Coupling of a Competitive and an Irreversible Ligand Generates Mixed Type Inhibitors ofTrypanosomacruziTrypanothione Reductase

Abstract

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.

Dithiol Proteins as Guardians of the Intracellular Redox Milieu in Parasites: Old and New Drug Targets in Trypanosomes and Malaria‐Causing Plasmodia

“…Unexpectedly, formation of chimeric ligands between a (2,2':6',2''-terpyridine)platinum(ii) complex and 9-aminoacridine did not maintain the irreversible type of inhibition but resulted in strong mixed-type inhibitors. [126] These findings underscore once again the difficulties of structure-activity predictions for trypanothione reductase inhibitors: the extended active site evidently allows many different binding modes.…”

Mechanistic aspects of the interaction of intercalating metal complexes with nucleic acids

“…Other important derivatives are 9-aminoacridine. This class of molecules is the object of extensive investigations due to a biological activity that ranges from anti-malarial properties [117], enzyme inhibition [118][119][120], anticancer activity [121] that led to chemotherapeutics development, photo-affinity labels [122] and fluorescent probes for cancer cell detection [123]. Despite the numerous studies on aminoacridine derivatives, mechanistic aspects of these molecules binding to polynucleotides have been seldom analysed.…”

Parallel synthesis of 9-aminoacridines and their evaluation against chloroquine-resistant Plasmodium falciparum

“…In the first set of entries (1-15) the synthesized 9-chloroacridines were coupled with commercially available sidechain 9{1,9}, while in the second set of entries (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31), the commercially available 9-chloroacridine heterocycle 7{4,6} of quinacrine was coupled with the set of synthesized diamines. Yields and purities of the coupled products were highly variable.…”