Inhibition of Trypanosoma cruzi trypanothione reductase by acridines: Kinetic studies and structure-activity relationships

Series of 9-amino and 9-thioacridines have been synthesized and studied as inhibitors of trypanothione reductase (TR) from Trypanosoma cruzi, the caus ative 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 mu M. The most effective inhibitors were those with the methoxy and chlorine substituents of mepacrine and NH2 or NHCH(CH3)(CH2)(4)N(Et)(2) at C9. Detailed kinetic analyses revealed tha t 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 stru cturally very similar acridine compounds can give rise to completely differ ent inhibition patterns renders modelling studies and quantitative structur e-activity relationships difficult.