A Medicinal Chemistry Perspective on 4-Aminoquinoline Antimalarial Drugs

O’Neill, Paul M.; Ward, Stephen A.; Berry, Neil G.; Jeyadevan, J. P.; Biagini, Giancarlo A.; Asadollaly, E.; Park, B. K.; Bray, Patrick G.

doi:10.2174/156802606776743147

Cited by 98 publications

(18 citation statements)

References 87 publications

(134 reference statements)

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“…Thus, a 10h incubation with DFMO starting in the early trophozoite stage may generate insufficient stress to result in a notable disruption of ATP homeostasis. The consensus view is that chloroquine becomes ionized and trapped in the low pH environment of the parasite food vacuole, where it disrupts haemozoin formation and causes an accumulation of toxic free haem and chloroquine-haem complexes [17]. The results of this study suggest that a 10h incubation with chloroquine from the early trophozoite stage does not generate sufficient haem complexes to exert a significant effect on parasite ATP levels and/or haem-induced toxicity is slow-acting.…”

Section: Discussionmentioning

confidence: 86%

ATP and luciferase assays to determine the rate of drug action in in vitro cultures of Plasmodium falciparum

Khan

Brummelen

Parkinson

et al. 2012

Malar J

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BackgroundKnowledge of the rate of action of compounds against cultured malaria parasites is required to determine the optimal time-points for drug mode of action studies, as well as to predict likely in vivo parasite clearance rates in order to select optimal hit compounds for further development. In this study, changes in parasite ATP levels and transgenic luciferase reporter activity were explored as means to detect drug-induced stress in cultured parasites.MethodsIn vitro cultures of Plasmodium falciparum 3D7 wild-type or firefly luciferase-expressing parasites were incubated with a panel of six anti-malarial compounds for 10 hours and parasite ATP levels or luciferase activity determined at two-hour intervals using luminescence-based reagents. For comparative purposes, parasite morphology changes were evaluated by light microscopy, as well as the extent to which parasites recover after 48 hours from a six-hour drug treatment using a parasite lactate dehydrogenase assay.ResultsChanges in parasite ATP levels displayed three phenotypes: mild or no change (chloroquine, DFMO); 2–4 fold increase (mefloquine, artemisinin); severe depletion (ritonavir, gramicidin). The respective phenotypes and the rate at which they manifested correlated closely with the extent to which parasites recovered from a six-hour drug treatment (with the exception of chloroquine) and the appearance and severity of morphological changes observed by light microscopy. Luciferase activity decreased profoundly in parasites treated with mefloquine, artemisinin and ritonavir (34-67% decrease in 2 hours), while chloroquine and DFMO produced only mild changes over 10 hours. Gramicidin yielded intermediate decreases in luciferase activity.ConclusionsATP levels and luciferase activity respond rapidly to incubation with anti-malarial drugs and provide quantitative read-outs to detect the appearance and magnitude of drug-induced stress in cultured parasites. The correlation between the observed changes and irreversible parasite toxicity is not yet sufficiently clear to predict clinical clearance rates, but may be useful for ranking compounds against each other and standard drugs vis-à-vis rate of action and for determining early time-points for drug mode of action studies.

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Section: Discussionmentioning

confidence: 86%

ATP and luciferase assays to determine the rate of drug action in in vitro cultures of Plasmodium falciparum

Khan

Brummelen

Parkinson

et al. 2012

Malar J

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“…This substructure has had much published on structure activity relationships [89–91]. Basically the quinoline nucleus is essential for heme binding, the chlorine and hydroxyl entities for heme crystal inhibition and the amino weak bases for digestive vacuole accumulation.…”

Section: Heme Crystal Inhibitionmentioning

confidence: 99%

Plasmodium Drug Targets Outside the Genetic Control of the Parasite

Sullivan¹

2013

Current Pharmaceutical Design

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Drug development often seeks to find “magic bullets” which target microbiologic proteins while not affecting host proteins. Paul Ehrlich tested methylene blue as an antimalarial but this dye was not superior to quinine. Many successful antimalarial therapies are “magic shotguns” which target many Plasmodium pathways with little interference in host metabolism. Two malaria drug classes, the 8-aminoquinolines and the artemisinins interact with cytochrome P450s and host iron protoporphyrin IX or iron, respectively, to generate toxic metabolites and/or radicals, which kill the parasite by interference with many proteins. The non 8-amino antimalarial quinolines like quinine or piperaquine bind heme to inhibit the process of heme crystallization, which results in multiple enzyme inhibition and membrane dysfunction. The quinolines and artemisinins are rapidly parasiticidal in contrast to metal chelators, which have a slower parasite clearance rate with higher drug concentrations. Iron chelators interfere with the artemisinins but otherwise represent a strategy of targeting multiple enzymes containing iron. Interest has been revived in antineoplastic drugs that target DNA metabolism as antimalarials. Specific drug targeting or investigation of the innate immunity directed to the more permeable trophozoite or schizont infected erythrocyte membrane has been under explored. Novel drug classes in the antimalarial development pipeline which either target multiple proteins or unchangeable cellular targets will slow the pace of drug resistance acquisition.

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“…Over the past two decades, a number of antimalarial agents, particularly the 4-aminoquinoline-based drugs, have been developed and tested against chloroquine-resistant parasites. 6, 7 Although there has been substantial improvement in the conventional organic synthetic strategies used for the development of antimalarial agents, researchers have sought out ways to develop more innovative approaches in order to develop more efficacious drugs to cure the disease. One of the most promising new approaches involves the use of transition metal ion complexes to produce novel antimalarial drugs.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and antimalarial activity of metal complexes of cross-bridged tetraazamacrocyclic ligands

Hubin

Amoyaw

Roewe

et al. 2014

Bioorganic & Medicinal Chemistry

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Using transition metals such as manganese(II), iron(II), cobalt(II), nickel(II), copper(II), and zinc(II), several new metal complexes of cross-bridged tetraazamacrocyclic chelators namely, cyclen- and cyclam-analogs with benzyl groups, were synthesized and screened for in vitro antimalarial activity against chloroquine-resistant (W2) and chloroquine-sensitive (D6) strains of Plasmodium falciparum. The metal-free chelators tested showed little or no antimalarial activity. All the metal complexes of the dibenzyl cross-bridged cyclam ligand exhibited potent antimalarial activity. The Mn2+ complex of this ligand was the most potent with IC50s of 0.127 and 0.157 µM against the chloroquine-sensitive (D6) and chloroquine-resistant (W2) P. falciparum strains, respectively. In general, the dibenzyl hydrophobic ligands showed better antimalarial activity compared to the activity of monobenzyl ligands, potentially because of their higher lipophilicity and thus better cell penetration ability. The higher antimalarial activity displayed by the manganese complex for the cyclam ligand in comparison to that of the cyclen, correlates with the larger pocket of cyclam compared to that of cyclen which produces a more stable complex with the Mn2+. Few of the Cu2+ and Fe2+ complexes also showed improvement in activity but Ni2+, Co2+ and Zn2+ complexes did not show any improvement in activity upon the metal-free ligands for anti-malarial development.

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A Medicinal Chemistry Perspective on 4-Aminoquinoline Antimalarial Drugs

Cited by 98 publications

References 87 publications

ATP and luciferase assays to determine the rate of drug action in in vitro cultures of Plasmodium falciparum

ATP and luciferase assays to determine the rate of drug action in in vitro cultures of Plasmodium falciparum

Plasmodium Drug Targets Outside the Genetic Control of the Parasite

Synthesis and antimalarial activity of metal complexes of cross-bridged tetraazamacrocyclic ligands

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