Chaubey Ajit kumar et al / IJRAP 2011, 2 (6) 1763-1767

International Journal of Research in Ayurveda & Pharmacy

ISSN 2229-3566 Research Article www.ijrap.net

SYNTHESIS, CHARACTERIZATION AND ANALGESIC ACTIVITY OF VARIOUS

PYRIDINE DERIVATIVES Chaubey Ajit kumar*, Pandeya S.N

Department of Pharmaceutical sciences, Saroj Institute of Technology & Management, Lucknow, (U.P.), India

Received on: 23/10/11 Revised on: 01/12/11 Accepted on: 14/12/11

*Corresponding author Ajit kumar chaubey, Student, Email: chaubeyajit80@gmail.com ABSTRACT The treatment of 2-amino pyridine (1) with isatine (2) affords (3Z)-3-(pyridin-2-ylimino)-1,3-dihydro-2H-indol-2-one (3) & then treatment with formaldehyde along with secondary amine, various N-substituted of (3Z)-3-(pyridin-2-ylimino)-1,3-dihydro-2H-indol-2-one (Schiff base) in the presence of glacial acetic acid results Mannich bases (4-8). (3Z)-3-(pyridin-2-ylimino)-1,3-dihydro-2H-indol-2-one (3) were synthesized by refluxing (1-2) in glacial acetic acid.The Mannich bases (4-8) of above condensed products were prepared by refluxing them with various secondary amines i.e., dimethylamine, diethylamine, piperazine, isopropyle amine , morpholine & with formaldehyde in the presence of glacial acetic acid in scheme 1. In scheme 2 the compound (2) was brominated and condensed with substituted pyridine (1) to give Schiff base (5-bromo-1H-indole-2,3-dione)(9) & also Mannich bases of (9) were synthesized(11-15) with secondary amines, in glacial acetic acid. Further the compound(2) was treated with conc. nitric acid in presence of sulfuric acid & condensed with 2- amino pyridine(1) & results 5-nitro-3-(pyridin-2-ylimino)-1,3-dihydro-2H-indol-2-one, the Mannich bases (18-22) of above condensed products were prepared by refluxing them with various secondary amines. The synthesized compounds were characterized by IR, NMR & elemental analysis. These compounds were screened for their analgesic activity using acetic acid induced writhing test & hot plate test. Some of these compounds (3,7,8,11,12,13,14,18,19,20 ) exhibit promising activities. Keywords: 2-amino pyridine, piperazine, isopropyl amine, morpholine, Analgesic activity

INTRODUCTION Non-steroidal anti-inflammatory drugs (NSAID’s) are the most widely used therapeutic agents, for the treatment of pain and inflammation for decades. In general, long term clinical usage of NSAIDs is associated with significant side effects of gastrointestinal lesions, bleeding, and nephrotoxicity. Therefore the discovery of new safer analgesics and anti-inflammatory agents represents a challenging goal for such a research area.1-4. Pyridine was first isolated and characterized by Anderson in 1846. It was obtained from bone oil and from coal tar. The cyclic nature of pyridine was recognized by Korner and Dewar in 1869.5 In the pharmaceutical industry, pyridine forms the nucleus of over 7000 existing drugs. In drug discovery pyridine has been a bioisosteric replacement of benzene ring. Literature reports show that pyridine containing compounds possess antioxidant6, antiviral7,8,9 anticancer10,11 antibacterial12,13

