SYNTHESIS OF 2-AZETIDINONES, THEIR …shodhganga.inflibnet.ac.in/bitstream/10603/8459/14/14_chapter...

265

CHAPTER-V

SYNTHESIS OF 2-AZETIDINONES, THEIR

CHARACTERIZATION AND EVALUATION

OF THEIR PHARMACOLOGICAL

ACTIVITY FOR DIFFERENT PROFILES

266

Introduction

2-Azetidinones are also known as β-lactams which are derivatives of

1. Azetidine 2. Azetine 3. 2 Azetine and 4. Azete derived from

nitrogen derivatives of cyclobutane, cyclobutene and cyclobutadiene.

2-azetidinones have become popular because of their anti bacterial

properties. Eg: penicilines and cephalosporins.

Structure

2-azetidinone(1) is a solid having melting point 73-74°C it is water

sensitive and colorless in nature. Normally 2-azetidiones are low

melting oils or solids.

NH1

2

4

3

(a)

N

(b)

NH

(c)

N

(d)

R-N

O

R2

R1

Azetidin-2-one

R-N

R1

R2

O

Azetidin-3-one

R-N

R1

O

R2

Azetidin-4-one

N-R

O(1)

267

Azetidin-2-ones as an antibacterial agents

Priyadarshini et al8 have prepared azetidinones and evaluated them

for antibacterial property.

Freedy et al9 prepared certain substituted azetidinones and carried

out their antimicrobial activity.

Mulwad et al10 reported the synthesis and antimicrobial property of

cetain 4-hydroxycoumarin azetidinones.

NN

NN

SH

N

O Cl

R1

R1=2-Cl, 3-OCH3

Br

MeO CONH N

O Cl

Ar

Ar=phenyl

R3

R1

R2 O

OH

O

N

Cl

HO

R

R1=R2=R3=HR=4-NO2

268

John11 obtained certain useful azetidinone deravitives and reported

their bacteriostatic activity against both types of organisms.

Myer12 synthesized the following azetidin-2-ones and noted their

antibacterial action.

Spasov et al13 have reported synthesis and bactericidal property of

different 2-azetidinones.

Kolaus et al14 prepared several 2 azetidinones which were proved to

be bactericidal agents.

N

Z-NH

H

O

S

COOH

MeMe

Z=monoacyl

N

Z-NH

H

O

S

CH2OAc

MeMe

COOH

N

R

H

O

S

COOR1

CH3

CH3

R = H, Ph-CH2, t-Butyl, -OMeR1 = OH

N

R

H

O

S

COOMe

CH3

CH3

N

Ph R1

R O

R = Ph, P-CH3C8H4R1 = H or Ph

N

R R1

O CH3

N

R2

O

S

MeOOC COOMe

N

N=CHPh

R3

O

S Me

Me

R = N3R1 = CH3 or SC2H5R2 = H or COOCH3R3 = CH2-Ph, CH3, CH2C6H4OCH3

269

The following azetidin-2-ones were found useful against B. substilis

and Serratia mercense by Stejepan et al15

Bose16 carried out synthesis and anti microbial property of 2-

azetidinones.

Takashi et al17 synthesized approx 545 deravitives and proved to be

active against bacillus subtillis, E coli and S. aureus.

They18 also prepared 2-Azetidinones and carried out their

antibacterial evaluation.

N

O

O

NH

H

O

S {CH (NHAC) }n

R

R1

COOH

N

O

O

NH

H

O

Cl

R,R1 = H, CH3

CH-CH2-CH2-O

H2N

HOOC

NOH

CONH

N

O

HC

COOH

OH

N-R

R

O

N-R1

HR2

O

R-NH

N-CH

H

R-NH

OCOOH

OH

R=H2 or acyl; R1 = H; R2=H, CH2OH, aryl

270

Hassan et al19 prepared 2-Azetidinones and observed that these are

active antibacterial agents..

Osman et al20 prepared several 2-Azetidinones and evaluated their

antibacterial property.

Desai et al21 prepared 2-Azetidinones derived from thiadiazole and

screened from antibacterial property.

Diumo et al22 prepared certain 2-Azetidinones and shown their

antibacterial property (invitro) few deravitives shown marked

antabactarial property.

Bhat et al23 prepared group of 2-azetidinones and evaluated them for

antifungal antituberclar and antibacterial properties.

Udupi et al24 prepareded certain 2-Azetidinones and evaluated them

for antibacterial and anti-inflammatory property.

