Antimalarial Quinine Research Articles

Synthesis, Characterization and Crystal Structure of a Polymeric Zinc(II) Complex Containing the Antimalarial Quinine as Ligand

A novel polymeric zinc(II) complex of quinine, [chlorosulphato (2-ethenyl)-4-azabicyclo[2.2.2]oct-5-ylium-(6-methoxyquinolin-4-yl) methanol zinc(II)] has been synthesized and characterized. Single-crystal X-ray diffraction analysis of the complex (C20H25ClN2O6SZn) revealed that quinine forms a zigzag coordination polymeric complex with Zn(II) of extended chains –ZnCl–O–SO2–O–Zn–O–SO2–O–ZnCl–. The crystals are monoclinic, space group C2 with a = 20.5035(5), b = 9.7943(2), c = 11.7814(4) A, β = 96.578(2)°, Z = 4, V = 2350.3(1) A3. The complex exhibits a tetrahedral geometry. Each Zn(II) centre is thus coordinated to an O atom from each of two sulphate bridges, a Cl atom and quinoline atom N(4) of the quinine moiety. The second quinuclidine nitrogen in the quinine is protonated. In the crystal, there is linkage of two polymeric chains related by a twofold rotation axis, resulting in a bilayer. The linking is achieved by hydrogen bonding from the quinine cation which provides two donors (–OH, N+–H), to oxygen atoms of sulphate groups which act as acceptors. The new polymeric zinc(II) complex of quinine, [chlorosulphato (2-ethenyl)-4-azabicyclo[2.2.2]oct-5-ylium-(6-methoxy quinolin-4-yl) methanol Zinc(II)] has been synthesized and structurally characterized The compound was characterized by IR spectroscopy, elemental analysis and X-ray diffraction. X-ray analysis showed that quinine forms a zigzag coordination polymeric complex with Zn(II) of extended chains –ZnCl–O–SO2–O–Zn–O–SO2–O–ZnCl–.

The antimalarial drugs quinine, chloroquine and mefloquine are antagonists at 5‐HT3 receptors

The antimalarial compounds quinine, chloroquine and mefloquine affect the electrophysiological properties of Cys-loop receptors and have structural similarities to 5-HT(3) receptor antagonists. They may therefore act at 5-HT(3) receptors. The effects of quinine, chloroquine and mefloquine on electrophysiological and ligand binding properties of 5-HT(3A) receptors expressed in HEK 293 cells and Xenopus oocytes were examined. The compounds were also docked into models of the binding site. 5-HT(3) responses were blocked with IC (50) values of 13.4 microM, 11.8 microM and 9.36 microM for quinine, chloroquine and mefloquine. Schild plots indicated quinine and chloroquine behaved competitively with pA (2) values of 4.92 (K (B)=12.0 microM) and 4.97 (K (B)=16.4 microM). Mefloquine displayed weakly voltage-dependent, non-competitive inhibition consistent with channel block. On and off rates for quinine and chloroquine indicated a simple bimolecular reaction scheme. Quinine, chloroquine and mefloquine displaced [(3)H]granisetron with K (i) values of 15.0, 24.2 and 35.7 microM. Docking of quinine into a homology model of the 5-HT(3) receptor binding site located the tertiary ammonium between W183 and Y234, and the quinoline ring towards the membrane, stabilised by a hydrogen bond with E129. For chloroquine, the quinoline ring was positioned between W183 and Y234 and the tertiary ammonium stabilised by interactions with F226. This study shows that quinine and chloroquine competitively inhibit 5-HT(3) receptors, while mefloquine inhibits predominantly non-competitively. Both quinine and chloroquine can be docked into a receptor binding site model, consistent with their structural homology to 5-HT(3) receptor antagonists.

