Synthesis and Analgesic Activity of 2, 5 Di-Substituted 1, 3, 4 Oxadiazoles

 

Rakesh Saini¹*, Saurabh Chaturvedi¹, AN Kesari¹, Rijuved Garg² and Amita Verma³

¹Dept. of Pharmacy, Pranveer Singh Institute of Technology, Kalpi Road, Bhauti, Kanpur-208020, (U. P.), India

²Department of Pharmacy, Aligarh College of Pharmacy , Aligarh (U.P)

³ Department of Pharmacy, Allahabad Agriculture Deemed University, Allahabad (U.P)

*Corresponding Author E-mail: rakeshpsit.saini@gmail.com

ABSTRACT:

1, 2, 3 benzotriazole derivative  also  show  several  pharmacological  activities viz.example.  Antimicrobial  activity,  Anti inflammatory,  Anti  analgesic  activity, Anticancer 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  Analgesic activity.  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) along with their derivatives has been done. The entire synthesized compounds were characterized by UV, IR and ¹H-NMR specteoscopy. The Antimicrobial activity of the synthesized compounds was evaluated, on albino rats. the present investigation deals with the synthesized compounds possessing good   Analgesic activity.

 

 

 

INTRODUCTION:

As part of our ongoing study in the design and synthesis of novel Heterocyclic Compounds, we have 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 Antimicrobial^1-3, Anticancer^4,5, Anti-inflammatory^6-8, 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 analgesic activity.

 

MATERIALS AND METHODS:

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 analgesic activity of the synthesized compounds was evaluated on   albino rats.

 

EXPERIMENTAL:

STEP 1:

Synthesis of (ethyl 2-(1H Benzo [d] [1, 2, 3] triazole – 1- yl] 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, λ max 1400-1600 (Ar), 1690 (ester gp.), 2100-2200 (N=N),      3000-3100 cm_1 (alkyl gp), HNMR   (δ 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 , λ max IR 1400-1600 (Ar), 1750 (CONH), 3400 (NH2), 2100-2200 (N=N), 3000-3100 (alkyl gp.)  HNMR (δ 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 D_1---D5.

 

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, λ max.IR 3422 (NH2), 2898-2983 (alkyl gp), 1400-1600 (M Ar ), 1123 (Ester Linkage), 2363 (N=N). HNMR (δ 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, λ max .IR 3898 -2983 (Alkyl gp), 1400- 1600(M, Ar region), 1123 (Ester linkage), 2363 (N=N).  HNMR (δ 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 – (4-chloro 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.

Yield – 50%, M.P. – 178-179⁰C, λ max.IR, 3898 -2983 (Alkyl gp), 1400- 1600(M, Ar region), 1123 (Ester linkage), 2363 (N=N).  HNMR (δ ppm)

7.5 -7.7 (M, Ar ring A), 6.5- 6.8 (M, Ar ring B), 3.35 (S, 2H, CH2).

 

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 moles) 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, λ max.IR, 3898 -2983 (Alkyl gp), 1400- 1600 (M, Ar region), 1123 (Ester linkage), 2363 (N=N).  HNMR (δ 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, λ max.IR 3550 (OH), 2898-2983 (Alkyl gp), 1400-1600 (M, Ar region), 1123 (Ester linkage), 2363 (N=N). ).HNM (δ 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).

 

Analgesic Activity:-

The activity was carried out on wistar mice weighing between 20-30 gm using tail flick method. The test compounds and standard drug (Pentazocaine, 5mg/kg) were administered orally. The results are given in Table.

 

RESULTS AND DISCUSSION:-

Analgesic activity of the synthesized compounds and their derivatives D₁-D₅ were analyzed and maximum activity was found in D₄ against albino rats. The percentage % inhibition in edema D4 was found to be 61.90 %. (Table no. 1). The study with albino rats of the same synthesized drugs (D₁ –D₅) maximum activity was observed with derivative D₄  the % inhibition in edema  was 61.90 %, Derivative D₁ 50%, D₂   49.20%, D₃  40.47 % and D₅ 42.85%. Reference drug indomethacin 70% showed inhibition in edema with albino rats taken. Thus we can conclude the D₄ derivative has excellent activity with albino rats.

 

Reaction Scheme

 

Ar =     Aromatic Acids-

(D₁)

 

(D₂)

 

(D₃)

 

(D₄)

 

(D₅)

 

Table-1: Biological activity of the synthesized compounds

S.N.	Compounds	Analgesic activity  (% Protection)
1	D1	58.85
2	D2	68
3	D3	50
4	D4	88.85
5	D5	76.32
6	Pentazocaine	92.3

 

ACKNOWLEDGEMENT:-

The author is thankful to the Director, Institute of Pharmacy Bundelkhand University, Jhansi (U.P) and to the Medicinal Chemistry Division and Pharmacology Division of Central Drug Research Institute (CDRI), Lucknow for providing necessary facilities.

 

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Received on 26.06.2009        Modified on 09.08.2009

Accepted on 15.09.2009        © AJRC All right reserved