Toward the Development of Dual‐Targeted Glyceraldehyde‐3‐phosphate Dehydrogenase/Trypanothione Reductase Inhibitors against Trypanosoma brucei and Trypanosoma cruzi. Issue 2 (8th January 2014)

• Record Type: Journal Article
• Authors: Belluti, Federica; Uliassi, Elisa; Veronesi, Giacomo; Bergamini, Christian; Kaiser, Marcel; Brun, Reto; Viola, Angelo; Fato, Romana; Michels, Paul A. M.; Krauth‐Siegel, R. Luise; Cavalli, Andrea; Bolognesi, Maria Laura
• Is Part Of: ChemMedChem. Volume 9:Issue 2(2014:Feb.)
• Page Start: 371
• Page End: 382
• Publication Date: 2014-01-08
• Subjects: Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201300399
• Languages: English
• ISSNs: 1860-7179

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>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 <italic>Trypanosoma brucei</italic> and <italic>Trypanosoma cruzi</italic>, 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<italic>H</italic>‐chromen‐7‐yl]oxy}anthracene‐1, 4‐dione (<bold>10</bold>) showed an IC<sub>50</sub> value of 5.4 μ<sc>M</sc> against <italic>Tb</italic>GAPDH and a concomitant <italic>K</italic><sub>i</sub> value of 2.32 μ<sc>M</sc> against <italic>Tc</italic>TR. Notably, 2‐{4‐[6‐(2‐dimethylaminoethoxy)‐2‐oxo‐2<italic>H</italic>‐chromen‐3‐yl]phenoxy}anthracene‐1, 4‐dione (compound <bold>6</bold>) displayed a remarkable EC<sub>50</sub> value for <italic>T. brucei</italic> parasites (0.026 μ<sc>M</sc>) combined with a very low cytotoxicity toward mammalian L6 cells (7.95 μ<sc>M</sc>). This promising low toxicity of compound <bold>6</bold> might be at least partially due to the fact that it does not interfere with human glutathione reductase.</p> </abstract>