DNA Cleavage Induced by Photoexcited Antimalarial Drugs: A Photophysical and Photobiological Study

The interactions and the photosensitizing activity of three antimalarial drugs quinine (Q), mefloquine (MQ) and quinacrine (QC) toward DNA was studied. Evidences obtained by absorption and emission spectroscopy and by linear dichroism measurements indicate that these derivatives bind the macromolecule with a high affinity (binding constants Ka approximately 10(5) M(-1)). The absorption characteristics of the drugs changed markedly by addition of DNA and their fluorescence was quenched with rate constants higher than that of diffusion. The geometry of binding involves predominantly the intercalation into the double helix. The DNA photocleavage properties of antimalarials was investigated using plasmid DNA as a model, at different [drug]/ [DNA] ratios. The results indicate that mainly MQ and Q are able to induce significant photodamage to DNA. In particular the marked effect of the former drug is evidenced after treatment of photosensitized DNA by two base excision repair enzymes, formamydo-pyrimidine glycosilase (Fpg) and Endonuclease III (Endo III). From a mechanistic point of view, experiments carried out in different experimental conditions indicate that these drugs photoinduce DNA damage through singlet oxygen and/or radical cation production. These findings are further supported by the determination of two photoproducts of 2'-deoxyguanosine, which are diagnostic for Type I and Type II pathways, namely 2,2-diamino(2-deoxy-beta-D-erythro-pentofuranosyl)-4-amino-5(2H)-oxazolone and (R,S)4-hydroxy-8-oxo-4,8-dihydro-2'-deoxyguanosine (4-OH-8-oxo-dGuo). Laser flash photolysis experiments carried out in the presence of DNA indicates that the excitation produces mainly the triplet state for Q and the triplet and radical cation for QC. Moreover the singlet and triplet states and radical cations of the drugs are quenched by 2'-deoxyguanosine monophosphate. The absorbances of these transients decrease with increasing DNA concentration.

Voltammetry of some catamphiphilic drugs with solvent polymeric membrane ion sensors

The transfer of some catamphiphilic drugs across a water–solvent polymeric membrane interface is researched using differential voltammetric techniques with a solvent polymeric membrane ion-sensor and a four-electrode potentiostat. The standard ion transfer potentials of the antiarrhythmic drugs procainamide and quinidine, the antimalarial quinine and the anesthetics bupivacaine, lidocaine, procaine and tetracaine have been determined. In addition to their main pharmacological action, these drugs are of interest as multidrug resistance reversers in the chemotherapy treatment for cancer. The relationship between the pharmacological potency of the different drugs and the corresponding standard ion transfer potentials obtained in the present work has been studied. The relationship between the sensitivity of an amperometric sensor based on the ion transfer across the water–solvent polymeric membrane interface towards the different catamphiphilic drugs and the standard ion transfer potentials has also been studied. A dependence between them was obtained when the applied potential of the sensor was set at a value previous to the diffusion controlled zone.

In situ UV Resonance Raman Micro-spectroscopic Localization of the Antimalarial Quinine in Cinchona Bark

Deep UV resonance Raman micro-spectroscopy (lambda(exc) = 244 nm) was applied for a highly sensitive, selective, and gentle localization of the antimalarial quinine in situ in cinchona bark. The high potential of the method was demonstrated by the detection of small amounts of the alkaloid in the plant material without any further sample preparation, where conventional (non-resonant) Raman microscopy was unsuccessful due to a strong fluorescence background. The resonance Raman spectrum of cinchona bark corresponds well with that of quinine; it can be distinguished from its diastereomer quinidine via the mode at 831 cm(-1), which is shifted to 843 cm(-1) in the case of quinidine. This vibration involves a bending motion within the side chain around the chiral center of quinine. Vibrations belonging to the quinoline ring (important for its antimalarial activity in forming pi-pi-interactions to hemozoin) and the vinyl group are resonantly enhanced in the UV Raman spectra. A convincing mode assignment is derived by means of a combination of NIR Raman spectroscopy and DFT calculations. The Raman spectra of quinine in cinchona bark are modeled by considering a hydrous environment that causes a shift of the band at 1362 compared with 1371 cm(-1) in anhydrous quinine. This intense vibration is therefore sensitive to the presence of an aqueous environment and is assigned mostly to a stretching motion within the quinoline ring. The presented results nicely show the sensitivity of Raman spectroscopy to monitor subtle differences within the molecular structure and the influence of a biological relevant hydrous environment and trace low concentrated pharmaceutical relevant active agents in plant material.

