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RESEARCH ARTICLE

Radhika Kalate et al. / IJIPSR / 1(1), 2013, 108-116

Department of Pharmaceutical Chemistry

ISSN (online) 2347-2154

International Journal of Innovative Pharmaceutical Sciences and Research www.ijipsr.com

SYNTHESIS ANTICONVULSANT AND ANTI MICROBIAL EVALUATION OF SUBSTITUTED FURAN DERIVATIVES 1

Radhika Kalate*, 2Shiny Geore, 3Vijeyaanandi, 4Sanjay Varma Department of Pharmaceutical chemistry, Vels University Chennai.

ABSTRACT In the present study a new series of 2-(naphtha[2,1-b] furan -2yl)-ethane-1,2-dione derivatives were synthesized by the incorporation of2(naphtha [2,1-b]furan2yl)acetic acid with appropriate aldehydes. The chemical structures of the synthesized compounds were confirmed by means of IR,1H NMR, Mass spectral and elemental analysis. All the synthesized compounds were evaluated for antimicrobial and anticonvulsant activity by MES and PTZ method by using phenytion(25 mg/kg) as standard drug The synthesized compounds 3c,3d,3e,3g was found to exhibit activity when compared with standard. Key words: Naphtho [2, 1-b] furan, Anticonvulsant, MES.

CorrespondingAuthor: Radhika Kalate Assistant Professor Pharmaceutical chemistry Email: radhika.pharmaradhikakalate@gmail.com 9963125941

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RESEARCH ARTICLE

Radhika Kalate et al. / IJIPSR / 1(1), 2013, 108-116

Department of Pharmaceutical Chemistry

ISSN (online) 2347-2154

INTRODUCTION [1] Furan is a heterocyclic organic compound, consisting of a five membered aromatic ring with four carbon atoms and one oxygen. It is colour less, flammable, highly volatile liquid with a boiling point close to room temperature. Literature [2,3,4] has suggested that naphtho[2,1-b]furan derivatives are reported to posses wide spectrum of biological activities like antifungal, antimicrobial, antitumor, antihelmintic activity, antiinflamatory, antibacterial, antimalarial, anti ulcer, anti tubercular, anticancer, antiviral. The aim of the present work describes the synthesis(Scheme 1) of 2hydroxy naphthaldehyde by Reimer tiemer reaction and finally the titled compounds were synthesized by the incorporation of 2(naphtho[2,1-b] furan 2yl)acetic acid with a series of aromatic aldehydes and the newly synthesized compounds were evaluated for their anti convulsant activity .All the experiment protocols were reviewed and accepted by the institutional Animal ethical committee(IAEC) prior to the initiation of the experiment.

MATERIALS AND METHODS The melting points were taken in open capillary tube and are un corrected 1H NMR spectra were recorded on 400 MHZ-Joel GSX 400 using DMSO-d6

as solvent, mass spectra were recorded on

Shimadzu GC-MS QP 5050A.The IR spectra were recorded on ABB Bomem FTIR spectrometer MB104 with KBR pellets.The purity of compounds was ascertained by thin layer chromatography (TLC) on precoatedaluminium sheets(silica gel 60 F)and visualized by exposure to iodine vapours. Elemental analysis was performed using Dumas method. The pharmacological evaluation was conducted at Vels college of pharmacy, Chennai, after obtaining clearance from institutional animal ethics committee. The physical data of the synthesized compounds was described in (Table 1). Synthesis of naphtho[2,1-b]furan-2-carboxylic acid (2a) 2 hydroxyl-1-naphthaldehyde(0.03mol)

was dissolved in the mixture of bromo acetic

acid(0.03mol),anhydrous potassium carbonate(0.3mol) and acetone(50ml) this solution was heated under reflux for 24h.The reaction mixture was filtered and the product was recrystallised from ethanol

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RESEARCH ARTICLE

Radhika Kalate et al. / IJIPSR / 1(1), 2013, 108-116

Department of Pharmaceutical Chemistry

ISSN (online) 2347-2154

Synthesis of 1 (substituted phenyl)-2-(naphtho[2,1-b]furan-2yl)-ethane-1,2-dione(3a-3e) 2(naptho[2,1]furan2yl)acetic acid(0.004mol) was dissolved in the solution containing hot ethanol and sodium hydroxide(1g). To the above solution appropriate aldehydes (1 g) were added with constant stirring

for 2h at 50-55˚C and cool water was added.The resultant solution was filtered and the

precipitate was recrystallised with appropriate solvent. 1-(3methoxy phenyl)-2-(naphtha [2,1-b] furan -2yl)-ethane-1,2-dione (3a) IR KBr 3032(Ar) ,1693 (C-O ,Stretch) ,3585(C=O, Stretch) ,3300(C-H, Stretch) 1H NMR (DMSO) δ ppm 7.32-7.67(m,6H),7.59(s,H)

