Toward the Development of Dual‐Targeted Glyceraldehyde‐3‐phosphate Dehydrogenase/Trypanothione Reductase Inhibitors against Trypanosoma brucei and Trypanosoma cruzi |
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Authors: | Prof. Dr. Federica Belluti Elisa Uliassi Giacomo Veronesi Dr. Christian Bergamini Dr. Marcel Kaiser Prof. Dr. Reto Brun Angelo Viola Prof. Dr. Romana Fato Prof. Dr. Paul A. M. Michels Prof. Dr. R. Luise Krauth‐Siegel Prof. Dr. Andrea Cavalli Prof. Dr. Maria Laura Bolognesi |
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Affiliation: | 1. Department of Pharmacy & Biotechnology, University of Bologna, Via Belmeloro 6 / Via Irnerio 48, 40126 Bologna (Italy);2. Swiss Tropical & Public Health Institute, Socinstrasse 57, 4002 Basel (Switzerland);3. University of Basel, Petersplatz 1, 4003 Basel (Switzerland);4. Institute of Structural & Molecular Biology, School of Biological Sciences, University of Edinburgh, Mayfield Road, Edinburgh EH9 3JR (UK);5. Biochemie‐Zentrum, Universit?t Heidelberg, Im Neuenheimer Feld 328, 69120 Heidelberg (Germany);6. Department of Drug Discovery & Development, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genova (Italy) |
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Abstract: | 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‐2H‐chromen‐7‐yl]oxy}anthracene‐1,4‐dione ( 10 ) showed an IC50 value of 5.4 μM against TbGAPDH and a concomitant Ki value of 2.32 μM against TcTR. Notably, 2‐{4‐[6‐(2‐dimethylaminoethoxy)‐2‐oxo‐2H‐chromen‐3‐yl]phenoxy}anthracene‐1,4‐dione (compound 6 ) displayed a remarkable EC50 value for T. brucei parasites (0.026 μM ) combined with a very low cytotoxicity toward mammalian L6 cells (7.95 μM ). 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. |
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Keywords: | framework combinations glyceraldehyde‐3‐phosphate dehydrogenase multitarget ligands neglected tropical diseases trypanothione reductase |
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