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Asian J. Research Chem. 2(1): Jan.-March, 2009 ,

ISSN 0974-4169 RESEARCH ARTICLE

www.ajrconline.org

Synthesis and Biological Evaluation of 2, 5 Di-substituted 1, 3, 4 oxadiazoles

1

Department of Pharmacy, Pranveer Singh Institute of Technology, kalpi road, bhauti, Kanpur-208020, Uttar Pradesh, India. 2 Department of Pharmacy, Jamia Hamdurd, New Delhi. *Corresponding Author E-mail: [email protected]

Rakesh Saini*1, Awani K Rai1 , AN Kesari1 and M Shahar Yar 2

ABSTRACT

Synthesis of (ethyl 2- (1H Benzo [d] [1, 2, 3] triazole ­1- yl] acetate) and (2H ­ benzo [d] [1, 2, 3] triazole ­ 1 ­ yl aceto hydrazine) alongwith their derivatives has been done. The entire synthesized compounds were characterized by UV, IR and 1 H-NMR specteoscopy. The Antimicrobial activity of the synthesized compounds was evaluated, on Sreptococcus aureus and Esteria coli. The present investigation deals with the synthesized compounds possessing good antimicrobial activity.

KEY WORDS

Esterification, Benztriazole, Antimicrobial activity EXPERIMENTAL STEP 1 Synthesis of (ethyl 2- (1H Benzo [d] [1, 2, 3] triazole ­ 1yl] acetate) . ( I ) A mixture of Benzotriazole (0.01 mole), ethyl chloro acetate (0.01 mole) and potassium carbonate 3gm in acetone 60ml was stirred for 6 hours. The solvent was removal under reduced pressure and the solid mass so obtained was extracted with ether (diethyl ether). The ether was removed under reduced pressure to get needle shaped Brown crystals. Yield: 89%, M.P- 600C , max 1400-1600 (Ar), 1690 (ester gp.), 2100-2200 (N=N), 3000-3100 cm_1(alkyl gp), HNMR ( ppm) 7.4 - 8.00 (m, Ar )3.5 (S, 2H, CH2), 4.2 (Q, 2H, CH2), 2.5 (T, 3H, CH3). STEP - II Synthesis of ( 2H ­ benzo [d] [1,2,3] triazole ­ 1 ­ yl aceto hydrazine) . ( II ) An ethanolic solution of Compound (I) (0.01mole) and Hydrazine hydrate (20ml.) of room temp. Was stirred for 4 hours and then refluxed on water bath for 3 hours the excess, solvent was removal by distillation. The solid crystals so separated were filtered. Washed with cold water and Reacystalised from ethanol. Yield ­ 80% M.P- 1200C , max IR 1400-1600 (Ar), 1750 (CONH), 3400 (NH2), 2100-2200 (N=N), 3000-3100 (alkyl gp.) HNMR ( ppm) 7.4 -8.00 (M, Ar), 3.5 (S, 2h, CH2), 3.0 (S, 2H, NH2), 5.4 (S, 1H, NH). Procedure (D1-D5) Compound (II) (0.01mole) was refluxed with Different amino acid (0.01 mole) is the presence of phosphoryl oxy chloride (10 ml) for 6 hours. The content then were poured into ice- cold water and basified with sodium bi carbonate solution. The separated solid was filtered and recrystallised from ethanol to give derivative D1---D5.

