Complex Formation between Chloroquine and Ferrihæmic Acid in vitro, and its effect on the Antimalarial Action of Chloroquine

Cohen, S.; Phifer, K O; Yielding, K. Lemone

doi:10.1038/202805a0

Cited by 113 publications

(64 citation statements)

References 6 publications

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“…In mixed aqueous solution (40% DMSO [vol/vol]), FP is expected to be monomeric, as shown by the sharp Soret band at 400 nm (21). It is known that the UV-visible spectrum of FP changes upon addition of CQ, with a decrease in the absorption of the Soret band which is indicative of the formation of CQ-FP complexes (9). The interaction of the aminoquinolines with FP was investigated by monitoring the quenching of the Soret band in 40% DMSO-10 mM sodium phosphate buffer, pH 6.0.…”

Section: Resultsmentioning

confidence: 99%

Novel Antimalarial Aminoquinolines: Heme Binding and Effects on Normal or Plasmodium falciparum -Parasitized Human Erythrocytes

Omodeo‐Salè¹,

Cortelezzi²,

Basilico³

et al. 2009

Antimicrob Agents Chemother

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Two new quinolizidinyl-alkyl derivatives of 7-chloro-4-aminoquinoline, named AM-1 and AP4b, which are highly effective in vitro against both the D10 (chloroquine [CQ] susceptible) and W2 (CQ resistant) strains of Plasmodium falciparum and in vivo in the rodent malaria model, have been studied for their ability to bind to and be internalized by normal or parasitized human red blood cells (RBC) and for their effects on RBC membrane stability. In addition, an analysis of the heme binding properties of these compounds and of their ability to inhibit beta-hematin formation in vitro has been performed. Binding of AM1 or AP4b to RBC is rapid, dose dependent, and linearly related to RBC density. Their accumulation in parasitized RBC (pRBC) is increased twofold compared to levels in normal RBC. Binding of AM1 or AP4b to both normal and pRBC is higher than that of CQ, in agreement with the lower pK a and higher lipophilicity of the compounds. AM1 or AP4b is not hemolytic per se and is less hemolytic than CQ when hemolysis is accelerated (induced) by hematin. Moreover, AM-1 and AP4b bind heme with a stoichiometry of interaction similar to that of CQ (about 1:1.7) but with a lower affinity. They both inhibit dose dependently the formation of beta-hematin in vitro with a 50% inhibitory concentration comparable to that of CQ. Taken together, these results suggest that the antimalarial activity of AM1 or AP4b is likely due to inhibition of hemozoin formation and that the efficacy of these compounds against the CQ-resistant strains can be ascribed to their hydrophobicity and capacity to accumulate in the vacuolar lipid (elevated lipid accumulation ratios).Chloroquine (CQ) has been effectively used for decades as an antimalarial drug for its efficacy, safety, and stability but is now largely ineffective because of widespread parasite resistance. This has led to the necessity of utilizing artemisininbased combination therapy as a first-line treatment for uncomplicated malaria (20). However, the recent reports of artemisinin-based combination therapy treatment failure in southeast Asia and the potential emergence of artemisinin resistance (26) indicate that the search for new drugs or new drug combinations is still highly necessary (40, 41). Quinolinetype antimalarials remain an attractive class of compounds because their mechanism of action and resistance are unrelated (14) and resistance has emerged very slowly over time. CQ and quinoline antimalarial drugs are thought to kill parasites by inhibiting the process of crystallization necessary to detoxify ferriprotoporphyrin IX (FP) into hemozoin (HZ) (5,30,34). This process is vital for Plasmodium falciparum and can be reproduced in vitro with hematin under acidic conditions, leading to the formation of beta-hematin (BH), a crystal product showing physicochemical properties identical to those of HZ (29).FP in the food vacuole of the parasite is considered the target of quinoline antimalarials (6, 15). The inhibition of HZ formation leads to the accumulation of free FP, potentially...

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Section: Resultsmentioning

confidence: 99%

Novel Antimalarial Aminoquinolines: Heme Binding and Effects on Normal or Plasmodium falciparum -Parasitized Human Erythrocytes

Omodeo‐Salè¹,

Cortelezzi²,

Basilico³

et al. 2009

Antimicrob Agents Chemother

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“…The combined toxic effect of heroin and the antimalarial drug chloroquine on cell membranes has been suggested to underly the pharmacological mode of action of this drug [16]. Hemin forms complexes with antimalarial drugs both in aqueous [1,17] and apolar [18] phases and in the presence of these complexes erythrocytes and malaria parasites lyse [1,4,5]. These observations, in conjunction with the present resurgence of malaria which is mostly due to chloroquine resistance and the lack of cross resistance to other 4-aminoquinolines [19,20], underscores the necessity for further probing of the molecular details of the interaction of hemin, drugs and heroin-drug complexes with phospholipids.…”

Section: Introductionmentioning

confidence: 99%

Interactions of hemin, antimalarial drugs and hemin-antimalarial complexes with phospholipid monolayers

