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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
The antimalarial ferroquine: Role of the metal and intramolecular hydrogen bond in activity and resistance
ACS Chemical Biology, Volume 6, No. 3, Year 2011
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Description
Inhibition of hemozoin biocrystallization is considered the main mechanism of action of 4-aminoquinoline antimalarials including chloroquine (CQ) but cannot fully explain the activity of ferroquine (FQ) which has been related to redox properties and intramolecular hydrogen bonding. Analogues of FQ, methylferroquine (Me-FQ), ruthenoquine (RQ), and methylruthenoquine (Me-RQ), were prepared. Combination of physicochemical and molecular modeling methods showed that FQ and RQ favor intramolecular hydrogen bonding between the 4-aminoquinoline NH group and the terminal amino group in the absence of water, suggesting that this structure may enhance its passage through the membrane. This was further supported by the use of Me-FQ and Me-RQ where the intramolecular hydrogen bond cannot be formed. Docking studies suggest that FQ can interact specifically with the {0,0,1} and {1,0,0} faces of hemozoin, blocking crystal growth. With respect to the structure-activity relationship, the antimalarial activity on 15 different P. falciparum strains showed that the activity of FQ and RQ were correlated with each other but not with CQ, confirming lack of cross resistance. Conversely, Me-FQ and Me-RQ showed significant cross-resistance with CQ. Mutations or copy number of pfcrt, pfmrp, pfmdr1, pfmdr2, or pfnhe-1 did not exhibit significant correlations with the IC50 of FQ or RQ. We next showed that FQ and Me-FQ were able to generate hydroxyl radicals, whereas RQ and me-RQ did not. Ultrastructural studies revealed that FQ and Me-FQ but not RQ or Me-RQ break down the parasite digestive vacuole membrane, which could be related to the ability of the former to generate hydroxyl radicals. © 2011 American Chemical Society.
Authors & Co-Authors
Dubar, Faustine
France, Lille
Université de Lille
Egan, Timothy John
South Africa, Cape Town
University of Cape Town
Pradines, Bruno
France, Bretigny-sur-orge
Institut de Recherche Biomédicale Des Armées
Kuter, David
South Africa, Cape Town
University of Cape Town
Ncokazi, Kanyile
South Africa, Cape Town
University of Cape Town
Forge, Delphine
Belgium, Mons
Université de Mons
Paul, Jean Francois
France, Lille
Université de Lille
Pierrot, Christine
France, Lille
Center for Infection and Immunity of Lille Ciil
Kalamou, Hadidjatou
France, Lille
Center for Infection and Immunity of Lille Ciil
Khalife, Jamal
France, Lille
Center for Infection and Immunity of Lille Ciil
Buisine, Eric
France, Villeneuve-d'ascq
Enscl École National Supérieure de Chimie de Lille
Rogier, Christophe
France, Bretigny-sur-orge
Institut de Recherche Biomédicale Des Armées
Vezin, Hervé
France, Lille
Université de Lille
Forfar, Isabelle
France, Bordeaux
Université de Bordeaux
Slomianny, Christian
France, Lille
Université de Lille
Trivelli, Xavier
France, Lille
Université de Lille
Kapishnikov, Sergey
Israel, Rehovot
Weizmann Institute of Science Israel
Leiserowitz, Leslie
Israel, Rehovot
Weizmann Institute of Science Israel
Dive, Daniel
France, Lille
Center for Infection and Immunity of Lille Ciil
Biot, Christophe
France, Lille
Université de Lille
France, Lille
Center for Infection and Immunity of Lille Ciil
Statistics
Citations: 160
Authors: 20
Affiliations: 8
Identifiers
Doi:
10.1021/cb100322v
ISSN:
15548929
e-ISSN:
15548937
Research Areas
Environmental