lavanya thallada phone: 8008756765, 9866686263 email

LAVANYA THALLADA Phone: 8008756765, 9866686263

Email: [email protected]

Education:

Degree University/Board Percentage Year of

Pass

Ph D Singhania University pursuing

M. Pharmacy Vaagdevi College of Pharmacy 71 2008

B. Pharmacy Vaagdevi College of Pharmacy 69 2003

Intermediate Board of Intermediate, A. P 81 1997

SSC Board of Secondary Education, A. P 81 1995

Skills:

TLC

Column Chromatography

HPLC (Shimadzu-LC-10, Waters-Empower-2 & Cyberlabs)

UV-Visible Spectrophotometer

IR Spectrophotometer

Professional Experience:

Working as Asst. Professor in Care College of Pharmacy since 2009

Publications:

Preparation and characterization of Benzimidazole derivatives as possible anti-

inflammatory agents in international journal of research in pharmacy and chemistry.

Rapid Synthesis of new 1,4-dihydropyridines as possible antimitotic agents in

international journal of research in pharmacy and chemistry.

Evaluation of anti-inflammatory activities of ethanolic whole plant extract of svensonia

hyderabadensisl in journal of pharmacy research.

Simultaneous estimation of Acebrophylline and Montelukast Sodium in tablet dosage

forms by HPLC. Inventi Rapid: Pharm Analysis & Quality Assurance, 2017(1):1-11,

2016.

A simple colorimetric method for estimation of Racecadotril in capsule dosage form.

Inventi Rapid: Pharm Analysis & Quality Assurance Vol. 2017, (2). 1-7.

Presentations & Participations:

Presented a poster on Method development and validation for the simultaneous

estimation of ivabradine and Metoprolol by RP HPLC Method at Two day national

conference on current scenario in pharmaceutical sciences

Presented a paper on simultaneous estimation of clotrimazole,Lignocaine HCL in ear

drops by RP HPLC method at University college of pharmaceutical sciences,Palamuru

university

Attended National Level Workshop in Bioanalytical Techniques and Methodologies held

at care college of pharmacy, Warangal.

Attended National Level 3 Day Workshop on Inter personnel skills held at care college

of pharmacy, Warangal.

Attended DST sponsored 3day workshop in Microbial analysis of food and potable water

held at Kakatiya degree college, Warangal

Attended QIP Programme during the year 2010 at Kakatiya University, Warangal

Participated in Recent Trends In Pharmaceutical Sciences and Research held at Vaagdevi

College of Pharmacy

Participated in National Conference on Architecture of Generic Trails held at Care

college of Pharmacy

Participated in Recent advances in Pharmaceutical sciences (RAPS - 2020) held at

Kakatiya university.

Participated in APP 5th

INDO-US conference on Modern trends and challenges in

Pharmaceutical technologies and sciences

Acted as Adjudicator in the national seminar held at Jangaon institute of pharmaceutical

sciences.

Computer Proficiency:

Proficient at computer-based software applications like Microsoft Office (MS Word, MS

Excel, Power Point, etc), Chem Office.

Strengths:

capable of persistent independent and group work.

Good technical writing of research articles and reports, good compilation and oral

presentation skills.

Self-motivating

Personal Information:

Father’s name : T. Prakash Rao

Date of birth : 02-07-1980

Place of birth : Warangal, Andhra Pradesh

Nationality : Indian

Marital status : Married

(THALLADA LAVANYA)

ISSN: 2231 2781 IJRPC 2011, 1(4) Lavanya et al.

1203

ABSTRACT

1,4 Dihydr opyridines and their derivates play vital role in biological field such as

antimicrobial, anticancer, antihypertensive, antianginal, antitubercular, anticonvulsant

activities. Therapeutic significance of these clinically useful drugs in treatment of tumors

encouraged the development of some potent and significant compounds. A series of 4 -

substituted DHP derivatives ( Ia-Ie, IIa -IIe ) were synthesized and evaluated for their possible

anti-mitotic activity. The structures of the synthesized compounds were confi rmed on the

basis of their spectral data and elemental analysis. Majority of the compounds were active in

germinating onions, Bengal gram seeds as antimitotic agents and the compound IIe has

shown significant antimitotic activity .

Keywords: 1, 4 DHP, germ inating onions, Beng al gram seeds and antimitotic activity .

INTERNATIONAL JOURNAL OF RESEARCH IN PHARMACY AND CHEMISTRY

Available online at www.ijrpc.com

RAPID SYNTHESIS AND EVALUATION OF NEW 1, 4 –

DIHYDROPYRIDINES AS POSSIBILE ANTI MITOTIC AGENTS

T. Lavanya1*, S. Manjula 1, Rajkiran Ellandala 2, T. Pradeep kumar1 and K. Madhavi 3.

1Department of Pharmaceutical chemistry, Care college of Pharmacy, Oglapur, Warangal,

Andhra Pradesh, India . 2Department of Pharmacology, Care college of Pharmacy, Oglapur, Warangal, Andhra Prades h, India .

3Department of Pharmaceutics, Care College of Pharmacy, Oglapur, Warangal, Andhra Pradesh,

India .

*Corresponding Author: [email protected]

INTRODUCTION

Hantzsch, almost over 100 years ago brought

out the synthesis of 1, 4 -dihyd ropyridines (1,4 -

DNP) without even anticipating and

visualizing their potency. The last two decades

mostly have witnessed the pharmacological

and therapeutic importance of a few such 1,4 -

dihydropyridines into the world market as

successful and useful drugs in the treatment

of some important cardiac ailments like

angina, hypertension etc. this property is

attributed mostly to their ability to block

effectively the calcium channels (L -type).

That’s how they are called as the ‘calcium

channel blockers or calc ium antagonists’.

Thus, 1, 4-Dihydropyridines have attracted the

attention of several chemists and

pharmacologists. As a result of it, several of

them have been synthesized and screened for

their effectiveness. Most of them vary in their

nature of substitu ent’s at 3,4 and 5 positions.

