title: Inhibition of Trypanosoma cruzi trypanothione reductase by acridines: kinetic studies and structure-activity relationships.
abstract: Series of 9-amino and 9-thioacridines have been synthesized and studied as inhibitors of trypanothione reductase (TR) from Trypanosoma cruzi, the causative agent of Chagas' disease. The compounds are structural analogues of the acridine drug mepacrine (quinacrine), which is a competitive inhibitor of the parasite enzyme, but not of human glutathione reductase, the closest related host enzyme. The 9-aminoacridines yielded apparent K(i) values for competitive inhibition between 5 and 43 microM. The most effective inhibitors were those with the methoxy and chlorine substituents of mepacrine and NH(2) or NHCH(CH(3))(CH(2))(4)N(Et)(2) at C9. Detailed kinetic analyses revealed that in the case of 9-aminoacridines more than one inhibitor molecule can bind to the enzyme. In contrast, the 9-thioacridine derivatives inhibit TR with mixed-type kinetics. The kinetic data are discussed in light of the three-dimensional structure of the TR-mepacrine complex. The conclusion that structurally very similar acridine compounds can give rise to completely different inhibition patterns renders modelling studies and quantitative structure-activity relationships difficult.
authors.affiliation: Biochemie-Zentrum Heidelberg, Heidelberg University, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Bonse
authors.forename: C
authors.initials: C
authors.lastname: Santelli-Rouvier
authors.forename: J
authors.initials: J
authors.lastname: Barbe
authors.forename: R L
authors.initials: RL
authors.lastname: Krauth-Siegel
mesh_terms: D000166:Acridines / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000201:enzymology
chemical_list: D000166:Acridines; D004791:Enzyme Inhibitors; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase