Inhibition of Trypanosoma cruzi Trypanothione Reductase by Acridines:  Kinetic Studies and Structure−Activity Relationships

• Published in: Journal of medicinal chemistry Vol. 42; no. 26; pp. 5448 - 5454
• Main Authors: Bonse, Susanne, Santelli-Rouvier, Christiane, Barbe, Jacques, Krauth-Siegel, R. Luise
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 30-12-1999
• Subjects: acridine; Acridines - chemistry; Acridines - pharmacology; aminoacrine; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiparasitic agents; Biological and medical sciences; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Kinetics; Magnetic Resonance Spectroscopy; Medical sciences; NADH, NADPH Oxidoreductases - antagonists & inhibitors; Pharmacology. Drug treatments; quinacrine; Structure-Activity Relationship; Trypanosoma cruzi; Trypanosoma cruzi - drug effects; Trypanosoma cruzi - enzymology; trypanothione reductase inhibitor; Kinetoplastida; Protozoa; Protozoal disease; Enzyme; Nitrogen heterocycle; Enzyme inhibitor; Chagas disease; Parasitosis; Tricyclic compound; In vitro; Trypanosoma cruzi; Infection; Antiprotozoal agent; Structure activity relation; Chlorine Organic compounds; Parasiticid; Tertiary amine; Aromatic compound; Oxidoreductases; Kinetics; Chemical synthesis; Trypanosomiasis; Trypanothione reductase
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm990386s

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 μM. The most effective inhibitors were those with the methoxy and chlorine substituents of mepacrine and NH2 or NHCH(CH3)(CH2)4N(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.