Chemistry of Polyhalogenated Nitrobutadienes, 1: A New Syn- thesis of Perfunctionalized 3-Amino-4-nitrothiophenes

Kaufmann, Dieter; Zapolォskii, Viktor A.; Namyslo, Jan C.; Adam, Arnold

doi:10.3987/com-04-10020

Cited by 25 publications

(3 citation statements)

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“…8. The synthesis and characterization of pyrimidine 2 (vz1731), pyridine 4 (vz1732), ketene aminal 8 (vz0882), carboxylic acid 10 (vz1204), aldehyde 13 (vz0288), and imidazolidine 18 (vz0909) are described in Additional file 3; the synthesis and characterization of imidazolidines 19 (vz0914) and 20 (vz0005) are described in [44] and [45], respectively, and thiophene 21 (vz0527) in [46]. All spectral data was in accordance with the literature.…”

Section: Methodsmentioning

confidence: 99%

Glucose 6-phosphate dehydrogenase 6-phosphogluconolactonase: characterization of the Plasmodium vivax enzyme and inhibitor studies

Haeussler

Berneburg

Jortzik

et al. 2019

Malar J

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BackgroundSince malaria parasites highly depend on ribose 5-phosphate for DNA and RNA synthesis and on NADPH as a source of reducing equivalents, the pentose phosphate pathway (PPP) is considered an excellent anti-malarial drug target. In Plasmodium, a bifunctional enzyme named glucose 6-phosphate dehydrogenase 6-phosphogluconolactonase (GluPho) catalyzes the first two steps of the PPP. PfGluPho has been shown to be essential for the growth of blood stage Plasmodium falciparum parasites.MethodsPlasmodium vivax glucose 6-phosphate dehydrogenase (PvG6PD) was cloned, recombinantly produced in Escherichia coli, purified, and characterized via enzyme kinetics and inhibitor studies. The effects of post-translational cysteine modifications were assessed via western blotting and enzyme activity assays. Genetically encoded probes were employed to study the effects of G6PD inhibitors on the cytosolic redox potential of Plasmodium.ResultsHere the recombinant production and characterization of PvG6PD, the C-terminal and NADPH-producing part of PvGluPho, is described. A comparison with PfG6PD (the NADPH-producing part of PfGluPho) indicates that the P. vivax enzyme has higher KM values for the substrate and cofactor. Like the P. falciparum enzyme, PvG6PD is hardly affected by S-glutathionylation and moderately by S-nitrosation. Since there are several naturally occurring variants of PfGluPho, the impact of these mutations on the kinetic properties of the enzyme was analysed. Notably, in contrast to many human G6PD variants, the mutations resulted in only minor changes in enzyme activity. Moreover, nanomolar IC50 values of several compounds were determined on P. vivax G6PD (including ellagic acid, flavellagic acid, and coruleoellagic acid), inhibitors that had been previously characterized on PfGluPho. ML304, a recently developed PfGluPho inhibitor, was verified to also be active on PvG6PD. Using genetically encoded probes, ML304 was confirmed to disturb the cytosolic glutathione-dependent redox potential of P. falciparum blood stage parasites. Finally, a new series of novel small molecules with the potential to inhibit the falciparum and vivax enzymes were synthesized, resulting in two compounds with nanomolar activity.ConclusionThe characterization of PvG6PD makes this enzyme accessible to further drug discovery activities. In contrast to naturally occurring G6PD variants in the human host that can alter the kinetic properties of the enzyme and thus the redox homeostasis of the cells, the naturally occurring PfGluPho variants studied here are unlikely to have a major impact on the parasites’ redox homeostasis. Several classes of inhibitors have been successfully tested and are presently being followed up.Electronic supplementary materialThe online version of this article (10.1186/s12936-019-2651-z) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

Glucose 6-phosphate dehydrogenase 6-phosphogluconolactonase: characterization of the Plasmodium vivax enzyme and inhibitor studies

