Soluble Synthetic Analogues of Malaria Pigment: Structure of Mesohematin Anhydride and its Interaction with Chloroquine in Solution

Bohle, D. Scott; Dodd, Erin L.; Kosar, Aaron J.; Sharma, Lauren; Stephens, Peter W.; Suárez, Liliana; Tazoo, Dagobert

doi:10.1002/ange.201100910

Cited by 4 publications

(5 citation statements)

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“…The evaluation of the nature, the stoichiometry and the strength of ferriprotoporphyrin Fe III PPIX complexes with antimalarial and antischistosomal redox biosensors, a focus of our ongoing research work and of this present report, is of fundamental importance. The nature of the hematin dimer in solution (μ-oxo [33] / ππ [34] / μ-Pr [35]), which has been established to be an important building block during the formation of hemozoin, was (and is still) a subject of interest and debates for more than sixty years. Iron(III) metalloporphyrins can undergo various equilibria in solution (self-association or dimerization, oligomerization) and protolytic reactions depending on the physico-chemical conditions of the medium (solvent, pH, ionic strength, temperature…).…”

Section: Thermodynamics and Structural Aspects Of Ferriprotoporphyrinmentioning

confidence: 99%

“…Hemozoin and models of hemozoin (β-hematin) [35,41] have been extensively analyzed in the past few years, and led recently to new sights about their biomineralization properties. Until very recently, hemozoin [35] and β-hematin were both regarded as repetitive occurrence of μ-Pr dimers (see vide infra for β-hematin) and the π-π stabilizing interactions were considered only in the context of crystal packing [35].…”

Section: Thermodynamics and Structural Aspects Of Ferriprotoporphyrinmentioning

confidence: 99%

“…Until very recently, hemozoin [35] and β-hematin were both regarded as repetitive occurrence of μ-Pr dimers (see vide infra for β-hematin) and the π-π stabilizing interactions were considered only in the context of crystal packing [35]. …”

Section: Thermodynamics and Structural Aspects Of Ferriprotoporphyrinmentioning

confidence: 99%

“… a Refer to references [20], [35] [39], [40] and [41] for schematic representation of μ-oxo Fe III PPIX , π-π Fe III PPIX and μ-Pr Fe III PPIX dimers and X-ray structures of β-hematin and hemozoin. …”

Section: Figurementioning

confidence: 99%

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A Physico-Biochemical Study on Potential Redox-Cyclers as Antimalarial and Antischistosomal Drugs

Johann

Lanfranchi²,

Davioud‐Charvet³

et al. 2012

cpd

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The role of redox enzymes in establishing a microenvironment for parasite development is well characterized. Mimicking human glucose-6-phosphate dehydrogenase and glutathione reductase (GR) deficiencies by redox-cycling compounds thus represents a challenge to the design of new preclinical antiparasitic drug candidates. Schistosomes and malarial parasites feed on hemoglobin. Heme, the toxic prosthetic group of the protein, is not digested and represents a challenge to the redox metabolism of the parasites. Here, we report on old and new redox-cycling compoundswhose antiparasitic activities are related to their interference with (met)hemoglobin degradation and hematin crystallization. Three key-assays allowed probing and differentiating the mechanisms of drug actions. Inhibition of β-hematin was first compared to the heme binding as a possible mode of action. All tested ligands interact with the hematin π-π dimer with K D similar to those measured for the major antiparasitic drugs. No correlation between a high affinity for hematin and the capacity to prevent β-hematin formation was however deduced. Inhibition of β-hematin formation is consequently not the result of a single process but results from redox processes following electron transfers from the drugs to iron(III)-containing targets. The third experiment highlighted that several redox-active compounds (in their reduced forms) are able to efficiently reduce methemoglobin to hemoglobin in a GR/NADPH-coupled assay. A correlation between methemoglobin reduction and inhibition of β-hematin was shown, demonstrating that both processes are closely related. The ability of our redox-cyclers to trigger methemoglobin reduction therefore constitutes a critical step to understand the mechanism of action of our drug candidates.

