SYNTHESIS AND BIOLOGICAL EVALUATION OF ACETIC ACID ...

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Kumar et al. World Journal of Pharmacy and Pharmaceutical Sciences

SYNTHESIS AND BIOLOGICAL EVALUATION OF ACETIC ACID

DERIVATIVE OF HETEROCYCLE AZOCINE

Dr. P. R. Logesh Kumar*1, Dr. P. Vasanth Kumar

2, Y. Praveen Kumar

3, S. Aslam

3,

S. Malika3, K. S. Shafiya Kowsar

3, G. Haritha

3, V. Lavanya

3, M. Sandhya

3 and

M. Praveen3

1Associate Professor, Department of Pharmaceutical Chemistry, Sri Krishna Chaithanya

College of Pharmacy, Nimmanapalli Road, Madanapalle, Chittoor (Dt), Andhra Pradesh-

517325, India. 2Professor & Principal, Sri Krishna Chaithanya College of Pharmacy, Nimmanapalli Road,

Madanapalle, Chittoor (Dt), Andhra Pradesh-517325, India. 3B. Pharmacy, Sri Krishna Chaithanya College of Pharmacy, Nimmanapalli Road,

Madanapalle, Chittoor (Dt), Andhra Pradesh-517325, India.

ABSTRACT

Azocine is the chemical species of unsaturated eight membered

heterocyclic ring with nitrogen as hetero atom. The IUPAC name of

Azocine is Azacyclooctatetraene. The saturated or partially saturated

azocine rings form the core structure of a group of opioid compounds

sometimes known as Azocines. These include cyclazocine,

pentazocine and phenazocine. The compounds possessing interesting

biological and pharmacological properties as anti-inflammatory, anti-

cancer, anti- bacterial, anti-fungal, anti-viral, anti-arrhythmic,

tranquilizing, muscle relaxing and anti-diabetic agents. Azocine rings

are found in many Natural products. The starting compounds for the

synthesis of azocine is Ethyl-3-oxobutanoate. The structural

assignments are supported by NMR, MASS, IR spectroscopy and

chromatography Thin Layer Chromatography and Paper

Chromatography.

KEYWORDS: Azocine, Anti-inflammatory, Ethyl-3-oxobutanoate, Anti oxidants.

WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

SJIF Impact Factor 7.632

Volume 9, Issue 2, 886-900 Research Article ISSN 2278 – 4357

Article Received on

02 Dec. 2019,

Revised on 23 Dec. 2019,

Accepted on 12 Jan. 2020,

DOI: 10.20959/wjpps20202-15441

*Corresponding Author

Dr. P. R. Logesh Kumar

Associate Professor,

Department of

Pharmaceutical Chemistry,

Sri Krishna Chaithanya

College of Pharmacy,

Nimmanapalli Road,

Madanapalle, Chittoor (Dt),

Andhra Pradesh-517325,

India.


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INTRODUCTION

The primary concern of this chapter is eight-membered aza heterocycles azocines. Azocines

are a diverse class of compounds that frequently occur as biologically active compounds as

well as being widely used in synthetic chemistry. Azocine is a heterocyclic organic

compound with the molecular formula C7H7N. It consists of an unsaturated eight-membered

ring having seven carbon atoms, one nitrogen atom and four double bonds. Saturated or

partially saturated azocine rings form the core structure of a group of opioid compounds

sometimes known as azocines. These include cyclazocine, pentazocine and phenazocine. The

fully saturated analog of azocine is azocane. Although foundations providing pioneering

work on azocines had been started in the 1920s and 1930s, only limited systematic or

comparative studies of azocines as a class have been done. In order to avoid repetition as well

as to cover all the relevant literature available, some sections such as Azocines are a

heterogeneous group of compounds. Most of the highly unsaturated azocines have been

obtained from bi- or tri-cyclic precursors by bond reorganization processes which often

consist of a single example. The properties and reactions of the azocines obtained by various

approaches are in large measure characteristic of the substituents associated with a particular

method, and for this reason, preparations and reactions have been discussed together. There

has been little systematic or comparative study of azocines as a class, but questions of general

interest include the relative stability of the eight-membered rings and bicyclic valence

isomers and the potential aromaticity of 10π-electron systems.

