Interactions between Artemisinins and other Antimalarial Drugs in Relation to the Cofactor Model-A Unifying Proposal for Drug Action

Artemisinins are proposed to act in the malaria parasite cytosol by oxidizing dihydroflavin cofactors of redox‐active flavoenzymes, and under aerobic conditions by inducing their autoxidation. Perturbation of redox homeostasis coupled with the generation of reactive oxygen species (ROS) ensues. Asco...

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Published in:ChemMedChem 2012-12, Vol.7 (12), p.2204-2226
Main Authors: Haynes, Richard K., Cheu, Kwan-Wing, Chan, Ho-Wai, Wong, Ho-Ning, Li, Ka-Yan, Tang, Maggie Mei-Ki, Chen, Min-Jiao, Guo, Zu-Feng, Guo, Zhi-Hong, Sinniah, Kumar, Witte, Amanda B., Coghi, Paolo, Monti, Diego
Format: Article
Language:English
Subjects:
Antimalarials - pharmacology
artemisinins
Artemisinins - pharmacology
Chloroquine - pharmacology
cofactor model
cytosolic iron(III)
Drug Interactions
Ferric Compounds - metabolism
Flavin-Adenine Dinucleotide - metabolism
Humans
malaria
Malaria - drug therapy
Methylene Blue - pharmacology
Mutation
NAD - analogs & derivatives
NAD - metabolism
NADP - metabolism
oxidative stress
Oxidative Stress - drug effects
Quinolines - metabolism
Riboflavin - metabolism
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Summary:Artemisinins are proposed to act in the malaria parasite cytosol by oxidizing dihydroflavin cofactors of redox‐active flavoenzymes, and under aerobic conditions by inducing their autoxidation. Perturbation of redox homeostasis coupled with the generation of reactive oxygen species (ROS) ensues. Ascorbic acid–methylene blue (MB), N‐benzyl‐1,4‐dihydronicotinamide (BNAH)–MB, BNAH–lumiflavine, BNAH–riboflavin (RF), and NADPH–FAD–E. coli flavin reductase (Fre) systems at pH 7.4 generate leucomethylene blue (LMB) and reduced flavins that are rapidly oxidized in situ by artemisinins. These oxidations are inhibited by the 4‐aminoquinolines piperaquine (PPQ), chloroquine (CQ), and others. In contrast, the arylmethanols lumefantrine, mefloquine (MFQ), and quinine (QN) have little or no effect. Inhibition correlates with the antagonism exerted by 4‐aminoquinolines on the antimalarial activities of MB, RF, and artemisinins. Lack of inhibition correlates with the additivity/synergism between the arylmethanols and artemisinins. We propose association via π complex formation between the 4‐aminoquinolines and LMB or the dihydroflavins; this hinders hydride transfer from the reduced conjugates to the artemisinins. The arylmethanols have a decreased tendency to form π complexes, and so exert no effect. The parallel between chemical reactivity and antagonism or additivity/synergism draws attention to the mechanism of action of all drugs described herein. CQ and QN inhibit the formation of hemozoin in the parasite digestive vacuole (DV). The buildup of heme–FeIII results in an enhanced efflux from the DV into the cytosol. In addition, the lipophilic heme–FeIII complexes of CQ and QN that form in the DV are proposed to diffuse across the DV membrane. At the higher pH of the cytosol, the complexes decompose to liberate heme–FeIII. The quinoline or arylmethanol reenters the DV, and so transfers more heme–FeIII out of the DV. In this way, the 4‐aminoquinolines and arylmethanols exert antimalarial activities by enhancing heme–FeIII and thence free FeIII concentrations in the cytosol. The iron species enter into redox cycles through reduction of FeIII to FeII largely mediated by reduced flavin cofactors and likely also by NAD(P)H–Fre. Generation of ROS through oxidation of FeII by oxygen will also result. The cytotoxicities of artemisinins are thereby reinforced by the iron. Other aspects of drug action are emphasized. In the cytosol or DV, association by π complex formation betwee
ISSN:1860-7179
1860-7187
DOI:10.1002/cmdc.201200383