Synthesis, Characterization and Anti-Microbial Evaluation of Substituted Isoxazole Derivatives

 

Moid A.*, Nikhat F., Purohit M.G. and Thouheed A.

Department of Pharmaceutical Chemistry, Luqman College of Pharmacy, Gulbarga - 585102

*Corresponding Author E-mail: moid_ans55@yahoomail.com

 

ABSTRACT:

The prevalence of isoxazole cores in natural and biologically active molecules has stimulated the need for elegant and efficient ways to make these heterocycles as lead. A systematic investigation of this class of heterocycle revealed that isoxazole containing pharmacoactive agentís possess analgesic, anti-inflammatory and antimicrobial activities. 4-(5′-substituted-aryl-4′,5′-dihydro-isoxazole-3′-yl-amino) phenols possessing potent biological activities. N-(4′-hydroxyphenyl) acetamide (2) was synthesized by the condensation of p-amino phenol (1) with acetyl chloride by refluxing in alkaline medium for 20 minutes. 3-substituted N-(4′-hydroxyphenyl) propanamides (3a-g) were prepared by the reaction of N-(4-hydroxy phenyl) acetamide with various substituted aryl aldehydes by refluxing for 6 hours in ethanol. The resultant compounds on refluxing for 6 hours with hydroxylamine hydrochloride gave the title compounds 4-(5′-substituted-aryl-4′, 5′-dihydro-isoxazole-3′-yl-amino) phenols (4a-g). The synthesized derivatives have been characterized by FT-IR, 1HNMR and Mass spectral analysis. All the derivatives synthesized were screened for their anti-bacterial and antifungal activities at the concentration level of 100 mg/ml by cup-plate method. Some of the compounds such as 4a, 4b, 4c, 4d and 4f have shown significant antibacterial and antifungal activity when compared to standard drugs Ciprofloxacin (antibacterial activity) and Clotrimazole (antifungal activity). The results obtained indicate that, when the phenyl group at 5th position of isoxazole nucleus contains the substituents as electron withdrawing atoms/groups particularly at ortho and meta positions could be a decisive factor for the compounds to have the increased potency over the other positions.

 

KEYWORDS: Isoxazoles derivatives, anti-bacterial activity, anti-fungal activity.

 

 


INTRODUCTION:

Isoxazole is a five membered heterocyclic ring system containing oxygen and nitrogen in the adjacent position. Isoxazole derivatives are known to passes anti-tubercular, analgesic1, anti-inflammatory2 and anti-microbial3 activities. Aim of present study is to synthesize substituted isoxazole derivatives and evaluate them for antimicrobial activity.

 

MATERIAL AND METHODS:

The entire chemicals used were procured from SDFCL Ltd, Himedia, central drug house (p) Ltd, and Loba-chemicals. Purity of starting materials used for reaction was confirmed by checking their melting point and by thin layer chromatography. All the reactions were monitored using thin layer chromatography. Melting points were determined in open capillary tube using precision melting point apparatus and were uncorrected.

 

Preparation of N-(4′-hydroxyphenyl)-3-phenyl-propanamides (3a-g):

To a mixture of N-(4′-hydroxy phenyl)-acetamide (2) (which was prepared by the condensation of p-amino phenol (1) with acetyl chloride) and substituted aryl aldehydes in ethanol, sodium hydroxide was added and stirred for 10 hours at room temperature. Then it was refluxed for 6 hours on a water bath. The excess solvent was removed under reduced pressure. It was poured onto ice-cold water. The solid thus separated was filtered, dried and recrystallized from ethanol.

 

4-(5′-substituted-aryl-4′, 5′-dihydro-isoxazole-3′-yl-amino) (4a-g):

To a mixture of N-(4′-hydroxyphenyl)-3-phenyl-propanamides (3a-g) and hydroxylamine hydrochloride in ethanol was refluxed on a water bath for 6 hours. The reaction mixture was concentrated under reduced pressure. It was cooled and poured onto ice-cold water. The solid separated was filtered, dried and recrystallized from ethanol. The synthesized were characterized by FT-IR, 1HNMR and Mass spectral data. The physical data of the compounds synthesized is listed in Table-1.


