: Maes
authors.forename: Thomas J J
authors.initials: TJ
authors.lastname: Müller
authors.forename: R Luise
authors.initials: RL
authors.lastname: Krauth-Siegel
authors.forename: Michael P
authors.initials: MP
authors.lastname: Barrett
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Davioud-Charvet
mesh_terms: D000241:Adenosine / Q000378:metabolism; D000818:Animals; D000977:Antiparasitic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008352:Mannich Bases / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D026901:Membrane Transport Proteins / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014227:Triazines / Q000138:chemical synthesis / Q000737:chemistry; D014346:Trypanosoma brucei brucei / Q000187:drug effects*; D014352:Trypanosomiasis / Q000188:drug therapy
chemical_list: D000977:Antiparasitic Agents; D008352:Mannich Bases; D026901:Membrane Transport Proteins; D014227:Triazines; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase; D005978:Glutathione; D000241:Adenosine; C011907:melamine