Interestingly, the 1, 4 -dihydropyridine

derivatives which have become drugs of

medical importance are their 3,5 -dicarboxylic

acid esters. Further, studies and investigations

by several scientists have proved these 1, 4 -

dihydr opyridine derivatives which have

become drugs of medical importance are their

3, 5-dicarboxylic acid ester. Further studies

and investigations by several scientists have

proved these 1, 4 -dihydropyridines to exhibit

not only the calcium channel blocking ac tion

or Calcium antagonism, but also to possess

several other actions, such as vasodilator,

bronchodilator and platelet aggregation

inhibition. They also have known to exhibit

cerebral anti -ischemic activity in the treatment

of Alzheimer’s disease, Chemo s ensitizers in

tumor therapy, Ant atherosclerotic,

Research Article

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1204

Genoprotective, Hepatoprotective,

Antidiabetic and Antiasthamatic activities 1,2,3.

Chemistry of 1, 4 – Dihydropyridines

The basic skeleton of 1, 4 -DHP is a doubly

unsaturated six membered cyclic system wit h

one hetero atom and two double bonds.

Owing to these double bonds and the lone

pair on the N -atom, this skeleton is prone to

react with electrophilic reagents. While the

lone pair on N -atom afford basicity to the

compounds containing this skeleton. The π

electrons in double bonds facilitate the

reactions with electron deficient species such

as carbocations. Substitution on this skeleton

shows remarkable rigid selectivity. Two

equivalent and iso energetic resonance forms

can be written for 1, 4 -DHP. Clearl y the 3 and

5 positions hold formal negative charges in

this rigid forms, and more likely to react with

electrophiles, when reacted with alkyl or aryl

halides. 1, 4 -DHP typically yields mono - or

disubstituted alkyl or aryl derivatives 4,5,6.

The potency and activity of 1, 4 -DHP is

connected to its structure. It is possible that the

basicity of the N -atom in 1, 4 -DHP is critical to

the function of 1, 4 -DHP based drugs in their

ability to bind to calcium channels. The N -

atom in 1, 4 -DHP is aliphatic tertiary n itrogen

that is more basic than the pyridyl N -atom.

The differences in basicity between these two

types of N -atom are relevant when one

considers the potential redox reactions that

can occur in liver. For example, Bocker has

studied the aromatization of 1, 4-DHP system

in the metabolism of the drugs. The oxidation

reaction is highly favored even under mild

conditions because the product, pyridine, is

aromatic. This aromatization of 1, 4 -DHP is

therefore an important factor in the design of

animitotic drugs 7. We considered the use of

electron with drawing constituents at 3 and 5 -

positions because they pull the π-electrons

away from the 1,4 -DHP ring and thwart the

aromatization 8.

EXPERIMENTAL

PROCEDURE

1. Synthesis of 4-alkyl 3, 5-bis carboethoxy 2,

6-dimethyl 1,4-dihydropyridines (I):

Ethyl aceetoacetate (0.02 moles) and an

appropriate aliphatic aldehyde (0.01 mole)

were taken into a beaker (250ml) and

dissolved in minimum quantity of solvent

methanol (5 -10ml). An appropriate aryl amine

(0.01 mole) was added while wtirring. A

funnel was hanged in the beaker and covered

with a watch -glass and then the reaction

mixture was subjected to the microwave

irradiation at 400 Watt each in a domestic LG

little chef microwave oven for 2 -4 min. the

solvent was removed, and the residue was

cooled and triturated with crushed ice. The

resultant produced was filtered, washed with

small portions of cold water and dried. It was

purified by recrystallization from hot

methanol 9,10.

Nomenclature

Ia – 3,5-bis carboethoxy -2,6-dimethyl 1,4-

dihydropyridine

Ib – 4-Methyl -3, 5-bis carboethoxy -2, 6-dimethyl

1, 4-dihydropyridine

Ic – 4-Ethyl -3, 5-bis carboethoxy -2, 6-dimethyl 1,

4-dihydropyridine

Id – 4-Propyl -3, 5-bis carboethoxy -2, 6-dimethyl


Ie - 4-Butyl -3, 5-bis carboethoxy -2, 6-dimethyl 1,

4-dihydropyridine

Characterization Compound Ia

Mol. Forml: C 13H24NO4; Mol wt. 258;

Solubility: Methanol; M.p 180°C; R f : 0.4

(Hexane; Ethyl acetate).

Compound Ib

Mol. Forml: C 14H26NO4; Mol wt. 272;

Solubility: Methanol ; M.p 118°C; Rf : 0.44

(Hexane; Ethyl acetate); 1H NMR -(CD3OD)

δppm: 0.8 (s, 3H, CH3), 1.3-1.5 (t, 6H,2CH 3 of

2COOCH 2 CH3), 2.56 (s, 6H, CH 3 at 2nd & 6th

position), 2.78 -2.85(m, H at C 4), 4.3-4.4 (q, 4H

CH2 of 2 COOCH 2CH3), 8.70(s, H, NH). Compound Ic

C15H28NO4; Mol wt. 286; Solubility: Methanol; M.p 110°C; R f : 0.5 (Hexane; Ethyl acetate →3:2); 1H NMR -(CD3OD) δppm: 0.60-0.75(t,

3H, CH 3 of C2H5), 1.25-1.40 (m, 6H, 2CH 3 of 2COOCH 2CH3), 2.50(s, 6H, 2CH 3 at 2nd & 6th

position), 3.2 -3.3 (t, H at C 4), 4.3-4.4 (q 4H,

2CH2 of 2COOCH 2CH3), 8.75(s, H-NH DHP), 1.45-154 9m, 2H, CH 2 of C2H5). Compound Id

C16H30NO4; Mol wt. 300; Solubility: Methanol; M.p 122°C; R f : 0.6 (Hexane; Ethyl acetate →3:2); 1H NMR -(CD3OD) δppm: 0.92(t, 3H,

CH3 of C3H7), 1.3-1.5(q, 6h, 2CH 3 of

2COOCH 2CH3), 1.6-1.7 (m, 2H, CH 2 of C3H7), 2.26(s, 6H, 2CH 3 at 2nd & 6th position, 3.1 -3.3

(t, H at C4), 4.2-4.4 (m, 4H, 2CH 2 of 2COOCH 2CH3), 8.75(s, H-NH).