 

Table 01:- Physical data of various substituted Isoxazole derivatives (4a-g)

Sl. No.

Compound

MP (oC)

Yield

Spectral Data of the compound 4a

Spectral Data of the compound 4b

1

4a

130

50%

IR(KBr,cm-1): 3320 (Ar-OH), 3140 (NH), 3037 (C-H), 1660 (C=N),

1HNMR ( ppm)(CDCl3):3.1(CH2), 7.1 (H of N-H), 8.2 (Ar-OH);

MS (m/z): 288(M+)

IR (KBr; cm-1): 3300 (Ar-OH), 3150 (NH), 3007 (C-H), 1630 (C=N);

1HNMR ( ppm)(CDCl3):2.3(CH2), 7.4 (H of N-H), 8.6 (Ar-OH);

MS (m/z): 288(M+)

2

4b

135

80%

3

4c

140

82%

4

4d

125

65%

5

4e

115

68%

6

4f

142

78%

7

4g

155

55%

 

Table-2: Antimicrobial activity of substituted Isoxazole derivatives (4a-g)

S. No.

Compound

Conc.

(Ķg/ml)

Diameter of zone inhibition (mm)

B. Subtilus

ATCC29212

E. fecalis

ATCC25923

E. coli

ATCC-27853

S. aurigenosa

A. niger

A. flavous

1

4a

100

17

19

22

19

21

22

2

4b

100

21

18

23

20

22

18

3

4c

100

19

22

17

20

23

19

4

4d

100

19

20

20

19

19

20

5

4e

100

13

14

21

18

16

17

6

4f

100

21

21

24

22

23

25

7

4g

100

12

12

16

17

15

15

8

Ciprofloxacin

100

23

25

27

25

-

-

9

Clotrimazole

100

-

-

-

-

25

28

 


 

Antimicrobial Screening4-5:

All the synthesized compounds were screened for their antimicrobial activity at the concentration level of 100mg/ml using cup and plate method against bacterial strains Pseudomonas aurigenosa, Escherichia coli, Bacillus subtilus, Enterococcus fecalis and fungal strains Aspergillus niger, Aspragellus fulvous. The antibacterial activities of the compounds were compared with that of antibacterial standard drug Ciprofloxacin, where as the antifungal activities of the test compounds were compared with that of standard antifungal drug Clotrimazole. The antimicrobial data is presented in Table-2.

 

RESULTS AND DISCUSSION:

Some of the compounds tested for antimicrobial activity such as 4a, 4b, 4c, 4d and 4f,† have shown good antibacterial and antifungal activity where as the other two compounds 4e, 4g have shown moderate activity in comparison with† standard drug ciprofloxacin and clotrimazole respectively. The results obtained clearly indicate that, when the phenyl group at 5th position of isoxazole nucleus contains the substituent as electron withdrawing atoms/groups particularly at Ortho and Meta positions could be a decisive factor for the compounds to have the increased potency over the other positions.

 

REFERENCE:

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2.       Rani P, Srivastava V. K. and Kumar A. Isoxazolinyl Derivatives of Anthranilic Acid as Anti-Inflammatory Agents. Ind. J. Chem 2003; 42B: 1729-1733.

3.       Diadone G, Raffa D, Maggio B, Plescia F, Curuli VMC, Mangano NG and Caruso A. Synthesis and Pharmacological Activities of Novel-3-(Isoxazol-3-yl)-Quinazolin-4(3H)-one. Archive Pharmazie2007; 340A: 163-164.

4.       Imran M and Khan SA. Synthesis of 3, 5-Disubstituted Isoxazoles as Antibacterial and Antifungal agents. Indian J. Heterocycl. Chem. 2004; 13: 213-216.

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Received on 17.01.2011††††††† Modified on 12.02.2011

Accepted on 28.02.2011††††††† © AJRC All right reserved

Asian J. Research Chem. 4(7): July, 2011; Page 1158-1160