Molecular formula - C7H7N

Molecular weight - 105.140 g·mol−1

Melting point - −37 °C

Boiling point - 138 °C

Solubility - Acetone, chloroform


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SCHEME AND MATERIALS METHOD

STEP 1: Synthesis of ethyl 2-methylnicotinate.

A mixture of ethyl 3-oxo butanoate (0.1 mole), toluene (0. 1 mole), acrolein (0.1 mole)

and ethanol (70 ml) reflex for 4 hours.

Ammonum acetate (0.5M) solution add drop wise with vigorous stirring.

The solution is washed with 0.1 N NaOH.

The reaction mixture is poured into crushed ice, the product is wash with water

repeatedly, dried and recrystallise from ethanol.

STEP 2: Synthesis of ethyl 2-(chloromethyl)nicotinate.

Equimolar quantities of compound 1, dimethyl formamide and tri chloro cyanuric

chloride were reflux in ethanol using dichloro methane as a catalyst for 16 hours. The

solution mixture is concentrated and poured on crushed ice. The compound thus obtained

is filter, dry and recrystallise from ethanol.


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STEP 3: synthesis of diethyl 2-((3-(ethoxycarbonyl)pyridin-2-yl)methyl)malonate.

Compound 2 (0.1 mole) is to be dissolve in diethyl malonate (0.1 water repeatedly and

recrystallised mole) is reflexed sodium in ethanol for 5 hours. The content is evaporated to

dryness and the product so obtained is washed with from ethanol.

STEP 4: synthesis of 5-butylnonan-5yl 5-oxo-6,7-dihydo-5H-cyclopentapyridine-6-

carboxylate.

Compound 3 (0.1 mole) is to be dissolve in tetra hydro furan ( 50ml) which is to be added

to sodium hydride (0.1 mole) in acetone (50ml) and the contents to be refluxed in ethanol in

for5 hours. The reaction mixture is reduced to half of its volume and poured onto crushed ice.

The product so obtain is wash with water repeatedly, dried and recrystallised from ethanol.


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STEP 5: Synthesis of (z)-6-methyl-7-phenyl-9,10-dihydropyrido(3,2)azocin-5(6H)-oxo-9-

acetic acid.

Compound 4 (0.1 mole) is to be dissolved in potassium carbonate (0.5M) is refluxed in

acetone for 8 hours. The content is evaporated to dryness and the product so obtained is

washed with water repeatedly and recrystallised from ethanol.

CHEMICALS

Ethyl 3-oxobutanoate, Acrolein, Toluene, Ethanol, Ammonium acetate, Sodium hydroxide,

Dimethyl formamide, Tri chloro cyanuric chloride, Dichloromethane, Diethyl malonate,

Tetra hydro furan, Acetone, Sodium hydride, Potassium carbonate.

APPARATUS

Round bottom flask, Reflex condenser, Measuring Cylinder, Beakers, Funnel, Petri plates,

Glass rods, Water bath, Weighing balance, Tripod stand.

PHYSICAL CHARACTERISATION

Molecular formula - C19H18N2O3

Molecular weight - 322gm/mole

Melting point - +40°C

Boiling point - 138 °C

Solubility - Acetone, Ethanol, Methanol, Water


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BIOLOGICAL ACTIVITY

ANTI INFLAMMATORY ACTIVITY

Non-steroidal anti-inflammatory drugs (NSAIDs) are the backbone for the management of

pain which arises due to inflammatory diseases. These drugs suppress natural processes that

are responsible for inflammation. A number of non-selective nonsteroidal anti-inflammatory

drugs (NSNS-AIDs) such as indomethacin, ibuprofen, phenylbutazone, oxyphenylbutazone,

diclofenac, fenoprofen, caprofen, benoxaprofen, sulindac and aspirin etc. are available in the

market. NSNSAIDs are nonselective inhibitors of the enzymes which are responsible for the

conversion of arachidonic acid to prostaglandins. The use of these drugs is associated with