1205

Compound Ie: C17H32NO4; Mol wt. 314;

Solubility: Methanol; M.p 143°C; R f : 0.65

(Hexane; Ethyl acetate →3:2); 1H NMR -

(CD3OD) δppm: 0.92(t, 3H, CH3 of C4H9), 1.3-

1.5(m, 6H, 2CH 3 of 2COOCH 2CH3), 1.6-1.7(t, 2H, CH 2 of C4H9), 2.26(s, 6H, 2CH 3 at 2nd & 6th

position), 3.1 -3.3(t, H at C 4), 4.2-4.4 (m, 4 H,

2CH2 of 2COOCH 2CH3), 8.75(s, H-NH).

2. Synthesis of 4-alkyl 3,5-biscarbamoyl 2,6-

dimethyl 1,4 -dihydropyridine ( II)

N-Acetoacetylation of Aniline:

Acetoacetanilide have been prepared from a

reaction of ethylacetoacetate with appropriate

aromatic primary amine. The acetoacetylation

of aniline is carried out by the microwave –

induced methods. This method has been

found to vary in their reaction times and

percentage yield of the product.

Condensation of Acetoacetanilide with different

Aliphatic Aldehyde, and Ammonium acetate:

Acetoacetanilide should subjected to a three

component condensation reaction involving

itself, an appropriate aliphatic aldehyde and

ammonium acetate by microwave irradiation

method, while monitoring the progress of the

reaction by TLC technique.

Nomenclature IIa – 3, 5-bis carbamoyl -2, 6-dimethyl 1, 4 -

dihydropyridine

IIb – 4-Methyl - 3, 5-bis carbamoyl -2, 6-dimethyl


IIc – 4-Ethyl -3, 5-bis carbamoyl -2, 6-dimethyl 1,

4-dihydropyridine

IId – 4-Propyl -3, 5-bis carbamoyl -2, 6-dimethyl


IIe – 4- Butyl -3, 5-bis carbamoyl -2, 6-dimethyl 1,

4-dihydropyridine Compound II a

C21H21O2N2; Mol wt. 347; Solubility:

Methanol; M.p 123 -125°C; RF: 0.7 (Hexane;

Ethyl acetate →4:3).

Compound IIb


Methanol; M.p 130 -132°C; Rf : 0.74 (Hexane;

Ethyl acetate →4:3); 1H NMR -(CD3OD) δppm:

0.82(d, 3H, CH 3), 2.56(s. 6H, CH 3), 6.5- 6.7(m,5H, C6H5), 7.2-7.3(m, 5H, C6H5), 8.75(s, H, -NH Dihydropyridines), 10.78(s, H, -NH

Carbamoyl).

Compound IIc


Methanol; M.p 110 -112°C; Rf: 0.8 (Hexane;

Ethyl acetate →4:3); 1H NMR -(CD3OD) δppm:

0.82(t, 2H, CH 2 of Ethyl group), 2.26(s, 6H, CH 3

Group at 2 nd & 6th position). 3.1 -3.3 (t, H), 6.6-

6.9 (t, 5H, C6H5), 7.2-7.4 (m, 5H, C6H5), 8.75 (s, - H, -NH Dihydropyridines), 10.78 (s, H, -NH,

Carbamoyl).

Compound IId


Methanol; m.p 126 -128°C; Rf : 0.9 (Hexane;

Ethylacetate →4:3); 1H NMR -(CD3OD) δppm:

0.6-0.9(t, 3H, CH 3 of Propyl), 1.1 -1.2(m, 2H, CH2 of Propyl), 1.4 -1.5(m, 2H, CH 2 of Propyl),

2.26( s, 6H, CH 3 groups at 2 nd

& 6th

position),

3.1-3.4(t, H), 6.81(t, 5H, C 6H5), 7.3-7.4(m, 5H,

C6H5), 8.75(s, -H, -NH DHP), 10.78(s, -H, -NH Carbamoyl).

Compound IIe


Methanol; m.p 143 -148°C; Rf : 0.94 (Hexane;

Ethylacetate →4:3); 1H NMR -(CD3OD) δppm:

0.6-0.9(t, 3H, CH 3 of Butyl), 1.1 -1.2(m, 2H, CH 2

of Butyl), 1.29 -1.31(m, 4H, 2CH 2 of Butyl),

2.26(s, 6H, CH3 groups at 2nd

& 6th

position),

3.1-3.4 (t, H), 6.81(t, 5H, C 6H5), 7.3-7.4(m, 5H, C6H5), 8.75(s, -H, -NH DHP), 10.78(s, -H, -NH Carbamoyl)

PHARMACOLOGICAL EVAL UATION FOR

ANTIMITOTIC ACTIVITY

1. Using Germinating Bengal gram seeds

A Bengal gram seed of a good quality was

taken and soaken overnight with water to

hasten the germination process. The next day,

the seeds were distributed in a group of 10

each in Petri dishes on moistened filter paper.

Drug solutions were prepared in 1% DMSO at

concentrations ranging from 125 -1000µg/ ml

and added to the filter paper the Petri dishes.

One Petri dish served as DMSO control and

one served as Paclitaxol (Positive) control. The

seeds were allowed to germinate for 7days

and care was taken to moisten the filter paper

with control and drug solutions for every

24hours. The length of the radicals was

measured in cm at the end of 7 th day and %

mean values of the DMSO (control) treated

and %inhibition in growth is calculated. The

values are plotted on a graph 11,12.

2. Using germinating Onions (Allium cepa)

Onions (Allium cepa) of a good quality were

taken and hasten the germination process. The

next day the bulbs were distributed in a group

of two each in Petri dishes on moistened filter

paper. Drug solutions were prepared i n 1%

DMSO at concentrations ranging from 125 -

1000µg/ ml and added to the filter paper in the

Petri dishes. One Petri dish served as solvent

control, and one served as Paclitaxol (Positive)


1206

control. The bulbs were allowed to germinate

for 7days and care was taken to moisten the

filter paper with control and extracts every

24hours. The length of the radicals was

measured in cm at the end of 7 th day and

percentage mean values of the control treated

and percentage inhibition in growth is

calculated the values ar e plotted on a graph.

