Issue 24, 2012

Exploring the trifluoromenadione core as a template to design antimalarial redox-active agents interacting with glutathione reductase

Abstract

Menadione is the 2-methyl-1,4-naphthoquinone core used to design potent antimalarial redox-cyclers to affect the redox equilibrium of Plasmodium-infected red blood cells. Exploring the reactivity of fluoromethyl-1,4-naphthoquinones, in particular trifluoromenadione, under quasi-physiological conditions in NADPH-dependent glutathione reductase reactions, is discussed in terms of chemical synthesis, electrochemistry, enzyme kinetics, and antimalarial activities. Multitarget-directed drug discovery is an emerging approach to the design of new antimalarial drugs. Combining in one single 1,4-naphthoquinone molecule, the trifluoromenadione core with the alkyl chain at C-3 of the known antimalarial drug atovaquone, revealed a mechanism for CF3 as a leaving group. The resulting trifluoromethyl derivative 5 showed a potent antimalarial activity per se against malarial parasites in culture.

Graphical abstract: Exploring the trifluoromenadione core as a template to design antimalarial redox-active agents interacting with glutathione reductase

Supplementary files

Article information

Article type
Paper
Submitted
31 Jan 2012
Accepted
17 Apr 2012
First published
17 Apr 2012

Org. Biomol. Chem., 2012,10, 4795-4806

Exploring the trifluoromenadione core as a template to design antimalarial redox-active agents interacting with glutathione reductase

D. A. Lanfranchi, D. Belorgey, T. Müller, H. Vezin, M. Lanzer and E. Davioud-Charvet, Org. Biomol. Chem., 2012, 10, 4795 DOI: 10.1039/C2OB25229E

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