Coupling of a competitive and an irreversible ligand generates mixed type inhibitors of Trypanosoma cruzi trypanothione reductase.
9-Aminoacridines and (terpyridine)platinum(II) complexes are competitive and irreversible inhibitors, respectively, of trypanothione reductase from Trypanosoma cruzi, the causative agent of Chagas' disease. Four chimeric compounds in which 2-methoxy-6-chloro-9-aminoacridine was covalently linked to the (2-hydroxyethanethiolate)(2,2':6',2' '-terpyridine)platinum(II) complex were synthesized and studied as inhibitors of the parasite enzyme. The derivatives differed by the nature and/or the length of the spacer connecting the two aromatic systems. All four compounds were effective mixed type inhibitors of trypanothione reductase with K(i) and K(i)' values of 0.3-4 and 2-11 microM, respectively. The most potent inhibitor had an ethylthioether linkage between the two aromatic ring systems, and the other compounds contained an alkyl ether group with 4-6 methylene groups. In contrast to the parasite enzyme, human glutathione reductase, the closest related host enzyme was not inhibited by these compounds. The finding that the conjugation of a competitive and an irreversible inhibitor can give rise to reversible mixed type inhibitors underlines the difficulties associated with inhibitor design based on the three-dimensional structure of trypanothione reductase.
Inhoff
Oliver
O
Biochemie-Zentrum, Heidelberg University, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany.
Richards
Jonathan M
JM
Brîet
Jan Willem
JW
Lowe
Gordon
G
Krauth-Siegel
R Luise
RL
D000166:Acridines / Q000138:chemical synthesis* / Q000737:chemistry; D000609:Aminoacridines / Q000138:chemical synthesis* / Q000737:chemistry; D000818:Animals; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D005980:Glutathione Reductase / Q000737:chemistry; D006801:Humans; D008024:Ligands; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors*; D009944:Organoplatinum Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000737:chemistry; D014349:Trypanosoma cruzi / Q000737:chemistry*
D000166:Acridines; D000609:Aminoacridines; D004791:Enzyme Inhibitors; D008024:Ligands; D009944:Organoplatinum Compounds; D014344:Trypanocidal Agents; C010847:9-amino-6-chloro-2-methoxyacridine; C008018:2-hydroxyethanethiolato(2,2',2''-terpyridine)platinum(II); D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase; D005980:Glutathione Reductase