Molecular design and targeted synthesis of N-substituted 4-oxo-1,4-dihydropyrimidine derivatives on the basis of inhibitory neurotransmitters

Кодониди, И. П.; Oganesyan, É. T.; Глушко, А. А.; Turenkov, I. N.; Багметова, В. В.; Золотых, Д. С.; Pogrebnyak, A. V.

doi:10.1007/s11094-010-0352-6

Cited by 3 publications

(1 citation statement)

References 7 publications

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“…Многочисленные работы по синтезу и изучению фармакологической активности производны 1,3-диазинонов-4, позволяют судить об их низкой токсичности в сочетании с высоким биологическим действием [6,7]. Объяснение этому выводу следует искать в структурной близости данных соединений к эндогенным пиримидиновым основаниям.…”

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Synthesis of 2,6-Dialkyl Substituted Sulfonamides and Sulfones Derivatives of Pyrimidine-4(1h)-On

Anenko¹,

Кодониди²,

Smirnova³

et al. 2018

Zdor. obraz. XXI veke (Ž. naučn. statej)

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Аннотация. Целью настоящего исследования является синтез различных 2,6-диалкилсульфаниламидных и сульфоновых производных пиримидин-4(1H)-она. Синтез целевых веществ осуществлялось путем нагревания N-ацил-βкетоамидов с 4-аминобензолсульфонамидом или 4,4-диаминодифенилсульфоном в среде ледяной уксусной кислоты. Контроль прохождения реакций осуществляли методом тонкослойной хроматографии. Строение полученных соединений подтверждено методами спектрофотометрии. Синтезированы 2,6-диалкильные производные пиримидин-4(1Н)-она, содержащие остатки сульфаниламида и дифенилсульфона в нуклеозидном положении ядра 4-оксопиримидина. Получение целевых продуктов осуществлялось реакцией циклоконденсации N-ацил-β-кетоамидов с 4-аминобензолсульфонамидом и с 4,4-диаминодифенилсульфоном. Оптимизация геометрии синтезированных соединений проведена в компьютерной программе HyperChem с помощью полуэмпирического квантово-химического метода расчета AM1. В результате исследования выявлено, что выход производных 6-метил-2-этильных производных пиримидин-4(1Н)-она больше такового для 2-метил-6-этилпиримидин-4(1Н)-онов. Ключевые слова: целенаправленный синтез, производные пиримидин-4(1H)-она, N-ацил-β-кетоамиды, квантово-химические методы расчета, стерические затруднения. Annotation. The aim of this study is the synthesis of various 2,6dialkylsulfonamides and sulfones derivatives of pyrimidine-4(1H)-one. The synthesis of target substances was carried out by heating N-acyl-β-ketoamides with 4-aminobenzenesulfonamide or 4,4-diaminodiphenylsulfone in the medium of glacial acetic acid. Control of the reactions was carried out by thinlayer chromatography. The structure of the obtained compounds was confirmed by spectrophotometry. 2,6-dialkyl derivatives of pyrimidine-4(1H)-one were synthesized, which are containing the remains of sulfonamide and diphenylsulfone in a nucleoside position of the nucleus 4-oxopyrimidine. The target products were obtained by the reaction of cyclocondensation of N-acyl-βketoamides with 4-aminobenzenesulfonamide and 4.4-diaminodiphenylsulfone. Geometry optimization of synthesized compounds was done in the computer program HyperChem using the semi-empirical quantum chemical method of calculation AM1. The research revealed that the yield of derivatives of 6methyl-2-ethyl derivatives of pyrimidine-4(1H)-one is greater than for derivatives 2-methyl-6-ethylpyrimidine-4(1H)-one.