adverse gastrointestinal effects, such as dyspepsia, gastroduodenal ulcers, gastritis and

bleeding. NSAIDs are useful not only in the treatment of inflammatory diseases but can also

prevent cancers, Alzheimer’s disease, neurodegenerative and related dementias,

immunodeficiency disorders, cataract formation , and even assist in the prevention of

cardiovascular complications in diabetic patients. NSAIDs etodolac and nabumetone, which

are mildly selectivec for COX-2 may lead to a some what lower risk for ulcers than

traditional NSNSAIDs. Celecoxib, rofecoxib and meloxicam are known as COX-2 selective

non-steroidal anti-inflammatory drugs . These drugs have improved gastrointestinal safety

but may cause acute renal failure. Since serious side 1effects are associated with the use of

various NSNSAIDs and COX-2 selective NSAIDs, they cannot be taken for long time

continuously. Before describing different approaches about the development of safer

antiinflammatory drugs it will be worthwhile to review what is known as the mode of action

of non-steroidal anti-inflammatory drugs.

HRBC Membrane Stabilisation method

The method involves the stabilization of human red blood cell membrane by hypotonicity

induced membrane lysis.

Principle

The lysosomal enzymes released during inflammatory condition produce a variety of

disorders. The extra cellular activity of these enzymes is said to be related to acute or chronic

inflammation. The anti-inflammatory agents act by either inhibiting the lysosomal enzymes

or by stabilizing the lysosomal membrane since the human red blood cell membrane are

similar to lysosomal membrane components. The prevention of hypotonicity induced HRBC

membrane lysis is taken as a measure of anti-inflammatory activity of the drug.


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Reagents

HRBC suspension: 10 %

Alsiever solution

Isotonic saline: 0.85%

Phosphate buffer: 0.15M,pH-7.2

Hypotonic saline: 0.36 %

Preparation of Alsievier’s solution

2g dextrose + 0.8g sodium citrate + 0.05g citric acid + 0.42g sodium chloride was made up

with distilled water to 100ml. Preparation of 0.5 ml of 10 % HRBC SuspensionTo 3 ml of

blood, add 3 ml of Alsievier’s solution and centrifuge at 3000 rpm for 20 minutes then

packed cells were washed with isotonic saline and later10% v/v suspension of the packed

cells was made with isotonic saline.

Preparation of Hypotonic Saline: 0.36g of sodium chloride in 100 ml of distilled water.

Preparation of Isotonic Saline: 0.85g of sodium chloride in 100 ml of distilled water.

MATERIALS AND METHOD

In vitro antioxidant activity

The in vitro antioxidant activity was carried out by DPPH radical scavenging assay method

with suitable modification. In brief, the assay was carried out using UV spectrophotometer at

517 nm. To the 2 mL solution of synthesized compounds (0.1 µM), 2 mL DPPH solution (25

µM) was added into the test tube. The solution was incubated at 37 °C for 30 min and the

absorbance of each solution was measured at 517 nm against the reagent blank solution. The

ascorbic acid (0.1 µM) was used as the reference antioxidant. The experimental values

summarized for DPPH radical scavenging assays are expressed as the mean ± standard error

of mean (m ± SEM). The percent free radical scavenging activity was calculated by the

formula given below.

% Scavenging = control absorbance – test absorbance/control absorbance ×100

Anti-inflammatory evaluation

Anti-inflammatory activity was evaluated by carrageenan-induced paw edema test using

groups of albino rats weighing 100-120 g each and 6 rats per group, as per the reported

method.[13]

The animals were injected with 0.1 mL of carrageenan (1% solution in normal

saline) in the plantar tissue of the right hind paw. The first group received only 0.5%


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carboxymethylcellulose (CMC) orally and served as untreated control. The test groups

received compounds suspended in 0.5% CMC orally at a dose of 25 mg kg-1 one hour prior

to carrageenan injection. While the positive control group received 25 mg kg-1 indomethacin

suspended in 0.5% CMC, orally one hour before carrageenan injection.

