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ChemMedChem
Volumn 7, Issue 12, 2012, Pages 2204-2226
Interactions between Artemisinins and other Antimalarial Drugs in Relation to the Cofactor Model-A Unifying Proposal for Drug Action
Author keywords

Artemisinins; Cofactor model; Cytosolic iron(III); Malaria; Oxidative stress
Indexed keywords

AMODIAQUINE; ANTIMALARIAL AGENT; ARTEMISININ; ARTESUNATE; ASCORBIC ACID; BENFLUMETOL; CARBENE; CHLOROQUINE; HEMOZOIN; LEUCOMETHYLENE BLUE; MEFLOQUINE; METHANOL; METHYLENE BLUE; N BENZYL 1,4 DIHYDRONICOTINAMIDE; OXIDOREDUCTASE; OXYGEN; PIPERAQUINE; PYRONARIDINE; QUERCETIN; QUININE; QUINOLINE; REACTIVE OXYGEN METABOLITE; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE; SARCOPLASMIC RETICULUM CALCIUM TRANSPORTING ADENOSINE TRIPHOSPHATASE; UNCLASSIFIED DRUG; VERAPAMIL;
EID: 84870289054     PISSN: 18607179     EISSN: 18607187     Source Type: Journal    
DOI: 10.1002/cmdc.201200383     Document Type: Article
Times cited : (59)
References (165)
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    • The ability of artemisinins to induce membrane damage, particularly in the presence of iron, is thus a secondary effect, namely artemisinin-induced generation of ROS, and iron-mediated Fenton chemistry of the ROS, a classical inducer of membrane autoxidation; see:
    • The ability of artemisinins to induce membrane damage, particularly in the presence of iron, is thus a secondary effect, namely artemisinin-induced generation of ROS, and iron-mediated Fenton chemistry of the ROS, a classical inducer of membrane autoxidation; see:
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    • Note
    • 2 is classified as a reactive oxygen species (ROS):
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    • An assay based on use of the Ellman reagent to determine turnover of FAD in rat liver TrxR and P.falciparum TrxR was used:
    • An assay based on use of the Ellman reagent to determine turnover of FAD in rat liver TrxR and P.falciparum TrxR was used:
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    • M.M.-K. Tang, PhD Thesis, The Hong Kong University of Science and Technology, January 2012;
    • M.M.-K. Tang, PhD Thesis, The Hong Kong University of Science and Technology, January 2012;
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    • P. Coghi, D. Monti, R.K. Haynes, unpublished results.
    • P. Coghi, D. Monti, R.K. Haynes, unpublished results.
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    • NOTE
    • A peer reviewer has pointed out that artemisinins kill parasites at nanomolar concentrations, and thus the generation of ROS alone may not explain the parasiticidal effects of artemisinins. Peroxides that rapidly oxidize reduced cofactors tend to be more active as antimalarial agents (ref.[8]). Thus, the focus is on the dynamics of intracellular processes and in particular how quickly the buildup of ROS occurs once the redox machinery capable of keeping ROS in check is blocked, if ever so transiently. We are unable to find data on the kinetics of ROS production, but given the diffusion-controlled nature of these reactions in general, ROS generation must be rapid. This becomes more important if iron is able to accelerate the turnover of reduced flavin cofactors and contribute to oxidative stress (Schemes1 and 5). It would be nice to quantify ROS production in the malaria parasite, and to determine how quickly this occurs relative to other organisms treated with artemisinins and synthetic peroxides, but this has to be a study for another time. Also significant here is the apparent ability of artemisinins to induce autoxidation of flavin cofactors under aerobic conditions; that is, they may initiate a catalytic process mediated by oxygen. We are also mindful of the potential ability of artemisinins to catalyze the formation of ROS such as singlet oxygen under aerobic conditions (ref.[9]).
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    • It is reported that parasite GR and TrxR are not essential for the proliferation of blood stages of P.berghei. The significance of this work is difficult to evaluate: the inference is that P.berghei either enhances scavenging of the host enzymes and/or must use functionally related enzymes such as flavin reductase (Fre) for controlling oxidative stress in order to survive. It is nevertheless stated that inhibitors of flavin disulfide reductases, such as MB, should still be considered as part of antimalarial strategies
    • It is reported that parasite GR and TrxR are not essential for the proliferation of blood stages of P.berghei. The significance of this work is difficult to evaluate: the inference is that P.berghei either enhances scavenging of the host enzymes and/or must use functionally related enzymes such as flavin reductase (Fre) for controlling oxidative stress in order to survive. It is nevertheless stated that inhibitors of flavin disulfide reductases, such as MB, should still be considered as part of antimalarial strategies: K. Buchholz, E. D. Putrianti, S. Rahlfs, R. H. Schirmer, K. Becker, K. Matuschewski, J. Biol. Chem. 2010, 285, 37388-37395.