In the design and synthesis of novel Heterocyclic compounds, recently reported the synthesis of Poly heterocyclic Compounds. Literature survey reveals that substituted 1, 3, 4-oxadiazole derivative posses broad spectrum biological activities, which include Antimicrobial1-3, Anticancer4,5, Anti-inflammatory6-8, Anticonvulsant 9,10, Anti-tuberculosatic 11,12, Insecticidal activity 13,14. 1, 2, 3 benzotriazole derivative also show several pharmacological activities viz. example Antimicrobial activity, Anti inflammatory, Anti analgesic activity, Anti cancer etc. On the basis of our observation the parent research work was carried out to synthesize 1, 2, 3 triazole substituted 1, 3, 4 oxadiazoles and to further evaluate Antimicrobial activity. All the chemicals are analytical grade and were purified by the established methods. Melting points were determined by open capillary tubes method Purity and homogeneity of the compounds was routinely determined by thin layer chromatography on glass plates using silica gel G as absorbent and solvent system Benzene : Methanol (8:2) Spots were visualized by iodine vapor by irradiation with UV light. 1H-NMRspectra was recorded on Brucker spetrospin dpx300 Spectrometer using 5-15% solutions in DMSO-D6 (TMS as internal standard). The Antimicrobial activity of the synthesized compounds was evaluated on Sreptococcus aureus and E. coli Received on 06.12.2008 Accepted on 22.02.2009 Modified on 13.01.2009 © AJRC All right reserved

INTRODUCTION:

MATERIALS AND METHODS:

Asian J. Research Chem. 2(1): Jan.-March, 2009;Page 34-36

34

Reaction Scheme

N N N H B e n z tria z o le

Asian J. Research Chem. 2(1): Jan.-March, 2009 ,

E th y l c h lo ro a c e ta te

C lC H

2

C O O C

2

H

5

N N N

(I)

C H 2C O O C 2H 5 e th y l - 2 ( 1 H - b e n z o [d ] [1 ,2 ,3 ] tr ia z o l - 1 - y l ) a c e ta te .

D1

NH2

D2

Cl

N H 2 .N H 2 .H - C 2H 5O H

N N

2

O

D3

(II)

N C H

2

C O N H N H

2

2 - ( 1 H b e n z o [ d ] [ 1 ,2 ,3 ] tr ia z o l - 1 - y l) a c e to h d r a z id e

D4

Cl

P O C l3 , C 2 H A r-C O O H

N N N

5

O H

D5

OH

N

2

N

Where, Ar= Aromatic Acids

C H

(D

1

- D

5

)

O

Ar

TABLE 1. Anti-bacterial activity of 2,5 - di substituted 1,3,4oxadiazoles.derivatives against S. aureus The reference Drug-oflaxacin showed the zone of inhibition calculated as diameter in mm as (29mm) Diameter of % inhibition S. of Compou Zone No nd inhibition(mm) . 50 g/ 100 g/ 50 g/ml 100 g/ml ml ml 1 D1 10 11 34.48 % 37.93 % 2 D2 15 17 51.72 % 58.62 % 3 D3 8 10 27.58 % 34.48 % 4 D4 12 14 41.37 % 48.27 % 5 D5 11 12 37.93 % 41.37 % % inhibition with ofloxacin-100%

Linkage), 2363 (N=N). HNMR ( ppm) 5.9 (S ,2H ,NH2),7.6 -7.8 (M, Ar ring A), 6.5- 6.8 (M, Ar ring B), 3.35 ( S, 2H ,CH2 ). DERIVATIVES (D2) Synthesis of 5-(Benztriazole 1 ­ yl ­ methyl) ­ 2 ­ (2 ­ chloro phenyl) 1, 3, 4- oxadiazole. Compound (II) (0.01mole) was refluxed with o-chloro benzoic acid (0.01 mole) is the presence of phosphorus oxy chloride (10 ml) for 6 hours. The content then were poured into ice- cold water and basified with sodium bi carbonate solution. The separated solid was filtered and recrystallised from ethanol to give derivative D2. Yield ­ 52%, M.P. ­ 170-1720C, max .IR 3898 -2983 (Alkyl gp), 1400- 1600(M, Ar region), 1123 (Ester linkage), 2363 (N=N). HNMR ( ppm) 7.6 -7.8 (M, Ar ring A), 6.5- 6.8 (M, Ar ring B), 3.35 (S, 2H, CH2). DERIVATIVES (D3) Synthesis of 5 ­ (Benztriazole 1 ­ yl ­ methyl) ­ 2 ­ (4chloro phenyl) 1, 3, 4 ­ oxadiazole. Compound (II) (0.01mole) was refluxed with benzoic acid (0.01 mole) is the presence of phosphorus oxy chloride (10 ml) for 6 hours. The content then were poured into ice- cold water and basified with sodium bi carbonate solution. The separated solid was filtered and recrystallised from ethanol to give derivative D3.