Four hours after carrageenan administration, the paw volumes (mL) were measured using the

mercury displacement technique with the help of a plethysmograph. The percent inhibition of

paw edema was calculated by using the following formula.

% Inhibition = (a-x/b-y) × 100

ANTI OXIDANTS

Antioxidant is a molecule that inhibits the oxidation of other molecules. Oxidation is a

chemical reaction that transfers electron or hydrogen from substances to an oxidizing agent.

Oxidation reactions can produce free radicals. In turn, these radicals can start chain reactions,

when the chain reactions occurs in a cell, it can cause damage or death to the cell.

Antioxidants terminate these chain reactions by removing free radical intermediates and

inhibit other oxidative reactions, (Ames et al., 1993, Shenoy & Shirwaiker 2002). They do so

by being oxidizing themselves. Antioxidants are often reducing agents such as, thiols,

ascorbic acid or polyphenols (Sies, 1997). The term antioxidant has been defined in a number

of ways like substances that in small quantities are able to prevent or greatly retard the

oxidation of easily oxidizable materials, or any substance when present in low concentrations

compared to those of an oxidizable substrate significantly delays or prevents oxidation of

those substances (Halliwell & Gutteridge 1999). In food science, it is defined as a substance

in foods when present at low concentrations compared to those of an oxidizable substrate

significantly decreases or prevents the adverse effects of reactive species such as reactive

oxygen and nitrogen species or normal physiological functions in human. Antioxidant is a

molecule that inhibits the oxidation of other molecules. Oxidation is a chemical reaction that

transfers electron or hydrogen from substances to an oxidizing agent. Oxidation reactions can

produce free radicals. In turn, these radicals can start chain reactions, when the chain

reactions occurs in a cell, it can cause damage or death to the cell. Antioxidants terminate

these chain reactions by removing free radical intermediates and inhibit other oxidative

reactions.


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Nitric oxide radical-Scavenging Activity

Reagents

Sodium nitroprusside

Standard phosphate buffer solution

Griess Reagent (mixing the equal volume of 1% sulphanilamide in 2% phosphoric acid &

0.1% naphthyl ethylene diamine dihydrochloride in water).

Standard: Acetic acid

Hydrogen peroxide (H2O2) Scavenging Activity

Reagents

Hydrogen peroxide

Methanol

Phosphate buffer saline(PH-7.4)

METHOD

Oxygen Radical Absorbance capacity method (ORAc)

When a free-radical generator such as an azo-initiator compound is added to a fluorescent

molecule such as β-phicoerythrin or fluorescein and heated, the azo-initiator produces

peroxyl free radicals, which damage the fluorescent molecule, resulting in the loss of

fluorescence. Curves of fluorescence intensity vs time are recorded, and the area under

thecurves with and without addition of an antioxidant is calculated and compared to a

standard curve generated using the antioxidant 6-hydroxy-2,5,7,8-tetramethylchromane-2-

carboxylic acid, a water-soluble vitamin E analog trademarked by Hoffman- LaRoche as

Trolox.

SPECTRAL ANALYSIS


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IUPAC Name

6-methyl-7-phenyl-9,10-dihydropyrido(3,2)azocine-5(6H)-oxo-9-acetic acid.

IR INTERPRETATION

I.R. Spectral data(KBr discs) ( in Cm-1

)

C=N 1675

C=C 2720

C=O 1325

C-N 1100

1HNMR INTERPRETATION

1HNMR Spectral data absorption position ( in PPM)

6.55-7.3 m, 10H, ArH

1.7 d, 3H, CH3

2.7 s, 2H, COOH

3.7-3.9 m, 3H, NH

RESULTS AND DISCUSSION

SYNTHESIS

The present study reports the symthesis of azocine derivatives. Electrophillic addition of

Ethyl 3-oxo butanoate in acrolein was carried out stepwise at different temperatures by

various acids. The final azocine derivative in the synthesized compound-5 was replaced by

acetic acid. Since the report regarding this compound suggest a azocine possesses a good

biological activity.

PHYSICAL CHARACTERIZATION

At room temperature of newly synthesized compound were determined by various organic

solvents and it was found that all compounds were freely soluble in ethanol, methanol, DMF,

DMSO and carbon tetra chloride.

