Synthesis, Characterization and Biological Activities of New Pyrimidines and Pyrazoles Derivative

 

Vijay Kumar Tirlapur* and Kashinath Noubade

Dept. of Pharmaceutical Chemistry, Karanataka College of Pharmacy. Manhalli Road Post Box No- 53 Bidar-585403.

*Corresponding Author E-mail: tirlapur_v@yahoo.com

 

ABSTRACT:

4-aminotoluidine on diazotization followed by coupling with ethylacetoacetate gave ethyl 2-[(4-methylphenyl)diazenyl]-3-oxobutanoate (2), which on condensation with substituted benzaldehydes in basic medium gave 1-[(4-methyl phenyl)diazenyl]-4-(substituted phenyl) but-3-en-2-ones (3a-e). The compound (3a-e) on reaction with urea in presence of alkali and ethanol afforded 4-(4-substituted phenyl)-6-{[(4-methylphenyl) diazenyl] methyl}-pyrimidin-2-ol (4a-e). Treatment of compound (3a-e) with hydrazine hydrate in presence of ethanol gave 5-(4-substituted phenyl)-3-{[(4-methyl phenyl) diazenyl] methyl}-4, 5-dihydro-1H pyrazole (5a-e). All newly synthesized compounds were characterized on the basis of IR, 1HNMR and mass spectral data and evaluated for antimicrobial, analgesic activities.

 

KEYWORDS: Pyrimidines, pyrazoles, antibacterial, antifungal, analgesic activity.

 

 

INTRODUCTION:

Pyrimidines and Pyrazoles constitute an important class of bioactive compounds exhibiting antioxidant1-2, anti-inflammatory3, analgesic4, anticancer5 and antimicrobial6-10, activity. In view of this fact it was thought worthwhile to synthesis some new pyrimidines and pyrazoles derivative.

 

Antimicrobial activity:

The newly synthesized compounds were subjected to invitro antibacterial activity against by Cup-Plate diffusion method11 using organisms E.coli, B.subtilis for antibacterial activity whereas A. Niger and C.albican for antifungal activity. All the test compounds were prepared at the concentration of 100mg/ml in distilled DMF. The solution of ciprofloxacin and flucanazole were prepared at the concentration of 100mg/ml in DMF as standard solution for comparison of antibacterial and antifungal activities and DMF was used as control for both activity, the results were presented in Table-2.

 

The compounds 4b, 4d, 5b and 5d shown significant antibacterial activity against E.coli, B.subtilis and the remaining compounds are exhibited moderate activity against the E. coli and B. subtilis.

 

In fungicidal activity the compounds 4b, 4d, 5b and 5d exhibited good antifungal activity against A. niger and C. albican where as remaining compounds are exhibited moderate to weak activity against the A. niger and C. albican.

 

Analgesic activity:

All the synthesized compounds (3a-e, 4a-e and 5a-e) were evaluated for their analgesic activity employed by Eddy’s hot plate method. Ibuprofen was used as a reference standard for comparison. Compounds 4b, 4d, 5b and 5d showed maximum activity when compared with standard drug and other compounds were shown moderate to weak activity. The analgesic activity results were presented in Table-3.

 

MATERIAL AND METHODS:

The melting points were determined by open capillaries and are uncorrected. The purity of the compounds was checked by TLC.  Infra red spectra were recorded on an FTIR-8400 Shimadzu Spectrophotometer Department of Pharmaceutical Chemistry, Karnataka College of pharmacy, Bidar. The 1HNMR spectra were recorded ACF 200 Supercon-Switzerland NMR Spectraphotometer and were procured from central University Hyderabad; Chemical shifts were expressed in ppm (delta scale). Mass spectra were taken by using LC-MS 2010 (SHIMADZU) Mass spectrometer from central University, Hyderabad.

 

Ethyl 2-[(4-methyl phenyl) diazenyl]-3-oxobutanoate (2)

To a solution of 4-aminotoludine (1) (0.01mol) in water (5ml) and conc. Hydrochloric acid (5ml) was cooled to 0-5oC in ice bath.


Table-1: Physical data of the synthesized compounds

Comp.

No

 

R

M P

(0C)

Yield

(%)

Molecular

formula

Solvent for

Cryst.