7.05-7.67(m,7H),

3.73(m,3H,OCH3)

mass(m/e) 330.09[M+] ,

331.09[M+1]. 1-(2,4chloro phenyl)-2-(naphtha [2,1-b] furan -2yl)-ethane-1,2-dione (3b) IR KBr 3089(Ar), 1050(C-O, Stretch), 3318(C=O Stretch) , 756(C-Cl) 1H NMR δ ppm 7.327.67(m,6H), 7.59(s,1H), 7.39-7.69(m,3H)mass (m/e) 368 [M+],

369 [M+1].

1-(4-dimethyl amino phenyl)-2-(naphtha [2,1-b] furan -2yl)-ethane-1,2-dione(3c) IR KBr 3043 (Ar), 986 (C-O Stretch) ,3489 (C=O), 1460 (C-N) 1H NMR δ ppm 7.32-7.67(m,6H), 7.59(s,1H), 6.49-7.25(m,10H),mass (m/e) 343 [M+], 344[M+1]. 1-(3chloro phenyl)-2-(naphtha [2,1-b] furan -2yl)-ethane-1,2-dione(3d) IR KBr 3064 (Ar) ,1068 (C-O),3589 (C=O),659 (Cl),1H NMR δ ppm 7.32-7.67(m,6H), 7.59(s,H), 7.39-7.69(m,4H) mass (m/e) 334 [M+],335[M+1]. 1-(3chloro phenyl)-2-(naphtha [2,1-b] furan -2yl)-ethane-1,2-dione(3e) IR KBr 3072 (Ar),859 (C-O), 3462 (C=O), 659 (Amine) ,1H NMR δ 7.32-7.67(m,6H), 7.59(s,1H), 7.32-8.38(d,4H)mass (m/e) 329[M+],330[M+1]. Anti -convulsant activity by maximal electro shock seizure test[11] Groups of 8-10 animals were used per dose of a drug.Eletrical stimulation is applied via corneal or electrodes with a stimulator that either delivers constant current at a frequency of 50-60/sec.The Available online: www.ijipsr.com

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RESEARCH ARTICLE

Radhika Kalate et al. / IJIPSR / 1(1), 2013, 108-116

Department of Pharmaceutical Chemistry

ISSN (online) 2347-2154

electrodes are moistened with a saline solution before application.All the animals are stimulated with the same supra maximal current strength that is usually 2-5 times the thresh hold current strength.With constant current stimulators ,typical stimulation parameters include 150 Ma in mice ,50-60/sec current delivered via ear corneal electrodes for sec25,26 with constant voltage stimulators ,250 V is used.The resultant seizure passes through various phases of tonic limb flexion of about 1.5 sec duration followed by phase of tonic limb extension lasting about 10 sec and finally followed by a variable short clonicinterval. Supressionof tonic hind limb is taken as a measure of efficacy in this test .Anticonvulsant potency is determined by calculation of its anticonvulsant ED50

for suppression of tonic hind limb

extension.Phenytoin is used as standard drug,saline is used as control, The newly synthesized compounds were evaluated for their anti convulsant activity by maximal eletroshock method(MES),phenytoin is used as standard drug.The data of activity is mentioned in Table2. Anticonvulsant screening by PTZ method[10] Pentylenetetrazole(PTZ) was used as convulsant. PTZ was dissolved in normal saline. The mice were divided into groups of six each, keeping the gropup weight as equal as possible. All the synthesized compounds( 3a-3g)were suspended in 2% CMC. The test compounds were injectedintraperitoneally into each group. The control animals were injected with vehicle only. Thirty min later, for the administration of either vehicle or test compounds, the animals were

injected with

Pentylenetetrazole(90mg/kg), this dose is shown to produce convulsions in all untreated mice and these animals exhibited 100% mortality during 24h. No protected animals in each group was recorded.