RESULTS

All the 1, 4 Dihydropyridines derivatives were

synthesized according to the standard

procedure as mentioned in the scheme. In all

the cases completion of reactions were

confirmed by TLC & characterized with the

help of spectr al data (IR, 1NMR). All the

derivatives were purified by column

chromatography. Melting points of the

compounds were measured using open

capillary tube.

Antimitotic activity of the derivatives showing

good cytotoxic activity was done on

germinating Allium cepa and Bengal gram

seeds derivatives Ib, Ic, Id, Ie, IIa, IIb, IIc, IId

tested for activity. Paclitaxol 10µg/ ml was

taken as positive control. The compounds

were solubilized in solvent. Solvent was taken

as control. The values of percentage inhibition

of growth at various concentrations are shown

in fig. 1-4.

Among all the 1, 4 -dihydropyridine

derivatives carbamoyl derivatives shown

better antimitotic activity than carboethoxy

derivatives.

Among all the carboethoxy derivatives of 1, 4 -

dihydropyridine, 4 -butyl 3, 5 -bis carboethoxy

2, 6-dimethyl 1, 4 -dihydropyridine have

shown better activity.

Among all the 1, 4 -dihydropyridine

derivatives 4 -Butyl 3, 5 - Biscarbamoyl 2, 6 -

dimethyl – 1,4-DHP shown significant activity.

DISCUSSION

1, 4 – Dihydropyridines we re prepared by

Hantzsch synthesis exclusively by microwave

irradiation method. In 1882 Hantzch reported

the first synthesized of 1, 4 – DHP. The

classical method for the synthesis of 1,4 –

Dihydropyridines is a one -pot condensation of

an aldehydropyridines is a one-pot

condensation of an aldehyde with ethyl

acetoacetate, and ammonia either in acetic acid

or refluxing in alcohol. However, the yields of

1,4-dihydropyridines obtained by this method

are generally low. Recently the solvent free

synthesis of 1,4 -DHP was reported. However

this method required more time for the

synthesis especially when electron

withdrawing group present on aromatic ring.

With these observation and continuous

research for the synthesis of 1, 4 –

Dihydropyridines derivatives we have

proposed an efficient and versatile method for

the preparation of 1,4 – Dihydropyridines that

provides scope for further improvement

towards milder reaction conditions and

improved yields.

CONCLUSION

In the present study all the proposed

carboethoxy (Ia, Ib, Ic, Id, Ie) and Carbamoyl

(IIb, IIc, IId, IIe) derivatives of 1, 4 -

dihydropyridines were synthesized and their

antimitotic activity was determined.

Compounds IIa, IIb, IIc, IId demonstrated

good antimitotic activity when compared to

that of respective par ent compound and the

control. Out of all the derivatives Carbamoyl

derivative IIe demonstrated significant activity

when compared to the all other derivatives

and control.

0 125 250 500 1000

Concetration in µg/ml

Ib

Ic

Id

ONIONS 100

80

60

40

20

0

Fig 1: Comparative % growth inhibition of 120

different derivatives Using GERMINATING


1207

E

Fig 2: Comparative % growth inhibition of

120 different derivatives Using BENGAL GRAIbM

100

80

60

40

20

0

Ic

Id

Ie

0 125 250 500 1000

Paclitaxol

(10µg/ml)

Concentration µg/ml

Fig 3: Comparative percentage grwoth

inhibition of derivatives Using

120 GERMINATING ONIONS II b

100 II c

80 II d

60

II e

40

20

0

Paclitaxol

(10µg/ml)

1% DMSO

0 125 250 500 1000

Concentration µg/ml

1% DMSO 0 125 250 500 1000

Concetration µg/ml

II d

II e

Paclitaxol

(10%µg/ml)

Fig 4: Comparative Percentage grIIobwth

inhibition of various compounds

using BENGAL GRAM SE DSII c

120

100

80

60

40

20

0

SEEDS


1208

ACKNOWLEDGEMENT

The Authors would like to sincerely thank

Prof. V. Malla Reddy for his great support and

encouragement.

REFERENCES

1. Desai B Sureja D, Naliapara Y, Shah

A. and Sarena AK. Bioorg & Med

chem. 2001;9:1993.

2. Pattan SR and Parate AN. Indian J

Heterocycl chem. 2003;12:387.

3. .Reddy VM. Indian Journal of

Pharmaceutical Sciences. 2001; 124-126.

4. Masami Kawase and Anamik Shah.

Bioorganic and MEDICAL Chemistry.

2002; 10:1051-55.

5. Xiao-Feizhou, Robert A and Coburn,

Journal of Pharmaceutical Sciences.

2005;94: 2256-65.

6. Pattan SR and Parate A N. Indi an

Journal of Heterocyclic Chem ,

2003;12:387.

7. Vanden Eynde and M ayence.

Synthetic Communications. 2000; 32(5):

422-425.

8. Masami Kawase and Anamik

Shah.Bioorganic and Medicinal

Chemistry. 2002; 10: 1051-1055.

9. Carmen Avendano and Carlos

Menendez J. Current Medicinal

Chemistry. 2002; 10: 159-193.

10. Vishal R Tandon and B.Kapoor.

Indian Journal of Pharmacology.

2006;38:13-24.

11. Rajesh Krishna and Lawrence Mayer D. Current Medicinal Chemistry, Anti -

cancer Agents. 2001;1: 163-174.

12. Swamy SK, Reddy TM and Reddy

VM. J Pharm Sci. 1998; 60:102.

ISSN: 2231 2781 IJRPC 2011, 1(2) Manjula et al.

148

ABSTRACT

Benzimidazole derivates play vital role in biological field such as antimicrobial, antiviral,

antidiabetic, and anticancer activity. Therapeutic significance of these clinically useful drugs in

treatment of microbial infections encouraged the development of some potent and significant

compounds. A series of 2 -substituted benzimidazoles derivatives ( Va-g) were synthesized and

evaluated for their possible anti -inflammatory activity. The structures of the synthesized

compounds were confirmed on the basis of their spectral data and elemental analysis. Majority of

the compounds were active in Carrageenan induce d hind paw edema method test and compounds

Vd and Vf had shown high potency in terms of % inhibition and are moderately potent to that of

standard drug diclofenac (20 mg/ kg body weight).