DERIVATIVES (D1) Synthesis of 5 ­ (Benztriazole 1- yl ­ methyl) ­ 2 ­ phenyl ­ 1, 3, 4 ­ oxadiazole. Compound (II) (0.01mole) was refluxed with p-amino benzoic acid (0.01 mole) is the presence of phosphorus oxy chloride (10 ml) for 6 hours. The content then were poured into ice- cold water and basified with sodium bi carbonate solution. The separated solid was filtered and recrystallised from ethanol to give derivative D1. Yield ­ 49%, M.P. ­ 185-1860C, max.IR 3422 (NH2), 2898-2983 (alkyl gp), 1400-1600 (M Ar ), 1123 (Ester

35

Yield ­ 50%, M.P. ­ 178-1790C, max.IR, 3898 -2983 (Alkyl gp), 1400- 1600(M, Ar region), 1123 (Ester linkage), 2363 (N=N). HNMR ( ppm ) 7.5 -7.7 (M, Ar ring A), 6.5- 6.8 (M,Ar ring B), 3.35 (S,2H,CH2).

Asian J. Research Chem. 2(1): Jan.-March, 2009 ,

DERIVATIVES (D4) Synthesis of 5 ­ (Benztriazole 1 ­ yl ­ methyl) ­2 ­ (4 ­ amino phenyl) 1,3,4 ­ oxadiazole. Compound (II) (0.01mole) was refluxed with 4- chloro benzoic acid (0.01 mole) is the presence of phosphorus oxy chloride (10 ml) for 6 hours. The content then were poured into ice- cold water and basified with sodium bi carbonate solution. The separated solid was filtered and recrystallised from ethanol to give derivative D4. Yield ­ 55%, M.P. ­ 167-1680C, max.IR, 3898 -2983 (Alkyl gp), 1400- 1600 ( M,Ar region), 1123 (Ester linkage), 2363 (N=N). HNMR ( ppm) 7.6 -7.8 (M,Ar ring A), 6.4- 6.9 (M,Ar ring B), 3.36 (S,2H,CH2). DERIVATIVES (D5) Synthesis of 5 ­ (Benzotriazole 1 ­ yl ­ methyl ) -2 ­ (di phenyl methanol ) 1,3,4 ­ oxadiazole. Compound (II) (0.01mole) was refluxed with benzilic acid (0.01 mole) is the presence of phosphorus oxy chloride (10 ml) for 6 hours. The content then were poured into ice- cold water and basified with sodium bi carbonate solution. The separated solid was filtered and recrystallised from ethanol to give derivative D5. Yield ­ 51%, M.P. ­ 159-1600C, max.IR 3550 (OH), 2898-2983 (Alkyl gp), 1400-1600 (M, Ar region), 1123 (Ester linkage), 2363 (N=N). ).HNM ( ppm ) 7.3 -7.5 (M, Ar ring A), 7.9- 8.1 (M, Ar ring B), 4.6 (S, OH) 3.36 (S, 2H, CH2). Evaluation of anti-Microbial activity Inoculum of the respective test organism was mixed with nutrient agar (1% v/v) and after mixing; 20ml of this seeded medium was poured in Petri dishes of 10 cm diameter. After the setting of medium two holes/wells were made in each plate and different concentration (50 g/ml and 100 g/ml) of the test compound were placed in each of the cavity. The volume added in each cavity was uniform. The reference was placed in the center of the Petri dishes. The plates were kept in cold for one hour and then incubated at 370C for 24 hours. The diameter of the zone of the inhibition formed around the cups after overnight incubation was measured and percentage inhibition of the compounds were evaluated. DMSO was used as a solvent for all the compounds as well as control. Ofloxacin was used as standard in a concentration of 30 g/disc. Antimicrobial activity of the synthesized compounds and their derivatives D1-D5 were analyzed and maximum activity was found in D2 against S. aureus. The percentage inhibition D2 was found to be 51.72 % with 50 g/ml and 58.62% 100 g/ml (Table no. 1). It was followed by D4