COOH

NO2

N

O

Ar

Ar

COOH

NO2

N

O

Ar

OAr

271

2-Azetidinones as fungicidal agents

Fungicidal25 activity was observed for 2-Azetidinones shown below

2-Azetidinones as effective antiviral drugs

Levinine et al26 synthesized certain 2- Azetidinones and carried out

their antiviral activity.

2-Azetidinones as cytotoxic agents

Takayanagi et al27 synthesized 2-azetidinones deravitives and carried

out the screening of cytotoxic activity.

CH2

S

N

N

O

H

C (COOCH2CCl3) C

Me

Me

CH2CONH

N

O

S

COOCH2CCl3

N

O

272

2-Azetidinones as anti-inflammatory drugs.

Piffer et al28 prepared large number of 2-Azetidinones and evaluated

them for anti inflammatory property.

Azetidinones of the following type has been synthesized and they

showed anti-inflammatory activity.

The compounds listed below showed anti-inflammatory property

proving their usefulness as anti-inflammatory agents.

Tandon et al29 prepared certain 2-Azetidinones and screened them

from different biological profiles.

1RN [CH2]mON

Cl Cl O

(CH2)n-R

m=2-5, n=0-4r= alkyl, cycloalkylR1=heteroalkyl

Cl N

Cl

Cl

O

CH2-CH2 N

NR'

Cl

(CH2)n R

ClO

n = 0-2R = dialkyl amines heteroaminesR' = aryl

NPh

ClCl

(CH2)3 NMe2

273

Azetidin-2-ones as anticonvulsant agents

Peter et al30 prepared several 2-Azetidinones and evaluated their

anticonvulsant property.

2-Azetidinones as hypotensive drugs

several 2-Azetidinones and 3-Azetidinones have been prepared and

screened against hypotensic property31-33

2-Azetidinones as hypnotics

Maffi34 synthesized several 2-azetidinones and reported their hypnotic,

sedative and anticonvulsant activity.

Cl N

O

R

Cl N

O

R

ClR = Benzoyl

Cl

Cl N

O

O

Cl N

O

O

N

HO Me

MeR1

RON

O Me

Me

RR1

R=H, CH3, C2H5, C(CH3)3R1=H, Ph

N

O

R

R1

R2

R=H, CH3, C2H5, Cyclohexyl, Ph, p-NO2 Ph, p-NH2PhR1=Ph, PhCH2, R2 : H, CH3, C2H5

274

Testa et al35-36 prepared certain disubstituted 2-azetidinones and

reported thier sedative property.

Emilio et al synthesized 2-Azetidinones and carried out thier

evaluation of central nervous system stimulant activity.

2-Azetidineones as an anti tubercular agent

Parekh et al37 reported synthes of certain 2-azetidinones bearing

Benzimidazole moiety and carried out their antimycobacterial activity.

Udupi et al38 synthesized certain 2-azetidinones from naproxen and

carried out their antimycobacterial and antimicrobial studies.

Pai et al39 carried out their work on the preparation and

pharmacological property of 2-azetidinones. The synthesized

N-R2

O

R1

R

O

R = HR1 = cyclohexylR2=H

NH

N

CO NH N

O Cl

R

R=aryl

MeO

CHCONH

CH3

N

O

Ar

Ar MeO

CHCONH

CH3

N

O

Ar

OAr

275

compounds were evaluated for antimicrobial and antifungal property.

The deravitives shown to posses significant antibacterial property and

not active as fungal agents.

Bhat et al40 carried out preparation and study on their antibacterial

property of some azetidinone derivatives with the p-anisidine moiety.

The antibacterial and antifungal potential of the synthesized

compounds were evaluated the compounds exhibited significant

antimicrobial activity.

HOOC S

N

NH C CH2 NH

O

N C H

R

ClO

HN

OCH3

H2C C

HN N

O

Cl

R

O

276

OHC

(1)

N

CH2-CH3

CH2-CH3

Scheme-1

2) (25% aq)

N

CH3-CH2

CH3-CH2

CH N N

Z - COCl, TEA

(2)

N

CH3-CH2

CH3-CH2

CH N N

Z O

BL1 - BL-16

1) N,N-Diphenyl hydramine HCl,ethanol room temp.

277

Synthesis of Schiff Base (4–Diethyl amino benzaldehyde diphenyl

hydrazone)

A mixture of alcohol (25 ml) and diethyl amino benzaldehyde (8gms,

0.0452mol) was taken in a 250 ml R.B. flask. The mixture was stirred

until a homogenous solution was obtained. N,N–Diphenyl hydrazine

hydrochloride (10gm, 0.0454mol) was added with stirring. (As the

reaction is exothermic it should be carried out by placing R.B. flask in

a freezing mixture). Reaction mass is stirred for another 45 min.