The potential inhibitory effect of antiparasitic drugs and natural products on P-glycoprotein mediated efflux

The potential inhibitory effect on P-glycoprotein (Pgp) by antiparasitic drugs and natural compounds was investigated. Compounds were screened for Pgp interaction based on inhibition of Pgp mediated [ 3H]-taxol transport in Caco-2 cells. Bidirectional transport of selected inhibitors was further evaluated to identify potential Pgp substrates using the Caco-2 cells. Of 21 antiparasitics tested, 14 were found to inhibit Pgp mediated [ 3H]-taxol with K iapp values in the range 4–2000 μM. The antimalarial quinine was the most potent inhibitor with a K iapp of 4 μM. Of the 12 natural compounds tested, 3 inhibited [ 3H]-taxol transport with K iapp values in the range 50–400 μM. Quinine, amodiaquine, chloroquine, flavone, genistein, praziquantel, quercetin and thiabendazole were further investigated in bidirectional transport assays to determine whether they were substrates for Pgp. Transport of quinine in the secretory direction exceeded that in the absorptive direction and was saturable, suggesting quinine being a Pgp substrate. The rest of the compounds inhibiting Pgp showed no evidence of being Pgp substrates. In conclusion, we have demonstrated that a substantial number of antiparasitic and natural compounds, in a range of concentrations, are capable of inhibiting Pgp mediated [ 3H]-taxol efflux in Caco-2 cells, without being substrates and this may have implications for drug interactions with Pgp.

Targeting of Hematin by the Antimalarial Pyronaridine

Pyronaridine, 2-methoxy-7-chloro-10[3',5'-bis(pyrrolidinyl-1-methyl-)4'hydroxyphenyl]aminobenzyl-(b)-1,5-naphthyridine, a new Mannich base schizontocide originally developed in China and structurally related to the aminoacridine drug quinacrine, is currently undergoing clinical testing. We now show that pyronaridine targets hematin, as demonstrated by its ability to inhibit in vitro beta-hematin formation (at a concentration equal to that of chloroquine), to form a complex with hematin with a stoichiometry of 1:2, to enhance hematin-induced red blood cell lysis (but at 1/100 of the chloroquine concentration), and to inhibit glutathione-dependent degradation of hematin. Our observations that pyronaridine exerted this mechanism of action in situ, based on growth studies of Plasmodium falciparum K1 in culture showing antagonism of pyronaridine in combination with antimalarials (chloroquine, mefloquine, and quinine) that inhibit beta-hematin formation, were equivocal.

In vitro activity of iron-binding compounds against Senegalese isolates of Plasmodium falciparum

The in vitro activities of FR160, a synthetic catecholate siderophore, and two iron-binding agents, desferrioxamine and doxycycline, were evaluated against Plasmodium falciparum isolates. Correlations between these compounds and standard antimalarial drugs (chloroquine, quinine, amodiaquine, pyronaridine, artemether, artesunate, atovaquone, cycloguanil and pyrimethamine) were assessed to determine any degree of cross-resistance. Between October 1997 and February 1998, and September and November 1998, 189 P. falciparum isolates were obtained in Dielmo and Ndiop (Dakar). Their susceptibilities were assessed using an isotopic, microwell format, drug susceptibility test. The 137 inhibitory concentrations (IC(50)) values of FR160 ranged from 0.1 to 10 microM and the geometric mean IC(50) was 1.48 microM (95% CI = 1.29-1.68 microM). The geometric mean IC(50) of doxycycline for 121 isolates was 18.9 microM (95% CI = 16.8-21.3 microM) and that of desferrioxamine for 73 isolates was 20.7 microM (95% CI = 17.3-24.8 microM). FR160 was significantly less active against the chloroquine-resistant isolates (P < 0.0001). The mean IC(50)s of doxycycline were significantly higher for the chloroquine-susceptible isolates than for the resistant parasites (P = 0.0447). There was a weak correlation between the responses to FR160, desferrioxamine or doxycycline and those to the other antimalarial compounds (r(2) < 0.22). The activities of FR160 and desferrioxamine, determined for P. falciparum clones, were confirmed against 137 isolates. The coefficients of determination between the responses to FR160, doxycycline or desferrioxamine and those to all the antimalarial drugs tested are too weak to suggest cross-resistance. FR160 could be a rationale partner to use in combination with doxycycline.

