DESIGN AND SYNTHESIS OF 4-SUBSTITUTED QUINAZOLINE DERIVATIVES FOR THEIR ANTICONVULSANT AND CNS DEPRESSANT ACTIVITIES
DOI:
https://doi.org/10.22159/ijpps.2017v9i1.15492Keywords:
7-chloro-2-phenyl-4H-benzo d 1, 3]oxazin-4-one, Quinazoline derivatives, Anticonvulsant activity, CNS depressant activityAbstract
Objective: The present work is designed to synthesise some isomeric new series of Quinazoline-4-one/4-thione derivatives, based on the pharmacophoric model of central nervous system (CNS) activity by structural modifications retaining the essential structural features for the activity and evaluated for their anticonvulsant and CNS depressant properties.
Methods: A series of 7-chloro-3-[substituted (amino/phenylamino)]-2-phenyl quinazolin-4 (3H)-one/thione derivatives and 1-(7-chloro-4-oxo/-2-phenylquinazoline-3 (4H-yl)) substituted urea derivatives were prepared. The reaction scheme proceeds through the intermediate 7-chloro-2-phenyl-4H-benzo[d] [1, 3] oxazin-4-one. The structures of the newly synthesised compounds were characterized from infrared (IR), 1H nuclear magnetic resonance (NMR) and mass spectra (m/z) and elemental analysis. The anti-convulsant and CNS depressant activity were investigated by maximum electroshock (MES) seizure test and porsolt's behavioural despair test (forced swimming) respectively. The rota-rod test was performed to assess any probable changes in motor coordination induced by the test compounds.
Results: The physicochemical and spectroscopic data clearly confirmed the synthesis of quinazoline derivatives with a common skeleton. The synthesised compounds were evaluated for their anticonvulsant and CNS depressant properties. Among them, six compounds (IIc, IIg, IIj, IIIc, IIIg, IIIj) exhibited a good activity profile in CNS depressant activity. Five compounds (IIc, IIg, IIj, IIIg, IIIh) showed protection against MES-induced seizures.
Conclusion: The Quinazoline derivatives obtained from this research work indicates that the methyl/methoxy group in phenyl ring, amine and thiourea substitution at 3rd position of quinazoline derivatives are essential for CNS depressant activity as well as anticonvulsant activity. Compounds IIc, IIg, IIj, IIIc, IIIg, IIIj, and IIIh were found to be a potent compound which may be effective as a potential source for the development of CNS depressant and anti-convulsant drugs with lesser side effects
Downloads
References
Donner EJ, Snead OC. New generation anticonvulsants for the treatment of epilepsy in children. J Am Soc Exp Neuro Ther 2006;3:170-80.
Mahendra RS, Mangesh G, Kailash GB, Shashikant VB, Ana N Kalyan CA, Nisheeth CD, et al. Synthesis and anticonvulsant activity of clubbed thiazolidinone–barbituric acid and thiazolidinone–triazole derivatives. ARKIVOC 2007;XIV:58-74.
Mochizucki D. Serotonin and noradrenaline reuptake inhibitors in animal models of pain. Human Psychopharmacol 2004;19:S15–S19.
Brodie MJ. Established anticonvulsants and treatment of refractory epilepsy. Lancet 1990;336:350-4.
Schmidt D, Löscher W. Drug resistance in epilepsy: putative neurobiologic and clinical mechanisms. Epilepsia 2005;46:858-77.
Kwan P, Brodie MJ. Early identification of refractory epilepsy. New Engl J Med 2000;342:314-9.
Pollard JR, French J. Antiepileptic drugs in development. Lancet Neurol 2006;5:1064-7.
Dichter MA, Brodie MJ. New antiepileptic drugs. New Engl J Med 1996;334:1583-90.
Brodie MJ, Dichter MA. Antiepileptic drugs. New Engl J Med 1996;334:168-75.
Kwan P, Brodie MJ. Drug treatment of epilepsy: when does it fail and how to optimize its use? CNS Spectr 2004;9:110-9.
Siddqui N, Akhtar JM, Ali R, Azad B. An updated review: emerging anticonvulsants. Int J Pharm Biosci Arch 2010;1:404-15.
Dimmock JR, Pandeya SN, Quail JW, Pugazhenthi U, Allen TM, Kao GY, et al. Evaluation of the semicarbazones, thiosemicarbazones and bis-carbohydrazones of some aryl alicyclic ketones for anticonvulsant and other biological activities. Eur J Med Chem 1995;30:303-14.
Mahato AK, Srivastava B, Nithya SC. Chemistry, structure activity relationship and biological activity of quinazolin-4 (3H)-one derivatives. Inventi Rapid Med Chem 2011;2:400-2.
Ilangovan P, Ganguly S, Pandit V. Design and synthesis of novel quinazolinone derivatives as broad spectrum anticonvulsant and antimicrobial agent. J Pharm Res 2010;3:703-6.
Hemlata K, Girija K. Synthesis of some novel 2, 3disubstituted quinazolinone derivatives as analgesic and anti-inflammatory agents. Int J Pharm Pharm Sci 2011;3:103-6.
Adel S, Azab E, Mohamed A, Omar A, Alaa AM, Naglaa I, et al. Design, synthesis and biological evaluation of novel quinazoline derivatives as potential antitumor agents: molecular docking study. Eur J Med Chem 2010;45:4188-98.
Krall RL, Penry JK, White BG, Kupeferberg HJ, Swinyard EA. Antiepileptic drug develpment: II. Anticonvulsant drug screening. Epilepsia 1978;19:409-28.
Porter RJ, Cereghino JJ, Gladding GD, Hessie BJ, Kupferberg HJ, Scoville B, et al. Antiepileptic drug development program. Cleveland Clin Quart 1984;51:293–305.
Ladda PL. Screening of Riccinus communis Linn. Leaves for anticonvulsant and analgesic activity. Asian J Pharm Clin Res 2014;7:110-4.
Rajak H, Desmukh R, Aggarwal N, Kashaw S, kharya MD, Mishra P, et al. Synthesis of novel 2, 5-disubstituted 1, 3, 4-thiadiazoles for their potential anticonvulsant activity: pharmacophoric model studies. Arch Pharm 2009;342:453.
Porsolt RD, Anton G, Blanet N, Jalbre M. Behavioral despair in rats: a new model sensitive to antidepressant treatments. Eur J Pharmacol 1978;47:379-91.
Ibrahim MK, El-Adl K, Al-Karmalawy AA. Design, synthesis, molecular docking and anticonvulsant evaluation of novel 6-iodo-2-phenyl-3-substituted-quinazoli-4(3H)-ones. Bull Faculty Pharm Cairo University 2015;53:101-16.
Adel S, Kamal EH. Design and synthesis of novel 7-amino Quinazoline derivatives: antitumor and anticonvulsant activities. Bioorg Med Chem Lett 2012;22:1879-85.
Kashaw SK, Kashaw V, Mishra P, Jain NK. Design, synthesis and potential CNS activity of some novel 1-(4-substituted-phenyl)-3-(4-oxo-2-propyl-4H-quinazolin-3-yl)-urea. ARKIVOC 2008; XIV:17-26.
Kashaw SK, Kashaw V, Mishra P, Jain NK, Stable JP. Synthesis, anticonvulsant and CNS depressant activity of some new bioactive 1-(4-substituted-phenyl)-3-(4-oxo-2-phenyl/ethyl-4H-quinazolin-3-yl)-urea. Eur J Med Chem 2009;44:4335-43.
Published
How to Cite
Issue
Section