Ammonia solution (5ml) was added over a period of 1hr at 300C

without external cooling. 4-Diethylaminobenzaldehyde

diphenylhydrazone was precipitated out. Cool the reaction mass to

50C with stirring. The isolated crude produt is purified by washing in

petroleum ether (60:95).

Preparation of acid chlorides:

The mixture of Aryl/Aryloxy acids, thionyl chloride and benzene was

reflexed for 2 hours. The excess of thionyl chloride was eliminated and

product was used for further step. The aryloxy acids required were

prepared from the corresponding phenol derivatives by known

method.

278

Synthesis of azetidin-2-ones (BL1–BL16)

The solution of Schiff base in anhydrous benzene and acid chloride

was taken in round bottom flask. To this few drops of triethyl amine

was added and heated for 2 hours . The solid cake formed was filtered

and concentration of the filtrate was carried out to obtain solid

residue which was purified by crystallization from ethyl alcohol.

Similar technique is used for obtaining remaining compounds. TLC

technique is used to confirm the purity mobile phase used was n-

hexane and ethyl acetate (ratio 8:2 v/v). The characteristic data of the

synthesized 2-azetidinones is presented in the table No 40.

279

Table 40: Characterization data of 2-Azetidinones

Sr.No.

Code Z mol. formulam.p.(°C)

yield(%)

01. BL1 Phenoxy C31H31O2N3 78-80

02. BL2 2–(2’,6’-dichloro anilino)phenyl C37H34ON4Cl2 80

03. BL3 4–Isobutyl phenyl C36H41ON3 86

04. BL4 2–Methyl phenoxy C32H33O2N3 68

05. BL5 2–Chloro phenoxy C31H30O2N3Cl 88-90

06. BL6 3–Chloro phenoxy C31H30O2N3Cl 58

07. BL7 4–Chloro phenoxy C31H30O2N3Cl 70

08. BL8 2–Chloro phenyl C31H30ON3Cl 86

09. BL9 2,4–Dichloro phenoxy C31H29O2N3Cl2 74


11. BL11 4–Amino phenoxy 94


13. BL13 4–Bromo phenoxy C31H30O2N3Br 100

14. BL14 4–Nitro phenoxy C31H30O4N4 70

15. BL15 2–Nitro phenoxy C31H30O4N4 72

16. BL16 Diphenyl C37H35ON3 60

N

CH3-CH2

CH3-CH2

CH N N

Z O

280

Spectral Data For 2-Azetidinones

Spectral data of Schiff Base (SB)

IR (KBr) CM-1:IR spectrum of Schiff base (SB) showed its characteristic absorption

bands in the following region.

3040 (Aromatic C-H Str), 2970 & 2893 (C-H Str of CH3 asymmetric

and symmetric) 2928 and 2866 (C-H Str of CH2 asymmetric and

symmetric) 1607 (C=N), 1596,1522,1495 (C=C ring Str), 1455 and

1375 (C-H bending of CH3 asymmetric and symmetric) , 1426 and

1354 (C-H bending of CH2 group, asymm and symm), 819(p-

substituted benzene ring) 740 (mono substituted phenyl)

1H NMR : ( ppm)

The 1HNMR data for Schiff base (SB) exhibited its peaks at

1.124-1.194 (6H,t, 2XCH3), 3.11 – 3.416 (4H,q,2XCH2)

6.606-7.488 (15H,m,14H of Ar-H and 1H of N=CH)

N

CH2

CH2

H3C

H3C

CH=N N

283

Spectral Data for BL-2

IR (KBr) CM-1:IR spectrum of 2-azetidinone (BL-2) showed its characteristic

absorption bands in the following region.

3430, 3040 (Ar. C-H. Str), 2970 & 2870 (C-H Str of CH3 group), 2930

& 2830 (C-H Str of CH2 group), 1708 (C=O of Betalactum)

1597,1521,1495(C=C ring Str), 1455 and 1355 (C-H bending of CH3

and CH2), 1299 (C-N), 880 (substituted phenyl ring), 818.8 (p-

substituted benzene ring) 746 (mono substituted phenyl ring)

541.63(C-Cl)

1H NMR : ( ppm)

The 1HNMR data for 2-Azetidinone (BL-2) exhibited its peaks as below

1.12-1.26 (6H,t,2XCH3), 3.1 (1H,s,H of N-CH of Betalactum ring), 3.4

(4H,q,2XCH2) 6.2 (1H,s,1H of C=O-CH of Azetidine ring), 6.5(1H,s,NH),

6.66-7.56 (21H,m,Ar-H)

N

CH2

CH2

H3C

H3C

CH N

O

N

NH

ClCl

284

13C NMR of BL-2

13CNMR13CNMR Spectrum of BL-2 gave the signal for its 37 magnetically

different environmental carbon atoms as indicated below.

