Potent Anticonvulsant 1H-Imidazol-5(4H)-One Derivatives with Low Neurotoxicity


We report here the synthesis and in vivo anticonvulsant/neurotoxicity activities of a series of compounds belonging to 2-aryl-4-arylidene-1-phenyl-1H-imidazol-5(4H)-one. The scaffold is based on the commonality of 5-membered lactam ring structures as successful anticonvulsant agents. The present compounds exhibited a range of anticonvulsant activity in pentylenetetrazole (PTZ)-induced seizure test. In particular, the protection was excellent by compounds bearing furylmethylidene on C4, possibly due to good pharmacokinetic properties. It was found that high lipophilicity and/or electron deficient aryl ring substitution at C4 compromised the anticonvulsant activities. For example, chloro analogues were found much less active than unsubstituted phenyl or furyl derivatives. Regarding side effects, active compounds exerted no observable neurotoxic effect at their therapeutic doses in Chimney test.

Share and Cite:

M. Mohamed, R. Mahmoud, A. Sayed and M. El-Araby, "Potent Anticonvulsant 1H-Imidazol-5(4H)-One Derivatives with Low Neurotoxicity," Open Journal of Medicinal Chemistry, Vol. 2 No. 2, 2012, pp. 24-29. doi: 10.4236/ojmc.2012.22004.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] D. F. Scott, “The History of Epileptic Therapy: An Account of How Medication was Developed,” Taylor & Francis, London, 1993.
[2] N. F. Moran, K. Poole, G. Bell, J. Solomon, S. Kendall, J. Solomon, S. Kendall, M. McCarthy, D. McCormick, L. Nashef, J. Sander and S. D. Shorvon, “Epilepsy in the United Kingdom: Seizure Frequency and Severity, Anti- Epileptic Drug Utilization and Impact on Life in 1652 People with Epilepsy,” Seizure, Vol. 13, No. 6, 2004, pp. 425-433. doi:10.1016/j.seizure.2003.10.002
[3] R. Sridharan, “Epidemiology of Epilepsy,” Current Science (India), Vol. 82, No. 6, 2002, pp. 664-670.
[4] N. Senanayake and G. C. Roman, “Epidemiology of Epilepsy in Developing Countries,” Bulletin of the World Health Organization, Vol. 71, No. 2, 1993, pp. 247-258.
[5] www.fda.gov
[6] P. Kwan and M. J. Brodie, “Early Identification of Re- fractory Epilepsy,” New England Journal of Medicine, Vol. 342, No. 5, 2000, pp. 314-319.
[7] W. L?scher and D. Schmidt, “Modern Antiepileptic Drug Development Has Failed to Deliver: Ways Out of the Current Dilemma,” Epilepsia, Vol. 52, No. 4, 2011, pp. 657-678. doi:10.1111/j.1528-1167.2011.03024.x
[8] C. J. Landmark, “Antiepileptic Drugs in Non-Epilepsy Disorders: Relations between Mechanisms of Action and Clinical Efficacy,” CNS Drugs, Vol. 22, No. 1, 2008, pp. 27-47.
[9] W. Raasch, “Antiepileptic Drug Market,” 2011. http://www.wikinvest.com/wiki/Antiepileptic_Drug_Market
[10] http://www.drugbank.ca
[11] U. Calis, S. Dalkara and M. Ertan, “Synthesis and Anticonvulsant Activity of Some New 4-Aryl-1,3-Dihydro- 2H-Imidazol-2-One Derivatives,” Arzneimittel Forschung, Vol. 42, No. 5, 1992, pp. 592-594.
[12] M. Amir and E. Singh, “1-p-(2-Arylimino-thiazolidon-3- yl)phenyl-2-methyl-4-arylidene-5-imidazolones as anticon- vulsants,” Acta Pharmaceutica, Vol. 42, No. 5, pp. 133- 137.
[13] H. Joshi, P. Upadhyay, D. Karia and A. J. Baxi, “Synthesis of Some Novel Imidazolinones as Potent Anticonvulsant Agents,” European Journal of Medicinal Chemistry, Vol. 38, No. 9, 2003, pp. 837-840. doi:10.1016/S0223-5234(03)00117-X
