Synthesis and Activity of Some Antimalarial Bisquinolines

Raynes, Kaylene J.; Galatis, Denise; Cowman, Alan F.; Tilley, Leann; Deady, Leslie W.

doi:10.1021/jm00001a026

Cited by 60 publications

(64 citation statements)

References 6 publications

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“…We have reexamined the abilities of a number of antimalarial drugs to inhibit haem-catalysed destruction of H # O # under the conditions of our experiments. Chloroquine, quinacrine and the novel bis-4-aminoquinoline, 8AC6 [6,16], were all effective inhibitors of the catalase-like activity of haem while mefloquine showed a lower level of inhibition and epiquinine had very little effect ( Figure 3B). Chloroquine had no effect on the activity of catalase (results not shown).…”

Section: Haem Also Displays Catalase-like and Peroxidase-like Activitmentioning

confidence: 99%

Inhibition of the peroxidative degradation of haem as the basis of action of chloroquine and other quinoline antimalarials

Loria

Miller

Foley

et al. 1999

Biochemical Journal

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192

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The malaria parasite feeds by degrading haemoglobin in an acidic food vacuole, producing free haem moieties as a by-product. The haem in oxyhaemoglobin is oxidized from the Fe(II) state to the Fe(III) state with the consequent production of an equimolar concentration of H2O2. We have analysed the fate of haem molecules in Plasmodium falciparum-infected erythrocytes and have found that only about one third of the haem is polymerized to form haemozoin. The remainder appears to be degraded by a non-enzymic process which leads to an accumulation of iron in the parasite. A possible route for degradation of the haem is by reacting with H2O2, and we show that, under conditions designed to resemble those found in the food vacuole, i.e., at pH 5.2 in the presence of protein, free haem undergoes rapid peroxidative decomposition. Chloroquine and quinacrine are shown to be efficient inhibitors of the peroxidative destruction of haem, while epiquinine, a quinoline compound with very low antimalarial activity, has little inhibitory effect. We also show that chloroquine enhances the association of haem with membranes, while epiquinine inhibits this association, and that treatment of parasitized erythrocytes with chloroquine leads to a build-up of membrane-associated haem in the parasite. We suggest that chloroquine exerts its antimalarial activity by causing a build-up of toxic membrane-associated haem molecules that eventually destroy the integrity of the malaria parasite. We have further shown that resistance-modulating compounds, such as chlorpromazine, interact with haem and efficiently inhibit its degradation. This may explain the weak antimalarial activities of these compounds.

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Section: Haem Also Displays Catalase-like and Peroxidase-like Activitmentioning

confidence: 99%

Inhibition of the peroxidative degradation of haem as the basis of action of chloroquine and other quinoline antimalarials

Loria

Miller

Foley

et al. 1999

Biochemical Journal

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192

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“…During the same period, Chinese researchers continued to develop piperaquine and hydroxypiperaquine for clinical use (23). Furthermore, several novel series of bisquinolines were synthesized during the 1990s (9,16,21).…”

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confidence: 99%

In Vitro Activities of Piperaquine and Other 4-Aminoquinolines against Clinical Isolates ofPlasmodium falciparumin Cameroon

Basco

Ringwald

2003

Antimicrob Agents Chemother

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The spread of chloroquine-resistant Plasmodium falciparum calls for a constant search for new drugs. The in vitro activity of piperaquine, a new Chinese synthetic drug belonging to the bisquinolines, was evaluated in 103 fresh clinical isolates of P. falciparum in Cameroon, Central Africa, and compared with that of other 4-aminoquinoline and Mannich base derivatives and dihydroartemisinin. Piperaquine was highly active (geometric mean 50% inhibitory concentration, 38.9 nmol/liter; range, 7.76 to 78.3 nmol/liter) and equally active (P > 0.05) against the chloroquine-sensitive and the chloroquine-resistant isolates. There was a significant but low correlation of response between chloroquine and piperaquine (r ‫؍‬ 0.257, P < 0.05). These results suggest that further development of piperaquine, in combination with dihydroartemisinin, holds promise for use in chloroquine-resistant regions of endemicity.

