SYNTHESIS OF NOVEL IMIDAZO [1, 2-a] PYRIDINE FOR THEIR POTENT ANTI-CONVULSANT ACTIVITY

SYNTHESIS OF NOVEL IMIDAZO [1, 2-a] PYRIDINE FOR THEIR POTENT ANTICONVULSANT ACTIVITY

Vivek Jain and Navjot Singh^*

NRI Institute of Pharmacy, Raisen Road, Bhopal - 462021, Madhya Pradesh, India.

ABSTRACT: Synthesis of a Derivatives of imidazo[1,2-a]pyridines with potent activity. Synthetic approaches allowing for variation of the 2-Amino Pyridines as well as other imidazopyridine substituents are outlined and resulting effects on anticonvulsant activity are highlighted. An experimental evaluation of anticonvulsant activity of synthesized Imidazo[1,2-a]pyridine derivatives by Maximal Electro Shock (MES) induce methods.

Imidazo[1,2-a]pyridine, Anticonvulsant, Imidazole, Pyridine, MES method, Amino Pyridine

INTRODUCTION: One aspect of medicinal chemistry deals with the incorporation of newly emerged pharmacophores on already existing biologically active moieties to produce newer molecules with higher efficacy. In the development of organic therapeutic agents, medicinal chemists have explored numerous approaches to find and develop organic compounds that are now available in dosage forms suitable for the treatment of illness and often for the maintenance of health of human beings. Imidazo[1,2-a]pyridine are having the number of biological activities. The biological activities like anti-tuberculosis, anti-inflammatory, anticonvulsant, antimicrobial, antiviral, herpesviruses, anticoccidal, antiprotozoal etc. Imidazo[1,2-a] pyridine showed diversified pharmacological activities. In view of potential biological activity of Imidazo[1,2-a]pyridine, it was considered worthwhile to synthesized some Imidazo[1,2-a]pyridine as possible anticonvulsant.

S. no	R	R’	R”
1.	H	H
2.	H	CH3
3.	OH	H

MATERIALS AND METHODS: Synthesized Imidazo[1,2-a]pyridine were prepared as per method described in the literature ^{1 - 3}. The procedure involves in the three steps (Scheme I) as stated below:

SCHEME: 1

Step 1: Synthesis of Ethyl 2-Methylimidazo[1,2-a]pyridine-carboxylate (i): To a suitably substituted 2-aminopyridine (0.02 mol) in n-Butanol (50ml) was added the 2-bromoacetoacetate (0.2 mol). The mixture was refluxed under stirring for 8-15 hr and then cooled. The progress of reaction was monitored by TLC. Solvent was evaporated under reduce pressure, and the residue in CHCl_3, washed with 5% NaHCO₃, and dried (Na₂SO₄). Evaporation of the solvent gave a residue of compound (i) was allowed to crystallize. The yield was obtained 72 % and m.p. was 72 °C.

Step 2: Synthesis of 2-Methylimidazo[1,2-a]pyridine-3-carboxylic Acid Hydrazide: Ethyl 2-methylimidazo[1,2-a]pyridine-3-carboxylate (i) (0.02 mol) was heated under reflux with 99% of H₂NNH₂.2H₂O in 96% C₂H₅OH (30ml) for 10 hr. and then cooled. The crystals formed of compound (ii) were washed with H₂O, dried and recrystallized from C₂H₅OH (96%). The yield was obtained 35% and m.p. was 180 °C.

Step 3: Synthesis of 4-(2-Methyl-Imidazo[1,2-a]pyridine-3yl)- [1,3,4] oxadiazolidine- 2’-thione (iii)a: To a solution of 2-Methylimidazo[1,2-a]pyridine-3-carboxylic acid hydrazide (ii) (0.01 mol) and potassium hydroxide (0.01 mol) in 96% C₂H₅OH (50ml) was added carbon di-sulphide (10ml) with stirring. When the addition was completed, the reaction mixture was refluxed for 14-15 hr. the contents were cooled and the solvent was distilled off. The residue was dissolved in water, filtered and the filtrate was finally acidified with acetic acid, the solidified product was finally filtered, dried and recrystallized from methanol.

