• Mohammed Farrag El-behairy Medicinal and Pharmaceutical Chemistry Department, Pharmaceutical and Drug Industries Research Division, National Research Centre (ID 60014618), 12622 Dokki, Giza, Egypt
  • Hanan Naeim Hafez Attia Medicinal and Pharmaceutical Chemistry Department (Pharmacology Group), Pharmaceutical and Drug Industries Research Division, National Research Centre (ID 60014618), 12622 Dokki, Giza, Egypt


Objective: Utilisation of the ligand-based design and molecular hybridization to design promising candidates with prospective efficacy and safety. Synthesis of the designed candidates using different synthetic methods. Biological evaluation of the newly synthesised candidates as anticonvulsant agents.

Methods: Three novel series of 5-(benzo[d][1,3]dioxol-5-yl)-3-tert-butyl-4,5-dihydropyrazoles have been designed via ligand-based drug discovery and molecular hybridization. Proper synthetic routes have been followed in the preparation of compounds (2-23) which have been characterised by different spectral techniques. Antiepileptic potential was assessed by biological evaluation using ‘classical’ animal models of epilepsy, in addition to rotarod test for toxicity.

Results: 4-Nitrophenyl derivatives (5, 13, and19) displayed the highest potency. Compound 5was the most active substituent in series A (N'-aroyl-3-tert-butyl-4,5-dihydro-1H-pyrazole-1-carbohydrazide). It was 2.7 and 1.3 times more active than reference drug Stiripentol (I) and lead compound III, respectively. Compound13 was the best candidate in series B (N'-arylidene-3-tert-butyl-4,5-dihydro-1H-pyrazole-1-carbohydrazide). It was 3.3, 1.5, and 1.2 times more potent than Stiripentol, lead compound III and new compound 5, respectively. Two members (19 and 21) of series C (1,3,4-oxadiazole derivatives) achieved 100 % protection at lower doses than I and III, being 2.6 and 2.4 times more active than Stiripentol. In scPTZ screen, the most active congeners (5, 13, 19) exhibited ED50 values of 45, 48, and 81 mg/kg, respectively, which are highly superior as compared to that of reference drug Stiripentol(I) and lead compound III (ED50 115 and 110 mg/kg, respectively).

Conclusion: Ligand-based design together with molecular hybridization in drug design succeeded to produce potent and wide spectrum candidates.

Keywords: Stiripentol, Anticonvulsant, Ligand-based drug design, Molecular hybridization, 2-pyrazoline


Download data is not yet available.