Rf value

 

Calculated (found) (%)

C

H

N

2

-

66

70

C13H16N2O3

Ethanol

0.41

62.69 (62.89)

6.30 (6.50)

11.18 (11.28)

3a

C6H5

110

76

C17H16N2O

Ethanol

0.61

77.25 (77.25)

6.10 (6.10)

10.60 (10.60)

3b

C6H4Cl(p)

121

80

C17H15ClN2O

Ethanol

0.70

68.04 (68.34)

5.00 (5.06)

9.18 (9.38)

3c

C6H4OH(p)

107

72

C17H16N2O2

Ethanol

0.54

72.24 (72.84)

5.34 (5.75)

9.09 (9.99)

3d

C6H4Br(p)

135

65

C17H15BrN2O

Ethanol

0.39

59.19 (59.49)

4.11 (4.41)

8.16 (8.16)

3e

C6H4N(CH3)2

128

70

C19H21N3O

Ethanol

0.48

74.04 (74.24)

6.81 (6.89)

13.51 (13.67)

4a

C6H5

120

60

C18H16N4O

Ethanol

0.47

71.04 (71.00)

5.30 (5.29)

18.41 (18.38)

4b

C6H4Cl(p)

165

50

C18H15ClN4O

Benzene

0.52

63.81 (63.80)

4.46 (4.45)

16.54 (16.51)

4c

C6H4OH(p)

149

68

C18H16N4O2

Ethanol

0.37

67.49 (67.44)

5.03 (5.00)

9.99 (9.98)

4d

C6H4Br(p)

102

59

C18H15BrN4O

Ethanol

0.48

56.41 (56.37)

3.95 (3.91)

14.62 (14.59)

4e

C6H4N(CH3)2

140

60

C20H21N5O

Ethanol

0.62

69.14 (69.09)

6.09 (6.07)

20.16 (20.13)

5a

C6H5

150

62

C17H18N4

Ethanol

0.51

73.35 (73.36)

6.52 (6.50)

20.13 (20.11)

5b

C6H4Cl(p)

155

56

C17H17ClN4

Ethanol

0.31

65.28 (65.22)

5.48 (5.46)

17.91 (17.89)

5c

C6H4OH(p)

105

76

C17H18N4O

Ethanol

0.65

69.37 (69.36)

6.16 (6.12)

19.03 (19.00)

5d

C6H4Br(p)

157

58

C17H17BrN4

Ethanol

0.69

57.15 (57.13)

4.80 (4.78)

15.88 (15.86)

5e

C6H4N(CH3)2

168

50

C19H23N5

Ethanol

0.71

71.00 (71.01)

7.21 (7.19)

21.79 (21.77)

 

 

Table-2: Antimicrobial activity of synthesized compounds of (2, 3a-e, 4a-e and 5a-e)

Compound

No

Zone of Inhibition in mm*

Antibacterial

Antifungal

E.coli

B.Subtilis

A.Niger

C.albicans

2

10

14

15

12

3a

12

14

16

15

3b

18

17

16

17

3c

12

17

14

16

3d

16

17

16

17

3e

12

11

12

10

4a

15

14

15

14

4b

22

24

19

20

4c

16

17

18

17

4d

23

24

20

20

4e

12

11

12

11

5a

16

16

18

13

5b

23

24

19

20

5c

17

17

19

17

5d

24

24

20

19

5e

16

18

19

14

Ciprofloxacin

(Std)

24

25

--

--

Fluconazole

(Std)

--

--

20

20

Control

6

6

6

6

* Zone of Inhibition in mm

 

The cold solution of NaNO2 (0.01mol) in water (8ml) was added drop wise to the above suspension. The diazonium salt thus obtained was filtered into cold solution of ethylacetoacetate (0.01mol) and sodiumacetate (8g) in ethanol (25ml) at 0-5oC. The resulting product was filtered, washed with cold water, dried and crystallized from ethanol.

 

The IR (KBr) cm-l: 1671, 1641 (C = O), 1575, 1461 (C = C). 1H NMR (δ ppm): 1.1 (t, 3H, OC2H5), 1.7 (s, 3H, CH3), 2.9 (s, 3H, Ar-CH3), 3.3 (s, 1H, CH), 4.1 (q, 2H, CH2 of ester), 7.5- 8.0 (m, 4H, Ar-H). MS (m+/z) 248.

 

1-[(4-methyl phenyl)diazenyl]-4-(substituted phenyl) but-3-en-2-ones (3a-e).

A solution of substituted aldehydes (0.01mol) in ethanol (10ml) was added to the compound (2) (0.01mol) in ethanol (5ml) and sodium hydroxide (4ml, 40%). The reaction mixture was stirred for 24hrs at room temp and then the contents were poured out to crushed ice and neutralized with hydrochloric acid (5%). The product thus separated was filtered, dried and crystallized from suitable solvent.

