Effects of solvent composition and ionic strength on the interaction of quinoline antimalarials with ferriprotoporphyrin IX

Egan, Timothy J.; Ncokazi, Kanyile K.

doi:10.1016/j.jinorgbio.2003.09.007

Cited by 37 publications

(53 citation statements)

References 45 publications

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“…Sequestration would completely suppress the growth of β-hematin crystals if the residual concentration of unliganded hematin ½H is lowered to values at or below its solubility c e . To compare the relative efficacy of complexation and crystal surface interaction as inhibition pathways and to test if complexation dictates the selection of the drug mode of action, we characterized drug (D)-hematin (H) binding equilibria in CBSO, using a method based on UV-visible spectroscopy, previously used for predominantly aqueous solvents (65)(66)(67)(68). The UV-visible spectra of hematin in the presence of six drugs reveal that PY and ART do not form complexes with hematin in CBSO (SI Appendix, Figs.…”

Section: How Important Is the Contribution Of Drug-hematin Complexation?mentioning

confidence: 99%

Antimalarials inhibit hematin crystallization by unique drug–surface site interactions

Olafson

Nguyen

Rimer

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

136

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In malaria pathophysiology, divergent hypotheses on the inhibition of hematin crystallization posit that drugs act either by the sequestration of soluble hematin or their interaction with crystal surfaces. We use physiologically relevant, time-resolved in situ surface observations and show that quinoline antimalarials inhibit β-hematin crystal surfaces by three distinct modes of action: step pinning, kink blocking, and step bunch induction. Detailed experimental evidence of kink blocking validates classical theory and demonstrates that this mechanism is not the most effective inhibition pathway. Quinolines also form various complexes with soluble hematin, but complexation is insufficient to suppress heme detoxification and is a poor indicator of drug specificity. Collectively, our findings reveal the significance of drug-crystal interactions and open avenues for rationally designing antimalarial compounds.

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Section: How Important Is the Contribution Of Drug-hematin Complexation?mentioning

confidence: 99%

Antimalarials inhibit hematin crystallization by unique drug–surface site interactions

Olafson

Nguyen

Rimer

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

136

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“…Association is driven by hydrophobic interactions involving the lipophilic moieties in each component, such as is held to be important for the interaction of CQ with heme. [37,38] The flexible linker between the aryl rings of VP would allow optimal overlap of the p systems in the putative complex (see Figure 8). …”

Section: Wwwchemmedchemorgmentioning

confidence: 99%

A Partial Convergence in Action of Methylene Blue and Artemisinins: Antagonism with Chloroquine, a Reversal with Verapamil, and an Insight into the Antimalarial Activity of Chloroquine

Haynes

Cheu

et al. 2011

ChemMedChem

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Artemisinins rapidly oxidize leucomethylene blue (LMB) to methylene blue (MB); they also oxidize dihydroflavins such as the reduced conjugates RFH₂ of riboflavin (RF), and FADH₂ of the cofactor flavin adenine dinucleotide (FAD), to the corresponding flavins. Like the artemisinins, MB oxidizes FADH₂, but unlike artemisinins, it also oxidizes NAD(P)H. Like MB, artemisinins are implicated in the perturbation of redox balance in the malaria parasite by interfering with parasite flavoenzyme disulfide reductases. The oxidation of LMB by artemisinin is inhibited by chloroquine (CQ), an inhibition that is abruptly reversed by verapamil (VP). CQ also inhibits artemisinin-mediated oxidation of RFH₂ generated from N-benzyl-1,4-dihydronicotinamide (BNAH)-RF, or FADH₂ generated from NADPH or NADPH-Fre, an effect that is also modulated by verapamil. The inhibition likely proceeds by the association of LMB or dihydroflavin with CQ, possibly involving donor-acceptor or π complexes that hinder oxidation by artemisinin. VP competitively associates with CQ, liberating LMB or dihydroflavin from their respective CQ complexes. The observations explain the antagonism between CQ-MB and CQ-artemisinins in vitro, and are reconcilable with CQ perturbing intraparasitic redox homeostasis. They further suggest that a VP-CQ complex is a means by which VP reverses CQ resistance, wherein such a complex is not accessible to the putative CQ-resistance transporter (PfCRT).

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“…The influence of ionic strength on the complex stability was also found by investigations in polar mixtures of water with ethylene-or propylene glycol [15] [28] [34]. However, no effects of ionic strength, which is characteristic of electrostatic interactions, have been observed in mixtures of water and DMSO probably due the weak polarity of the medium [18]. One could attribute the decrease of affinity to the influence of the ionic strength on the formation of FeTPPS μ-oxo-Dimer.…”

Section: Uv-visible Spectrophotometrymentioning

confidence: 78%

“…The interaction of quinoline antimalarial with FePPIX plays the important role of bringing back the porphyrin into solution in order to block FePPIX unities, and to prevent the formation of hemozoin. The binding of FePPIX and its derivate Iron(III)-deuteroporphyrin IX (FeDPIX) to quinoline-based antimalarials Chloroquine, Quinine and Quinidine (Figure 2) have been demonstrated in vitro using mixtures of water with ethylene glycol, propylene glycol and DMSO [4] [11] [12] [15] [16] [17] [18]. It has been shown that the interaction depends on steric, stereochemical and electrostatic effects.…”

Section: Introductionmentioning

confidence: 99%

Interaction of Iron(III)-5,10,15,20-Tetrakis (4-Sulfonatophenyl) Porphyrin with Chloroquine, Quinine and Quinidine

Bibelayi¹,

Kilunga²,

Lundemba³

et al. 2017

CSTA

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Iron(III)-5,10,15,20-tetrakis(4-sulfonatophenyl) porphyrin (FeTPPS) is used as non-physiological metalloporphyrin model for the natural iron (III)-protoporphyrin IX (FePPIX) resulting from hemoglobin degradation to investigate ligand binding reactions in aqueous solution. Studies were conducted on the interaction of FeTPPS with Chloroquine, Quinine, and Quinidine, which are historically the most common quinoline-based drugs used to treat malaria, an infectious disease afflicting several hundred millions every year worldwide, mainly in tropical regions. Using UV-Visible spectrophotometry, the binding reaction was studied at pH 7.40 in purely aqueous solution, and in aqueous solution containing NaNO 3 at concentration of 0

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Effects of solvent composition and ionic strength on the interaction of quinoline antimalarials with ferriprotoporphyrin IX

Cited by 37 publications

References 45 publications

Antimalarials inhibit hematin crystallization by unique drug–surface site interactions

Antimalarials inhibit hematin crystallization by unique drug–surface site interactions

A Partial Convergence in Action of Methylene Blue and Artemisinins: Antagonism with Chloroquine, a Reversal with Verapamil, and an Insight into the Antimalarial Activity of Chloroquine

Interaction of Iron(III)-5,10,15,20-Tetrakis (4-Sulfonatophenyl) Porphyrin with Chloroquine, Quinine and Quinidine

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