1. WHO, Epilepsy Fact sheet N °999; Available from 2015. [Last accessed on 06 Feb 2017]
2. Chang BS, Lowenstein DH. Epilepsy. N Engl J Med 2003;349:1257-66.
3. Kamiński K, Rapacz A, Łuszczki JJ, Latacz G, Obniska J, Kieć-Kononowicz K, et al. Design, synthesis and biological evaluation of new hybrid anticonvulsants derived from N-benzyl-2-(2,5-dioxopyrrolidin-1-yl)propanamide and 2-(2,5-dioxopyrrolidin-1-yl)butanamide derivatives. Bioorg Med Chem 2015;23:2548-61.
4. Perucca E, French J, Bialer M. Development of new antiepileptic drugs: challenges, incentives, and recent advances. Lancet Neurol 2007;6:793-804.
5. Cramer JA, Mintzer S, Wheless J, Mattson RH. Adverse effects of antiepileptic drugs: a brief overview of important issues. Expert Rev Neurother 2010;10:885-91.
6. Khan HN, Kulsoom S, Rashid H. Ligand-based pharmacophore model development for the identification of a novel antiepileptic compound. Epilepsy Res 2012;98:62-71.
7. Stiripentol. BCX 2600. Drugs RD 2002;3:220-2.
8. Aboul-Enein MN, El-Azzouny AA, Attia MI, Maklad YA, Amin KM, Abdel-Rehim M, et al. Design and synthesis of novel stiripentol analogues as potential anticonvulsants. Eur J Med Chem 2012;47:360-9.
9. Rajak H, Deshmukh R, Veerasamy R, Sharma AK, Mishra P, Kharya MD. Novel semicarbazones based 2,5-disubstituted-1,3,4-oxadiazoles: one more step towards establishing four binding sites pharmacophoric model hypothesis for anticonvulsant activity. Bioorg Med Chem Lett 2010;20:4168-72.
10. Harish KP, Mohana KN, Mallesha L, Prasanna k, Basavapatna N. Synthesis of novel 1-[5-(4-methoxy-phenyl)-[1,3,4]oxadiazol-2-yl]-piperazine derivatives and evaluation of their in vivo anticonvulsant activity. Eur J Med Chem 2013;65:276-83.
11. Rajak H, Singh T, Bhupendra S, Avineesh R, Kamlesh S, Anil K, et al. Novel limonene and citral-based 2,5-disubstituted-1,3,4-oxadiazoles: a natural product coupled approach to semicarbazones for antiepileptic activity. Bioorg Med Chem Lett 2013;23:8648.
12. Pandeya SN, Ponnilavarasan I, Pandey A, Lakhan R, Stables JP. Evaluation of p-nitrophenyl substituted semicarbazones for anticonvulsant properties. Pharmazie 1999;54:923-5.
13. Dimmock JR, Vashishtha SC, Stables JP. Anticonvulsant properties of various phenylhydrazones, oxamoylhydrazones and semicarbazones derived from aromatic and unsaturated carbonyl compounds. Eur J Med Chem 2000;35:241-8.
14. Krall RL, Penry JK, White BG, Kupferberg HJ, Swinyard EA. Antiepileptic drug development: II. Anticonvulsant drug screening. Epilepsia 1978;19:409-28.
15. Alam O, Mullick P, Verma SP, Gilani SJ, Khan SA, Siddiqui N, et al. Synthesis, anticonvulsant and toxicity screening of newer pyrimidine semicarbazone derivatives. Eur J Med Chem 2010;45:2467-72.
16. Luszczki JJ, Czuczwar M, Gawlik P, Sawiniec-Pozniak G, Czuczwar K, Czuczwar SJ. 7-Nitroindazole potentiates the anticonvulsant action of some second-generation antiepileptic drugs in the mouse maximal electroshock-induced seizure model. J Neural Transm 2006;113:1157-68.
17. Dunham NW, Miya TS. A note on a simple apparatus for detecting neurological deficit in rats and mice. J Am Pharm Assoc 2006;46:208-9.
18. Augustine JK, Vairaperumal V, Narasimhan S, Alagarsamy P, Radhakrishnan A. Propylphosphonic anhydride (T3P®): an efficient reagent for the one-pot synthesis of 1,2,4-oxadiazoles, 1,3,4-oxadiazoles, and 1,3,4-thiadiazoles. Tetrahedron 2009; 65:9989-96.
19. Löscher W. Critical review of current animal models of seizures and epilepsy used in the discovery and development of new antiepileptic drugs. Seizure 2011;20:359-68.
20. White HS. Preclinical development of antiepileptic drugs: past, present, and future directions. Epilepsia 2003;44:2-8.
21. Pandeya SN, Raja AS, Stables JP. Synthesis of isatin semicarbazones as novel anticonvulsants- the role of hydrogen bonding. J Pharm Pharm Sci 2002;5:266-71.
22. Yogeeswari P, Ragavendran JV, Thirumurugan R, Induja S, Sriram D, Stables JP. Synthesis and structure-activity relationship on anticonvulsant aryl semicarbazones. Med Chem 2006;2:55-62.
23. Dimmock JR, Puthucode RN, Smith JM, Hetherington M, Quail JW, Pugazhenthi U, et al. (Aryloxy)aryl semicarbazones and related compounds: a novel class of anticonvulsant agents possessing high activity in the maximal electroshock screen. J Med Chem 1996;39:3984-97.
323 Views | 719 Downloads
How to Cite
El-behairy, M. F., and H. N. H. Attia. “DESIGN, SYNTHESIS AND ANTICONVULSANT PROFILE OF 5-(BENZO [D][1,3]DIOXOL-5-YL)-3-TERT-BUTYL-4, 5-DIHYDROPYRAZOLE DERIVATIVES”. International Journal of Pharmacy and Pharmaceutical Sciences, Vol. 9, no. 6, June 2017, pp. 180-8, doi:10.22159/ijpps.2017v9i6.17520.
Original Article(s)