C13 – 147.79C21&C25 – 144.23C20 – 137.29C51, C19 – 135.26C26, C32 – 133.00C6, C10 – 132.62C7, C9 – 130.95C27&C31 – 129.57C28&C30 – 127.73C34&C36 – 124.00C33&C37 – 123.10C8, C14 – 119.23C22, C24 – 118.00C23, C35 – 116.85C15, C18, C17 – 115.00C16, C29 – 108.00C2 – 45.84C3 – 44.45C1&C4 – 12.5C11 – 11.11C12 – 8.57

Mass Spectra:The massspectra of (BL-2 molecular wt. 621) showed parent ion peak

at m/e 621. The base peak is at m/e 559, other important daughter

ions are m/e 255, 219,130.9,97.

1 2

3 4 5

6 7

8

910

11

1213

1415

16

1718

19

20

21

22

2324

25

2627

28

2930

31

3233

34

3536

37

N

CH2

CH2

H3C

H3C

CH N

O

N

NH

ClCl

289


IR (KBr) CM-1:IR spectrum of 2-Azetidinone (BL-13) showed its characteristic

absorption bands in the following region. 3041 (Ar. C-H Str)

2970,2931,2830 (C-H Str of CH3 and CH2) 1678 (C=O)

1597,1521,1495 (C=C ring Str) 1400 and 1355. (C-H bending of

CH3&CH2) 1055 (C-H-O) 819 (p-disubstituted benzene) 747-

(monosubstituted benzene ring) 625 (C-Br)

1H NMR : ( ppm)

The 1H NMR data of 2-Azeidinone (BL-13) exhibited its peaks at.

1.12 – 1.32 ( 6H,t, 2XCH3) 3.36-3.49 (4H,q, 2XCH2), 4.58 (1H,s, CH

of N-CH of Betalactum ring), 4.65 (1H,s, 1H of O-CH of Betalactum

ring), 6.72,8.57 (18H,m, Ar-H)

N

CH2

CH2

H3C

H3C

CH N

OO

N

Br

290

Mass Spectrum (Mol. Wt. 556)

The mass Spectrum of (BL-13 Mol Wt. 556) showed a parent ion peak

at m/e 556. The base peak is observed at m/e 344 other prominent

daughter ions are seen at m/e 176,161,149.

N

CH2

CH2

H3C

H3C

CH N

CH

OO

N

Br

m/e = 556

1)

2)

N

CH2

CH2

H3C

H3C

CH2 N N

m/e = 344

3)N

CH2

CH2

H3C

H3C

CH2 N

m/e = 176

4)N

CH2

CH2

H3C

H3C

CH

m/e = 161

5)N

CH2

CH2

H3C

H3C

m/e = 149

294




3040(Ar-C-H Str), 2969-2866 (C-H Str of CH2 and CH3 groups), 1697

(C=O of Betalactum ring), 1607, 1596, 1494.69 (C=C ring Str), 1426-

1375 (C-H bending of CH3), 1456 (C-H bending of CH2), 1375(C-N),

1055 (C-O-C), 818 (p- substituted benzene ring), 748.69 (mono

substituted benzene ring)

N

CH2

CH2

H3C

H3C

CH N

CH

OO

N

296


IR (KBr) CM-1:IR spectrum of 2-azetidinone (BL-3) showed its characteristic

absorption bands in the following region. 3040.54 (Aromatic C-H Str),

2970 and 2870 (C-H Str of asymmetric and symmetric of –CH2 group),

2930 and 2830 (C-H Str of asymmetric and symmetric of –CH2 group),

1708 (C=O of betalactum ring) 1596, 1521, 1495 (C=C ring Str), 1455

and 1354, 1375 (C-N), (C-H bending of CH3 and CH2 groups), 818 (p-

substituted benzene ring), 747 (mono substituted benzene ring)

Mass Spectrum (Mol. Wt: 531)

The mass spectrum of (BL-3, Mol. Wt. 531) didnt show a parent ion

peak at m/e 531. May be due to decomposition of Betalactum ring.