Keywords: Benzimidazoles, Anti -inflammatory, Carrageenan -induced hind paw edema.

INTERNATIONAL JOURNAL OF RESEARCH IN PHARMACY AND CHEMISTRY

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SYNTHESIS AND ANTI -INFLAMATORY ACTIVITY OF 2 -[(1H-BENZIMIDAZOLE -2YL

METHYL) SULFONYL] –N- (PHENYL ME THYLIDINE) ACETO HYDRAZIDE DERIVATIVES

Manjula Samudrala 1*, Lavanya Thallada1, Pradeep Kumar Thallada 1 and

Punnam Chander Veerati 2

1Department of pharmaceutical chemistry, Care College of Pharmacy, Oglapur, Warangal ,

Andhra Pradesh, India. 2Department of Pharmacology, Care College of Pharmacy, Oglapur, Warangal, Andhra Pradesh,

India.

*Corresponding Author: [email protected]

INTRODUCTION

Benzimidazole derivatives are of broad

interest because of their various bi ological

activity and clinical applications, they are

remarkably effective compounds both with

respect to their inhibitory activity and their

favorable selectivity ratio. 1-3 Benzimidazoles

are regarded as a promising class of bioactive

heterocyclic compoun ds that exhibit a range of

biological activities. Specifically, this nucleus

is a constituent of vitamin -B12.4 It is evident

from the literature that the benzimidazole

nucleus is present in numerous antioxidant 5,

antiparasitic 6, antihelmintics 7,

antiprolif erative 8, anti-HIV 9, anticonvulsant 10,

anti-inflammatory 11, antihypertensive 12,

antineoplastic 13, and antitrichinellosis 14

activities. Varied bioactivities exhibited by

benzimidazoles, efforts have been made from

time to time to generate libraries of these

compounds and screened them for potential

biological activities.

2- substituted analogs of benzimidazoles are

known to be more potent biologically active

compounds. Jincheng Huang et -al reported

the synthesis of 4 - (2 – pyridyl) piperazine – 1-

benzimidaz oles are used as potent TRPV1

antagonists for the treatment of anti -

inflammatory and neuropathic pain. 15

The present work was aimed to plan the

synthesis of new benzimidazoles derivatives

containing different schiff’s bases as

derivatives led to formation of biologically

more active compounds. Such reactions are

not reported so far. To evaluate new products

for anti -inflammatory activity.

Drugs and Chemicals

All the chemicals and solvents obtained from

local firms from India:

Research Article

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149

1. Carrageenan - Sd.Fine Chem.Ltd

2. OPDA (ortho phenylene diamine) -

Moly Chem.

3. Thioglycollic acid – Himedia

4. Acetone – Merck

5. Chloroform – Merck

6. NaOH – Merck

7. Ethylchloroacetate - Sd.Fine Chem.

Ltd.

8. Methanol – Merck

9. Glacial acetic acid – Merck

10. Anhydrous K 2CO3 - Universal Laboratories

11. Hydrazen e hydrate (99%) - Sd Fine

Chem Ltd.

SCHEME


150

EXPERIMENTAL PROCEDUR E

1: Synthesis of 1H -Benzimidazol-2-

ylmethane thiol (ll)

3.5gms of o-phenylenediamine was taken in

250ml round bottom flask. It is dissolved in

30-40 ml of 4N Hcl .Then Add 1.5ml of

thioglycolicacid.This reaction mixture was

kept for reflux for about 3 -4hours. The

solution was made alkaline by adding

saturated sodium hydroxide solution (2 -3ml).

The base precipitated was filtered and dried.

The compound was recrystalised from

Acetone or ch loroform [Yield: 85%] as a light

brown solid mp 154 -1600C Mobile phase –

chloroform:methanol = 2:0.5ml

2: Synthesis of Ethyl [(1H -benzimidazol-2-

ylmethyl) sulfanyl] acetate (lll)

1H-Benzimidazol -2-ylmethane thiol(II) was

dissolved in 40 -50ml of dry aceto ne in 250ml

round bottom flask then add 0.65ml of

Ethylchloroacetate drop wise ,add potassium

carbonate(0.01m) and shaken thoroughly. It

was refluxed for 12 -16hours by taking proper

care that no moisture should enter in to the

flask. Calcium guard tube wa s fixed to the

condenser and temperature was maintained at

560C.

The compound was recrystalised from

methanol [Yield: 70%] as a dark brown solid.

Mobile phase -chloroform: methanol=2:0.5

3: Synthesis of 2-[(1H-benzimidazol-2-yl

methyl) sulfanyl] acetohydrazide (IV)

Ethyl 1H -benzimidazol -2-yl methyl) sulfanyl]

acetate (III, 0.01m) was taken in 250ml round

bottom flask and dissolved in 30ml of

methanol. To this hydrazine hydrate (0.01m)

was added drop wise and shaken well. The

reaction mixture was refluxed f or 1-2hours by

maintaining temperature 64 0C.Methanol was

evaporated and the compound was collected

and dried.

Recrysalised from ethanol (Yield: 74%) as a

light brown solid. mobile phase -chloroform:

methanol=2:0.5ml.

4: Synthesis of 2-[(1H-benzimidazol-2yl

methyl) sulfanyl)] –N1-(phenylmethylidene)

acetohydrazide (V)

A mixture of compound ( IV, 0.01 mol.) and an

appropriate aromatic aldehyde (0.01 ml) in

methanol ( 50ml) containing 3 -4 drops of

glacial acetic acid was reflexed on a water bath

for about 2 hours and cooled . After cooling

the resulting solid was filtered, washed

thoroughly with small quantities of methanol,

dried and recrystalized from suitable solvent

(s).

Adapting this procedure 7 different

compound was prepared by following the

above detail ed procedure and their physical

data is presented in table I.