Development and validation of a reversed-phase LC method for analysing potentially counterfeit antimalarial medicines

Pharmaceutical counterfeiting is more and more a public health problem, especially in developing countries where the most counterfeit drugs are antibiotics, antimalarials and other life-saving drugs. The evaluation of the phenomenon extent is of great concern to the World Health Organization for carrying out a global strategy to combat the phenomenon. To this purpose, a reversed-phase liquid chromatographic method to perform the separation and simultaneous determination of three different kinds of antimalarial drugs (chloroquine, quinine and mefloquine) was developed. The method was validated by using both commercial and in-laboratory produced tablets and was then verified on various in-laboratory produced formulations differing in excipient composition. Finally, the method was successfully applied to the analysis of medicinal samples purchased from the informal market in Congo, Burundi and Angola.

L’impact des antipaludiques sur la cellule myocardique. Approche pathogénique et nouvelles recommandations thérapeutiques

The cardiotoxicity of halofantrine was a major concern during the past decade. Other old antimalarials (quinine, mefloquine, etc.) and more recent drugs may carry a similar risk. Studies of ventricular repolarization and myocardial cells can throw light on these adverse effects. Studies of QT dispersion measured on the surface electrocardiogram and of QT dynamicity and variability (QT/RR slope) during long-term Holter recording help to identify patients at risk of drug-induced ventricular arrhythmia. Such electrocardiographic investigations have shown that quinine, mefloquine and artemisinin derivatives do not alter ventricular repolarization. In contrast, halofantrine significantly increases QT dispersion and the QT regression slope. At the cellular level, most major antimalarial drugs inhibit potassium channels, which are regulated by the LQT1 and HERG genes responsible for the congenital long-QT syndrome. We propose new recommendations for the use of these drugs in the treatment and prevention of malaria.

Medikamentensensibilität von Plasmodium falciparum entlang der thailändischen Grenze bestimmt mittels des neuen HRP2-in-vitro-Feldtests

Drug resistance in Plasmodium falciparum has turned into a major problem throughout the malaria endemic regions of the world. Surveillance of antimalarial drug resistance is therefore essential for early changes in drug policies. In the course of this first major application of the new field-deployable histidine-rich protein 2 (HRP2) in vitro drug sensitivity assay, we investigated the current status of drug sensitivity to the standard antimalarial drugs dihydroartemisinin, mefloquine, quinine, and chloroquine in an area with an exceptionally high level of multidrug resistance in Thailand. The geometric mean of 50 and 90% inhibitory concentrations determined for 44 successfully tested samples by the HRP2 assay were comparable to earlier published results from the same area suggesting relatively little change in the local drug resistance pattern during the past years. The HRP2 field test was found to be highly sensitive and simple enough to be entirely performed in the field.

Bitterness Suppression with Zinc Sulfate and Na-Cyclamate: A Model of Combined Peripheral and Central Neural Approaches to Flavor Modification

Zinc sulfate is known to inhibit the bitterness of the antimalarial agent quinine [R. S. J. Keast. The effect of zinc on human taste perception. J. Food Sci. 68:1871-1877 (2003)]. In the present work, we investigated whether zinc sulfate would inhibit other bitter-tasting compounds and pharmaceuticals. The utility of zinc as a general bitterness inhibitor is compromised, however, by the fact that it is also a good sweetness inhibitor [R. S. J. Keast, T. Canty, and P. A. S. Breslin. Oral zinc sulfate solutions inhibit sweet taste perception. Chem. Senses 29:513-521 (2004)] and would interfere with the taste of complex formulations. Yet, zinc sulfate does not inhibit the sweetener Na-cyclamate. Thus, we determined whether a mixture of zinc sulfate and Na-cyclamate would be a particularly effective combination for bitterness inhibition (Zn) and masking (cyclamate). We used human taste psychophysical procedures with chemical solutions to assess bitterness blocking. Zinc sulfate significantly inhibited the bitterness of quinine-HCl, Tetralone, and denatonium benzoate (DB) (p < 0.05), but had no significant effect on the bitterness of sucrose octa-acetate, pseudoephedrine (PSE), and dextromethorphan. A second experiment examined the influence of zinc sulfate on bittersweet mixtures. The bitter compounds were DB and PSE, and the sweeteners were sucrose (inhibited by 25 mM zinc sulfate) and Na-cyclamate (not inhibited by zinc sulfate). The combination of zinc sulfate and Na-cyclamate most effectively inhibited DB bitterness (86%) (p < 0.0016), whereas the mixture's inhibition of PSE bitterness was not different from that of Na-cyclamate alone. A combination of Na-cyclamate and zinc sulfate was most effective at inhibiting bitterness. Thus, the combined use of peripheral oral and central cognitive bitterness reduction strategies should be particularly effective for improving the flavor profile of bitter-tasting foods and pharmaceutical formulations.