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    • Although, in notable contrast to artemisinins, trioxolanes capped with an adamantyl group provide C-radicals that are rigid, relatively incapable of undergoing internal quenching, and therefore easily trapped by external spin-unpaired non-biological agents (ref.[24]), invitro antimalarial activities of such trioxolanes do not exceed those of the best artemisinins, Thus, on the basis of the C-radical theory, the assumption is made that the adamantyl group, in generating such a radical, is part of the pharmacophoric unit. However, the intact adamantyl group must enhance drug pharmacokinetics by facilitating permeation through cell membranes. For examples that espouse the C-radical idea with adamantyl systems, see:
    • Although, in notable contrast to artemisinins, trioxolanes capped with an adamantyl group provide C-radicals that are rigid, relatively incapable of undergoing internal quenching, and therefore easily trapped by external spin-unpaired non-biological agents (ref.[24]), invitro antimalarial activities of such trioxolanes do not exceed those of the best artemisinins: J. Marfurt, F. Chalfein, P. Prayoga, F. Wabiser, G. Wirjanata, B. Sebayang, K. A. Piera, S. Wittlin, R. K. Haynes, J. Möhrle, N. M. Anstey, E. Kenangalem, R. N. Price, Antimicrob. Agents Chemother. 2012, 56, 5258-5263. Thus, on the basis of the C-radical theory, the assumption is made that the adamantyl group, in generating such a radical, is part of the pharmacophoric unit. However, the intact adamantyl group must enhance drug pharmacokinetics by facilitating permeation through cell membranes. For examples that espouse the C-radical idea with adamantyl systems, see:
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    • In the absence of any information to the contrary, it is assumed that in refs.[46-60], all drugs used for antagonism/synergism studies with each of MB and artemisinins are used as the commercially available salts.
    • In the absence of any information to the contrary, it is assumed that in refs.[46-60], all drugs used for antagonism/synergism studies with each of MB and artemisinins are used as the commercially available salts.
  • 106
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    • The results of a detailed examination of pH effects on the rate of artemisinin reduction by the BNAH-RF and NADPH-Fre-FAD systems, the use of quinoline free bases versus salts, and the role of ion-pairing in association of the quinolines with the reduced flavins will be reported separately.
    • The results of a detailed examination of pH effects on the rate of artemisinin reduction by the BNAH-RF and NADPH-Fre-FAD systems, the use of quinoline free bases versus salts, and the role of ion-pairing in association of the quinolines with the reduced flavins will be reported separately.
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    • See Supporting Information accompanying ref.[1] and figuresS6 and S7 for full details of the NMR method employing BNAH-RF.
    • See Supporting Information accompanying ref.[1] and figuresS6 and S7 for full details of the NMR method employing BNAH-RF.
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    • Full details may be obtained from Prof. K. Sinniah, Dr. A. Witte, E-mail: ksinniah@calvin.edu.
    • Full details may be obtained from Prof. K. Sinniah, Dr. A. Witte, E-mail: ksinniah@calvin.edu.
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    • 9-Deshydroxyquinine shows little or no tendency to bind heme or to inhibit the formation of β-hematin, an invitro assay routinely used to establish the efficacy of a drug in inhibiting hemozoin formation. This highlights the impaired ability of the quinoline ring in QN, in the absence of coordinating hydroxy group, to generate a physiologically meaningful πcomplex with heme, Conversion of the 9-hydroxy group of quinine into methoxy has the same effect: the ether has no significant antimalarial activity invitro, nor does it inhibit the formation of β-hematin: D. Monti, P. Coghi, D. Taramelli, S. Parapini, unpublished results.
    • 9-Deshydroxyquinine shows little or no tendency to bind heme or to inhibit the formation of β-hematin, an invitro assay routinely used to establish the efficacy of a drug in inhibiting hemozoin formation. This highlights the impaired ability of the quinoline ring in QN, in the absence of coordinating hydroxy group, to generate a physiologically meaningful πcomplex with heme: J. N. Alumasa, A. P. Gorka, L. B. Casabianca, E. Comstock, A. C. deDios, P. D. Roepe, J. Inorg. Biochem. 2011, 105, 467-475. Conversion of the 9-hydroxy group of quinine into methoxy has the same effect: the ether has no significant antimalarial activity invitro, nor does it inhibit the formation of β-hematin: D. Monti, P. Coghi, D. Taramelli, S. Parapini, unpublished results.
    • (2011) J. Inorg. Biochem. , vol.105 , pp. 467-475
    • Alumasa, J.N.1    Gorka, A.P.2    Casabianca, L.B.3    Comstock, E.4    deDios, A.C.5    Roepe, P.D.6

* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.