antidiabetic14 antichagagic15 and antifungal16 and analgesic17 activities. Generally NSAIDs provide their anti-inflammatory & analgesic action by blocking the cyclo-oxygenase pathway. Most notably COX-1 and COX-2 have been sequenced, but a COX-3 isoform that is a splice variant of COX-1 has recently been described. It has been found that acetaminophen (Paracetamol) has minimal effects on peripheral COX-1 or COX-2 in vitro, were as exert central analgesic actions through inhibition of COX-3.18 As well as the peripheral action of NSAIDs, there is increasing evidence that they exert their analgesic effects through central mechanisms involved in the development and maintenance of spinal cord sensitization. This phenomenon showed that the same compound, which is an effective peripheral analgesic could be a good central analgesic also. Opioid receptors modulate nociceptive input at many sites in the CNS, although functionally these can be divided into two main sites i.e. supraspinal and spinal sites of analgesia.19 MATERIALS AND METHODS Chemistry The target compounds were synthesized as outlined in scheme 1, scheme 2 and scheme 3. The starting material Pyridine-2-amine(1) and 1H-indole-2,3-dione(2) were dissolved in acetic acid, and allowed to reflux(3hr.) to produce (3Z)-3-(pyridin-2-ylimino)-1,3-dihydro-2H-indol-2-one (3), a Schiff base. The compounds 4,5,6,7,8

were synthesized by refluxing (3Z)-3-(pyridin-2-ylimino)-1,3-dihydro-2H-indol-2-one with piperazine, dimethyl amine, diethyl amine, isopropyl amine and morpholine respectively in acetic acid,(scheme1). The compound 5-bromo-1H-indole-2,3-dione(9) synthesized by bromination of compound (2) and the scheff base (3Z)-5-bromo-3-(pyridin-2-ylimino)-1,3-dihydro-2H-indol-2-one (10) was synthesized by condensing with compound (1). The compounds 11, 12,13,14,15 were synthesized by condensation of above mentioned amines respectively in presence of formaldehyde, (scheme 2).compound (16) was synthesized by nitration of 1H-indole-2,3-dione(2),and 5-nitro-3-(pyridin-2-ylimino)-1,3-dihydro-2H-indol-2-one (17) was synthesi-zed by condensation with Pyridine-2-amine(1), and finally compound 18,19,20,21,22 were synthesized by refluxing(3hr.) above mentioned secondary amines in presence of formaldehyde, using acetic acid as solvent.(SCHEME 3). Experimental All melting points are in degree centigrade and were determined on Jindal melting point apparatus and were uncorrected. The reactions were monitored and the purity of the products was checked by Thin Layer Chromatography (TLC) using Chloroform: Methanol (4:1) as solvent system. The IR spectra were recorded (KBr) on Jasco FT-IR 6100 spectro-photometer. 1H NMR were recorded on Bruker Avauce II 300MHz NMR spectrometer using DMSO as a solvent. Tetramethylsilane serves as internal standard in 1H NMR. Elemental analysis was done on Vario EL-III analyser.

NH

O

ON

NH 2

NH

O

N

N1. HCHO2. CH3COOH3. R

(1) (2)N

O

N

N

CH2

R

R =

(3)

(4)

NH

HN

(5) CH3-NH-CH3 (6) C2H5-NH-C2H5 (7) CH3-CH-CH3

N H 2

(8)

NH

O

+CH3COOH

Scheme-1

Reflux Reflux

Chaubey Ajit kumar et al / IJRAP 2011, 2 (6) 1763-1767

International Journal of Research in Ayurveda & Pharmacy

NH

O

O

N

N H 2

NH

O

N

N

1 . H C H O2 . C H 3 C O O H3 . R

( 1 )

( 2 )

C H 3 C O O H

N

O

N

N

C H 2

R

R =

( 1 0 )

( 1 1 )

NH

HN

( 1 2 ) C H 3 - N H - C H 3

( 1 3 ) C 2 H 5 - N H - C 2 H 5

( 1 4 ) C H 3 - C H - C H 3

N H 2

( 1 5 )

NH

O

S c h e m e - 2

+

NH

O

( 9 )

o

C H 3 C O O H

B r 2

B r

B r

B r

R e f l u x

R e f l u x

R e f l u x

NH

O

O

N

NH 2

NH

O

N

N

1. H CHO2. CH 3CO OH3. R

(1)

(2)

CH 3CO O H

N

O

N

N

CH 2

R

R =

(17)

(18)