Acute Oral Toxicity Test

Acute oral toxicity of the synthesized

compound was determined using female

albino mice. The animals were fasted for 3 h

prior to the experiment according to the

recommended procedure (OECD guideline no.

425). As per the guidelines, the animals were

observed for 48 h for any mortality following

oral administration of the different doses of

preparation. Based on this observation, a dose

of 100 mg/ kg was selected for the anti-

inflammatory studies.

Experimental Section: The protocol followed

was approved by the Institutional Animal

Ethical Committee, University College of

Pharmaceutical Sciences, Warangal.

ANTI -INFLAMMATORY ACTIVITY BY

CARRAGEENAN IN DUCED RAT HIND

PAW ED EMA METHOD

Wister strain albino rats weighing between

180-250gm, fasted 24 hours before the test,

were divided into eight groups of five animals

each. The volume of the right hind paw was

measured using a plethysmometer. This

constituted the initial readin g. Compounds

were tested in the dose of 100mg/ kg body

weight. Diclofenac 20mg/ kg was used as

standard. The compounds were administered

as suspensions in sodium CMC (0.1%w/ v)

intraperitonially 1 hr before the injection of

carrageenan. Control group of anima ls

received a suspension of sodium CMC only.

0.1ml of 1.0%w/ v carrageenan suspension in

normal saline was injected into the plantar

region (aponeurosis) of the right hind paw.

The swelling produced after injection of the

phlogistic agent was measured at ho urly

intervals for 4 hrs. Percentage inhibition of

edema was calculated using the formula given

below and the results were presented in table

II.


151

% inhibition of edema = mean edema of control group–mean edema of treated group x 100 Mean edema of control group

SPECTRAL DATA

N

C

N H2

H

S C CONHNH2

H2

(IV)

The IR Spectrum of (IV) exhibits characteristic peaks at (cm -1) (FIG. 1)

H-N-H Stretching (3322.88); N -H Stretching (3282.48); =C -H (2977.23); C-H (2931.10); C=O (1665.65);

C=C (1627.00); C=N (1525.81).

The MASS Spectrum of the compound (IV) exhibite d its molecular ion peak at m/ z 236 (FIG. 2).

N

C

N H2

H

OH

S C CONHN CH

H2

(Va)

The NMR spectrum of compound (Va) exhibits its charectaristic proton signals at 5.5 (s, OH);

4.5(s,2H, -CH2 -SH); 5.1(s,2H,S –CH2– CO); 6.4(s,1H,HC – Ar); 6.8 – 7.4 (m, 8H, Ar -H); 10.0(s,1H, -CO – NH) (FIG.3).

The MASS Spectrum of compound (Va) exhibited its molecular ion peak (m+1) at 340 (FIG. 4).

RESULTS AND DISCUSSION

The anti-inflammatory activity of 7 test

compounds has been evaluated and the data

are presented in Table II using Diclofenac (20

mg/ kg) as the standard.

The compounds Vd and Vf showed the

percentage inhibition of 55.80 and 48.75

respectively. These two compounds are the

most relatively potent of all the compounds

tested for anti -inflammatory activity. The

compounds Ve & Vg showed moderate anti -

inflammatory activity with percentage

inhibition of 48.75 & 42.50 respectively. The

compounds Vb,Vc , and Va showed minimum

anti-inflammatory activity with percentage

inhibition of 24.36,24.14,16.60 respectively.

CONCLUSION

The following conclusions have been drawn

from the results of these investigations:

All the new Benzimidazole derivatives

were evaluated for anti -inflammatory

activity and the results were found to

be encouraging.

All the new synthesized compounds

exhibited mild to moderate anti -

inflammatory activity.

Compound with methyl group at 3 rd

position, hydroxyl group at 4 th

position of phenyl ring exhibited

maximum activity with percentage

inhibition of 55.80. Compounds Vd,

Vf, Ve, Vg,Vb,Vc and Va, were

found to be next in the order of

activity.

The promising results gave us scope

for further work in this area. It has

been felt necessary from the results of


152

the present anti -inflammatory activity

that there is a need for further

advanced studies, at least on t he few

of the test compounds which are

found to be superior.

TABLE I: PHYSICAL DATA OF { 2 (1H – BENZIMIDAZOL -2 YL METHYL)

SULFANYL} – N - ( PHENYLMETHYLIDENE) ACETOHYDRAZIDE S. No. COMPOUND R M.F. Mol. wt M.P (OC ) % Yield

1 Va OH C17H 16N 4SO 306 197-200 70

2 Vb Cl C17H 15ClN 4SO 337.5 190-192 45

3 Vc F C17H 16FN 4SO 302 170-173 60

4 Vd 3-OCH 3, 4-OH C18H 18N 4SO3 353 232-235 54

5 Ve 4-N,N -dimethyl C19H 21N 5SO 349 226-230 65

6 Vf 4-OCH 3 C18H 18N 4SO2 336 195-198 67

7 Vg 3-OCH 3, 4-OCH 3 C19H 22N 4SO3 367 254-257 56

TABLE II: ANTI - INFLAMMATORY ACTIVITY OF {2 (1H – BENZIMIDAZOL – 2 – YL

METHYL) SULFANYL} – N - (PHENYLMETHYLIDENE) ACETOHYDRAZINE (V)

DERIVATIVES

S. No.

COMPOUND

R

CONTROL

TEST

DIFFERENCE

% INHIBITION

1 Va OH 4.1 3.421 0.681 16.60

2 Vb 4-Cl 4.1 3.201 0.999 24.36

3 Vc 4-F 4.1 3.113 0.990 24.14

4 Vd 3-OCH3, 4 -OH 4.1 1.812 2.228 55.80

5 Ve 4-N,N -dimethyl 4.1 2.103 1.999 48.75

6 Vf 4-OCH3 4.1 1.98 2.102 50.02

7 Vg 3-OCH3, 4 -OCH3 4.1 2.32 1.742 42.50

8 Diclofenac sodium

20mg/kg

4.1 .812 3.288 80.19

Dose of test compound = 100mg/ kg

N

C

N H 2

H

S C C O N H N H 2

H 2

FIG. 1: IR spectrum of 2 - [(1H - benzimidazol – 2 - yl methyl) sulfanyl] acetohydrazide (IV)


