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Current Bioactive Compounds


ISSN (Print): 1573-4072
ISSN (Online): 1875-6646

Research Article

Evaluation of Anticonvulsant Activity and Toxicity Screening of Semicarbazones Derived from Quinazolinone Scaffold

Author(s): Meena K. Yadav, Laxmi Tripathi* and Diptendu Goswami

Volume 15, Issue 5, 2019

Page: [573 - 581] Pages: 9

DOI: 10.2174/1573407214666180710143557

Price: $65


Background: Epilepsy is one of the most prevalent noncommunicable neurological conditions. More than 10 million people in India are afflicted with epilepsy. Treatment available has many detrimental side effects. Up to one-third of epilepsy patients remain resistance to optimum drug treatment. These facts triggered the further scope and search for newer more effective and less toxic anticonvulsants.

Methods: Quinazolinone semicarbazone derivatives showing protection in chemoconvulsant induced seizure models (as reported in our previous study) were further screened in MES and scPTZ induced seizure models. Neurotoxicity was determined; quantification of anticonvulsant activity and toxicity was also done. Finally compounds were screened by liver functional test to ascertain the possible hepatotoxicity in the active compounds.

Results: Compounds N-1- (menthone) -N- {[3-(4-(substituted)-phenyl) -4-oxo- 3,4-dihydroquinazolin- 2-yl] methyl} semicarbazone (3A-d-4, 3B-d-4 and 3C-d-4) showed significant protection in both MES and scPTZ induced seizure model with no neurotoxicity at the given dose. In MES test, compounds showed an ED50 close to that of phenytoin and carbamazepine. They also showed Protective Index (PI) higher as compared to phenytoin and carbamazepine. A high safety profile (HD50/ED50 values) was noted and hypnosis, analgesia, and anesthesia were only observed at higher doses.

Conclusion: Compounds showed no significant increase or decrease in the concentration of alkaline phosphatase, Serum Glutamate Oxaloacetate Transaminase (SGOT), Serum Glutamate Pyruvate Transaminase (SGPT), albumin and bilirubin.

Keywords: Quinazolinone semicarbazones, anticonvulsant activity, quantitative anticonvulsant evaluation, neurotoxicity, hepatotoxicity, epilepsy.