NH

HN

(19) CH 3-NH -CH 3

(20) C 2H 5-N H -C 2H 5

(21) CH 3-CH -CH 3

NH 2

(22)

NH

O

Schem e-3

+

NH

O

(16)

NO 2

NO 2

NO 2

o

CH 3CO O H

Conc.HNO 3 / H 2SO 4

Reflux

Reflux

Reflux

Synthesis of (3Z)-3-(pyridin-2-ylimino)-1,3-dihydro-2H-indol-2-one The equimolar amount of 2-amino pyridine (0.940gm:01 mol) &1H-indole-2,3-dione (0.470gm: 01mol.) were taken in separate beakers and dissolved completely in acetic acid (qs). These solutions were taken in a round bottom flask. The reaction mixture was refluxed for 3 hr. on heating mental with occasional shaking. After completion of reaction, the product was then filtered and washed with water. The completion of reaction was monitored by TLC. The product was dried at room temperature & finally recrystallised with ethanol. Synthesis of Mannich bases with different sec.amines(4,5,6,7,8) The equimolar amount (0.01 mol.) of (3Z)-3-(pyridin-2-ylimino)-1,3-dihydro-2H-indol-2-one and formaldehyde were taken in round bottom flask along with acetic acid and dissolved properly. Then different secondary amines were taken (for the synthesis of 4,5,6,7,8) in acetic acid. Then these reaction mixtures with different sec. amines, were refluxed for 3-4 hr. ( R= Piperazine for (4),dimethyle amine for (5), diethylamine for (6), morpholine for (7), isopropylamine for (8) were used respectively). After completion of reaction, the products were then filtered and recrystallised with ethanol and dried . The TLC was performed on silica gel 60 using chloroform: methanol (4:1) as a solvent system. Synthesis of 5-bromo-1H-indole-2,3-dione Eequimolar amount of 1H-indole-2,3-dione (5 gm., 0.01 mol.) & bromine was taken in round bottom flask along with acetic acid. The temperature was maintained up to 0-50C on ice bath throughout the reaction. This condition was maintained about 1 hr. After completion of reaction, the reaction mixture was poured in cold water & filtered, and washed with distilled water. The product was then dried at room temperature and its TLC was performed by using chloroform : methanol (4:1) as mobile phase. Synthesis of (3Z)-5-bromo-3-(pyridin-2-ylimino)-1,3-dihydro-2H-indol-2-one (10) The equimolar amount of 2-amino pyridine &5-bromo-1H-indole-2,3-dione(9) was taken in acetic acid in a round bottom flask and dissolved properly. This reaction mixture was refluxed for about 3-4 hr. After completion of reaction these mixture was poured in distilled water and filtered then washed properly. The completion of reaction was monitored by TLC analysis for several times in chloroform: methanol (4:1). Synthesis of various mannich bases of (3Z)-5-bromo-3-(pyridin-2-ylimino)-1,3dihydro-2H- indol-2-one :(11,12,13,14,15) The equimolar amount of (3Z)-5-bromo-3-(pyridin-2-ylimino)-1,3-dihydro-2H-indol-2-one(10) (0.2gm, .01 mol) different secondary amines [ R= Piperazine for (11),dimethyle amine for (12), diethylamine for (13), morpholine for (14), isopropylamine for (15)] were taken in around bottom and dissolved in acetic acid. A small quantity of formaldehyde was added to this reaction mixture. These reaction mixtures were refluxed for 3-4 hr. on heating mental. The completion of reaction was monitored by TLC analysis for several times in chloroform: methanol (4:1). Then product was evaporated on water bath and dried. Synthesis of 5-nitro-1H-indole-2,3-dione (16) An equimolar amount of conc. nitric acid(0.01 mol.) &1H-indole-2,3-dione (0.01 mol.) were taken in round bottom flask in glacial acetic acid along with few drop of sulfuric acid. Then the reaction mixture was refluxed on heating mental for 3 hr. After completion of reaction , the product was poured in cold water & filtered , dried at room temperature & recrystallise with ethanol. Synthesis of 5-nitro-3-(pyridin-2-ylimino)-1,3-dihydro-2H-indol-2-one (17) The equimolar amount of 2-amino pyridine & 5-nitro-1H-indole-2,3-dione (16) was taken in acetic acid in a round bottom flask and dissolved properly. This reaction mixture was refluxed for about 3-4 hr. After completion of reaction these mixture was poured in