153

N

C

N H2

H

S C C ONHNH 2

H2

FIG. 2: Mass spectrum of 2 -[(1H- benzimidazol – 2 - yl methyl) sulfanyl] acetohydrazide (IV)

N

C

N H 2

H

O H

S C C O N H N C H

H 2

FIG. 3: 1H NMR spectrum of 2 -[(1H- benzimidazol - 2yl methyl) sulfanyl)] - N-(phenylmethylidene) acetohydrazide (Va)


154

N

C

N H2

H

OH

S C CONHN CH

H2

FIG. 4: Mass spectrum of 2 -[(1H-benzimidazol - 2yl methyl) sulfanyl)]- N-phenyl methylidene)

acetohydrazide (Va)

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and Castelli M. Synthesis and

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Journal of Pharmacy Research Vol.5 Issue 3.March 2012 1398-1399

Research Article ISSN: 0974-6943

T.Pradeep kumar et al. / Journal of Pharmacy Research 2012,5(3),1398-1399

Available online through http://jprsolutions.info

Evaluation of anti-inflammatory activities of ethanolic whole plant

extract of svensonia hyderabadensis L.

T.Pradeep kumar1*, Nusrath Yasmeen2, T.Lavanya3 , K.Sujatha4

1 * Department of Pharmacognosy, St.Peter’s college of Pharmacy, Warangal, AndhraPradesh, India 2Department of Pharmacology, UCPSC, KU, Warangal, Andhra Pradesh, India

3 Department of Pharmaceutical chemistry, Care college of Pharmacy, Warangal, A.P., India.

4Department of Pharmacognosy, St.Peters college of Pharmacy, Warangal, A.P., India.

Received on:10-12-2011; Revised on: 15-01-2012; Accepted on:12-02-2012

ABSTRACT

In the present Study of methanolic extract of whole plant of Svensonia hyderabadensis Linn.(verbanaceae) was screened for anti-inflammatory activity in carrageenan induced paw oedema rats. The effect was assessed by difference in paw oedema volume, before & after the low & high dose administration of the extract in Rats. Methanolic extract of whole plant of Svensonia hyderabadensis (100 & 200 mg. /kg. /ml.) were administered orally. Anti- inflammatory effects were compared with Standard drug- Diclofenac (10mg. /kg/ml.). These observations helped us to conclude that Methanolic Extract high dose is endowed with anti-inflammatory property.

Key words: Anti-inflammatory, Diclofenac, Svensonia hyderabadensis, Plethysmograph.

INTRODUCTION Inflammation is considered as a primary physiologic defense mechanism

that helps body to protect itself against infection, burn, toxic chemicals, allergens or other noxious stimuli. An uncontrolled and persistent inflammation may act as an etiologic factor for many of these chronic illnesses

(Kumaret al., 2004). Although it is a defense mechanism, the complex

events and mediators involved the inflammatory reaction can induce, main- tain or aggravate many diseases (Sosa et al., 2002). Currently used anti- inflammatory drugs are associated with some severe side effects. Therefore, the development of potent anti-inflammatory drugs with fewer side effects is necessary.

Svensonia hyderobadensis is shrub or perennial herb, often bushy, about 1 m tall. It belongs to family of verbanaceae. . The youngest parts are pur- plish with short and scattered hairs. Leaves decussate,opposite, elliptic- ovate to obovate, coarsely serrate, acute, and base rounded to decurrent. .Petioles slender 0.7-2.9 cm long, convex beneath, flattened and canaliculate above. Young leaves ovate or lanceolate, 2. 7-10.7 cm long1.6-5 cm wide, acute at apex. Flowers pink-purple, in terminal spikes; bracts linear-lanceolate, scarious. It is widely used by the folklore for antiinflammatory activity.

So far no systematic study has reported for anti-inflammatory property of whole plant extract of Svensonia hyderobadensis In the present study effort has made to establish the scientific validity to the anti-inflammatory property of Svensonia hyderobadensis whole plant extract using Indometha- cin & Carrageenan induced paw oedema model in Rats.

MATERIALS AND METHODS:

Collection of drug

Whole plant of Svensonia hyderobadensis were collected from Tirupati

Hills, A.P. It is commonly known as adivi chiki. Botanist of Sri. Venkateshwara University, Tirupathi, authenticated the plant. The whole plant was carefully dried in shade for 15 days, to ensure complete dryness; it was kept in hot air oven at 45ºC for 5 minutes and then subjected to size reduction to make powder. The crushed mass was then ready for extraction.

Extraction

The dried and powdered whole plant was subjected to hot extraction in Soxhlet apparatus with methanol. The residue in the R.B flask was trans- ferred into a beaker and was concentrated under reduced vacuum pressure

to give an average yield of70% (w/w).Solutions oftheSvensonia

hyderobadensis extract (MSH) were prepared freshly for the pharmacological studies.

Drugs and chemicals

Carrageenan was purchased from Merc Pvt.Ltd, and Diclofenac Sodium was obtained from Zydus Cadilla Ltd.All the solvents used were of analyti- cal grade and were obtained from Sd. Fine Chemicals, Mumbai,India.

Animals: The study was carried out on Wistar Rats weighing 125-130gm of either sex, which were procured from Sai Animal Distributors, Musheerabad. The animals were acclimatized for 1week. The animals were kept in polyacrylic cages and maintained under standard housing conditions of temperature (24-27°C) and humidity (60-65%) with 12 h light–12 h dark cycle. They were fed with commercial pelleted chow and were given free access to water ad libitum throughout the study. The animals were handled gently to avoid giving them too much stress, which could result in an increased adrenal output. All animal experiments strictly complied with the approval of institutional animal ethical committee.

Acute Toxicity Studies The acute toxicity study was carried out in adult female albino rats by the ‘up and down’ method [11]. The animals were fasted overnight and next day extracts of the Cordia dichotoma forst dissolved in normal saline was administered orally at different dose level. Then the animals were observed continuously for 3 hours for general behavioral, neurological and autonomic profiles and then every 30 minutes for next 3 hour and finally death after 24 hours [12].