ANTIBACTERIAL EVALUATION The antibacterial activity of synthesizedcompounds was carried out against various micro-organisms namely: 1. Staphylococcus aureus (gram positive bacteria) 2.E.coli(gram negative bacteria) Available online: www.ijipsr.com

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RESEARCH ARTICLE

Radhika Kalate et al. / IJIPSR / 1(1), 2013, 108-116

Department of Pharmaceutical Chemistry

ISSN (online) 2347-2154

3. Bacillus subtilis(gram positive bacteria) 4.Pseudomonasaeruginosa(gram negative bacteria) Preparation of nutrient agar Nutrient agar serves as the basal medium for the growth of organisms. The composition is as follows: 1. Peptone (Bacteriological) 2. Beef extrat(Bacteriological)

10 gm 0.5gm

3. Sodium chloride (Bacteriological) 0.5 gm 4. Agar (Bacteriological)

20 gm

5. Distilled water up to

1000ml

Nutrient agar was prepared by dissolving all the solids in water and pH adjusted to 6.8, autoclaved at 151/inch2 pressure for 20 min. Standard drug: Test:

3a-3g

Control:

DMF

Chloramphenicol (100 µg/ ml)

Antibacterial activity by Cup plate method [12] The in vitro antibacterial activity was carried out against 24 hr old cultures of bacteria by cup plate method. The compounds were tested

at a concentration of

100µg/ml .The solution of

Chloramphenicol 100µg/ml was prepared and it is used as standard. Nutrient agar was used as culture medium & DMF was used as solvent control. Laminar airflow bench was swapped with 70 % alcohol and UV lamp was switched on. After 30 min, the UV lamp was switched off. All the reagents media, inoculums and glassware were placed in laminar airflow bench observing all aseptic conditions. The plates were inoculated within minutes of the preparation of suspension, so that the density does not change. A sterile cotton swab over was dipped into the suspension and the medium was inoculated by even streaking of the swab over the entire surface of the plate in three directions. After the inoculums Available online: www.ijipsr.com

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RESEARCH ARTICLE

Radhika Kalate et al. / IJIPSR / 1(1), 2013, 108-116

Department of Pharmaceutical Chemistry

ISSN (online) 2347-2154

had dried, cups of diameter 6mm were made in the agar plate with a sterile cork borer. The drugs solutions were added to these cups with a micropipette and the plates were then incubated at 37◦C for 24 hours. The diameter of the inhibition of growth of the microorganisms after 24 hrs was measured as the zone of inhibition in millimeters(Table4).

RESULTS AND DISCUSSION The present aim of the study is to synthesize 1 (subtituted phenyl) -2-(naphtha[2,1b]furan-2yl)-ethane1,2-dione by the incorporation of 2(naptho[2,1]furan2yl)acetic acid with appropriate aldehydes. The structures of newly synthesized compounds were confirmed by their spectral data .IR spectra of the compounds and their structure was further supported by their 1H NMR spectral data. Physical data of the compounds is listed in Table1,Some of the. Naphtho[2,1-b]furan derivatives 3(c), 3(d), 3(e) has shown anticonvulsant activity when compared with the standard has listed in Table2 and 3 . The compound (3g) showed good activity against Staphylococcus aureus and Bacillus subtilis at 100 µg/ml when compared to standard drug chloramphenicol, and (3b) showed good activity against E.coliat 100 µg/ml and (3a) showed good activity against Pseudomonas aeruginosawhen compared to standard (Table 4). Table 1: Physical data of the synthesized compounds Compound 3a 3b 3c 3d 3e

R C7 H8 O C6 H4 Cl2 C7 H11 N C 6H 5Cl C 6H5NO2

Mol.Formula

Mol.Wt

Yield%

Melting point

C21 H 14O4

330

60

170 ̊C

C20 H 10O3 Cl2

368

54

141 ̊C

C22 H 17O3 N

343

70

181 ̊C

C 20H 11O 3Cl

334

66

132 ̊C

C20 H 11O 4N

329

55

150 ̊C

3f

C9H8O

C20 H13 O3

358.16

50

158˚C

3g

C7H6O

C20 H11 O3

316.11

48

150˚C

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RESEARCH ARTICLE

Radhika Kalate et al. / IJIPSR / 1(1), 2013, 108-116

Department of Pharmaceutical Chemistry

ISSN (online) 2347-2154

Fig: 1 Schematic representation of the synthesized compounds CHO OH

BrCH2COOH

COOH O

K2 CO3 1 2

NaOH

H

R O

R O

3a-3g

O O

Table 2 : Anticonvulsant activity of synthesized compounds by MES method Compound (100 mg/kg)

Flexion

Extension

Clonus

stupor

Mortality%

3a

2.93 +0.53

9.31+ 0.52

3.19+0.24

95+0.32

0

3b

3.54 +0.47

11.73 + 0.4

2.92+ 0.31

99 + 0.16

0

3c

0.29 + 0.32**

8 .93+0.41

3.02 + 0.11

97 + 0.23

0

3d

1.83 +0.33***

7.02 + 0.4

1.51 + 0.04

94 +0.24

0

3e

0.51 + 0.17

8.54 +0.21

2.53 +0.20

100+0.4

0

Control (2% CMC)