Chaubey Ajit kumar et al / IJRAP 2011, 2 (6) 1763-1767

International Journal of Research in Ayurveda & Pharmacy

distilled water and filtered, then washed properly. The completion of reaction was monitored by TLC analysis for several times in chloroform: methanol (4:1). Then reaction mixture was evaporated on water bath and dried. Synthesis of various Mannich bases of 5-nitro-3-(pyridin-2-ylimino)-1,3-dihydro-2H-indol-2-one: (18,19,20,21,22) The equimolar amount of 5-nitro-3-(pyridin-2-ylimino)-1,3-dihydro-2H-indol-2-one (0.3gm, .01 mol) and different secondary amines

[eg. Piperazine for (18), dimethylamine for (19), diethyleamine for (20), morpholine for (21), isopropyle amine for (22) respectively] were taken in around bottom flask and dissolved in acetic acid . A small quantity of formaldehyde was added to this reaction mixture. These reaction mixtures were refluxed for 3-4 hr. on heating mental. The completion of reaction was monitored by TLC analysis for several times in chloroform: methanol (4:1). Then product was evaporated on water bath and dried .

Physico-Chemical Properties

S.N. Compound code Molecular formula Molecular wt. m.p. (°C) Rf-value Solubility in DMSO

1. 3 C13H9N3O 223.23 180-182 0.83 Soluble

2. 4 C18H19N5O 321.38 120-122 0.88 Soluble

3. 5 C16H16N4O 280.32 72-80 0.80 Soluble

4. 6 C18H20N4O 308.38 120-122 0.92 Soluble

5. 7 C18H18N4O2 322.36 72-74 0.80 Soluble

6. 8 C17H18N4O 294.35 82-84 0.79 Soluble 7. 9 C8H4BrNO2 226.03 220-222 0.76 Soluble

8. 10 C13H8BrN3O 302.13 182-184 0.80 Soluble

9. 11 C18H18BrN5O 400.27 130-132 0.86 Soluble

10. 12 C16H15BrN4O 359.22 75-77 0.85 Soluble

11. 13 C18H19BrN4O 387.27 80-82 0.84 Soluble 12 14 C18H17BrN4O2 401.26 60-62 0.84 Soluble

13. 15 C17H17BrN4O 373.25 78-80 0.91 Soluble

14. 16 C8H4N2O 192.02 140-142 0.85 Soluble 15. 17 C13H8N4O3 268.23 175-177 0.81 Soluble 16. 18 C18H18N6O3 366.37 95-97 0.76 Soluble 17. 19 C16H15N5O3 325.32 65-67 0.85 Soluble

18. 20 C18H19N5O3 353.38 96-98 0.94 Soluble

19. 21 C18H17N5O4 367.36 76-78 0.93 Soluble 20. 22 C17H17N5O3 339.35 84-86 0.84 Soluble