However the base peak was observed at m/e 344.2

N

CH2

CH2

H3C

H3C

CH N

O

N

H3C

CH2 CH

CH3

CH3

N-CH-N=N

CH2

CH2

H3C

H3C

299



absorption bands in the following region. 3040 (Ar-C-H Str), 2970 &

2870 (C-H Str of –CH3 group asymmetric & symmetric), 2930 & 2830

(C-H Str of –CH2 group asymm and symm) 1708 (C=O of Betalactum

ring) 1597, 1521, 1495 (C=C ring Str), 1375 & 1321(C-H bending of –

CH3 and –CH2 groups), 880 (substituted phenyl ring) 819 (p-

substituted benzene ring), 787 (mono substituted benzene ring)


IR (KBr) CM-1:IR spectrum of 2-Azetidinone BL11 showed its characteristic


3400 (Broad band, NH2 Hydrogen banded), 3060 (Ar C-H Str) 2973,

2870 (C-H Str of CH3 and CH2 groups), 1698 (C=O of Betalactum

ring), 1596, 1521, 1494 (C=C ring Str), 1376 (C-N), 1494 & 1355 (C-H

bending of CH3 and CH2 groups) 1055 (C-O-C), 819.2 (p-substituted

benzene ring), 747.67 (monosubstituted benzene ring)

N

CH2

CH2

H3C

H3C

CH N

OO

CH3

N

N

CH2

CH2

H3C

H3C

CH N

CH

OO

N

NH2

300


IR (KBr) CM-1:IR spectrum of 2-Azetidinone BL-14 showed its characteristic


3040 (Ar C-H Str), 2970 & 2870 (C-H Str of CH3 asymm & symm),

2930 & 2840 (C-H Str of –CH2 group asymm & symm), 1758 (C=O of

Betalactum ring) 1596, 1521, 1494 (C=C ring Str), 1521 & 1354 (NO2),

1494, 1375 (C-H bending of CH3 and CH2 groups), 1054.64 (C-O-C),

818.97 (P-disubstituted benzene ring), 747.62 (monosubstituted

benzene ring)

N

CH2

CH2

H3C

H3C

CH N

OO

N

NO2

304

Anti-Bacterial Activity of 2-Azetidinones

The invitro antibacterial screening was carried out at microbiology

department at Navodaya Medical College and Research Centre,

Raichur. The same procedure was used for antibacterial testing as

described in Chapter-III. The results are presented in Table No. 41

Sr.No. Sample No.

Zone of Inhibition (mm)Staphylococcus

aureus E.Coli Pseudomonasaeruginosa

1 BL1 00 30 00

2 BL2 20 34 00

3 BL3 00 32 00

4 BL4 00 34 00

5 BL5 42 34 00

6 BL6 00 32 00

7 BL7 -- -- --

8 BL8 00 32 00

9 BL9 22 24 00

10 BL10 00 34 00

11 BL11 00 30 00

12 BL12 -- -- --

13 BL13 00 28 00

14 BL14 00 28 00

15 BL15 00 34 00

16 BL16 22 30 00

17 Ciprofloxacin 30 28 27

18 Gentamycin 34 30 3519 Tobramycin 30 32 34

305

Results and Discussion

All the deravitives of the 2-azetidinone series were evaluated for

antibacterial studies against the organisms Staphylococcus aureus,

E.coli and Pseudomonas aeruginosa at the Conc 10 µg/ml.

Ciprofloxacin, Gentamycin and Tobramycin of Conc 10 µg/ml were

used as reference drugs for comparison. Majority of the deravitives

showed significant antibacterial property against the organism E.coli.

The compounds BL9 showed medium activity while remaining

deravitives exhibited much significane activity as compared with the

standard drugs. None of the deravitives in this group showed activity

against Pseudomonas aeruginosa. The compound BL5 showed

significane activity against Staphylococcus aureus, where as BL2, BL9

and BL16 exhibited moderate activity. Rest of the compounds in this

series did not show activity.

306

Anti-Fungal Activity of 2-Azitidinones

The invitro antifungal activity of the Azitidinones synthezied was

carried at Maratha Madals Nathaji Rao Dental college and Research

Centre, Belgaum recognized by Rajiv Gandhi University of Health

Sciences, Bangalore as nodal centre for carrying out biological

evaluation.

