Toward the development of dual-targeted glyceraldehyde-3-phosphate dehydrogenase/trypanothione reductase inhibitors against Trypanosoma brucei and Trypanosoma cruzi.

摘要: A significant improvement in the treatment of trypanosomiases has been achieved with recent development nifurtimox-eflornithine combination therapy (NECT). As an alternative to drug combinations and as a means overcome most antitrypanosomatid discovery challenges, multitarget design strategy envisaged. To begin testing this hypothesis, we designed developed series quinone-coumarin hybrids against glyceraldehyde-3-phosphate dehydrogenase/trypanothione reductase (GAPDH/TR). These enzymes belong metabolic pathways that are vital Trypanosoma brucei cruzi, have thus considered promising targets. The synthesized molecules were characterized for their dual-target antitrypanosomal profile, both enzyme assays vitro parasite cultures. merged derivative 2-{[3-(3-dimethylaminopropoxy)-2-oxo-2H-chromen-7-yl]oxy}anthracene-1,4-dione (10) showed IC50 value 5.4 μM TbGAPDH concomitant Ki 2.32 TcTR. Notably, 2-{4-[6-(2-dimethylaminoethoxy)-2-oxo-2H-chromen-3-yl]phenoxy}anthracene-1,4-dione (compound 6) displayed remarkable EC50 T.brucei parasites (0.026 μM) combined very low cytotoxicity toward mammalian L6 cells (7.95 μM). This toxicity compound 6 might be at least partially due fact it does not interfere human glutathione reductase.