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Section: Thermodynamics and Structural Aspects Of Ferriprotoporphyrinmentioning

confidence: 99%

Section: Thermodynamics and Structural Aspects Of Ferriprotoporphyrinmentioning

confidence: 99%

Section: Thermodynamics and Structural Aspects Of Ferriprotoporphyrinmentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

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A Physico-Biochemical Study on Potential Redox-Cyclers as Antimalarial and Antischistosomal Drugs

Johann

Lanfranchi²,

Davioud‐Charvet³

et al. 2012

cpd

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“…Whether the quinoline or side chain nitrogen atoms of CQ also coordinate with iron is a matter of contention, but if there is such a coordination, this must be weak 78. 79 The side chain tertiary amino group of CQ forms a salt bridge with the heme carboxylate in solution ( cf. Scheme ) 78.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2012

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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-Fe(III) results in an enhanced efflux from the DV into the cytosol. In addition, the lipophilic heme-Fe(III) 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-Fe(III) . The quinoline or arylmethanol reenters the DV, and so transfers more heme-Fe(III) out of the DV. In this way, the 4-aminoquinolines and arylmethanols exert antimalarial activities by enhancing heme-Fe(III) and thence free Fe(III) concentrations in the cytosol. The iron species enter into redox cycles through reduction of Fe(III) to Fe(II) largely mediated by reduced flavin cofactors and likely also by NAD(P)H-Fre. Generation of ROS through oxidation of Fe(II) 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 between pairs of lipophilic drugs must adversely influence the pharmacokinetics of each drug. This explains the antagonism between PPQ and MFQ, for example. The basis for the antimalarial activity of RF mirrors that of MB, wherein it participates in redox cycling that involves flavoenzymes or Fre, resulting in attrition of NAD(P)H. The generation of ROS by artemisinins and ensuing Fenton chemistry accommodate the ability of artemisinins to induce membrane damage and to affect the parasite SERCA PfATP6 Ca(2+) transporter. Thus, the effect exerted by ...

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Deconstructing Quinoline‐Class Antimalarials to Identify Fundamental Physicochemical Properties of Beta‐Hematin Crystal Growth Inhibitors

Olafson

Nguyen

Vekilov

et al. 2017

Chemistry A European J

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A versatile approach to control crystallization involves the use of modifiers, which are additives that interact with crystal surfaces and alter their growth rates. Elucidating a modifier's binding specificity to anisotropic crystal surfaces is a ubiquitous challenge that is critical to their design. In this study, we select hematin, a byproduct of malaria parasites, as a model system to examine the complementarity of modifiers (i.e., antimalarial drugs) to β-hematin crystal surfaces. We divide two antimalarials, chloroquine and amodiaquine, into segments consisting of a quinoline base, common to both drugs, and side chains that differentiate their modes of action. Using a combination of scanning probe microscopy, bulk crystallization, and analytical techniques, we show that the base and side chain work synergistically to reduce the rate of hematin crystallization. In contrast to general observations that modifiers retain their function upon segmentation, we show that the constituents do not act as modifiers. A systematic study of quinoline isomers and analogues shows how subtle rearrangement and removal of functional moieties can create effective constituents from previously ineffective modifiers, along with tuning their inhibitory modes of action. These findings highlight the importance of specific functional moieties in drug compounds, leading to an improved understanding of modifier-crystal interactions that could prove to be applicable to the design of new antimalarials.

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Soluble Synthetic Analogues of Malaria Pigment: Structure of Mesohematin Anhydride and its Interaction with Chloroquine in Solution

Cited by 4 publications

References 32 publications

A Physico-Biochemical Study on Potential Redox-Cyclers as Antimalarial and Antischistosomal Drugs

A Physico-Biochemical Study on Potential Redox-Cyclers as Antimalarial and Antischistosomal Drugs

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

Deconstructing Quinoline‐Class Antimalarials to Identify Fundamental Physicochemical Properties of Beta‐Hematin Crystal Growth Inhibitors

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