Interactions of mefloquine with ABC proteins, MRP1 (ABCC1) and MRP4 (ABCC4) that are present in human red cell membranes

Human erythrocyte membranes express the multidrug resistance-associated proteins, MRP1, MRP4 and 5, that collectively can efflux oxidised glutathione, glutathione conjugates and cyclic nucleotides. It is already known that the quinoline derivative, MK-571, is a potent inhibitor of MRP-mediated transport. We here examine whether the quinoline-based antimalarial drugs, amodiaquine, chloroquine, mefloquine, primaquine, quinidine and quinine, also interact with erythrocyte MRPs with consequences for their access to the intracellular parasites or for efflux of oxidised glutathione from infected cells. Using inside-out vesicles prepared from human erythrocytes we have shown that mefloquine and MK-571 inhibit transport of 3 μM [ 3H]DNP-SG known to be mediated by MRP1 (IC 50 127 and 1.1 μM, respectively) and of 3.3 μM [ 3H]cGMP thought but not proven to be mediated primarily by MRP4 (IC 50 21 and 0.41 μM). They also inhibited transport in membrane vesicles prepared from tumour cells expressing MRP1 or MRP4 and blocked calcein efflux from MRP1-overexpressing cells and BCECF efflux from MRP4-overexpressing cells. Both stimulated ATPase activity in membranes prepared from MRP1 and MRP4-overexpressing cells and inhibited activity stimulated by quercetin or PGE 1, respectively. Neither inhibited [α- 32P]8-azidoATP binding confirming that the interactions are not at the ATP binding site. These results demonstrate that mefloquine and MK-571 both inhibit transport of other substrates and stimulate ATPase activity and thus may themselves be substrates for transport. But at concentrations achieved clinically mefloquine is unlikely to affect the MRP1-mediated transport of GSSG across the erythrocyte membrane.

Quinoline antimalarials decrease the rate of β-hematin formation

The strength of inhibition of β-hematin (synthetic hemozoin or malaria pigment) formation by the quinoline antimalarial drugs chloroquine, amodiaquine, quinidine and quinine has been investigated as a function of incubation time. In the assay used, β-hematin formation was brought about using 4.5M acetate, pH 4.5 at 60°C. Unreacted hematin was detected by formation of a spectroscopically distinct low spin pyridine complex. Although, these drugs inhibit β-hematin formation when relatively short incubation times are used, it was found that β-hematin eventually forms with longer incubation periods (<8h for chloroquine and >8h for quinine). This conclusion was supported by both infrared and X-ray powder diffraction observations. It was further found that the IC50 for inhibition of β-hematin formation increases markedly with increasing incubation times in the case of the 4-aminoquinolines chloroquine and amodiaquine. By contrast, in the presence of the quinoline methanols quinine and quinidine the IC50 values increase much more slowly. This results in a partial reversal of the order of inhibition strengths at longer incubation times. Scanning electron microscopy indicates that β-hematin crystals formed in the presence of chloroquine are more uniform in both size and shape than those formed in the absence of the drug, with the external morphology of these crystallites being markedly altered. The findings suggest that these drugs act by decreasing the rate of hemozoin formation, rather than irreversibly blocking its formation. This model can also explain the observation of a sigmoidal dependence of β-hematin inhibition on drug concentration.

