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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Conjugation to 4-aminoquinoline improves the anti-trypanosomal activity of Deferiprone-type iron chelators

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Gehrke, Sebastian S. [1, 2, 3] ; Pinto, Erika G. [4, 5] ; Steverding, Dietmar [2] ; Pleban, Karin [1] ; Tempone, Andre G. [5] ; Hider, Robert C. [1] ; Wagner, Gerd K. [1, 6]
Total Authors: 7
[1] Kings Coll London, Inst Pharmaceut Sci, Sch Biomed Sci, London SE1 9NH - England
[2] Univ E Anglia, Biomed Res Ctr, Norwich Med Sch, Norwich NR4 7TJ, Norfolk - England
[3] Univ E Anglia, Sch Pharm, Norwich NR4 7TJ, Norfolk - England
[4] Univ Sao Paulo, Inst Trop Med, Sao Paulo - Brazil
[5] Adolfo Lutz Inst, Dept Parasitol, Sao Paulo - Brazil
[6] Kings Coll London, Dept Chem, Sch Biomed Sci, London SE1 9NH - England
Total Affiliations: 6
Document type: Journal article
Source: Bioorganic & Medicinal Chemistry; v. 21, n. 3, p. 805-813, FEB 1 2013.
Web of Science Citations: 12

Iron is an essential growth component in all living organisms and plays a central role in numerous biochemical processes due to its redox potential and high affinity for oxygen. The use of iron chelators has been suggested as a novel therapeutic approach towards parasitic infections, such as malaria, sleeping sickness and leishmaniasis. Known iron chelating agents such as Deferoxamine and the 3-hydroxypyridin-4-one (HPO) Deferiprone possess anti-parasitic activity but suffer from mammalian toxicity, relatively modest potency, and/or poor oral availability. In this study, we have developed novel derivatives of Deferiprone with increased anti-parasitic activity and reduced cytotoxicity against human cell lines. Of particular interest are several new derivatives in which the HPO scaffold has been conjugated, via a linker, to the 4-aminoquinoline ring system present in the known anti-malaria drug Chloroquine. We report the inhibitory activity of these novel analogues against four parasitic protozoa, Trypanosoma brucei, Trypanosoma cruzi, Leishmania infantum and Plasmodium falciparum, and, for direct comparison, against human cells lines. We also present data, which support the hypothesis that iron starvation is the major cause of growth inhibition of these new Deferiprone-Chloroquine conjugates in T. brucei. (C) 2012 Elsevier Ltd. All rights reserved. (AU)

FAPESP's process: 11/50577-7 - From trypanosomes to Leishmania: novel drug candidates for the treatment of neglected parasitic diseases
Grantee:André Gustavo Tempone Cardoso
Support type: Regular Research Grants