*Corresponding author. Thallada Pradeep Kumar S/o. Prakash Rao,H.no: 5-1-109, Kothur Bazar,Hanamkonda, Warangal- 506001. Andhra Pradesh India

http://jprsolutions.info/

Journal of Pharmacy Research Vol.5 Issue 3.March 2012 1398-1399

T.Pradeep kumar et al. / Journal of Pharmacy Research 2012,5(3),1398-1399

Table 1: Anti-inflammatory activity of Svensonia hyderabadensis fruit extracts on carrageenan induced paw edema in rats

Treatment

Dose (mg/ml)p.o.

Volume displaced in ml

1Hr 2Hr

3Hr

4Hr

5Hr

Control - 0.17 ± 0.06 0.24 ± 0.09 0.29 ± 0.07 .32 ± 0.07 00.35 ± 0.06

Diclofenac sodium 10 0.15 ± 0.03 (11.77) 0.16 ± 0.05* (33.33) 0.12 ± 0.04* (58.63) 0.10±0.04* (68.75) 0.10 ± 0.03* (71.43)

Ethanol Extract 100 0.16 ± 0.04 (5.89) 0.17 ± 0.04 (29.16) 0.19 ± 0.06* (34.49) 0.18 ± 0.06* (43.75) 0.18 ± 0.04* (48.57 )

Ethanol Extract 200 0.15 ± 0.04 (11.77) 0.16 ± 0.05* (33.33) 0.17 ± 0.04* (41.39) 0.16 ± 0.03* (50.00) 0.14 ± 0.06* (60.00)

Results expressed as Mean ± SEM, n = 4 animals in each group; Values within parentheses represent the percentage inhibition. Statistical evaluation by one- way ANOVA

followed by Dunnett’s t – test; Symbols represent statistical significance: * - P< 0.001

Experimental Design:

Twenty five rats were used and were classified into5 groups (5animals/ group; n=5) as follows:

Group ?: Served as normal control and received 5% Tween80 (1 ml/kg body weight).

Group ??: Paracetamol control and received Paracetamol(2 g/kg body weight).

Group III: Received Silymarin (100 mg/kg body weight) as standard drug.

Group ?V: Received ESH 200 mg/Kg body weight.

Group V: Received ESH 400 mg/Kg body weight.

Anti-inflammatory activities

Carrageenan-induced rat paw oedema: Four group of rats containing four animals in each group received either plant extract (100, 200mg/kg body weight), Diclofenac(10mg/kg body weight) or vehicle control (0.9% normal saline in 3% Tween 80 (2ml/ kg).These were administered orally. Acute inflammation was produced by the sub-plantar administrationof 0.1ml of 1% carrageenan in normal saline that contained Tween 80 in the hind paw of rats. The paw volume was measured at 0 and 3h after carrageenan injection using a micrometer screw gauge. Increases in the linear diameter of the right hind paws were taken as an indication of paw oedema. Oedema was assessed in terms of the difference in the zero time linear diameter of the injected hind paw and its linear diameter at time t (i.e. 60, 120,180min) following carrageenan administration.The anti-inflammatory effect of the extractwas calculated by the following equation:

anti-inflammatory activity (%)=(1-D/C) x 100, where D represented the percentage differencein paw volume after the extract was administered to the rats and C represents the percentage difference of volume in the control groups.

The percentage inhibition of the inflammation was calculated from the formula: % inhibition=D0-Dt/D0x100 where D0 was the average inflammation (hind paw oedema) of the control group of rats at a given time; and Dt was the averageinflammation of the drug treated (i.e. extracts or reference indomethacin) rats at the same time (Gupta et al. 2005, Sawadogo et al. 2006,Moody et al. 2006).

StatisticalAnalysis

The results are expressed as mean ± S.E.M. The statistical analysis was performed by analysis of variance (ANOVA) test.

RESULTS:

Anti-inflammatory activity

Carrageenan-induced paw oedema:

When compared with the control, the extract and Diclofenac significantly reduced the paw oedema 3h after carrageenan injection.The anti-inflammatory effect of the extract and the reference drug increased with time. This was dose-dependent for the extract (Table 1).

DISCUSSION Percentage inhibition of edema volume of ethanolic, aqueousand standard drugs were calculated after every hour upto 5 h duration. There is dose dependent inhibition of paw edema in rats as shown in Fig. 1. Prostaglan- dins and bradykinins were suggested to play important role in carrageenan induced edema. [11-12] Both steroidal and non steroidal anti-inflammatory drugs can be tested by the carrageenan-induced paw inflammation test. The edema induced in the rat paw by the injection of 1% carrageenan is brought about by autocoids, histamine and 5-hydroxy tryptamine (5-HT) during the first one hour, after which kinins act, to increase the vascular permeabil- ity upto two and a half hours. The maximum inflammation is seen approxi- mately three hours post the carrageenan injection, after which it begins to decline. Following that the prostaglandins act from two and a half hours to six hours, which results in the migration of leucocytes into the inflamed site. [13-14] The carrageenan induced paw edema model in rats is known to be sensitive to cyclo-oxygenase (COX) inhibitors and has been used to evaluate the effect of non-steroidal anti-inflammatory agents. [15-16] Ammomum subulatum shows a significant inhibition of inflammation, which is comparable to the standard drug diclofenac sodium. Further studies are required to identify the actual chemical constituents that are present in the crude extracts of this plant which are responsible for anti-inflammatory activity.

ACKNOWLEDGEMENT My deepest thanks to my Guide and Lecturer, Mr. DEVENDER KODATI, Department of Pharmacology , St.Peter’s College of Pharmacy for con- stant surveillance, vital feedbacks, immense encouragement and extreme supports and care .I express my special thanks to Mr. G. Shashank Reddy for his immence support and guidance. I express my thanks to the Princi- pal, Prof. A. Jaya Prakash Reddy, St. Peter’s College of Pharmacy, for providing all the necessary facilities to carry out this work.

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Source of support: Nil, Conflict of interest: None Declared

lavanya thallada phone: 8008756765, 9866686263 email

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