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, quinazolin, benzyl, docking, GABA, anticonvulsant activity


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

Author Biographies

Wassim El Kayal, National University of Pharmacy

Postgraduate Student

Department of Pharmaceutical Chemistry

Hanna Severina, National University of Pharmacy

Doctor of Pharmaceutical Science, Associate Professor

Department of Pharmaceutical Chemistry

Vadim Tsyvunin, National University of Pharmacy

PhD, Assistant

Department of Pharmacology and Pharmacotherapy

Sergiy Zalevskyi, National University of Pharmacy

Postgraduate Student

Department of Pharmacology and Pharmacotherapy

Sergiy Shtrygol’, National University of Pharmacy

Doctor of Medical Sciences, Professor

Department of Pharmacology and Pharmacotherapy

Sergiy Vlasov, National University of Pharmacy

Doctor of Pharmaceutical Sciences, Professor

Department of Pharmaceutical Chemistry

Olga Golovchenko, National University of Pharmacy

PhD, Associate Professor

Department of Pharmaceutical Chemistry

Sergiy Kovalenko, Karazin Kharkiv National University

Doctor of Chemical Sciences, Professor

Department of Organic Chemistry

Victoriya Georgiyants, National University of Pharmacy

Doctor of Pharmaceutical Sciences, Professor, Head of Department

Department of Pharmaceutical Chemistry


  1. Devinsky, O., Vezzani, A., O’Brien, T. J., Jette, N., Scheffer, I. E., de Curtis, M., Perucca, P. (2018). Epilepsy. Nature Reviews Disease Primers, 4 (1). doi:
  2. Janmohamed, M., Brodie, M. J., Kwan, P. (2020). Pharmacoresistance – Epidemiology, mechanisms, and impact on epilepsy treatment. Neuropharmacology, 168. doi:
  3. Löscher, W., Klein, P. (2021). The Pharmacology and Clinical Efficacy of Antiseizure Medications: From Bromide Salts to Cenobamate and Beyond. CNS Drugs, 35 (9), 935–963. doi:
  4. Keezer, M. R., Sisodiya, S. M., Sander, J. W. (2016). Comorbidities of epilepsy: current concepts and future perspectives. The Lancet Neurology, 15 (1), 106–115. doi:
  5. Yuen, A. W. C., Keezer, M. R., Sander, J. W. (2018). Epilepsy is a neurological and a systemic disorder. Epilepsy & Behavior, 78, 57–61. doi:
  6. Vossler, D. G., Weingarten, M., Gidal, B. E. (2018). Summary of Antiepileptic Drugs Available in the United States of America: working toward a world without epilepsy. Epilepsy Currents, 18 (4), 1–26. doi:
  7. Gaitatzis, A., Sander, J. W. (2013). The Long-Term Safety of Antiepileptic Drugs. CNS Drugs, 27 (6), 435–455. doi:
  8. Chen, B., Choi, H., Hirsch, L. J., Katz, A., Legge, A., Buchsbaum, R., Detyniecki, K. (2017). Psychiatric and behavioral side effects of antiepileptic drugs in adults with epilepsy. Epilepsy & Behavior, 76, 24–31. doi:
  9. Gesche, J., Christensen, J., Hjalgrim, H., Rubboli, G., Beier, C. P. (2020). Epidemiology and outcome of idiopathic generalized epilepsy in adults. European Journal of Neurology, 27 (4), 676–684. doi:
  10. Łukawski, K., Czuczwar, S. J. (2021). Understanding mechanisms of drug resistance in epilepsy and strategies for overcoming it. Expert Opinion on Drug Metabolism & Toxicology, 17 (9), 1075–1090. doi:
  11. Khan, H. N., Kulsoom, S., Rashid, H. (2012). Ligand based pharmacophore model development for the identification of novel antiepileptic compound. Epilepsy Research, 98 (1), 62–71. doi:
  12. McCarthy, G., Myers, B., Siegfried, N. (2005). Treatment for Methaqualone dependence in adults. Cochrane Database of Systematic Reviews, 2. doi:
  13. Ibrahim, M.-K., El-Adl, K., Al-Karmalawy, A. A. (2015). Design, synthesis, molecular docking and anticonvulsant evaluation of novel 6-iodo-2-phenyl-3-substituted-quinazolin-4(3H)-ones. Bulletin of Faculty of Pharmacy, Cairo University, 53 (2), 101–116. doi:
  14. Abuelizz, H. A., Dib, R. E., Marzouk, M., Anouar, E.-H., A. Maklad, Y., N. Attia, H., Al-Salahi, R. (2017). Molecular Docking and Anticonvulsant Activity of Newly Synthesized Quinazoline Derivatives. Molecules, 22 (7), 1094. doi:
  15. El Kayal, W. M., Shtrygol, S. Y., Zalevskyi, S. V., Shark, A. abu, Tsyvunin, V. V., Kovalenko, S. M. et. al. (2019). Synthesis, in vivo and in silico anticonvulsant activity studies of new derivatives of 2-(2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)acetamide. European Journal of Medicinal Chemistry, 180, 134–142. doi:
  16. Jain, D., Singh, A., Patel, V., Veerasamy, R., Aggarwal, N., Rajak, H. (2017). Drug Design Strategies for the Discovery of Novel Anticonvulsants Concerned with Four Site Binding Pharmacophoric Model Studies. Central Nervous System Agents in Medicinal Chemistry, 17 (1), 30–50. doi:
  17. Tasso, S. M., Bruno-Blanch, L. E., Moon, S. C., Estiú, G. L. (2000). Pharmacophore searching and QSAR analysis in the design of anticonvulsant drugs. Journal of Molecular Structure: THEOCHEM, 504 (1-3), 229–240. doi:
  18. Severina, H. I., Skupa, O. O., Voloshchuk, N. I., Georgiyants, V. A. (2020). Synthesis, docking study, and pharmacological evaluation of S-acetamide derivatives of 4,6-dimethyl-2-thiopyrimidine as anticonvulsant agents. Journal of Applied Pharmaceutical Science, 10 (7), 1–8. doi:
  19. Al-Salem, H. S. A., Hegazy, G. H., El-Taher, K. E. H., El-Messery, S. M., Al-Obaid, A. M., El-Subbagh, H. I. (2015). Synthesis, anticonvulsant activity and molecular modeling study of some new hydrazinecarbothioamide, benzenesulfonohydrazide, and phenacylacetohydrazide analogues of 4(3H)-quinazolinone. Bioorganic & Medicinal Chemistry Letters, 25 (7), 1490–1499. doi:
  20. Zayed, M., Ihmaid, S., Ahmed, H., El-Adl, K., Asiri, A., Omar, A. (2017). Synthesis, Modelling, and Anticonvulsant Studies of New Quinazolines Showing Three Highly Active Compounds with Low Toxicity and High Affinity to the GABA-A Receptor. Molecules, 22 (2), 188. doi:
  21. Matias, M., Campos, G., Silvestre, S., Falcão, A., Alves, G. (2017). Early preclinical evaluation of dihydropyrimidin(thi)ones as potential anticonvulsant drug candidates. European Journal of Pharmaceutical Sciences, 102, 264–274. doi:
  22. Severina, Н., Skupa, O., Khairulin, A., Voloshchuk, N., Georgiyants, V. (2019). Synthesis and anticonvulsant activity of 6-methyl-2-thioxo-2, 3-dihydropyrimidin-4(1H)-one acetamides. Journal of Applied Pharmaceutical Science, 9 (2), 12–19. doi:
  23. Kehne, J. H., Klein, B. D., Raeissi, S., Sharma, S. (2017). The National Institute of Neurological Disorders and Stroke (NINDS) Epilepsy Therapy Screening Program (ETSP). Neurochemical Research, 42 (7), 1894–1903. doi:
  24. Morris, G. M., Huey, R., Lindstrom, W., Sanner, M. F., Belew, R. K., Goodsell, D. S., Olson, A. J. (2009). AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. Journal of Computational Chemistry, 30 (16), 2785–2791. doi:
  25. Protein Data Bank. Available at: Last accessed: 04.06.2021
  26. Trott, O., Olson, A. J. (2009). AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. Journal of Computational Chemistry, 31 (2), 455–461. doi:
  27. Vogel, H. G.; Vogel, H. G. (Ed.) (2008). Chapter E: Psychotropic and neurotropic activity. Drug Discovery and Evaluation: Pharmacological Assays. Berlin: Springer-Verla, 565–876. doi:
  28. Hock, F.J. (2016). Drug Discovery and Evaluation: Pharmacological Assays. Cham: Springer International Publishing, 4314. doi:
  29. Severina, H., Skupa, O. O., Voloshchuk, N. I., Suleiman, M. M., Georgiyants, V. A. (2019). Synthesis and anticonvulsant activity of 6-methyl-2-((2-oxo-2-arylethyl)thio)pyrimidin-4(3 H)-one derivatives and products of their cyclization. Pharmacia, 66 (3), 141–146. doi:
  30. Miller, P. S., Aricescu, A. R. (2014). Crystal structure of a human GABAA receptor. Nature, 512 (7514), 270–275. doi:
  31. Masiulis, S., Desai, R., Uchański, T., Serna Martin, I., Laverty, D., Karia, D. et. al. (2019). GABAA receptor signalling mechanisms revealed by structural pharmacology. Nature, 565 (7740), 454–459. doi:
  32. Storici, P., Capitani, G., De Biase, D., Moser, M., John, R. A., Jansonius, J. N., Schirmer, T. (1999). Crystal Structure of GABA-Aminotransferase, a Target for Antiepileptic Drug Therapy. Biochemistry, 38 (27), 8628–8634. doi:
  33. Bialer, M., White, H. S. (2010). Key factors in the discovery and development of new antiepileptic drugs. Nature Reviews Drug Discovery, 9 (1), 68–82. doi:
  34. Egorova, E. V., Dmitrenko, D. V., Usoltseva, A. A., Iptyshev, A. M., Shnayder, N. A., Nasyrova, R. F. (2020). Modeling of chronic epilepsy in animals through chemical methods. Bulletin of Siberian Medicine, 18 (4), 185–196. doi:
  35. Lipinski, C. A. (2016). Rule of five in 2015 and beyond: Target and ligand structural limitations, ligand chemistry structure and drug discovery project decisions. Advanced Drug Delivery Reviews, 101, 34–41. doi:
  36. Löscher, W. (2017). Animal Models of Seizures and Epilepsy: Past, Present, and Future Role for the Discovery of Antiseizure Drugs. Neurochemical Research, 42 (7), 1873–1888. doi:




How to Cite

El Kayal, W., Severina, H., Tsyvunin, V., Zalevskyi, S., Shtrygol’, S., Vlasov, S., Golovchenko, O., Kovalenko, S., & Georgiyants, V. (2022). Synthesis and anticonvulsant activity evaluation of n-[(2,4-dichlorophenyl)methyl]-2-(2,4-dioxo-1h-quinazolin-3-yl)acetamide novel 1-benzylsubstituted derivatives. ScienceRise: Pharmaceutical Science, (1(35), 58–69.



Pharmaceutical Science