compound the % inhibition were 41.37% with and 48.27% with 50 g/ml and 100 g/ml respectively. The study with E.coli of the same synthesized drugs (D1 ­D5) maximum activity was observed with derivative D2 the % inhibition was 32.14 % and 35.71% with dose of 50 g/ml and 100 g/ml respectively. Derivative D3 andD5 do not show any activity against E.coli. (Table 2). The reference drug oflaxacin showed 100 % inhibition with both micro organisms taken. Thus we can conclude the D2 derivative has excellent activity with both microorganism Streptococcus aureus and E. coli.

TABLE 2. Anti-bacterial activity of 2,5 - di substituted 1,3,4oxadiazoles.derivatives against E. coli. The reference Drug-oflaxacin showed the zone of inhibition calculated as diameter in mm as (28mm) Diameter of % inhibition S Zone of . inhibition(mm) N Compound 50 g/ 100 g 50 g/ml 100 g/ml o. ml /ml 1 D1 8 9 28.57 % 32.14 % 2 D2 9 10 32.14 % 35.71 % 3 D3 ----4 D4 7 9 25 % 32.14 % 5 D5 ----% inhibition with ofloxacin-100%

ACKNOWLEDGEMENT:

The author are thankful to the Director institute of pharmacy Bundelkhand University Jhansi (U.P) and Dr. H.P Bhartiya for providing facilities necessary for evaluation of the antimicrobial activity.

REFERENCES:

1 2 3 4 5 6 7 8 9 10 11 12 13

RESULT AND DISCUSSION:

Barry A L, The antimicrobial susceptibility test; Principle and Practice (Lea and Febiger, Philadelphia) 1976, 180-93. Khan M.S.Y and Akhtar M. , Indian journal of chemistry , vol.42B, April2003, 900-904. Peesapati Venkateswarlu and Srikant BVenkata Chitty, Indian journal of chemistry, .42B, March 2003, 616-620. Holla B. Shivrama, Prasnna C S, Poojary Boja, Rao K S, Shriava and Bhatt U, Ganesh Indian journal of chemistry , 43B, 2003, 864. Gonsalves R, PhD Thesis, Mangalore University 1999. Nargund L V G, Reddy G R N, and Hari Pashad V, Journal of Pharmaceutical Chemistry 1994, 264. Mullican M D, Wilson M W, Connor D T, Kostlan C R, Schrier D J and Dyer R D, J. Med. Chem., 36, 1993, 1090. Ram V J, Indian journal of Chemistry, 27 B, 1988 , 825. Omar E A, Mohfouz ME , and Rahman M.A , Eur. Journal of Medicinal Chemistry , 31, 1996, 819. Sudha B.H, Sashikanth S, Khanum S.A and Srihavsa Indian Journal of Pharmaceutical Science, 2003, 65(5) 465-470. Libermann D.N,Rist and F, GrumBach, Neal J.B.O, Rosen, Rusel P.B, AC Adams andBlumenthal A, A.J Med. Pharma Chem. 1962, Chem. Abst. 57. Silesirni B and Pagatili C, Journal of Pharmacology Vol. 16 , 1961, 209. Hassrt (Jr) G.L,Pulsiaka J.W, Papna drianos D, Burk JCA, Graver BN, Taxtal, Appl. Pharmacology ,3, 1961, 726.

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