Haeussler

Berneburg

Jortzik

et al. 2019

Malar J

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Section: Introductionmentioning

confidence: 99%

“…The corresponding syntheses that we have developed up to now [2–13], always start with the attack of an appropriate nucleophile at the activated terminal carbon atom of the nitrodichlorovinyl group within 1 to undergo a vinylic substitution. Thus, in case of, e.g., sulfur nucleophiles, the corresponding thioperchlorobutadiene derivatives are easily accessible [2,5,16–17]. In this paper, we describe the formation of uniquely substituted thiazolidin-4-ones, a class of compounds which has proven to exhibit distinctive bioactivity, e.g., antifungal, antibacterial, antitubercular, and anticonvulsant properties [18–28].…”

Section: Introductionmentioning

confidence: 99%

Chemistry of polyhalogenated nitrobutadienes, 14: Efficient synthesis of functionalized (Z)-2-allylidenethiazolidin-4-ones

Zapol’skii¹,

Namyslo²,

Gjikaj³

et al. 2014

Beilstein J. Org. Chem.

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SummaryThe reaction of mercaptoacetic acid esters with pentachloro-2-nitro-1,3-butadiene (1) provides an appropriate precursor for the synthesis of special thiazolidin-4-ones. Applying different anilines as the second constituent for the requisite cyclization step, a series of (Z)-2-allylidenethiazolidin-4-ones was obtained in yields up to 81%. Some subsequent reactions have been examined too, such as the formation of perfunctionalized 1H-pyrazoles upon treatment with hydrazine. Thiazolidinones are as well known for their physiological activities as for their application in optoelectronics.

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New Ketene Dithioacetals Generated from 2‐Nitroperchlorobutadiene and Investigation of Their Antibacterial, Antifungal, Anticonvulsant and Antidepressant Activities

Aydınlı

Bulut

Deniz

et al. 2022

Chemistry & Biodiversity

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The ketene dithioacetal 3 generated from 2‐nitroperchlorobutadiene 1 reacted with various heterocyclic amines and aliphatic, aromatic and heterocyclic thiols to produce functionalized new ketene‐N,S,S‐acetals and S,S,S‐acetals 4a–f, 5a–h as heterocyclic dithiolanes. They were separated/purified by chromatographic methods and their exact structure characterization were made clear by spectroscopic methods. These compounds synthesized could act as effective drugs for versatile activity. Evaluation of the antimicrobial effect of the obtained substances determined derivatives 4e and 5h, which have MIC=15.6 μg/mL for the test culture of Mycobacterium luteum bacteria closing to the control drug Vancomycin. The obtained compounds can be proposed as a promising synthetic objects for future molecular design to enhance the antimicrobial action. Ketene dithioacetals 3, 4a, 4b, 4e, 5g (50 mg/kg) exhibited antiseizure effect comparable with reference drug (valproic acid) on the model of pentylenetetrazole‐induced convulsions after single oral administration both at 3 h and 24 h. Furthermore, tested dithioacetals possessed prolonged antidepressant activity in forced swim test (FST) considerable decreasing the duration of immobility time compared to reference drug amitriptyline. This is the first study of the investigation of anticonvulsant and antidepressant activities of ketene dithioacetals.

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Chemistry of Polyhalogenated Nitrobutadienes, 1: A New Syn- thesis of Perfunctionalized 3-Amino-4-nitrothiophenes

Cited by 25 publications

References 38 publications

Glucose 6-phosphate dehydrogenase 6-phosphogluconolactonase: characterization of the Plasmodium vivax enzyme and inhibitor studies

Glucose 6-phosphate dehydrogenase 6-phosphogluconolactonase: characterization of the Plasmodium vivax enzyme and inhibitor studies

Chemistry of polyhalogenated nitrobutadienes, 14: Efficient synthesis of functionalized (Z)-2-allylidenethiazolidin-4-ones

New Ketene Dithioacetals Generated from 2‐Nitroperchlorobutadiene and Investigation of Their Antibacterial, Antifungal, Anticonvulsant and Antidepressant Activities

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