Graphical Abstract
WHO Epilepsy in the WHO Africa Region. Bridging the Gap: The Global Campaign Against Epilepsy: Out of the Shadows; WHO: Geneva, Switzerland, 2004.
Wasteralin, C.; Siegel, G.; Agranoff, G.; Albers, R.; Molinoff, P. Basic Neurochemistry: Molecular, 4th ed; Cellular and Medical Aspects Raven: New York, NY, USA, 1989, pp. 225-234.
Sridharan, R.; Murthy, B.N. Prevalence and pattern of epilepsy in India. Epilepsia, 1999, 40(5), 631-636.
[] [PMID: 10386533]
Leonardi, M.; Ustun, T.B. The global burden of epilepsy. Epilepsia, 2002, 43(6)(Suppl. 6), 21-25.
[] [PMID: 12190974]
Paswerk, G. Annual report of the WHO/IBE/ILAE. Global Campaign Against Epilepsy: Out of the Shadows; International Bureau of Epilepsy: Heemstede, The Netherlands, 2003.
Singh, B.K.; Sachan, N.; Chawla, P. Synthesis and pharmacological screening of novel 1,3-disubstituted 5-pyrazolones as anticonvulsant agents. Curr. Bioact. Compd., 2013, 9(4), 279-287.
Danta, C.C.; Sahu, S.B.; Swain, T.R. 2D pharmacophoric design and synthesis of novel pyrimidine derivatives as anticonvulsants. Curr. Bioact. Compd., 2017, 13(2), 130-136.
Bialer, M.; Johannessen, S.I.; Kupferberg, H.J.; Levy, R.H.; Perucca, E.; Tomson, T. Progress report on new antiepileptic drugs: a summary of the Seventh Eilat Conference (EILAT VII). Epilepsy Res., 2004, 61(1-3), 1-48.
[] [PMID: 15570674]
Wolfe, J.F.; Greenwood, T.D.; Mulheron, J.M. Recent trends in the development of new anti-epileptic drugs. Expert Opin. Ther. Pat., 1998, 8(4), 361-381.
Noureldin, N.A.; Kothayer, H.; Lashine, E.M.; Baraka, M.M.; El-Eraky, W.; Awdan, S.A. Synthesis, anticonvulsant activity, and sar study of novel 4-quinazolinone derivatives. Arch. Pharm. (Weinheim), 2017, 350(2)1600332
[] [PMID: 28177550]
Ibrahim, M.K.; Ahmed, E.A.; Karmalawy, A.A. Design, synthesis, molecular docking and anticonvulsant evaluation of novel 6-iodo-2-phenyl-3-substituted-quinazolin-4(3H)-ones. Bull. Fac. Pharm. Cairo Univ., 2015, 53(2), 101-116.
Kumar, P.; Shrivastava, B.; Pandeya, S.N.; Stables, J.P. Design, synthesis and potential 6 Hz psychomotor seizure test activity of some novel 2-(substituted)-3-[substituted]aminoquinazolin-4(3H)-one. Eur. J. Med. Chem., 2011, 46(4), 1006-1018.
[] [PMID: 21306800]
Zayed, M.F.; Ihmaid, S.K.; Ahmed, H.E.A.; El-Adl, K.; Asiri, A.M.; Omar, A.M. 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, 2017, 22, 188.
Abuelizz, H.A.; Dib, R.E.; Marzouk, M.; Anouar, E.H.A.; Maklad, Y.N.; Attia, H.; Al-Salahi, R. Molecular docking and anticonvulsant activity of newly synthesized quinazoline derivatives. Molecules, 2017, 22(7), 1094.
[] [PMID: 28665338]
Yadav, M.K.; Tripathi, L.; Goswami, D. Designing of glutamate receptor inhibitors of quinazolinone derivatives by a comparative QSAR analysis and \molecular modeling studies. Int. J. Med. Pharmaceut. Sci., 2017, 7(1), 29-46.
Yadav, M.K.; Tripathi, L.; Goswami, D. Synthesis and anticonvulsant activity (chemo shock) of n-1(substituted-n- 4[(4-oxo-3-phenyl-3, 4-dihydro-quinazoline-2-ylmethyl) semicarbazones. Asian. J. Pharm. Clin. Res, 2017, 10(4), 359-366.
Porter, R.J.; Kupferberg, H.J. The anticonvulsant screening program of the national institute of neurological disorders and stroke, NIH: History and contributions to clinical care in the twentieth century and beyond. Neurochem. Res., 2017, 42(7), 1889-1893.
[] [PMID: 28275952]
Krall, R.L.; Penry, J.K.; White, B.G.; Kupferberg, H.J.; Swinyard, E.A. Antiepileptic drug development: II. Anticonvulsant drug screening. Epilepsia, 1978, 19(4), 409-428.
[] [PMID: 699894]
Swinyard, E.A.; Woodhead, J.H.; White, H.S.; Franklin, M.R. Antiepileptic Drugs; Raven-Press: NewYork, USA, 1989, pp. 989-995.
Yogeeswari, P.; Sriram, D.; Saraswat, V.; Ragavendran, J.V.; Kumar, M.M.; Murugesan, S.; Thirumurugan, R.; Stables, J.P. Synthesis and anticonvulsant and neurotoxicity evaluation of N4-phthalimido phenyl (thio) semicarbazides. Eur. J. Pharm. Sci., 2003, 20(3), 341-346.
[] [PMID: 14592700]
Forney, R.B.; Halpien, H.P.; Hughes, F.W. The comparative enhancement of phenobarbital activity by co-administration of other anticonvulsants. Experientia, 1962, 18, 468.
Reitman, S.; Frankel, S. A colorimetric method for the determination of serum glutamic oxalacetic and glutamic pyruvic transaminases. Am. J. Clin. Pathol., 1957, 28(1), 56-63.
[] [PMID: 13458125]
Varley, H. Practical Clinical Biochemistry; CBS Publishers and Distributors: New Delhi, India, 1988, pp. 236-238.
Tietz, N. Fundamentals of Clinical Chemistry, W. B. (Eds.) Saunders Company, U.S.A,; , 1957, pp. 68-72.
Toro, G.; Ackermann, P.G. Practical clinical chemistry, 1st ed; Little Brown and Company: New York, 1975, pp. 117-125.
King, E.J.; Armstrong, A.R. A convenient method for determining serum and bile phosphatase activity. Can. Med. Assoc. J., 1934, 31(4), 376-381.
[PMID: 20319659]
Brackett, C.C.; Bloch, J.D. Phenytoin as a possible cause of acetaminophen hepatotoxicity: Case report and review of the literature. Pharmacotherapy, 2000, 20(2), 229-233.
[] [PMID: 10678302]
Kalapos, M.P. Carbamazepine-provoked hepatotoxicity and possible aetiopathological role of glutathione in the events. Retrospective review of old data and call for new investigation. Adverse Drug React. Toxicol. Rev., 2002, 21(3), 123-141.
[] [PMID: 12298421]

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