Elemental Analysis

S.N. Comp. code Elemental analysis

Calculated found 1. 3 C(69.95),H(4.06),N(18.82). C(69.93),H(4.03),N(18.). 2. 4 C(67.27),H(5.96),N(21.79). C(67.25),H(5.95),N(21.77). 3. 5 C(68.55),H(5.75),N(19.99). C(68.52),H(5.73),N(19.97). 4. 6 C(70.11),H(6.54),N(18.17). C(70.09),H(6.52),N(18.15). 5. 7 C(67.07),H(5.63),N(17.38). C(67.04),H(5.60),N(17.35). 6. 8 C(69.37),H(6.16),N(19.03). C(69.35),H(6.15),N(19.00). 7. 9 C(42.51),H(1.78),N(6.20). C(42.49),H(1.76),N(6.17). 8. 10 C(51.68),H(2.67),N(13.91). C(51.66),H(2.65),N(13.89). 9. 11 C(54.01),H(4.53),N(17.50). C(54.00),H(4.50),N(17.48). 10. 12 C(53.50),H(4.21),N(15.60). C(53.48),H(4.19),N(15.56). 11. 13 C(55.82),H(4.95),N(14.47). C(55.80),H(4.93),N(14.45). 12. 14 C(53.88),H(4.22),N(13.96). C(53.86),H(4.20),N(13.94). 13. 15 C(54.70),H(4.59),N(15.01). C(54.68),H(4.57),N(15.00). 14. 16 C(50.01),H(2.10),N(14.58). C(50.01),H(2.08),N(14.56). 15. 17 C(58.21),H(3.01),N(20.89). C(58.20),H(3.00),N(20.87). 16. 18 C(59.01),H(4.95),N(22.94). C(59.00),H(4.93),N(22.92). 17. 19 C(59.79),H(4.65),N(21.53). C(59.77),H(4.63),N(21.51). 18. 20 C(61.18),H(5.42),N(19.82). C(61.16),H(5.40),N(19.80). 19. 21 C(58.85),H(4.66),N(19.06). C(58.83),H(4.64),N(19.03).

20. 22 C(60.17),H(5.05),N(20.46). C(60.15),H(5.03),N(20.44).

Chaubey Ajit kumar et al / IJRAP 2011, 2 (6) 1763-1767

International Journal of Research in Ayurveda & Pharmacy

Spectral Analysis S.N. Comp. code IR Spectra NMR Spectra

1. 3 3038(C-H),1697(C=O), 1604(C=N), 1580(C=C).

7.0-7.5(4H,m,Ar.),7.8-8.0(4H,m,Pyri.), 9.5(1H,s,NH).

2. 4 3038(C-H),1697(C=O), 1604(C=N), 1580(C=C).

7.0-7.5(4H, m, Ar.), 7.8-8.0 (4H,m,Pyri.), 4.03 (2H,s,-CH2), 2.4-3.0 (8H,t,Piperi.), 9.5 (1H,s,-NH).

3. 5 3037(CH),1696(C=O), 1605(C=N),1340(>N-)

7.0-7.5(4H, m, Ar.),7.8-8.0 (4H, m, Pyri.), 4.03(2H,s,-CH2),2.2-2.4(6H,t,-CH3).

4. 6 3038(C-H),1695(C=O), 1605(C=N),1342(>N-)

7.0-7.5(4H, m, Ar.), 7.8-8.0 (4H, m, Pyri.), 4.03 (2H,s,-CH2),2.2-2.4(4H,q,-CH2),1.0-1.2(6H,t,-CH3).

5. 7 3039(C-H),1698(C=O), 1280(-O-)1605(C=N)

7.0-7.5(4H, m, Ar.), 7.8-8.0 (4H,m, Pyri.), 4.03 (2H,s,-CH2),2.4-2.6(8H,t,-CH2).

6. 8 1310(NH),1697(C=O), 1605(C=N)

7.0-7.5(4H, m, Ar.), 7.8-8.0 (4H, m, Pyri.), 4.03 (2H,s,-CH2), 9.4(1H,s,-NH), 3.8(1H,s,-CH), 1.0-1.2(6H,t,-CH3).

7. 10 1710(C=O),1560(>N-H), 660(C-Br)

7.5-7.8(3H,m,Ar.),7.4-8.0(4H,m,Pyri.),9.5(1H,s,-NH).

8. 12 1705(C=O),3037(C-H), 1610(C=N),1335(>N-)

7.5-7.8(3H,m,Ar.),7.4-8.0 (4H,m,Pyri.), 4.03(2H,s,-CH2-),1.0-1.2(6H, t,-CH3).