Table 42: Antifungal Activity of Azetidinones

Sr.No. Compounds

Concentration (µg/ml)

75 50 25 10

1 BL-1 R R R R

2 BL-2 R R R R

3 BL-3 R R R R

4 BL-4 R R R R

5 BL-5 R R R R

6 BL-6 18mm 16mm 16mm R

8 BL-8 26mm R R R

9 BL-9 740mm 740mm 38mm 32mm

10 BL-10 16mm 14mm R R

11 BL-11 14mm 14mm 12mm R

13 BL-13 18mm 16mm 12mm R

14 BL-14 22mm 20mm 18mm 14mm

15 BL-15 R R R R

16 BL-16 R R R R

307

Results and Discussions

Among the 2-azitidinones series of compounds (BL1 - BL16), only BL9

has shown excellent activity. The compounds BL6, BL11, BL13 and

BL14 showed moderate activity and remaining deravitives of this

group have not shown any antifungal activity at all the

concentrations. Thus the synthetic β-lactum series of compounds as

expected failed to show antifungal activity against the standard drug

at all concentration levels used for the study.

Anticancer Activity of 2-Azetidinones

The anticancer activity of representative compounds of 2-azetidinone

were carried out in the department of microbiology at Maratha

Mandal’s Nathaji Rao Dental college and Research Centre, Belgaum.

During the present work selected few representative compounds of 2-

azetidinones namely BL3, BL9, BL10, BL14 and BL16 were evaluated

for anticancer activity as described in the previous chapter (IIIA).

308

Table 43: MTT Assay Results (IC50 Values) of 2-Azetidinones

Sr.No

CompoundCode

Hela Cell Line(HumanCervix) A-549-Human Lung Carcinoma

10 μl 20 μl 30 μl Average 10 μl 20 μl 30 μl Average

01 BL3(ATC11) 35.35 34.46 32.64 34.15 29.34 26.45 25.1 26.96

02 BL9(ATC15) 36.15 32.76 25.82 31.57 112 114.86 124.96 117.27

03 BL10(ATC14) 121.54 132.6 132.76 128.96 118.76 12.48 128.26 86.5

04 BL14(ATC13) 36.76 32.32 29.7 32.926 37.68 30.98 31.11 33.25

05 BL16(ATC12) 37.16 35.47 34.38 35.67 29.18 26.52 25.16 26.95

Table 44

Sr.No.

CompoundCode

MDA-MB Human Adino carcinomaMammary gland

HT-29 Human Colorectal Adenocarcinoma

10 μl 20 μl 30 μl Average 10 μl 20 μl 30 μl Average

1 BL3(ATC11) 28.68 27.34 26.86 27.62 28.18 26.46 25.68 26.77

2 BL9(ATC15) 38.46 36.86 36.24 37.18 31.48 29.82 28.98 30.09

3 BL10(ATC14) 108.64 102.84 39.84 83.77 99.98 92.64 91.88 94.83

4 BL14(ATC13) 34.26 31.48 31.08 32.273 32.64 30.88 30.26 31.26

5 BL16(ATC12) 29.56 27.86 27.28 28.23 28.84 26.58 25.46 26.96

309

Figure 2: Graph Showing IC 50 Values of 2-Azetidinone compounds

I C 5 0 v a lu e s a g a in s tH e la C e l l l in e s ( H u m a n C e r v ix )

)11

(ATC

3BL

)15

(ATC

9BL

)14

(ATC

10BL

)14

(ATC

14BL

)12

(ATC

16BL

0

5 0

1 0 0

1 5 0

2 - A z e t id in o n e C o m p o u n d s

IC50

valu

es

I C 5 0 v a lu e s a g a in s tA -5 4 9 -H u m a n L u n g C a rcim o m a

) 11(AT

C3

BL

) 15(AT

C9

BL

) 14(AT

C10

BL

) 14(AT

C14

BL

) 12(AT

C16

BL

0

50

100

150

2 -A ze t idin o n e C o m po u n ds

IC50

valu

es

I C 5 0 v a l u e s a g a i n s t M D A - M B H u m a n A d i n o C a r c i n o m a m a m m a r y G l a n d

) 11(AT

C3

BL

) 15(AT

C9

BL

) 14(AT

C10

BL

) 14(AT

C14

BL

) 12(AT

C16

BL

0

2 0

4 0

6 0

8 0

1 0 0

2 - A z e t i d i n o n e C o m p o u n d s

IC50

value

s

I C 5 0 v a l u e s a g a i n s t H u m a nC o l o r e c t a l A d e n o C a r c i n o m a

) 11(AT

C3

BL

) 15(AT

C9

BL

) 14(AT

C10

BL

) 14(AT

C14

BL

) 12(AT

C16

BL

0

2 0

4 0

6 0

8 0

1 0 0

2 - A z e t i d i n o n e C o m p o u n d s

IC50

value

s

310

Results & Discussions:

Except BL-10 all other 2-Azetidinone derivative like BL-3, BL-9, BL14

and BL16 showed potent anti cancer activity against the cell line. Hela

(Human Cervix). The same 2-azetidinone derivatives when screened

against A549 Human lung carcinoma cell line showed that BL-9 which

was potent against Hela cell line was inactive. Further the derivatives

like BL-3, BL14 and BL16 exhibited much significant activity and the

derivative BL-10 showed moderate activity against the same cell line.

