Synthesis, in vivo and in silico anticonvulsant activity studies of new derivatives of 2-(2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)acetamide

Kayal, Wassim Mokhamad El; Shtrygol, S. Yu.; Zalevskyi, Sergiy; Shark, Amjad abu; Tsyvunin, Vadim; Kovalenko, Sergiy M.; Bunyatyan, N. D.; Perekhoda, Lina; Severina, Hanna I.; Georgiyants, Victoriya

doi:10.1016/j.ejmech.2019.06.085

Cited by 16 publications

(16 citation statements)

References 24 publications

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“…N-[(2,4-dichlorophenyl)methyl]-2-(2,4-dioxo-1H-quinazolin-3-yl)acetamide (1) was obtained and described previously [15].…”

Section: Methodsmentioning

confidence: 99%

“…The quinazoline 1 derivative has shown low toxicity and no muscle relaxant effect on the laboratory animals in the rotarod test, but it also has shown slight activity on the model of MES. Based on the principles of the pharmacophore model of AEDs development [16], the study was continued to modify the structure of the leader compound in the previous research [15] to possibly improve the pharmacological profile.…”

Section: Mecloqualonementioning

confidence: 99%

“…1) [13,14], but none of them is currently used due to its ability to become addictive. 1), and its strong anticonvulsant potential in the model of pentylenetetrazole induced (PTZ) seizures in mice was detected [15]. It was found that the studied compound completely protects the laboratory animals from seizures and mortality and exceeds the reference drug sodium valproate.…”

Section: Introductionmentioning

confidence: 97%

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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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“…N-[(2,4-dichlorophenyl)methyl]-2-(2,4-dioxo-1H-quinazolin-3-yl)acetamide (1) was obtained and described previously [15].…”

Section: Methodsmentioning

confidence: 99%

Section: Mecloqualonementioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

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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 severity of seizures was evaluated according to a scale ranging from 1 to 6: 1 -trembling; 2 -circus movement; 3 -clonic seizures; 4 -clonic-tonic seizures with a lateral position; 5 -tonic extension; 6tonic extension leading to the death of the animal). If seizures were not observed within 1 h, it was considered that the latency period was 60 min (in the model of thiosemicarbazide seizures -240 min) [18].…”

Section: Methodsmentioning

confidence: 99%

Low-dose digoxin enhances the anticonvulsive potential of carbamazepine and lamotrigine in chemo-induced seizures with different neurochemical mechanisms

Havrylov

Tsyvunin

Shtrygol

et al. 2021

SR: PS

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"Non-antiepileptic" drugs have a strong potential as adjuvants in multidrug-resistant epilepsy treatment. In previous study the influence of low doses of digoxin, which do not affect the myocardium, on the anticonvulsant potential of classical commonly used anti-epileptic drugs under conditions of seizures, induced by pentylenetetrazole and maximal electroshock, has been investigated. The aim of the study was to investigate the influence of digoxin at a sub-cardiotonic dose on the anticonvulsant potential of carbamazepine and lamotrigine in experimental seizures with different neurochemical mechanisms. Material and methods: A total of 192 random-bred male albino mice weighting 22–25 g were used. Carbamazepine and lamotrigine were administered intragastrically in conditionally effective (ED50) and sub-effective (½ ED50) doses: carbamazepine at doses of 100 and 50 mg/kg; lamotrigine at doses of 25 and 12.5 mg/kg. Digoxin was administered subcutaneously at a sub-cardiotonic dose of 0.8 mg/kg as an adjuvant to carbamazepine and lamotrigine in ½ ED50. Picrotoxin (2.5 mg/kg subcutaneously); thiosemicarbazide (25 mg/kg intraperitoneally); strychnine (1.2 mg/kg subcutaneously); camphor (1000 mg/kg intraperitoneally) were used as convulsant agents. Results: It was found that digoxin not only has its own permanent anticonvulsant effect on different models of paroxysms with different neurochemical mechanisms of development, but also significantly enhances the anticonvulsant potential of carbamazepine (to a lesser extent – lamotrigine) regardless of the pathogenesis of experimental paroxysms. Conclusion: Based on the results, it can be concluded that digoxin has a high potential as an adjuvant medicine in complex epilepsy treatment because it enhances the efficiency of low-dose traditional anticonvulsants carbamazepine and lamotrigine

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“…erapeutic agents acting through the modulation of the GABA A receptor have been reported to inhibit seizures in both experimental animals and humans [40]. It has been reported that PTZ mediates its convulsive action through direct inhibition of the GABAergic process in the CNS [41]. Since the synthesized compounds antagonized the convulsion induced by PTZ, it probably may exert its anticonvulsant activities through activation of GABAergic transmission in similar mechanisms of barbiturates such as phenobarbital [42].…”

Section: Docking On Gaba a Receptor (3ip9)mentioning

confidence: 99%

Schiff Bases of Isatin and Adamantane-1-Carbohydrazide: Synthesis, Characterization and Anticonvulsant Activity

Osman

Elsaman

Yousef

et al. 2021

Journal of Chemistry

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Epilepsy is the most common neurological condition and cause of substantial morbidity and mortality. In the present study, the molecular hybridization tool was adopted to obtain six Schiff bases of isatin and adamantane-1-carbohydrazide (18–23). Then, their anticonvulsant activity was evaluated using pentylenetetrazole- (PTZ-) induced seizure model using phenobarbitone as a positive control. Our findings showed that compounds 18–23 provided significant protection against PTZ-induced seizure, and maximum activities were associated with compound 23. Moreover, all investigated compounds increased the latency of induced convulsion and reduced the duration of epilepsy with compound 23 being the best. Interestingly, most of the synthesized molecules showed reduction in neurological symptoms and severity of the seizure. Molecular docking studies suggest GABA-A receptor as a potential target, and in silico ADME screening revealed that the pharmaceutical properties of compound 23 are within the specified limit. Thus, compound 23 was identified as a promising candidate that warrants further drug discovery processes.

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Synthesis, in vivo and in silico anticonvulsant activity studies of new derivatives of 2-(2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)acetamide

Cited by 16 publications

References 24 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

Low-dose digoxin enhances the anticonvulsive potential of carbamazepine and lamotrigine in chemo-induced seizures with different neurochemical mechanisms

Schiff Bases of Isatin and Adamantane-1-Carbohydrazide: Synthesis, Characterization and Anticonvulsant Activity

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