Ginsburg

Demel

1984

Chemistry and Physics of Lipids

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Hemin, antimalarial drugs and complexes formed between them, have demonstrable effects on biological membranes. Using the phospholipid monolayer model, we show that hemin intercalates into the membrane and increases its surface pressure, depending on the lipid composition and the initial surface pressure: negative surface charges and particularly looser compaction of the phospholipids reduce the effect of hemin. With increasing surface pressure hemin tends to intercalate as a monomer, and the half-saturation concentration of its effect increases exponentially. The antimalarial monovalent drugs quinine and mefloquine, but not chloroquine, also penetrate into the membrane and expand it. All three drugs markedly increase the effect of hemin, but chloroquine reduces the effect in monolayers composed of unsaturated phospholipids. The drugs' effect is mostly due to an increase in the maximal surface pressure and suggests a complexation of heroin and drug within the membrane phase. Preformed hemindrug complexes decrease the half-saturation concentration of the effect and suggest that the complexes adsorb to the membrane, releasing the hemin through an apolar continuum into the phospholipid phase. The implications of the results to the membrane toxicity mechanism proposed for the molecular mode of action of antimalarial drugs are discussed.

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“…11 The detailed mechanism of inhibition has been a matter of debate, with one school of thought proposing that it involves complex formation in solution, [12][13][14] while another postulates inhibition of crystal growth via interaction with the crystal surface. 15 It is known that quinolines form complexes with Fe(III)PPIX in solution, 12,16 while it is also the case that the inhibitory effects of these compounds can be described by a surface interaction model. 15,17,18 4…”

Section: -10mentioning

confidence: 99%

“…Thus, a role for solution association cannot necessarily be ruled out for all series of 4-aminoquinoline compounds. Finally, the correlation equations permit the prediction of both log K and log BHIA 50 for these series of [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] aminoquinolines. Interestingly, they do not suggest that the lipophilicity of the group X plays a major role in -hematin inhibition.…”

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confidence: 99%

Structure–activity relationships for ferriprotoporphyrin IX association and β-hematin inhibition by 4-aminoquinolines using experimental and ab initio methods

Nsumiwa

Kuter

Wittlin

et al. 2013

Bioorganic & Medicinal Chemistry

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In order to probe structure-activity relationships of association with ferriprotoporphyrin IX (log K) and inhibition of -hematin formation, a series of 4-aminoquinolines with varying substituents at the 7-position (X) have been synthesized. These have been further elaborated by introduction of two different R groups on the 4-amino nitrogen atom in the form of methyl (R = Me) and ethylamine (R = EtNH 2 ) side chains. Data for a previously investigated series containing an N,N-diethyl-ethylamine side chain were also compared with the findings of this study. Experimentally, log K values for the simple 4-aminoquinoline series (R = H) were found to correlate with the hydrophobicity constant () of the group X. The log K values for the series with R = Me and EtNH 2 were found to correlate with those of the series with R = H. The log of the 50% -hematin inhibitory activity (log BHIA 50 ) was found to correlate with log K and either meta ( m ) or para ( p ) Hammett constants for the series with R = Me and EtNH 2 , but not the simple series with R = H. To further improve predictability, correlations with ab initio electrostatic parameters, namely Mulliken and CHelpG charges were investigated. The best correlations were found with CHelpG charges which indicated that log K values can be predicted from the charges on atom H-8 and the group X in the quinolinium species computed in vacuum, while log BHIA 50 values can be predicted from the CHelpG charges on C-7, C-8 and N-1 for the neutral species in vacuum. These correlations indicate that association and inhibition of -hematin formation are separately determined. They also suggest that electron withdrawing groups at the 7-position, but not necessarily hydrophobic groups are required for hemozoin inhibition. The upshot is that the correlations imply that considerably more hydrophilic hemozoin inhibitors are feasible.Keywords: hemozoin; DFT; antimalarials; quinolines; structure-activity relationships; ferriprotoporphyrin IX 3 IntroductionQuinoline antimalarials such as quinine and chloroquine have had a long and successful history. 1 Subsequent emergence of chloroquine resistance has led to the use of other quinoline derivative antimalarials such as mefloquine and amodiaquine. Indeed, the development and clinical deployment of new quinoline antimalarials continues to this day.For example, piperaquine, a bis-4-aminoquinoline effective against chloroquine-resistant strains that consists of two 4-aminoquinoline moieties attached by a linker has only recently been introduced into clinical use. 2 Ferroquine, a 4-amino-7-chloroquinoline with a ferrocenyl side-chain is currently in phase IIB clinical trials. 3 In addition, research on new quinoline antimalarials retains considerable interest, such as that on so-called "reversed chloroquines"and related compounds that are both antimalarially active and inhibit the chloroquine resistance mechanism of the parasite. 4-10The class of 4-aminoquinoline antimalarials are believed to act by inhibiting the incorporation of ferrih...

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Complex Formation between Chloroquine and Ferrihæmic Acid in vitro, and its effect on the Antimalarial Action of Chloroquine

Cited by 113 publications

References 6 publications

Novel Antimalarial Aminoquinolines: Heme Binding and Effects on Normal or Plasmodium falciparum -Parasitized Human Erythrocytes

Novel Antimalarial Aminoquinolines: Heme Binding and Effects on Normal or Plasmodium falciparum -Parasitized Human Erythrocytes

Interactions of hemin, antimalarial drugs and hemin-antimalarial complexes with phospholipid monolayers

Structure–activity relationships for ferriprotoporphyrin IX association and β-hematin inhibition by 4-aminoquinolines using experimental and ab initio methods

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