In contrast to the compounds belonging to triazole thiadiazoles all the

2-azetidinone derivatives screened showed anticancer activity against

MDA-MB Adeno Carcinoma (Mammary gland) surprisingly all the

derivatives namely BL3, BL9, BL14, BL16 showed potent anti cancer

activity, where as the BL10 showed moderate activity against the HT-

29 Human Colorectal Adeno Carcinoma. The anti cancer results of the

compounds fallow the same pattern against HT-29 Human Colorectal

Adeno carcinoma. In comparison it can be said that the 2-azetidinone

derivatives having -lactum ring posses potent activity than the

triazole thiadiazole.

311

Anti Inflammatory and analgesic activity of 2-Azetidinones

The Antiinflammatory and analgesic activity was carried out at

Navodaya Medical College & Research Centre, Raichur, Karnataka

following the same procedure as described in Chapter-IIIB.

Table 45: Anti-inflammatory Activity of 2-Azetidinones

Result: The compounds showed weak activity as compared with the

standard.

Sl.No Treatment

Percentage inhibition of rat’s hind paws Oedema atdifferent time intervals

30min 1 hr 2 hr 4 hr 6 hr 8 hr

01 Control 0.00 0.00 0.00 0.00 0.00 0.00

02 DiclofenacSodium 18.47 19.94 19.81 36.76 38.08 36.36

03 SB 17.39 32.63 21.62 4.41 4.76 4.95

04 BL2 4.34 24.21 30.63 6.61 7.14 7.43

05 BL3 11.95 28.425 27.92 4.41 4.67 4.95

06 BL5 9.80 34.75 37.84 37.84 0.80 4.96

07 BL6 4.34 9.48 9.01 2.95 0.81 2.47

08 BL7 8.70 30.5 33.33 11.76 7.14 4.95

09 BL10 32.62 37.91 20.74 8.83 0.01 3.31

10 BL14 17.40 32.64 21.64 4.42 4.76 4.96

312

Table 46: Analgesic Activity of 2-Azetidinones

Result: The compounds exhibited weak to moderate analagesic activity.

Sl. No TreatmentMean +- S.E.M

0 hr 30min 1 hr 2 hr 4 hr 6 hr 8 hr

01 Control

02 Pentazocin 6.24+0.889 12.87+1.33 12.91+1.32 13.87+0.279 13.65+0.85 11.83+1.04 11.83+1.04

03 SB 5.83+0.60 7.16+0.48 4.66+0.49 4.33+0.49 5.50+0.56 4.16+0.48 5.50+1.06

04 BL2 5.33+0.49 8.66+1.14 4.50+0.43 4.00+0.52 5.00+0.58 5.00+0.58 4.16+0.91

05 BL3 5.66+0.56 6.83+0.83 4.83+0.70 4.50+0.88 4.50+0.43 4.33+0.49 4.66+0.61

06 BL5 5.33+0.49 5.16+0.40 3.33+0.67 3.16+0.17 4.33+0.49 3.00+0.26 5.16+1.17

07 BL6 4.50+0.43 5.16+0.70 3.502+0.43 4.16+0.60 5.16+0.94 4.83+0.94 3.66+0.33

08 BL7 5.66+0.67 5.50+0.50 4.83+0.83 3.33+0.21 4.50+0.56 5.00+0.86 4.16+0.65

09 BL10 6.00+0.58 3.50+0.43 3.80+0.31 3.10+0.40 3.33+0.33 3.33+0.33 3.33+0.33

10 BL14 5.82+0.60 7.17+0.48 4.65+0.49 4.33+0.49 5.50+0.56 4.17+0.50 5.50+1.06

313

List of References

1. Karl C, Grimm D, Prossel G. Liebegs Ann Chem

1974; 1974: 539.

2. Chiba K, Mori M, Baw Y. J Chem Soc Chem

Commun 1980: 770.

3. Floyd DM, Fritz AW, Cimarusti CM. J Org Chem

1982; 47: 176.

4. Cimarnsti CM, Applegate HE, Chang HW, Flyod

DM, Koster WH, Sluserchyk WA et al. J Org

Chem 1982; 47: 179.

5. Kikuchi T, Uyeo S. Tetrahedron Lett 1965; 6:

3473.

