Synthesis, docking study, and pharmacological evaluation of S-acetamide derivatives of 4,6-dimethyl-2-thiopyrimidine as anticonvulsant agents

Severina, Hanna I.; Skupa, Olha O.; Волощук, Н. І.; Georgiyants, Victoriya

doi:10.7324/japs.2020.10701

Cited by 8 publications

(11 citation statements)

References 20 publications

(17 reference statements)

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“…But the introduction of lamotrigine statistically significantly -6.25 times -extended the latent period, significantly reduced the severity and duration of seizures compared to those of the control group, and the lethality was 14.3%. As shown in the previous studies (Severina et al 2013), Epirimil prevented convulsions development, completely protected the test animals from seizures and absolutely prevented lethality.…”

Section: Anticonvulsant Activity On the Model Of Ptz-induced Seizuressupporting

confidence: 75%

“…pyrimidin-4-yl)thio)acetamide on the PTZ-induced seizure model (Severina et al 2013 suggests that the mentioned compound may act as a GABA agonist or inhibit GABA aminotransferase. At the same time, such drugs as phenobarbital, benzodiazepine, gabapentin, vigabatrin, felbamate, etc.…”

Section: Selecting Biotargetsmentioning

confidence: 99%

“…Our previous research (Severina et al 2012) resulted in a number of new compounds, e.g. : 2,5,6-substantiated derivatives of pyrimidine-4(3H)-one (thione) and carrying out their pharmacological screening on the basic model of pentylenetetrazole-induced seizures in rats (Severina et al 2013). This pharmacological model is recognized as the gold standard for screening tests and allows predicting anticonvulsant activity in relation to generalized myoclonic seizures (Krall et al 1978, Bialer andWhite 2010).…”

Section: Introductionmentioning

confidence: 99%

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Molecular docking, ADMET study and in vivo pharmacological research of N-(3,4-dimetoxyphenyl)-2-{[2-methyl-6-(pyridine-2-yl)-pyrimidin-4-yl]thio}acetamide as a promising anticonvulsant

Severina¹,

Skupa²,

Волощук³

et al. 2020

RRP

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Introduction: The search for new anticonvulsants for epilepsy treatment with higher efficacy and better tolerability remains important. The aim of the present research was an in silico and in vivo pharmacological study of N-(3,4-dimethoxyphenyl)-2-((2-methyl-6-(pyridin-2-yl)pyrimidin-4-yl)thio)acetamide (Epirimil) as a promising anticonvulsant. Materials and methods: A 1H and 13C NMR spectroscopy, LS/MS, and an elemental analysis were used to determine Epirimil structure. An ADMET analysis, as well as a docking study using anticonvulsant biotargets, e.g.: GABAAR, GABAAT, CA II, NMDAR, and AMPAR, was carried out. Anticonvulsant activity was proved, using PTZ- and MES-induced seizures in rats and mice, and neurotoxicity was determined using a rotarod test. Influence of Epirimil on the psycho-emotional state of the laboratory animals was determined by an open field test. Results and discussion: A synthesis method of a promising anticonvulsant Epirimil was modified. The calculated ADMET parameters and a molecular docking into the active sites of anticonvulsant biotargets allowed evaluating the research prospects and predicting possible mechanisms for implementing anticonvulsant activity. A prominent anticonvulsant activity of Epirimil was established using in vivo studies on the model of PTZ-induced seizures in rats and MES-induced seizures in mice. In terms of toxicity, Epirimil belongs to class IV – low toxic substances. The open field test showed that Epirimil had almost no effect on the animals’ behavioral responses: it neither changed their psycho-emotional activity, nor increased their anxiety level. ED50, TD50 and protective index of Epirimil according to its anticonvulsant activity were calculated. Conclusion: The obtained experimental results substantiate the prospects of N-(3,4-Dimethoxyphenyl)-2-((2-methyl-6-(pyridin-2-yl)pyrimidin-4-yl)thio)acetamide as a promising active pharmaceutical ingredient having a multifactor mechanism of anticonvulsant activity. Graphical abstract

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Section: Anticonvulsant Activity On the Model Of Ptz-induced Seizuressupporting

confidence: 75%

Section: Selecting Biotargetsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Molecular docking, ADMET study and in vivo pharmacological research of N-(3,4-dimetoxyphenyl)-2-{[2-methyl-6-(pyridine-2-yl)-pyrimidin-4-yl]thio}acetamide as a promising anticonvulsant

