Synthesis and anticonvulsant activity of 6-methyl-2-((2-oxo-2-arylethyl)thio)pyrimidin-4(3 H)-one derivatives and products of their cyclization

Severina, Hanna I.; Skupa, Olga O.; Волощук, Н. І.; Suleiman, Marharyta M.; Georgiyants, Victoriya

doi:10.3897/pharmacia.66.e38137

Cited by 9 publications

(13 citation statements)

References 20 publications

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“…Alkylation of N-[(2,4-dichlorophenyl) methyl]-2-(2,4-dioxo-1H-quinazolin-3-yl) acetamide (1) was carried out by interaction with the corresponding 1chloromethylbenzene (2) in dimethylformamide medium in the presence of potassium carbonate excess at a temperature of 7080 ˚C, i.e. under traditional alkylation conditions [18,29].…”

Section: Resultsmentioning

confidence: 99%

Synthesis and anticonvulsant activity evaluation of n-[(2,4-dichlorophenyl)methyl]-2-(2,4-dioxo-1h-quinazolin-3-yl)acetamide novel 1-benzylsubstituted derivatives

Kayal

Severina

Tsyvunin

et al. 2022

SR: PS

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The aim. Synthesis of 1-benzylsubstituted derivatives of N-[(2,4-dichlorophenyl)methyl]-2-(2,4-dioxo-1h-quinazolin-3-yl)acetamide, and determination of affinity to GABAergic biotargets with the following anticonvulsant activity estimation using PTZ-induced seizures model in mice. Materials and methods. Standard organic synthesis methods were used; the structure of the synthesized compounds was proved by elemental analysis, 1H and 13C NMR spectroscopy, and LC/MS method; composition of the synthesized compounds – by elemental analysis, their individuality – by TLC and LC/MS methods. AutoDockTools-1.5.6, as well as AutoDock Vina software, was used to perform molecular docking. Anticonvulsant activity was studied using pentylenetetrazole-induced seizures in mice. Results. A targeted N-[(2,4-dichlorophenyl)methyl]-2-(1-(R-benzyl)-2,4-dioxo-quinazolin-3-yl)acetamides were obtained by alkylation of N-[(2,4-dichlorophenyl)methyl]-2-(2,4-dioxo-1H-quinazolin-3-yl)acetamide by corresponding 1-chloromethylbenzene in dimethylformamide environment with excess of potassium carbonate at a temperature 70-80 ˚С. Prediction of activity of 1-benzyl derivatives in the pentylenetetrazole-induced seizures in an in vivo experiment was carried out according to the obtained results of docking studies – affinity calculation for GABA receptor and GABA enzyme active sites, as well as analysis of conformational placement in them. In relation to the binding energy, the studied ligands were inferior to the reference drugs: GABA receptor positive allosteric modulators – benzamidine and diazepam, and GABA inhibitor – vigabatrin. The synthesized substances did not show anticonvulsant activity: only 2 compounds have shown a tendency to their activity manifestation according to the criterion of integral protective indicator – reduction of mortality by 17 % compared to control, as well as prolonging the time death of the animals. Comparison with the preliminary obtained results of the activity of the promising anticonvulsant N-[(2,4-dichlorophenyl)methyl] -2-(2,4-dioxo-1H-quinazolin-3-yl) acetamide N-[(2,4-dichlorophenyl)methyl]-2-(2,4-dioxo-1H-quinazolin-3-yl)acetamide made possible to prove the pharmacophore role of the cyclic amide fragment in anticonvulsant activity manifestation. Conclusion. The synthesis of N-[(2,4-dichlorophenyl)methyl]-2-(1-(R-benzyl)-2,4-dioxo-quinazolin-3-yl)acetamides, which have not still described in the literature, was carried out, as well as the structure of the mentioned compounds was proved. Unfortunately, the substances did not show anticonvulsant activity on the model of pentylenetetrazole-induced seizures. However, the obtained results allowed establishing the key role of the NHCO cyclic fragment on anticonvulsant activity. A positive correlation between the results of in vivo studies and in silico calculations was found – the model of pentylenetetrazole-induced seizures and docking into the active sites of PAMs GABAА receptor and enzyme inhibitor GABAАТ, which allows to recommend the given docking methodology as a tool to streamline and optimize the screening on the mentioned model