9. 13 1703(C=O),3040(C-H), 1610(C=N),1337(>N-)

7.5-7.8(3H,m,Ar.), 7.48.0(4H,m,Pyri.), 4.03(2H,s,-CH2-),2.4(4H,q,-CH2),1.0-1.2(6H,t,-CH3).

10. 14 3036(C-H), 1698(C=O),1280(-O) 1585(C=C), 1600(C=N)

7.5-7.8(3H,m,Ar.), 7.48.0(4H,m,Pyri.), 4.03(2H,s,-CH2-),2.4-3.8(8H,m,Morpho.).

11. 17 1705(C=O),1555(>NH), 1590(-NO2)

7.8-8.5(3H,m,Ar.),7.48.0(4H,m,Pyri.), 9.6(1H,s,-NH).

12. 18 1705(C=O),1310(>NH-), 1310(-NH-)

7.5-7.8 (3H,m,Ar.), 7.4-8.0 (4H,m,Pyri.), 4.03 (2H,s,-CH2-),2.4-2.8 (8H,t, Pipera.), 9.4 (1H,s,-NH).

13. 19 1705(C=O),1310(>NH-), 1339(>N-)

7.5-7.8 (3H,m,Ar.), 7.4-8.0 (4H,m,Pyri.), 4.03 (2H,s,-CH2-),1.0-1.2(6H, t,-CH3).

14. 20 1703(C=O),1312(>NH-), 1339(>N-)

7.6-7.8(3H, m, Ar.), 7.8-8.0 (4H, m, Pyri.), 4.03 (2H,s,-CH2),2.2-2.4(4H,q,-CH2),1.0-1.2(6H,t,-CH3).

Pharmacology The analgesic activity was determined by the hot –plate test (central analgesic), and acetic acid induced writhing assays (peripheral analgesic).20,21,22. The activity was performed using standard procedures & ethics. Animals The healthy Swiss albino mice of both sexes weighing 25-30 g were taken for the study. The animals were kept in large spacious hygienic cages during the course of experimental period. The animals had free access to standard commercial diet and water ad libitum and were kept in rooms maintained at 22±10C with 12h light dark cycle. Analgesic activity using hot plate test The experiment was carried out using Glassman’s method19, using hot plate apparatus, maintained at 55±0.5 0C. The mice were divided into 14 groups of 6 animals each. The reaction time of mice to the thermal stimulus was the time interval between placing the animal above the hot plate and it licked its hind paw or jumped. The reaction time was measured prior to administration of synthesized compounds and drug administration (0 min). Group1 was kept as normal control. The synthesized compounds were injected subcutaneously to mice of groups 2-14 at a dose of 5mg/kg. Mice of group 14 served as standard and were treated with morphine sulphate 5mg/kg. The reaction time was again measured at 0, 30, 60, 90 min. after the treatment. To avoid tissue damage to the mice paws, cut-off time for the response to the thermal stimulus was set at 60s. The increase in the reaction time against control was calculated. Analgesic activity using acetic acid induced writhing response model The compounds were selected for investigating their analgesic activity in acetic acid induced writhing response in Swiss albino mice, following the method of Koster et al.,23.. The 14 groups of mice having 6 each were used for the experiment. The 1st group served as control and received only vehicle & the group’s between 2-12 received the tested compounds. The last

two groups received reference drugs as diclofenac at a dose of 20 mg/kg & indomethacin at a dose of 10mg/kg24. After 30 min, each mouse was administered 0.6% of an aqueous solution of acetic acid (10mL/kg) and the mice were then kept in transparent boxes for observation. The numbers of writhes were counted for 20min after acetic acid injection. The number of writhes in each treated groups was compared to that of control group. The number of writhes was recorded and the percentage protection was calculated using the following ratio: % protection = (control mean- treated mean/control mean) ×100. Table 1: The table shows the result of central analgesic assay using hot-plate test

(Eddy’s hot-plate method): Compd. code

Reaction time (min.)