Severina¹,

Skupa²,

Волощук³

et al. 2020

RRP

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“…Therefore, special attention has also been given to acetamide medications because of their possible use as a therapeutic agent. Acetamide derivatives and their analogs representing a high potential of biological activities including anti-inflammatory [ 63 ], anti-oxidant [ 64 ], anti-cancer [ 65 ], anti-convulsant [ 66 ], anti-hypoxic and anti-microbial [ 67 ], antituberculosis agents [ 68 ] and anti-COVID-19 molecules [ 69 ]. In addition, several acetamide derivatives are used to improve some enzymes that inhibit HIV virus activity from replicating [ 70 ].…”

Section: An Overview Of Acetamide Derivatives As Possible Therapeuticmentioning

confidence: 99%

“…Many chalcones also can be obtained via coupling reactions by using different reactants (63)(64)(65)(66)(67)(68)(69). Several reactions involved C-C and C-heteroatom covalent bond via oxidative addition transmetalation-reductive elimination, as illustrated in Scheme 12 [93].…”

Section: Introduction To Synthesis Of Chalcone and Its Derivativesmentioning

confidence: 99%

Recent investigations into synthesis and pharmacological activities of phenoxy acetamide and its derivatives (chalcone, indole and quinoline) as possible therapeutic candidates

2021

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Graphical abstract Medicinal chemistry can rightfully be regarded as a cornerstone in the public health of our modern society that combines chemistry and pharmacology with the aim of designing and developing new pharmaceutical compounds. For this purpose, many chemical techniques as well as new computational chemistry applications are used to study the utilization of drugs and their biological effects. In the biological interface, medicinal chemistry constitutes a group of interdisciplinary sciences, as well as controlling its organic, physical and computational pillars. Therefore, medicinal chemists working to design an integrated and developing system that portends an era of novel and safe tailored drugs either by synthesizing new pharmaceuticals or to improving the processes by which existing pharmaceuticals are made. It includes researching the effects of synthetic, semi-synthetic and natural biologically active substances based on molecular interactions in terms of molecular structure with triggered functional groups or the specific physicochemical properties. The present work focuses on the literature survey of chemical diversity of phenoxy acetamide and its derivatives (Chalcone, Indole and Quinoline) in the molecular framework in order to get complete information regarding pharmacologically interesting compounds of widely different composition. From a biological and industrial point of view, this literature review may provide an opportunity for the chemists to design new derivatives of phenoxy acetamide and its derivatives that proved to be the successful agent in view of safety and efficacy to enhance life quality.

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An insight on medicinal attributes of pyrimidine scaffold: An updated review

Vyas

Sahu

Pathania

et al. 2022

Journal of Heterocyclic Chem

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Pyrimidine itself or in different fused forms is an important chemical motif for every step of cell life. Alongside, it exists as a key pharmacophoric part in thiamine, alloxan, orotic acid, and other isoforms of nucleotide bases. It has emerged as a privileged scaffold in medicinal chemistry due to its various possible structural and pharmacological attributes. In a number of clinically used chemical agents, pyrimidine or its fused/clubbed form with other moieties act as a key pharmacophore. Structure activity relationship (SAR) studies of the explored derivatives demonstrated that slight modifications with various substitutions on the pyrimidine rings can deviate biological activity to a large extent. 2-Pyrimidone and 2,4-pyrimidione derivatives are largely explored by a number of research groups for various pharmacological targets and due to their similarity to nucleotide bases, it has a great impact on the biological profile of these molecules. The current review focuses on describing the recent advancements (2015 onward) in the development of pyrimidine-based biologically active molecules along with drug candidates under different clinical trials. The aim of this review is to provide structural features associated with pyrimidine along with their SAR studies, which are believed to be valuable for the scientists working on the development of pyrimidine-based small molecules in the aforementioned disease conditions. We believe that the results of this research will help to provide a structural idea that may be used in the design and development of new pyrimidine-based small molecules that target a variety of receptors or enzymes.

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Synthesis, docking study, and pharmacological evaluation of S-acetamide derivatives of 4,6-dimethyl-2-thiopyrimidine as anticonvulsant agents

Cited by 8 publications

References 20 publications

Molecular docking, ADMET study and in vivo pharmacological research of N-(3,4-dimetoxyphenyl)-2-{[2-methyl-6-(pyridine-2-yl)-pyrimidin-4-yl]thio}acetamide as a promising anticonvulsant

Molecular docking, ADMET study and in vivo pharmacological research of N-(3,4-dimetoxyphenyl)-2-{[2-methyl-6-(pyridine-2-yl)-pyrimidin-4-yl]thio}acetamide as a promising anticonvulsant

Recent investigations into synthesis and pharmacological activities of phenoxy acetamide and its derivatives (chalcone, indole and quinoline) as possible therapeutic candidates

An insight on medicinal attributes of pyrimidine scaffold: An updated review

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