Preparative Separation of Indole Alkaloids from the Rind of Picralima nitida (Stapf) T. Durand & H. Durand by pH‐Zone‐Refining Countercurrent Chromatography

Picralima nitida alkaloids have been shown to possess in vitro antimalarial activity comparable to the clinical antimalarial chloroquine and quinine. The in vitro IC50 values for these alkaloids ranged from 0.01 to 0.9 µg/mL against chloroquine‐sensitive (D6) and chloroquine‐resistant (W2) strains of Plasmodium falciparum. As part of our continuing research aimed at identifying new antimalarial leads from African rain forest plants, we have been highly successful in employing pH‐zone‐refining counter‐current chromatography (CCC) to separate and isolate the Picralima alkaloids. The separation was performed in two steps with a two‐phase solvent system composed of tert‐butyl methyl ether (MTBE)/acetonitrile/water (2∶2∶3, v/v), in which the lower phase was used as the mobile phase at a flow‐rate of 2.0 mL min−1 in the head‐to‐tail elution mode pH‐zone‐refining counter‐current chromatography. The resulting fractions contained the alkaloids alstonine, akuammigine, akuammine, picraline, akuammine, akuammicine, picratidine were identified using thermospray liquid chromatography‐mass spectrometry (LC‐MS) and by TLC co‐elution experiments with authentic samples. The application of pH‐zone‐refining CCC to perform successful separations at the multigram level will be discussed. The Picralima alkaloids may represent an entirely new antimalarial chemotype with possible pharmacokinetics advantages over the existing drugs.

Antimalarials Inhibit Human Erythrocyte Membrane Acetylcholinesterase

The current study examined the ability of antimalarials chloroquine (CQ), primaquine (PQ), and quinine (Q) to inhibit human erythrocyte membrane acetylcholinesterase (AChE) and the mechanisms underlying their inhibitory action. CQ was found to be the most effective inhibitor of the enzyme followed by PQ and Q. The concentrations required to obtain 33% inhibition (IC33) for CQ and PQ were 22 and 38 µM, respectively, whereas that for Q was 3.2 mM. The concentrations required to obtain 67% inhibition (IC67) were about 9 and 7 times higher for CQ and PQ, whereas that for Q was only about 2.5 times higher. Hill plot analysis revealed that CQ shows de-binding above 40 µM. The two kinetic components of AChE were inhibited by the three antimalarials, and the inhibition was of mixed type. Increasing concentrations of antimalarials caused progressive decrease in the Vmax of both components. IC33 concentrations resulted in 1.6- to 6-fold increase in Km of both the components while IC67 concentration caused 2.8- to 13-fold increases in Km with maximum effect being seen with Q. The Ki values were lowest for CQ suggesting that it was the most potent inhibitor; these values were 3.3 and 60 times higher for PQ and Q. Antimalarials represent the bifunctional compounds that possess anti-inflammatory properties and also inhibit cholinesterases. The results of our studies suggest that 4-aminoquinoline–based antimalarials like CQ and hydroxychloroquine, which are both potent anti-inflammatory agents and inhibitors of cholinesterases, may have potential use as the most effective neuroprotective agents against amyloid-β-peptide (Aβ) neurotoxicity in Alzheimers disease.

Treatment with Antimalarials Adversely Affects the Oxidative Energy Metabolism in Rat Liver Mitochondria

Effects of in vivo treatment with the three antimalarials chloroquine, primaquine and quinine on rat liver mitochondrial energy transduction functions were examined. Treatment with all the three antimalarials decreased the state 3 and state 4 respiration rates drastically. The extent of inhibition was higher with pyruvate + malate as the substrate than with glutamate. The antimalarials also acted as uncouplers. The uncoupling effect was seen on site II and site III of phosphorylation; site I was unaffected. As a consequence the ADP phosphorylation rates also decreased significantly. Following antimalarials treatment the basal and Mg2 +stimulated ATPase activities increased while the DNP‐stimulated ATPase activity was reduced by half. Treatment with chloroquine resulted in decreased contents of cytochromes aa3 and b; primaquine and quinine treatments increased the contents of the two cytochromes in 14 day treatment groups.