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“…The cells were washed once and plated at about 1% parasitemia (2% hematocrit) in 96-well trays in medium with [ 3 H]-hypoxanthine and maintained for 24 h under culture conditions. Growth curves based on the uptake of [ 3 H]-hypoxanthine were obtained in triplicate as described previously (27) to determine the concentration of compound required to produce 50% inhibition of growth (IC 50 ).…”

Section: Parasitesmentioning

confidence: 99%

A phosphatidylcholine‐BODIPY 581/591 conjugate allows mapping of oxidative stress in P. falciparum‐infected erythrocytes

Klonis

Suarna

et al. 2009

Cytometry Pt A

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The chromophore, BODIPY 581/591, has an extended conjugated system that reacts with oxygen centered-radicals leading to changes in its spectral characteristics. Fatty acid-conjugated BODIPY 581/591 transfers readily between membrane bilayers and can be used as a sensor of oxidative stress in cell populations. We report here the use of a phosphatidylcholine (PC) derivative of BODIPY 581/591, which transfers much less rapidly between membranes. This allows the analysis of oxidative stress in individual cells and in different compartments within cells. Quantitative imaging and flow cytometry were used to measure the ratio of fully conjugated to oxidized probe in model systems and in Plasmodium falciparum-infected erythrocytes. We observed an increase in the oxidation of the parasite-associated BODIPY 581/591-PC as the intraerythrocytic parasite matures. By contrast, BODIPY 581/591-PC associated with the erythrocyte membrane experiences a low level of oxidation even in the later stages of parasite development. Treatment with a pro-oxidant compound caused increased oxidation of the probe in the parasite compartment, but less so in the host cell membrane. Conversely, treatment with ferricyanide increases oxidation of the probe in the erythrocyte cell membrane but does not inhibit parasite growth. Chromatographic analysis of the lipids in infected erythrocytes shows no evidence for loss of a-tocopherol or the accumulation of lipid hydroperoxides indicating that, despite the increased oxidative stress, the parasite membranes remain protected from substantial lipid oxidation. We have established BODIPY 581/591-PC as a useful probe of the spatial distribution of oxidative stress in P. falciparum-infected erythrocytes; however, the probe appears to be more sensitive to oxidative damage than endogenous lipids. ' 2009 International Society for Advancement of Cytometry Key terms malaria; Plasmodium falciparum; oxidative stress; BODIPY 581/591-PC; lipid oxidation OXIDATIVE damage to protein and membrane components plays important roles in various diseases and in the aging process (1), and a number of methods have been developed for measuring oxidative stress in cellular systems. In some studies, the levels of oxidized lipids and proteins have been measured directly (2,3). In other studies, secondary reaction products, such as malondialdehyde, have been used as a surrogate measure of lipid oxidation (4). These approaches offer useful insights into oxidative events; however, they usually require physical disruption of the system under investigation.Recently, fluorescence-based probes of oxidative stress have gained popularity as relatively nonperturbing sensors of cellular stresses (5-7). The fatty acid (FA) analogue, cis-paranaric acid (8), has been used as an oxidant-sensitive fluorophore; however, its fluorescence in the UV range is a disadvantage in some applications. BODIPY 581/591 is an alternative probe that can be excited in the visible range and

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Synthesis and Activity of Some Antimalarial Bisquinolines

Cited by 60 publications

References 6 publications

Inhibition of the peroxidative degradation of haem as the basis of action of chloroquine and other quinoline antimalarials

Inhibition of the peroxidative degradation of haem as the basis of action of chloroquine and other quinoline antimalarials

In Vitro Activities of Piperaquine and Other 4-Aminoquinolines against Clinical Isolates ofPlasmodium falciparumin Cameroon

A phosphatidylcholine‐BODIPY 581/591 conjugate allows mapping of oxidative stress in P. falciparum‐infected erythrocytes

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