 

Bar graph of antimicrobial activity of compounds (2, 3a-e, 4a-e and 5a-e)

 

Bar graph of analgesic activity of compounds (3a-e, 4a-e and 5a-e)

 

 

Table-3: Analgesic activity of synthesized compounds (3a-e), (4a-e) and (5a-e)

Comp

No

R

Dose (mg/kg)

Per oral

Average (±SE) reaction time (sec)

Time after drug treatment (min)

0

30

60

90

Control

--

100

3.00 (±0.00)

3.00 (±0.05)

3.00 (±0.00)

3.00 (±0.05)

Standard Ibuprofen

 

100

3.00 (±0.25)

6.25 (±0.40)

9.50 (±0.25)

10.50 (±0.40)

3a

C6H5

100

3.00 (±0.25)

3.50 (±0.00)

3.50 (±0.40)

3.75 (±0.25)

3b

C6H4Cl(p)

100

3.00 (±0.00)

4.00 (±0.25)

6.75 (±0.25)

7.75 (±0.00)

3c

C6H4OH(p)

100

3.00 (±0.42)

3.75 (±0.25)

5.25 (±0.40)

6.00 (±0.25)

3d

C6H4Br(p)

100

3.00 (±0.25)

4.25 (±0.00)

6.00 (±0.25)

7.00 (±0.25)

3e

C6H4N(CH3)2

100

2.75 (±0.00)

3.50 (±0.25)

4.50 (±0.25)

7.00 (±0.25)

4a

C6H5

100

3.00 (±0.00)

3.00 (±0.00)

3.00 (±0.00)

3.00 (±0.25)

4b

C6H4Cl(p)

100

3.00 (±0.25)

4.50 (±0.25)

6.75 (±0.40)

9.50 (±0.25)

4c

C6H4OH(p)

100

3.00 (±0.42)

3.25 (±0.25)

3.25 (±0.25)

4.75 (±0.40)

4d

C6H4Br(p)

100

3.00 (±0.00)

5.50 (±0.25)

7.00 (±0.25)

8.75 (±0.25)

4e

C6H4N(CH3)2

100

2.75 (±0.40)

3.00 (±0.25)

3.25 (±0.00)

5.00 (±0.25)

5a

C6H5

100

3.00 (±0.40)

3.00 (±0.40)

3.75 (±0.25)

3.75 (±0.40)

5b

C6H4Cl(p)

100

3.00 (±0.25)

6.00 (±0.25)

9.25 (±0.40)

10.25 (±0.25)

5c

C6H4OH(p)

100

3.00 (±0.00)

3.25 (±0.25)

4.75 (±0.25)

5.00 (±0.25)

5d

C6H4Br(p)

100

3.25 (±0.40)

6.00 (±0.25)

9.25 (±0.40)

10.00 (±0.00)

5e

C6H4N(CH3)2

100

3.00 (±0.048

4.00 (±0.25)

5.75 (±0.00)

6.75 (±0.40)

 

RESULTS AND DISCUSSION:

Pyrimidine, pyrazole and its derivatives have been associated with its wide range of its biological and pharmacological properties 4-aminotoluidine on diazotization followed by coupling with ethylacetoacetate gave ethyl 2-[(4-methylphenyl)diazenyl]-3-oxobutanoate(2), which on condensation with substituted benzaldehydes in basic medium gave 1-[(4-methyl phenyl)diazenyl]-4-(substituted phenyl) but-3-en-2-ones (3a-e). The compound (3a-e) on reaction with urea in presence of alkali and ethanol afforded 4-(4-substituted phenyl)-6-{[(4-methylphenyl) diazenyl] methyl}-pyrimidin-2-ol (4a-e). Treatment of compound (3a-e) with hydrazine hydrate in presence of ethanol gave 5-(4-substituted phenyl)-3-{[(4-methyl phenyl) diazenyl] methyl}-4, 5-dihydro-1H pyrazole (5a-e). These compounds were screened for their analgesic, antibacterial and antifungal activities and some of the compounds were exhibited good activity.

 

ACKNOWLEDGEMENT

The authors thank to Principal, Krantikumar M Sirse, K C P Bidar for providing research facilities to carry out this work. The authors also wish to thank Mr. M. Mugali, Asst. Prof. Dept of Microbiology and Mr. Sunil Gandhe Asst. Prof. Dept of Pharmacology K.C.P. Bidar, for the help rendered to carrying out the antibacterial, antifungal and analgesic activities.

 

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Received on 05.03.2010        Modified on 01.04.2010

Accepted on 18.04.2010        © AJRC All right reserved

Asian J. Research Chem. 3(3): July- Sept.  2010; Page 659-662