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Chanteux, Hugues; Paternotte, Isabelle; Mingeot‐Leclercq, Marie‐Paule; Brasseur, Robert; Sonveaux, Etienne; Tulkens, Paul M.

doi:10.1023/a:1023203017300

Cited by 15 publications

(4 citation statements)

References 26 publications

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“…This suggests that the three esters as well as ester 1 are adsorbed to membranes and other macromolecular constituents in the host milieu and do not penetrate into infected red blood cells. Such a behavior has recently been observed with ester prodrugs of ampicillin (pivaloyloxymethyl, phthalimidomethyl) that were analyzed for membrane-binding properties and membrane penetration . These weak bases were shown to remain located at the cell surface without entering the cell.…”

Section: Discussionmentioning

confidence: 76%

5-Substituted Tetrazoles as Bioisosteres of Carboxylic Acids. Bioisosterism and Mechanistic Studies on Glutathione Reductase Inhibitors as Antimalarials

et al. 2004

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Plasmodium parasites are exposed to elevated fluxes of reactive oxygen species during intraerythrocytic life. The most important antioxidative systems are based on the glutathione reductases of the malarial parasite Plasmodium falciparum and the host erythrocyte. The development of menadione chemistry has led to the selection of the carboxylic acid 6-[2'-(3'-methyl)-1',4'-naphthoquinolyl] hexanoic acid M(5) as an inhibitor of the parasitic enzyme. As reported here, revisiting the mechanism of M(5) action revealed an uncompetitive inhibition type with respect to both NADPH and glutathione disulfide. Masking the polarity of the acidic function of M(5) by ester or amide bonds improved antiplasmodial activity. Bioisosteric replacement of the carboxylic function by tetrazole to increase bioavailability and to maintain comparable acidity led to improved antimalarial properties as well, but only with the cyanoethyl-protected tetrazoles. Using computed ab initio quantum methods, detailed analyses of the electronic profiles and the molecular properties evidenced the similarity of M(5) and the bioisoteric tetrazole T(4). The potential binding site of these molecules is discussed in light of the recently solved crystallographic structure of P. falciparum enzyme.

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Section: Discussionmentioning

confidence: 76%

5-Substituted Tetrazoles as Bioisosteres of Carboxylic Acids. Bioisosterism and Mechanistic Studies on Glutathione Reductase Inhibitors as Antimalarials

et al. 2004

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“…Zanamivir has one basic pKa estimated to be approximately 11.3 and one acidic pKa estimated to be approximately 3.8 [18]. Previously, the neuraminidase inhibitor oseltamivir and its metabolite oseltamivir carboxylate have been analyzed successfully on a ZIC HILIC LC coupled to MS/MS [19].…”

Section: Resultsmentioning

confidence: 99%

Quantification of The Anti-Influenza Drug Zanamivir in Plasma Using High-Throughput Hilic–MS/MS

et al. 2011

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Background Parenteral zanamivir is a promising drug for the treatment of severe influenza. However, quantification of this polar drug in biological matrices has traditionally been difficult and the methods developed have been relatively insensitive. Results A high-throughput bioanalytical method for the ana lysis of zanamivir in human plasma using SPE in the 96-well plate format and LC coupled to positive MS/MS has been developed and validated according to US FDA guidelines. The method uses 50 μl of plasma and covers a large working range from 1–50, 000 ng/ml with a LOD of 0.50 ng/ml. Conclusion This new LC–MS/MS assay is more sensitive than previous methods despite using a small plasma volume sample. It is particularly suitable for clinical studies on both parenteral and inhaled zanamivir.

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“…23) These characteristics of intracellular accumulation of AZM in AMs are similar to that of PMN. 33) Chanteux et al have reported that AZM slightly bonds with the lipid bilayers of membrane. 34) Therefore, AZM is considered to accumulate in phagocytes mediated by energy independent binding and/or trapping in cells.…”

Section: Discussionmentioning

confidence: 99%

Subcellular Distribution of Azithromycin and Clarithromycin in Rat Alveolar Macrophages (NR8383) <i>in Vitro</i>

Togami

Chono

Morimoto

2013

Biological & Pharmaceutical Bulletin

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Azithromycin (AZM), a 15-membered ring macrolide antimicrobial agent, has an antibacterial spectrum that includes intracellular parasitic pathogens that survive or intracellularly multiply in alveolar macrophages (AMs). The subcellular distribution of AZM in AMs was evaluated in vitro in comparison with clarithromycin (CAM). AZM and CAM (50 µM) were applied to the NR8383 cells, used as an in vitro model of AMs, followed by incubation at 37°C or 4°C. The total amount of AZM in cells and subcellular distribution (cell fractionation) was determined after incubation. High level of AZM accumulation was observed in the NR8383 cells at 37°C, and the equilibrium intracellular to extracellular concentration ratio (I/E ratio) was approximately 680, which was remarkably higher than that of CAM (equilibrium I/E ratio=28). The intracellular accumulation of AZM and CAM was temperature dependent. In addition, AZM distributed to the granules fraction including organelles and soluble fraction including cytosol in the NR8383 cells, whereas CAM mainly distributed in soluble fraction. The amount of AZM in the granules fraction was markedly reduced in the presence of ammonium chloride for increase in intracellular pH. These results indicate that AZM is distributed in acidic compartment in AMs. This study suggests that high AZM accumulation in the NR8383 cells is due to the trapping and/or binding in acidic organelles, such as lysosomes.

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Abstract: Although they are weak organic bases, PIVA and PIMA show none of the properties of lysosomotropic agents. We hypothesize that they remain locked onto the pericellular membrane and may never penetrate cells as such in significant amounts.

Cited by 15 publications

References 26 publications

5-Substituted Tetrazoles as Bioisosteres of Carboxylic Acids. Bioisosterism and Mechanistic Studies on Glutathione Reductase Inhibitors as Antimalarials

5-Substituted Tetrazoles as Bioisosteres of Carboxylic Acids. Bioisosterism and Mechanistic Studies on Glutathione Reductase Inhibitors as Antimalarials

Quantification of The Anti-Influenza Drug Zanamivir in Plasma Using High-Throughput Hilic–MS/MS

Subcellular Distribution of Azithromycin and Clarithromycin in Rat Alveolar Macrophages (NR8383) <i>in Vitro</i>

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