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Section: Resultsmentioning

confidence: 99%

Synthesis and anticonvulsant activity evaluation of n-[(2,4-dichlorophenyl)methyl]-2-(2,4-dioxo-1h-quinazolin-3-yl)acetamide novel 1-benzylsubstituted derivatives

Kayal

Severina

Tsyvunin

et al. 2022

SR: PS

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“…The synthesis of the new thiopyrimidine compounds (6a-e) was achieved by reacting 2-thiopyrimidines (4) with benzyl halides in the presence of a base [18] (Figure 1). The starting 2-thiopyridines were obtained by a stereospecific process between ethyl acetoacetate, thiourea and p-alkylbenzaldehydes under reflux of ethanol in the presence of hydrochloric acid [19].…”

Section: Chemistrymentioning

confidence: 99%

Study of the influence of N-alkylation of 2-benzylthiopyrimidines on the growth of two bacteria of medical interest

ACHI¹,

ZON²,

TIMOTOU³

et al. 2022

GSC Adv. Res. Rev.

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The present work highlights the synthesis and effect of introducing substituents on the nitrogen at position -1 of five 2-benzylthiopyrimidine derivatives (6a-e). The compounds (6a-e) were obtained by condensation of 2-thiopyrimidines (4) with benzyl halides in the presence of a base. As for the N-alkylated/arylated-2thiobenzylpyrimidines (8a-k), they were obtained by nucleophilic substitution reaction on nitrogen in basic medium. All the synthesized compounds were characterized by 1H proton, 13C carbon NMR spectroscopic analyses and high resolution mass spectrometry. All compounds were subjected to antibacterial testing on two multidrug resistant strains of Escherichia coli and Staphylococcus aureus. The results revealed that compounds 6a, 6b, 6c, 6d and 6e showed no minimum inhibitory concentration on either E. coli or S. aureus. However, compounds 8b, 8c, 8d and 8f showed a MIC on S. aureus1174. As for the bacterial strain E. coli 1178, only compound 8h showed a minimum inhibitory concentration. N-alkylation/arylation enhanced the antibacterial effect of some 2-benzylthiopyrimidine derivatives.

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“…Sahu et al synthesized 5,6-dihydropyrimidine-2(1H)-thi one analogues (Scheme 27) and evaluated their anticonvulsant activity using maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) test in mice. 57 and 58 were most potent with IC50 of 18.42 and 19.23 μM, respectively (Sahu et al, 2017;Severina et al, 2019). Huang et al,synthesized 2,2,4]-triazolo[1,5-a]pyrimidine-7(4H)-one analogues (Scheme 28) and screened them using MES and PTZ.…”

Section: Anticonvulsant Activitymentioning

confidence: 99%

Pyrimidine: An elite heterocyclic leitmotif in drug discovery‐synthesis and biological activity

Nadar

Khan

2021

Chem Biol Drug Des

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Nitrogen containing heterocycles have a quintessential role in synthetic chemistry, cell biology and are part of enormous natural products. Compounds of these classes playing a cardinal role are the six-membered unsaturated rings having nitrogen referred as azines. Similar analogues with two ring nitrogen are termed as diazines. The diazines exist in three isomeric forms depending on the position of the nitrogen, pyridazine (1, 2-diazine), pyrimidine (1, 3-diazine), and pyrazine (1, 4-diazine) (Figure 1). Pyrimidines have remarkable biotic relevance and are the omnipresent isomer among the diazines (

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Synthesis and anticonvulsant activity of 6-methyl-2-((2-oxo-2-arylethyl)thio)pyrimidin-4(3 H)-one derivatives and products of their cyclization

Cited by 9 publications

References 20 publications

Synthesis and anticonvulsant activity evaluation of n-[(2,4-dichlorophenyl)methyl]-2-(2,4-dioxo-1h-quinazolin-3-yl)acetamide novel 1-benzylsubstituted derivatives

Synthesis and anticonvulsant activity evaluation of n-[(2,4-dichlorophenyl)methyl]-2-(2,4-dioxo-1h-quinazolin-3-yl)acetamide novel 1-benzylsubstituted derivatives

Study of the influence of N-alkylation of 2-benzylthiopyrimidines on the growth of two bacteria of medical interest

Pyrimidine: An elite heterocyclic leitmotif in drug discovery‐synthesis and biological activity

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