6. Stewart WW. Nature 1971; 229: 174.

7. Muraoka Y, Fujji A, Yoshika T, Takita T,

Umezawa H. J Antibiot 1977; 30: 178.

8. Priyadarshini R, Vijayaraj R. Indian J Heterocycl

Chem 2004; 13: 165.

9. Freedy HH, Kumar JMS. Indian J Heterocycl

Chem 2003; 13: 197.

10. Mulwad VV, Shirodkar. Indian J Heterocycl

Chem 2002; 11: 199.

314

11. John CS, Bristol Meyer Co, Ger Offen 1969;

161: 1943. Chem Abstr 1971; 75: 49103y.

12. Myer Fr. Demenge-2055832; Chem Abstr 1972;

76: 59615b.

13. Spasov AL, Phensioova. Tetrahedron Lett 1971;

571. Chem abstr 1972; 77: 48199p, 48008a.

14. Kolaus K, Jensen Harold. Farbwerke Hoschet A-

G, GerOffen 1974; 2: 337: 473; Chem Abstr

1975; 82: 1710022.

15. Stjepan K, Stevere RL, Eli Lilly and Co. Chem

Abstr 1976; 84: 126132a.

16. Bose A. Tetrahedron 1975; 93: 291. Chem Abstr

1976; 85: 21077a.

17. Takashi K, Takrazuka Y, Mosahi H, Tautomu T,

Takao T, Tadaaki K. Fusisawa Pharma Co Ltd.,

Ger Offen 1976; 2: 529: 941, Japan Chem Abstr

1976; 85: 210786.

18. Takashi K, Yoshihisa S, Mosahi H, Tsutomu T,

Takao T. Fusisawa Pharma Co Ltd, Japan Kokai

1976; 76: 110556. Chem Abstr 1977; 86:

139716g. 1977; 87: 151998d.

315

19. Hassan KM, Mohammad AME, Sherief HA. J O

G Chem 1978; 42. Chem Abstr 1979; 90:

168496y.

20. Osman AM, Hassan KHM, Kaseq HS, Elmahravy

MA, Hassan MA. J Ind Chem Soc 1979: 521.

21. Desai K, Baxi AJ. Ind J Pharm Sci 1993; 55:

183.

22. Diumo MV, Mazzoni O, Pircopo E, Bolgnese A.

IL Farmaco 1992; 47: 39.

23. Bhat AR, Shetty S. Ind J Pharma Sci 1987; 49:

194.

24. Udupi RH, Jesson M. Ind J Pharma Sci 1987;

49: 194.

25. Kumar R, Giri S, Nizamuddin. Synthesis and

fungicidal activity of 1-substituted phenyl-3-

substituted-4-styryl-2-azetidinones as potential.

J Pesticide Sci 1993; 18: 9.

26. Chavan AA, Pai NR. Synthesis and biological

activity of n-substituted-3-chloro-2-

azetidinones. Molecules 2007; 12(11): 2467.

27. Freihammer PM, Detty MR. J Org Chem 2000;

65(21): 7203-7.

316

28. Piffer, Giorgio Tests, Emillio, Gruppo. Research

Lab. Lepetit SPA, Chem Abstr 1970; 73:

55961b.

29. Tandon M, Kumar P, Tandon P, Bhalla TN,

Bharatwal JP. Act Pharm Jugosl 1983; 33: 93.

30. Peter W, Beel HL, Stanley C. American Home

Product Corp. USA 1972; 36401. Chem Abstr

1972; 76: 140500g.

31. Chem Abstr 1973; 78: 136054p

32. Chem Abstr 1970; 72: 55231t

33. Chem Abstr 1972; 77: 126404f

34. Maffi G. Lepetit Research Lab. SPA. Milan Italy

Ann 1958; 514: 154. Chem Abstr 1959; 53:

20553b.

35. Testa E, Luigi, Fontanella, Lepetit Research Lab.

SPA Milan Ann 1963; 724: 254, Chem Abstr

1963; 59-1561c.

36. Testa E, Luigi, Fontanella, Aresi, Lepetit

Research Lab. SPA Milan Ann 1963; 734: 525.

Chem Abstr 1964; 61: 3050e.

37. Parekh HH, Tejas U, Preeti K. Indian J

Heterocycl Chem 2008; 10: 9.

317

38. Udupi RH, Kashinath N, Bhat AR. Indian J

Heterocycl Chem 1977; 7: 221.

39. Pai NR and Chavan AA. Moleculas 2007; 12:

2467.

40. Bhat IK, Chaitanya SK, Satyanarayan PD and

Kalluraya B. J. Serb Chem Soc. 2007; 72(5).

437.

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