6.1 Need For The Study:-
Epilepsy is chronic and often progressive disorder characterized by recurrent transient attacks which are caused by an abnormal discharge of cerebral neurons. The current therapy of epilepsy with antiepileptic drugs is associated with side effects, dose-related , chronic toxicity & teratogenic effects.1
Epilepsy inflicts more then sixty millions people worldwide according to epidemiological studies. Research to find more effective, safer antiepileptic drugs is therefore imperative & challenging in medicinal chemistry.2
4-hydroxy-2(1H)- quinolone is a fundamental structural unit in a large number of alkaloids such as dictamine, flindersine. Many pharmacologically active derivatives of 4-hydroxy -2(1H)-quinolones are known to be orally active and selective antagonist of the glycine site on the NMDA receptor.3
1,2,3-Triazoles and its derivatives enhanced considerable attention for the past few decades due to their chemotherapeutical value. Many 1,2,3-triazoles are found to be potent antimicrobial, analgesic, anticonvulsant antineoplastic, antimalarial, antiviral agents.4
Several 1,2,3-triazoles derivatives have received much attention because of their wide range of applications as light stabilizers, fluorescentwhiteners, optical brightening agents, dyestuffs, asymmetric dihydroxylation catalysts, photo-sensitizers, fungicidal, herbicidal, cytostatic, virostatic, anti-inflammatory, anti-HIV, antimicrobial. antitumor, antithrombotic, antiplatelets.5,6
Since anticonvulsants currently used have certain disadvantages such as sedation, ataxia and inefficient therapy in some seizure types, a clear need for the safer and more effective antiepileptic drugs is realized. In view of these facts, our attention is drawn towards synthesis of biheterocyclic 2-quinolones with 1,2,3-triazoles as another heterocyclic component as possible anticonvulsants.
6.2 Review of Literature
Ø Li-ping Guan et al reported the synthesis 5-Phenyl-4,5-dihydro-1,2,4 – triazolo[4,3-a] quinolin-1(2H)-one derivatives as potent anticonvulsant agents.2
Ø Sarah Grimwood et al reported four novel series of 4-hydroxy -2-quinolone as the selective antagonist for the glycine site on the N-methyl-D-aspartate receptor (NMDA).3
Ø Shivarama Holla et al developed a new method for synthesis of some substituted 1,2,3-triazoles as antimicrobial. agents.4
Ø A Komaraiah et al reported the synthesis Bisheterocycles of some novel 1,2,3- triazolyl oxadiazole and 4(3H)- quinazolinones through azide cycloaddition reaction.5
Ø Quinazolinone
Ø Zhi-Feng Xie et al reported the synthesis & anticonvulsant activity of 7-alkoxyl-4,5-dihydro-[1,2,4] triazolo[4,3-a] quinolines.6
Ø Necessary background literature relevant to the present target molecules and their biological importance is collected by an up to date literature survey. For this purpose the libraries of Karnataka University, Dharwad, and K.L.E.’S College of Pharmacy, Belgaum, our own library and various websites through internet are used.
6.3 Objectives of the study:
The main objective of the present investigation is to synthesize and explore 3-acetyl- 2-quinolone derivatives for anticonvulsant activity.
(a) To synthesize proposed target compounds by appropriate methods as per the following scheme:-
Diphenyl amine + Diethyl malonate
Pyranoquinolone
Hydrolysis
3-acetyl-4-hydroxy-1-phenyl-2(1H) quinolone
Br2 in Gl. Acetic acid
3-Bromo -4-hydroxy-1-phenylquinolin-2(1H)-quinolone
NaN3
3azido acetyl-4-4hydroxyl -1-phenyl-2(1H)- Quinolone
DMAD/Acetone
4 – Hydroxy-1-Phenyl-3-quinolinyl acetyl-4-substituted 1,2,3-triazoles.
b) To confirm the structure of these compounds by spectral and elemental analysis.
(c) To investigate anticonvulsant activity of the compounds prepared in the course of present work by standard method .7,8.
7. / MATERIALS AND METHODS:
7.1 Sources of data
a) Spectroscopic data :
UV and IR spectra shall be obtained from spectrophotometers available in the college. Necessary NMR and Mass spectra of some selected compounds shall be procured on commercial basis.
b) Elemental analysis data: Elemental analysis data shall be obtained from Karnataka University, Dharwad.
7.2 Method of collection of data:
Extensive literature survey was carried out using the libraries of K.L.E.’S college of Pharmacy, Belgaum, Karnataka university Dharwad, our own college library, and visiting various Websites through internet.
7.3 Does the study required any investigation or intervention to be conducted on patients or humans or animals? If so, please describe briefly:
The study requires investigations on rats. About 08 new compounds shall be synthesized & evaluated for anticonvulsant activity by following Maximal Electroconvulsant Shock (MES) method. Animals shall be divided into 10 groups each containing 6 animals. One group shall be used as control, another as standard & remaining 08 groups for test compounds. All animal shall be recovered & rehabilitated.7,8
7.4 Has ethical clearance been obtained from your institution in case of 7.3?
Ethical clearance shall be obtained in due course of time.
8. /
LIST OF REFERENCES
1. Foroumadi A, Sheibani V, Sakhteman A, Rameshk M , Abbasi M et al. Synthesis & anticonvulsant activity of novel 2- amino-5-[4-chloro-2-(2-chlorophenoxy) phenyl]-1,3,4-thiadiazole derivatives. Daru 2007; 15: 89-93.2. Guna LP, Jin QH, Tian GR, Chai, KY and Quan ZS Synthesis quinoline-2(1H)-one and 1,2,4-triazolo [ 4,3-a] quinoline derivatives as potent anticonvulsants J Pharm Pharmaceut Sci 2007; 10(3) : 254-62.
3. Grimwood S, Kulagowski JJ, Mawe I, Rowley M, Leeson PD, Foster AC. Allosteric modulation of the glutamate site on the NMDA receptor by four novel glycine site antagonists. Eur J Pharamacol.1995;290:221-26
4. Holla BS, Mahalinga M, Karthikeyan MS, Poojary B, Akberali PM , Kumari NS . Synthesis characterization and antimicrobial activity of some substituted 1,2,3.-triazoles. Eur J Med Chem 2005; 40: 1173-78
5. Komaraiah A, Ramakrishna K, Sailu B, Reddy PSN. Synthesis Bisheterocycles some novel 1,2,3- triazolyl oxadiazole and 4(3H)- quinazolinones azide cycloaddition rection. Arkivoc 2007; 14: 110-16.
6. Xie ZF, Chai KY, Piao HR, Kwak KC and Quan ZS. Synthesis of anticonvulsant activity of 7-alkoxyl-4,5-dihydro-[1,2,4] triazolo[4,3-a] quinolines. Bioorg Med Chem. 2005; 15: 4803-05.
7. Vogel GH, Vogel WH. Drug discovery and Evaluation 2ed (NY): Springer-Velag Berlin Heidelberg; 1996.
8. Kulkarni SK. Experimental Pharmacology 6th ed. 2004 : Vallabh Prakashan.
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