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Molecules 2017, 22(2), 210;

Role of Quinone Reductase 2 in the Antimalarial Properties of Indolone-Type Derivatives

UMR 152 Pharma-Dev, Université de Toulouse, IRD, UPS, 31062 Toulouse, France
Synchrotron SOLEIL, L’Orme des Merisiers, BP 48 Saint-Aubin, 91190 Gif sur Yvette CEDEX, France
Vectalys S.A., Parc Technologique du Canal, Bâtiment Canal Biotech 2, 3, Rue des Satellites, 31400 Toulouse, France
Expertise Biotechnologie, Chimie, Biologie, Institut de Recherches Servier, 125, Chemin de Ronde, 78290 Croissy sur Seine, France
These authors contributed equally to this work.
Author to whom correspondence should be addressed.
Received: 14 December 2016 / Accepted: 20 January 2017 / Published: 30 January 2017
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Indolone-N-oxides have antiplasmodial properties against Plasmodium falciparum at the erythrocytic stage, with IC50 values in the nanomolar range. The mechanism of action of indolone derivatives involves the production of free radicals, which follows their bioreduction by an unknown mechanism. In this study, we hypothesized that human quinone reductase 2 (hQR2), known to act as a flavin redox switch upon binding to the broadly used antimalarial chloroquine, could be involved in the activity of the redox-active indolone derivatives. Therefore, we investigated the role of hQR2 in the reduction of indolone derivatives. We analyzed the interaction between hQR2 and several indolone-type derivatives by examining enzymatic kinetics, the substrate/protein complex structure with X-ray diffraction analysis, and the production of free radicals with electron paramagnetic resonance. The reduction of each compound in cells overexpressing hQR2 was compared to its reduction in naïve cells. This process could be inhibited by the specific hQR2 inhibitor, S29434. These results confirmed that the anti-malarial activity of indolone-type derivatives was linked to their ability to serve as hQR2 substrates and not as hQR2 inhibitors as reported for chloroquine, leading to the possibility that substrate of hQR2 could be considered as a new avenue for the design of new antimalarial compounds. View Full-Text
Keywords: malaria; inhibitor; mechanism; human quinone reductase 2; indolones malaria; inhibitor; mechanism; human quinone reductase 2; indolones

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Cassagnes, L.-E.; Rakotoarivelo, N.; Sirigu, S.; Pério, P.; Najahi, E.; Chavas, L.M.G.; Thompson, A.; Gayon, R.; Ferry, G.; Boutin, J.A.; Valentin, A.; Reybier, K.; Nepveu, F. Role of Quinone Reductase 2 in the Antimalarial Properties of Indolone-Type Derivatives. Molecules 2017, 22, 210.

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