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Toward the Development of Dual‐Targeted Glyceraldehyde‐3‐phosphate Dehydrogenase/Trypanothione Reductase Inhibitors against Trypanosoma brucei and Trypanosoma cruzi
Author(s) -
Belluti Federica,
Uliassi Elisa,
Veronesi Giacomo,
Bergamini Christian,
Kaiser Marcel,
Brun Reto,
Viola Angelo,
Fato Romana,
Michels Paul A. M.,
KrauthSiegel R. Luise,
Cavalli Andrea,
Bolognesi Maria Laura
Publication year - 2014
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201300399
Subject(s) - trypanosoma brucei , trypanosoma cruzi , biochemistry , reductase , glyceraldehyde 3 phosphate dehydrogenase , biology , enzyme , dehydrogenase , chemistry , pharmacology , parasite hosting , world wide web , gene , computer science
A significant improvement in the treatment of trypanosomiases has been achieved with the recent development of nifurtimox–eflornithine combination therapy (NECT). As an alternative to drug combinations and as a means to overcome most of the antitrypanosomatid drug discovery challenges, a multitarget drug design strategy has been envisaged. To begin testing this hypothesis, we designed and developed a series of quinone–coumarin hybrids against glyceraldehyde‐3‐phosphate dehydrogenase/trypanothione reductase (GAPDH/TR). These enzymes belong to metabolic pathways that are vital to Trypanosoma brucei and Trypanosoma cruzi , and have thus been considered promising drug targets. The synthesized molecules were characterized for their dual‐target antitrypanosomal profile, both in enzyme assays and in in vitro parasite cultures. The merged derivative 2‐{[3‐(3‐dimethylaminopropoxy)‐2‐oxo‐2 H ‐chromen‐7‐yl]oxy}anthracene‐1,4‐dione ( 10 ) showed an IC 50 value of 5.4 μ M against Tb GAPDH and a concomitant K i value of 2.32 μ M against Tc TR. Notably, 2‐{4‐[6‐(2‐dimethylaminoethoxy)‐2‐oxo‐2 H ‐chromen‐3‐yl]phenoxy}anthracene‐1,4‐dione (compound 6 ) displayed a remarkable EC 50 value for T. brucei parasites (0.026 μ M ) combined with a very low cytotoxicity toward mammalian L6 cells (7.95 μ M ). This promising low toxicity of compound 6 might be at least partially due to the fact that it does not interfere with human glutathione reductase.