STRUCTURAL CONFIRMATION

The Infared spectroscopy was performed with potassium bromide on perking FTIR

instrument presence of stretching the range 1100cm-1

to 3000cm-1

. Integrating the presence of

C=N functional group between 1500cm-1

to 2000cm-1

. C=O functional group stretching

between 1300cm-1

to 2000cm-1

.

HNMR spectroscopy was recorded on buker 400MHZ. HNMR a chemical shift were

reported as parts per million downfield, from tetra methylsilane and solvent used as


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chloroform. Presence of chemical shift in the range 6.55-7.3 (m, 10H, ArH), 3.7-3.9 (m, 3H,

NH).

IN VITRO ANTI-INFLAMMATORY ACTIVITY

The synthesized compounds are to be used for this study. They are to be made into doses of

1000 µg/ml with DMSO (5.0 %) solution. Diclofenac sodium is taken as standard. The

reaction mixture (4.5 ml) consist of 2 ml of hypotonic saline (0.36 % sodium chloride), 1 ml

of 0.15 M phosphate buffer (Ph 7.4), 1 ml of the test solution (1000 µg/ml) in normal saline

and 0.5 ml of HRBC suspension in normal saline. For control test, 1 ml isotonic saline is to

be used instead of test solution while product control lacked RBC. The mixture is then

incubated at 56˚C for 30 minutes, then to be cooled under running tap water and centrifuged

at 3000 rpm for 20 minutes. The absorbances of the supernatants are read at 560 nm.Percent

membrane stabilization activity is calculated as follows.

% Stabilization = X 100

S. No Compound code Percentage stabilization

1 Acetic acid 80

2 Paracetamol 84

ANTI OXIDANT ACTIVITY

Nitric oxide radical-Scavenging Activity

In the assay, 2ml of sodiumnitroprusside (10mM) in 0.5ml phosphate –buffered saline (PBS)

was mixed with 0.5ml of different concentration of sample ranging from (50-250µg/ml)

prepared in methanol and incubated at 25ºC for 150min. A control without the test

compound, but with an equivalent amount of methanol, was taken. After 30 min, 1.5ml of

incubated solution was removed and diluted with 1.5ml of Griess reagent. Absorbance of

chromosphore formed during diazotization of the nitrite with sulphanilamide and subsequent

coupling with NEDD was measured at 546nm and the percentage scavenging activity

measured with reference to the standard.

% Inhibition = x 100

Hydrogen peroxide (H2O2) Scavenging Activity

All the compounds and the standard are dissolved in methanol and the various concentration

of sample ranging from 50-250µgm/ml) was prepared using methanol in different 10ml

volumetric flasks. To each solution 2ml hydrogen peroxide (2ml) was added and the volume


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made 10ml with phosphate buffer saline (PH-7.4). A control solution was prepared with

methanolic solution in phosphate buffer saline without hydrogen peroxide solution. The

absorbance at 230nm was recorded using a UV-visible spectrophotometer against blank

samples. The percentage inhibition of Hydrogen peroxide scavenging activity will be

calculated using the following formula,

% Inhibition = x 100

Compounds 50µg/ml 100µg/ml 150µg/ml 200µg/ml 250µg/ml

Acetic acid

derivative 79 65 77 79 89

STD 80 82 79 84 79

CONCLUSION

In the present study certain Azocine derivatives were synthesized and characterized

by1HNMR. The synthesized compound show characteristic absorption peaks –in

1HNMR spectra. Expected molecules in (m+) fragments were observed for the entire

compounds in mass spectra.

The synthesized compound was subjected to biological evaluation. The compound were

evaluated for anti-inflammatory studies revealed that the substitution of different acids

parent Azocine nucleus show the moderate activity.

The compound were subjected to in-vitro anti-oxidant activity using acetic acid as a

standard by two methods i.e. by Hydrogen peroxide scavenging method and nitric oxide

radical scavenging method. Antioxidant activity revealed that the synthesize compound

(50µg/ml) have shown significant anti-oxidant activity when compared with that of

standard drug.

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