13C NMR Study of the Self-Association of Chloroquine, Amodiaquine, and Quinine

Experimental and calculated 13C NMR chemical shifts of quinoline ring carbons are used to investigate the self-association of the antimalarial drugs chloroquine, amodiaquine and quinine. The chemical shifts of each quinoline carbon in the monomer and dimer forms of each drug are extrapolated from plots of the observed chemical shifts at various concentrations. In the equation used to extrapolate the dimer and monomer chemical shift, a linear term is added to account for medium effects but is found to be unnecessary if an internal standard is used to correct for bulk susceptibility. The experimental changes in chemical shift are compared to changes in chemical shift calculated using the continuous set gauge transformation1 method with the polarizable continuum model2,3 (PCM-CSGT)4 for several possible structures of the dimer. The deviations between calculated and experimental chemical shifts are used to select the best dimer structure for each drug.

Solvent effects on reactions of singlet molecular oxygen, O2(1Δg), with antimalarial drugs

Detection of O2(1Δg) emission, λmax=1270nm, following laser excitation and steady-state methods were employed to measure total reaction rate constants, kT, for the reaction between singlet oxygen and the antimalarial drugs quinine (QU), quinacrine (QC), chloroquine (CQ) and amodiaquine (AQ) in several solvents. Values for kT range from 0.45±0.03×107M−1s−1 for AQ in benzene to 25.1±0.88×107M−1s−1 for CQ in N,N-dimethylformamide. Analysis of solvent effect on kT for QU, QC, and CQ by using the LSER formalism indicates that singlet oxygen deactivation by these drugs is accelerated by solvents with large π∗ values and hydrogen bond acceptor (HBA) properties and is inhibited by hydrogen bond donors (HBD) solvents. This result support the formation of an exciplex intermediate of charge transfer character, as proposed for reactions of tertiary amines with singlet oxygen, process largely governed by physical quenching. AQ behaves in a different manner. The LSER equation for this drug shows that kT increases in solvents with large π∗ values and diminishes in HBD solvents. In this case, reaction mechanism probably involves a partially concerted cycloaddition of singlet oxygen to the aminophenolic ring in position 4.

Characterization of noncovalent complexes of antimalarial agents of the artemisinin-type and FE(III)-Heme by electrospray mass spectrometry and collisional activation tandem mass spectrometry

In this study, we demonstrate, using electrospray ionization mass spectrometry (ESI-MS) and collision-induced dissociation tandem mass spectrometry (ESI-MS/CID/MS), that stable noncovalent complexes can be formed between Fe(III)-heme and antimalarial agents, i.e., quinine, artemisinin, and the artemisinin derivatives, dihydroartemisinin, α- and β-artemether, and β-arteether. Differences in the binding behavior of the examined drugs with Fe(III)-heme and the stability of the drug-heme complexes are demonstrated. The results show that all tested antimalarial agents form a drug-heme complex with a 1:1 stoichiometry but that quinine also results in a second complex with the heme dimer. ESI-MS performed on mixtures of pairs of various antimalarial agents with heme indicate that quinine binds preferentially to Fe(III)-heme, while ESI-MS/CID/MS shows that the quinine-heme complex is nearly two times more stable than the complexes formed between heme and artemisinin or its derivatives. Moreover, it is found that dihydroartemisinin, the active metabolite of the artemisinin-type drugs in vivo, results in a Na +-containing heme-drug complex, which is as stable as the heme-quinine complex. The efficiency of drug-heme binding of artemisinin derivatives is generally lower and the decomposition under CID higher compared with quinine, but these parameters are within the same order of magnitude. These results suggest that the efficiency of antimalarial agents of the artemisinin-type to form noncovalent complexes with Fe(III)-heme is comparable with that of the traditional antimalarial agent, quinine. Our study illustrates that electrospray ionization mass spectrometry and collision-induced dissociation tandem mass spectrometry are suitable tools to probe noncovalent interactions between heme and antimalarial agents. The results obtained provide insights into the underlying molecular modes of action of the traditional antimalarial agent quinine and of the antimalarials of the artemisinin-type which are currently used to treat severe or multidrug-resistant malaria.