Synthesis of 2-Methyl-3-[1,3,4]oxadiazolidin-3-yl-Imidazo[1,2-a]pyridine (iii)b: To a solution of 2-Methylimidazo[1,2-a]pyridine-3-carboxylic acid hydrazide (ii) (0.01 mol) and potassium hydroxide (0.01 mol) in 96% C₂H₅OH (50ml) with stirring. When the addition was complete, the reaction mixture was refluxed for 14-15 hr the contents were cooled and the solvent was distilled off. The residue was dissolved in water, filtered and the filtrate was finally acidified with acetic acid, the solidified product was finally filtered, dried and recrystallized from methanol.

Synthesis of 5-Methyl-2- (2-Methyl-Imidazo[1,2-a]pyridine-3-Carbonyl)-2,4-dihydro-Pyrazol-3-one (iii)c: To a mixture of 2-Methylimidazo[1,2-a]pyridine-3-carboxylic acid hydrazide (ii) and ethyl acetoacetate both in equimolar amount (0.02 mol) were refluxed in methanol (50ml) for 6-8 hr. after cooling the reaction mixture, a solid separated out which was filtered and dried after washing with pet ether (60-80 °C). Recrystallization was done from methanol.

RESULT AND DISCUSSION: Spectral data of synthesized imidazo[1,2-a]pyridine.

TABLE 1: IR SPECTRA, PMR SPECTRA, MASS SPECTRA

Determination of Anti-Convulsant Activity: An experimental evaluation of anticonvulsant activity of synthesized Imidazo[1,2-a]pyridine derivatives by Maximal Electro Shock (MES) induce methods. The Maximal Electro Shock (MES) induced convulsion in animal’s represents grand mal type of epilepsy. In Maximal Electro Shock convulsion electric shock is applied through the corneal. The maximal Electro Shock convulsions are divided in five phases.

• Tonic Flexion
• Tonic Extensor
• Clonic Convulsion
• Stupor
• Recovery/Death

Male albino mice weight (25-35gm) were used to test drug (synthesized Imidazo[1,2-a]pyridine Maximal Electro Shock (MES) method induced seizures. Female animals were excluded because of fact that estrus cycle influences the sezures threshold.

Animal were housed in polypropylene cage with dust free rice husk as bedding material under laboratory condition with controlled environment of temperature 25 °C ± 2 °C humidity (60% ± 10%) and before subjecting them to experimentation, the animals were given a week of time to get acclimatized with laboratory condition. The animals were fasted overnight before the experiment.

Drugs:

Standard Sample: The concentration of Phenytoin Sodium was prepared in 1% Tween 80 solution and the concentration of final solution was 2.5mg/ml and to equate the activity with that of compound synthesized.

Test Sample: Suspension of synthesized derivatives was prepared in 1% Tween 80 having concentration of 2.5mg/ml.

Requirements: Test tube, Mice, Syringes, Needles, Electroconvulsometer, Volumetric Flask, Oral Feeding Needle etc.

Study of Activity: Weighed and numbered the animals, divided into fourteen groups. Each group contain six animals. One group was used for the study the effect of control (Distilled Water). One group was used for the study the effect of standard drug (Phenytoin Sodium) and another twelve groups were used for the study of the effect of twelve synthesized derivatives. Female mice were excluded for this screening.

Maximal Electro Shock (MES) Induced Seizure in Albino Mice: The albino mice were chosen preliminary screening. Mice which showed extension of hind limb were induced in the study. The seizure was induced by Maximal Electro Shock in albino mice (weight 25-35gm) with help of electro convulsometer by passing current of 60mA for 0.2 second using electrode to the cornea of mice. The drug and distilled water were given one hour prior to induction of convulsion. The animal observed for the extensor phase as well as its duration. The abolition of the extensor phase (tonic phase) in drug treated group was taken as criteria for anticonvulsant activity.

TABLE 2: ANTICONVULSANT ACTIVITY OF SYNTHESIZED DERIVATIVES

Animals were divided into eleven groups (1-11) for studing anticonvulsant effect of some Imidazo[1,2-a]pyridines derivatives

n = Number of animals, SEM = Standard Error Mean; Standard Drug = Phenytoin Sodium (25mg/kg); Control = Distilled Water, R/D = Recovery / Death.