0 min. 30 min. 60 min. 90 min. Control 3 5 6 7 10 11 12 13 14 15 17 18 19 20 Morphine

3.80±0.28 3.50±0.20 3.60±0.19 3.50±0.20 3.60±0.19 3.50±0.20 3.5±0.20 3.10±0.15 3.30±0.19 3.60±0.19 3.50±0.20 3.60±0.28 3.60±0.19 3.50±0.20 3.30±0.31 3.60±0.19

3.80±0.28 7.50±0.20** 5.30±0.19 5.30±0.31 6.30±0.19** 6.00±0.34** 10.30±0.31** 6.60±0.19** 5.50±0.20 6.80±0.15** 7.60±0.19** 5.80±0.28* 7.60±0.19** 8.50±0.20** 4.50±0.31 9.00±0.24**

4.10±0.31 6.50±0.20** 8.60±0.19** 7.30±0.19** 6.30±0.19** 12.10±0.28** 12.5±0.39** 7.50±0.28** 6.60±0.19** 5.50±0.20 6.60±0.19** 8.00±0.24** 8.60±0.19** 8.60±0.19** 4.60±0.35 13.60±0.31**

3.60±0.19 4.80±0.28 5.30±0.19 4.50±0.20* 4.00±0.24 7.00±0.24** 8.50±0.20** 6.50±0.20** 4.30±0.19 4.30±0.19 3.60±0.19 4.10±0.28 6.30±0.19** 5.30±0.19* 5.60±0.19* 9.80±0.28**

Value represents the mean ± SEM of 6 animals for each groups. *significant at <0.05, **significant at <0.01(Dunnett test), morphine(dose 5mg/kg body wt.)

Chaubey Ajit kumar et al / IJRAP 2011, 2 (6) 1763-1767

International Journal of Research in Ayurveda & Pharmacy

Table 2: The table shows the result of peripheral analgesic assay using acetic acid induced writhing test

Compd. code No. of writhings response in mice % analgesic activity Control 3 4 5 6 7 10 12 13 14 17 18 19 20 Diclofenac Indomethacin

63±0.23 29.67±0.38 23.50±0.39 21.33±0.30 21.33±0.30 18.67±0.38 26.67±0.31 18.00±0.23 16.00±0.23 22.33±0.19 26.67±0.48 23.67±0.19 20.67±0.30 18.67±0.30

6.3±0.19 21.83±0.28

--------- 51.90* 62.69* 66.14* 66.14* 70.36* 57.66* 71.42* 74.60* 64.55* 57.66* 62.42* 67.19* 70.36* 90.00* 64.47*

Each value represents the mean ± SEM (n=6), Significant levels *p<0.01 as compared with respective control.

RESULT & DISCUSSION The results (table 1 and 2) revealed that all the tested compounds exhibited significant activity. Most of the tested compounds have nearly the same activity as the reference drug (indomethacin) in peripheral analgesic assays and the remaining tested compounds have good activities in both central and peripheral analgesic assays. Few compounds show even more activity than reference one in peripheral analgesic assay. The synthesized pyridine containing compounds were screened for their analgesic activity using both central analgesic and peripheral analgesic assays. The compounds 8,12,13 and 20 were found to be good analgesic when compared with reference drug i.e., Diclofenac & even more active than another reference drug Indomethacin using peripheral analgesic assay. The compound 12 was found to be most active among all the screened compounds using acetic acid induced writhing test. The evaluation of all the synthesized derivatives against hot-plate test revealed that the compounds 11, 15, 18 and 19 were active central analgesics & compound 11 was the most active among all the derivatives tested for the central analgesic activity using morphine as a standard drug. CONCLUSION The results showed that the compound 12 is an active compound against peripheral and compound 11is active compound against central analgesic assays. The other active compounds such as 8,12,13,15,18 &19 revealed that the pyridine containing compound possesses potent analgesic activity. Thus the present investigation offers the synthesis of newer potent analgesics having pyridine nucleus along.

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Source of support: Nil, Conflict of interest: None Declared