[14] H. S. White, J. H. Woodhead, M. R. Franklin, E. A. Swinyard and H. H. Wolf, “General Principles: Experimental Selection, Quantification, and Evaluation of Antiepileptic Drugs,” In: R. H. Levy, R. H. Mattson and B. S. Meldrum, Eds., Antiepileptic Drugs, 4th Edition, Raven Inc., New York, 1995, pp. 99-121.
[15] J. R. Boissier, J. Tardy and J. C. Diverres, “Une Nouvelle Methode Simple Pour Explorer l’Action Tranquilisante: Le Test de la Cheminee,” The Journal of Experimental Medicine, Vol. 3, 1960, pp. 81-84.
[16] Molinispiration Cheminformatics, “Calculation of Mole- cular Properties and Bioactivity Score,” 2011. http://www.molinspiration.com/cgi-bin/properties
[17] P. Ertl, B. Rohde and P. Selzer, “Fast Calculation of Molecular Polar Surface Area as a Sum of Fragment Based Contributions and Its Application to the Prediction of Drug Transport Properties,” Journal of Medicinal Che- mistry, Vol. 43, No. 20, 2000, pp. 3714-3717. doi:10.1021/jm000942e
[18] P. Raghavendra, G. Veena, G. A. Kumar, E. R. Kumar, N. Sangeetha, B. Sirivennela, S. Smarani, H. Kumar, S. Praneeth and R. Suthakaran, “Microwave Synthesis and Anti-Inflammatory Evaluation of Some New Imidazolo Quinoline Analogs,” RASAYAN Journal of Chemistry, Vol. 4, No. 1, 2011, pp. 91-102.
[19] B. M. Trost and P. J. Morris, “Palladium-Catalyzed Dia- stereo- and Enantioselective Synthesis of Substituted Cyclo- pentanes through a Dynamic Kinetic Asymmetric Formal [3 + 2]-Cycloaddition of Vinyl Cyclopropanes and Alky- lidene Azlactones,” Angewandte Chemie International Edi- tion, Vol. 50, No. 27, pp. 6167-6170. doi:10.1002/anie.201101684
[20] M. Kidwai and R. Mohan, “Solid Supported Reaction of Substituted 2-Oxazoline with Amines under Microwave Irradiation,” Journal of the Chinese Chemical Society, Vol. 50, No. 5, 2003, pp. 1075-1078.
[21] C. W. Bird and J. D. Twibell, “Rearrangement of 3-(Acy- lamino)Azetidinones,” Journal of the Chinese Chemical Society, Vol. 19, 1971, pp. 3155-3158.
[22] P. Kumar and K. A. Mukerjee, “Synthesis of 4-Arylidene- 1,2-Disubstituted-Δ2-Imidazolin-5-Ones,” Indian Journal of Chemistry—Section B: Organic and Medicinal Che- mistry Indian, Vol. 20B, No. 5, 1981, pp. 416-418.
[23] M. Z. A. Badr, H. A. H. El-Sherief and M. E. Tadros, “Synthesis of 1,2-Disubstituted-4-Benzylidene-2-Imida- zolin-5-Ones and Their Thione Derivatives,” Indian Jour- nal of Chemistry—Section B: Organic and Medicinal Che- mistry Indian, Vol. 18, No. 3, pp. 240-242.
[24] A. S. Girgis, “Facile Regioselective Synthesis of 1,2,6,8- Tetraazaspiro[4.4]Nona-2,6-Dien-9-Ones,” Zeitschrift für Naturforschung B (Chemical Sciences), Vol. 31, No. 24, 2010, pp. 222-226.
[25] O. A. Miqdad, N. M. Abunada and H. M. Hassaneen, “Regioselectivity of Nitrilimines 1,3-Dipolar Cycloaddi- tion: Novel Synthesis of Spiro[4,4] Nona-2,8-Dien-6-One Derivatives,” Heteroatom Chemistry, Vol. 22, No. 2, 2011, pp. 131-136. doi:10.1002/hc.20666
[26] M. A. Abdallah, M. E. Zayed and A. S. Shawali, “Reaction of Benzonitrilium N-Phenylimide with (Z)-4-Ary- lmethyleneimidazol-5(4H)-Ones,” Indian Journal of Che- mistry—Section B: Organic and Medicinal Chemistry Indian, Vol. 40, No. 3, pp. 187-190.
[27] F. M. Ismail and N. G. Kandile, “Reaction of 4-(Ary- lmethylene)-2-Phenyl-2-Oxazolin-5-Ones with Schiff Bases and Benzalazine,” Asian Journal of Chemistry, Vol. 1, No. 3, 1989, pp. 254-260.
[28] G. V. S. R. Sarma and V. M. Reddy, “1,2-Disubstituted -4-[(Furan-2-yl)Methylene]Imidazolin-5(4H)-Ones,” Jour- nal of the Institution of Chemists (India), Vol. 72, No. 3, 2000, pp. 106-110.

Copyright © 2023 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.