GRAPH 1: GRAPH PLOTTED BETWEEN EXTENSOR PHASE OF SYNTHESIZED DERIVATIVES, STANDARD (S) AND CONTROL (C)

Standard (S): Phenytoin Sodium

Control (C): Distilled Water

SUMMARY: An experimental evaluation of anticonvulsant activity of synthesized Imidazo[1,2-a]pyridine derivatives by Maximal Electro Shock (MES) induce methods.

ACKNOWLEDGMENT: Authors are thankful to the Institute of Pharmacy, Bundelkhand University, Jhansi for providing laboratory facilities, instruments, chemicals and IR analysis. We also thanks to CDRI Lucknow and IIT, New Delhi for analyze the Mass and PMR Spectral data.

CONFLICTS OF INTEREST: Nil

REFERENCES:

1. Trapani G, Franco M, Ricciardi L, Latrofa A and Genchi G: Journal of Medicinal Chemistry 1997; 40: 3109-3118.
2. Nair S, Garg SP and Sah P: Indian Journal of Heterocyclic Chemistry 2002; 12: 09-12.
3. Kasimogullari BO and Cesur Z: Molecules Journals 2004; 9: 894-901.
4. Pharmacopoeia of India, 3^rd Edition, Ministry of Health and Family welfare, government of India, Delhi 1985; 2: 85.
5. Scribner A, Dennis R, Hong J and Lee S: European Journal of Medicinal Chemistry 2007; 42: 1334-1357.
6. Liang G, Qian X, Feng D and Fisher M: Bioorganic and Medicinal Chemistry Letters 2007; 17: 3558-3561.
7. Yurchenko RI, Ponomarenko AD, Svarvskaya NN and Tolmachev AA: Chemistry of Hetrocyclic Compounds 2005; 41(5): 656-661.
8. Feng D, Fisher M, Liang G and Qian X: Bioorganic and Medicinal Chemistry Letters 2006; 16: 5978-5981.
9. Gueiffier A, Movel S, Lhassani M and Elhakmaoui A: Journal of Medicinal Chemistry 1998; 41: 5108-5112.
10. Trapani G, Franco M, Latrofa A and Ricciardi L: Journal of Medicinal Chemistry 1999; 42: 3934-3941.
11. Fookes CJR, Pham TQ, Mattener F and Gueguric I: Journal of Medicinal Chemistry 2008; 51: 3700-3712.
12. Chezal Jean M, Moreau E, Delmas G and Gueiffier A: Journal of Organic Chemistry 2001; 66: 6576-6584.
13. Suloeva E, Yure M, Gudrimiece E, Beyakov S, Petro M and Kalnite I: Chemistry of Heterocyclic Compounds 2001; 37(3): 329-337.
14. Cai L, Liow J and Zoghbi S: Cuevas J., Journal of Medicinal Chemistry 2008; 51: 148-158.
15. Hamdouchi C, Blas Jesus D, Prado Mirian D, Gruber J, Heing Beverly A and Vance L: Journal of Medicinal Chemistry 1999; 42: 50-59.
16. Barun O, Ila H, Junjappa H and Singh Okram M: Journal of Organic Chemistry 2000; 65: 1583-1587.
17. Dimauro Erin F and Kennedy Joseph M: Journal of Organic Chemistry 2007; 72: 1013-1016.
18. Laquintana V, Denora N and Lpedota A: Bioconjugate Chemistry 2007; 18: 1397-1407.
19. Keenan Richerd M, Lago MA, Miller William H and Ali Fadia E: Bioorganic and Medicinal Chemistry Letters 1998; 8: 3171-3176.
20. Caron S, Do Nga M, McDermott Ruth E and Bahmunyar S: Organic Process Research and Development 2006; 10: 257-261.
21. Nair S, Garg SP and Sah P: Indian Journal of Heterocyclic Chemistry 2002; 12: 09-12.
22. Shanmungasundaram B and Vasella A: Helvetica Chimica Acta 2005; 88: 2593-2602.
23. Kasimogullari BO and Cesur Z: Molecules Journals 2004; 9: 894-901.
24. Dumont F, Waterhouse Rikki N, Montoya Julie A and Mattner F: Nuclear Medicine and Biology 2003; 30: 435-439.
    

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    How to cite this article:

    Jain V and Singh N: Synthesis of novel imidazo [1, 2-a] pyridine for their potent anticonvulsant activity Int J Pharm Sci Res 2017; 8(8): 3498-02.doi: 10.13040/IJPSR.0975-8232.8(8).3498-02.

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