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Synthesis of 2,6-Dialkyl Substituted Sulfonamides and Sulfones Derivatives of Pyrimidine-4(1h)-On

Anenko¹,

Кодониди²,

Smirnova³

et al. 2018

Zdor. obraz. XXI veke (Ž. naučn. statej)

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Molecular Design of N-Acyl Derivatives of 2-(2-Oxopyrolidin-1-Yl)-Acetamide With Gaba-Ergic and Glutamatergic Activities

Кодониди

Chiriapkin

Творовский

2021

Farm. farmakol. (Pâtigorsk)

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The first of the most successfully implemented nootropic drugs in medical practice is piracetam, which should be attributed to cyclic derivatives of gamma-aminobutyric acid. The production of new piracetam derivatives with high nootropic activity is a promising direction in the development of new neuroprotective drugs.The aim of the study is to predict GABA-ergic and glutamatergic activities of N-acyl derivatives of 2-(2-oxopyrolidin-1-yl)- acetamide by a molecular docking method through the energy analysis of interaction of modeled structures with GABAA and AMPA receptors with their subsequent targeted synthesis.Materials and methods. The objects of the research are new N-acyl derivatives of 2-oxo-1-pyrrolidineacetamide and a virtual model of the GABAA receptor of the Homo sapiens organism with the identification code 6D6U and a three-dimensional model of the AMPA-receptor of the Rattus norvegicus organism with the identification code 3LSF from the RCSB PDB database. The simulated compounds were designed in the HyperChem 8.0.8 program. This program was also used to optimize geometry using the force field of molecular mechanics MM+. Molecular docking was carried out using the Molegro Virtual Docker 6.0.1 program. The preparation of N-acyl derivatives of 2-(2-oxopyrrolidin-1-yl)-acetamide was carried out by the interaction of 2-(2-oxopyrrolidin-1-yl)-acetamide with an excess of the corresponding anhydride under conditions of acid catalysis.Results. Based on the results of molecular docking, a high affinity of all simulated compounds for the binding site of GABAA and AMPA receptors can be estimated. According to the predict, the maximum GABA-ergic activity should be expected for (N-[2-(2-oxopyrrolidin-1-yl)-acetyl]-butyramide. N-acyl derivatives of 2-oxo-1-pyrrolidineacetamide form a more stable complex with amino acid residues Arg207, Phe200, Thr202, Tyr97, Tyr157, Tyr205 and Phe65 of the GABAA receptor binding site than the GABA molecule. In terms of the minimum interaction energy, the N-acyl derivatives of 2-(2-oxopyrrolidin-1-yl)- acetamide are superior to a number of known ligands such as GABA, piracetam, anipiracetam, picamilon and pramiracetam. The tested compounds have also shown a high affinity for the binding site of the AMPA receptor. The leader compound is also the compound PirBut, as in the case of the GABAА receptor.Conclusion. Molecular modeling of the ligands interaction with the active binding site of gamma-aminobutyric acid of the GABAA receptor by molecular docking showed that all virtual N-acyl derivatives of 2-oxo-1-pyrrolidineacetamide can exceed a number of nootropic drugs by activity. In the course of molecular design, a method for predicting a glutamatergic activity for 2-pyrrolidone derivatives has been developed. It suggests a significant nootropic activity for N-[2-(2-oxopyrrolidin-1-yl)- acetamide amides.

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ELECTROPHILE CYCLIZATION OF N (S, Se)-ALKENYL DERIVATIVES OF PYRIMIDINONE WITH p-METOXYPHENYLTELLURIUM TRICHLORIDE

Kut¹,

Onysko²,

Lendel³

2019

Scientific Bulletin of the Uzhhorod University. Series «Chemistry»

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Molecular design and targeted synthesis of N-substituted 4-oxo-1,4-dihydropyrimidine derivatives on the basis of inhibitory neurotransmitters

Cited by 3 publications

References 7 publications

Synthesis of 2,6-Dialkyl Substituted Sulfonamides and Sulfones Derivatives of Pyrimidine-4(1h)-On

Synthesis of 2,6-Dialkyl Substituted Sulfonamides and Sulfones Derivatives of Pyrimidine-4(1h)-On

Molecular Design of N-Acyl Derivatives of 2-(2-Oxopyrolidin-1-Yl)-Acetamide With Gaba-Ergic and Glutamatergic Activities

ELECTROPHILE CYCLIZATION OF N (S, Se)-ALKENYL DERIVATIVES OF PYRIMIDINONE WITH p-METOXYPHENYLTELLURIUM TRICHLORIDE

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