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

Gehrke, Sebastian S, Pinto, Erika G, Steverding, Dietmar, Pleban, Karin, Tempone, Andre G, Hider, Robert C and Wagner, Gerd K (2013) Conjugation to 4-aminoquinoline improves the anti-trypanosomal activity of Deferiprone-type iron chelators. Bioorganic & Medicinal Chemistry, 21 (3). pp. 805-13. ISSN 0968-0896

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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.

Item Type: Article
Additional Information: Copyright © 2012 Elsevier Ltd. All rights reserved.
Uncontrolled Keywords: aminoquinolines,antiprotozoal agents,dose-response relationship, drug,iron chelating agents,leishmania infantum,molecular structure,parasitic sensitivity tests,plasmodium falciparum,pyridones,structure-activity relationship,trypanosoma brucei brucei,trypanosoma cruzi,sdg 3 - good health and well-being ,/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being
Faculty \ School: Faculty of Science > School of Pharmacy
Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups: Faculty of Medicine and Health Sciences > Research Groups > Gastroenterology and Gut Biology
Depositing User: Pure Connector
Date Deposited: 24 Jan 2014 12:42
Last Modified: 24 Oct 2022 05:48
DOI: 10.1016/j.bmc.2012.11.009

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