4.61 +0.57

12.05 +0.12

3.26+0.45

120 +0.25

0

Phenytoin 1.85 +0.34 7.24 +0.56 1.56 +0.21 94+0.32 0 (25mg/kg) One way ANOVA followed by Dunnet’s 't' test. Values are expressed in mean ± SEM (n = 6) *** = P<0.001, ** = P<0.01, * = P<0.05. Table 3: Anticonvulsant activity of synthesized compounds by PTZ method Compound

Treatment

100 mg/Kg 3a 100 mg/Kg 3b 100 mg/Kg 3c 100 mg/Kg 3d 100 mg/Kg 3e 100 mg/Kg Control 150mg/Kg Ethosuximide *P<0.05 when compared to control A= Absence of seizure Available online: www.ijipsr.com

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Onset of clonic convulsions 382.5±11.6 100.3±9.4 A A A 109.5±9.8 A

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RESEARCH ARTICLE

Radhika Kalate et al. / IJIPSR / 1(1), 2013, 108-116

Department of Pharmaceutical Chemistry

ISSN (online) 2347-2154

Table 4: Antibacterial activity of synthesized compounds by cup plate method

Compound

3a

3b

3c

3d

3e

3f

3g

chloramphenicol

Treatment

Zone of inhibition in mm E. coli

B. subtilis

P. aeruginosa

S. aureus

50 µg/ml

12

15

16

20

100 µg/ml

15

22

23

23

50 µg/ml

19

14

15

19

100 µg/ml

22

21

20

21

50 µg/ml

18

12

15

17

100 µg/ml

21

24

21

21

50 µg/ml

17

15

14

18

100 µg/ml

21

22

19

20

50 µg/ml

19

14

16

17

100 µg/ml

22

20

21

20

50 µg/ml

18

16

13

18

100 µg/ml

20

22

18

23

50 µg/ml

18

17

15

21

100 µg/ml

19

25

22

25

100 µg/ml

30

30

30

29

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RESEARCH ARTICLE

Radhika Kalate et al. / IJIPSR / 1(1), 2013, 108-116

Department of Pharmaceutical Chemistry

ISSN (online) 2347-2154

ACKNOWLEDGEMENT The authors are thankful to Velsuniversity,Chennai for providing the infrastructure and facilities.The authors are also thankful to Indian institution of technology for providing spectral data

REFERENCES 1. http://en.wikipedia.org/wiki/Furan 2. Joshi S.D ,Ashwini.J, Vagdevi .H, Vaidya.V.P. Synthesis and antimicrobial evaluation of some new pyrrolylnaphtho[2,1-b]furan derivatives, Indian J.Pharma.Educ.Re, 2010; 44:481. 3. Diana patriza, Carbone.A, Barraja.P, Kelter.G, Fiebig H. Synthesis and antitumor activity of 2,5bis(3’indoyl)furans and 3,5-bis(3’-indoyl)isoxazolesnortopsentin analogues . Bio.org Med Chem.2010; 18:4524. 4. Bahl.B.S. Advanced organic chemistry, pg no 1210-1212. 5. Dodd.M.C, Stillman.W, Martha.R, Catherene.C. Invitro bacteriostatic action of some simple furan derivatives, J.Pharmacology.2010; 22:141-145 6. Behrouzi-Fardmoghadam M, Poorrajab F, Ardestani SK, Emami S, Shafiee A, Foroumadi A. synthesis and in vitro anti-leishmanial activity of 1-[5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2yl]-

and

1-[5-(5-nitrothiophen-2-yl)-1,3,4-thiadiazol-2-yl]-4-aroylpiperazines.Bioorg

Med

chem ,2008; 16: 15. 7. Vagdevi.H.M, Ravindra.K, Vagdevi.H, Vaidya. Synthesis antimicrobial and anti inflammatory activities of 1,3,4 oxadiazoles linked to naphtha[2,1-b]furan, Indian J Chem,2006; 45: 25062511. 8. Chakravarthy.E ,Geeta.B, Srinivasulu.D, Ugandhar.V. Synthesis of 2-(5 azido-5 deoxy β D ribofuranosyl)-4-methyl-5-nitro-1,2,3triazole, Indian J Chem,2006; 45: 1920-1923. 9. Rajitha.B, NaveenKumar.V. Efficient synthesis of 3-(4-methyl-3-phenyl-furo[3,2-c]quinoline2 carbonyl)-chromen 2-ones under microwave irradiation, Indian J Chem, 2006;

45: 1995-

1957. 10. Silambujanaki.P, Chitra.V, SumaKumari, Raju.D. Anticonvulsant activity of methanolic extract of Buteamonosperma leaves, RJPBCS, 2010; 1: 431. 11. Gupta.SK. Drug screening methods. 93-94.

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