chapter ii: section a - shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/8149/9/09_chapter 2...

CHAPTER II: SECTION A


38

CHAPTER II

SECTION A: Synthesis and biological evaluation of 2-cyclic amine substituted

benzoxazoles

2.1.1 Methods reported for the synthesis of 2-substituted benzoxazoles

Benzoxazoles are an important class of heterocycles and form core of number of natural

products. Much work has been done to develop methods for the synthesis of benzoxazoles and

especially for the 2-substituted benzoxazoles due to their biological and synthetic significance.

There are various methods reported in the literature for the synthesis of 2-substituted

benzoxazoles. Some of them are listed here.

Do and his coworkers had recently carried out copper catalyzed arylation of benzoxazole at 2-

carbon with aryliodides in DMF with very high yields.1 This is a very rare method which involve

direct functionalization of heterocycle C-H bonds. This method is applicable for various

heterocycles like oxazoles, thiazoles, benzthiazoles, imidazoles, benzimidazoles etc.

O

N

ArO

N10 mol% CuI

ArI, DMF, LiOtBu

140°C, 10 min

A series of lipophilic 2-substituted-5,7-di-tert-butylbenzoxazoles were prepared with average

yields by the reaction of 3,5-di-tert-butyl-1,2-benzoquinone with amino acids and dipeptides

bearing N-terminal glycine.2 The mechanism involves formation of emine which undergoes

decarboxylation to form corresponding Schiff base. The cyclization and aromatization of Schiff

base finally gives corresponding benzoxazoles. These compounds had shown potential

antimicrobial activity.

O

O O

N

RNH2CH R

COO+ 50°C, 5 h

Ethanol

N

O

CH

O

O

R

-CO2

N

OH

CHR

O

N

R

H

+O

O

+

OH

OH


39

Parallel synthesis of a library of benzoxazoles and benzthiazoles can be achieved by using

ligand-accelerated copper-catalyzed cyclizations of ortho-halobenzanilides.3

This reaction

involves an intramolecular C-O cross-coupling of ortho-halobenzanilides and is believed to

proceed via an oxidative insertion/reductive elimination pathway through a Cu(I)/Cu(III)

manifold. Most examples utilized the cyclization of ortho-bromoanilides, but orthoiodoanilides

and ortho-chloroanilides also undergo a reaction under these conditions. The rate of reaction of

the ortho-haloanilides follows the order I > Br > Cl, consistent with oxidative addition being the

rate-determining step.

Benzoxazoles, benzthiazoles and benzimidazoles can be rapidly and efficiently synthesized in

excellent yields by condensing a variety of carboxylic acids with 2-aminophenol, 2-

aminothiophenol and 1,2-phenylenediamines respectively using the ionic liquid 1-butyl 3-methyl

imidazolium tetraflouroborate [(bmim)BF4] at higher temperatures.4 Ionic liquid act as a reaction

medium and promoter. Absence of catalyst and recyclability of the ionic liquid are the highlights

of this method.

NH

2

XR X

NR'

R

+

R'

HOOC [(bmim)BF4]

100°C

X= O, S, NH

2-Substituted benzoxazoles were synthesized via condensation reaction of 2-aminophenol with

various aldehydes using molecular iodine in solvent-free conditions under microwave irradiation

in short time with good to excellent yields.5

NH

2

OH O

NArAr H

O I2

Microwave

(800 W, 130°C)

+

X

NH

R

z

R

X=Cl, Br, I

Z=O, S

N

z

R

R1

2

12

CuI (5 mol%)

Ligand (10 mol%)

Cs2CO3, DMF

reflux, 24 h

Ligand =

N N


40

Kangani and his coworkers reported one pot direct synthesis of benzoxazoles by the reaction of

2-aminophenols with carboxylic acids using the Deoxo-Fluor reagent with high yields.6 This

method is also applicable for the synthesis of oxadiazoles and oxazolines.

NH

2

OHR' O

NR"

R' Deoxo-Fluor,

CH2Cl2

+ R" COOH

iPr2NEt, 0°C

Prakash and his coworkers reported synthesis of 2-benzoxazoles using hypervalent iodine i.e.

iodobenzene diacetate mediated oxidative cyclization of Schiff’s bases in methanol as an

oxidant.7 Schiff’s bases were prepared by the reaction of o-aminophenols and aldehydes.

OH

NCH

Ar

O

NArX X

PhI(OAc)2

Methanol,

45-50 min

2-Substituted benzoxazoles can be smoothly synthesized by treatment of N-(2-hydroxyaryl)

cyclopropyl amides with PPh3/CCl4 in acetonitrile in good yields.8 When reaction was carried

out using PPh3/CBr4 in 1,2-dichloroethane (DCE) corresponding 2(3-chloropropyl)benzoxazoles

were formed.

NH

OHO

R 4PPh3, 2CBr4

DCE, 60°C, 3-5 h

R

O

NCl

NH

OHO

R

O

NR4PPh3, 2CCl4

Acetonitrile

60°C, 2 h

The one-pot thermal reaction of 1,3-bis(o-acylamino phenyloxy)-2-methylene propane

derivatives gave the bis(benzoxazole) derivatives via tandem Claisen rearrangement in good

yields.9

O

NHR'

RO

O

NH

R O

R'

180°C

NMPO

NN

O

R R

R' R'


41

The synthesis of 2-arylbenzthiazoles and 2-arylbenzoxazoles can be achieved by direct coupling

of benzthiazoles or benzoxazoles with aryl bromides.10

This is a another very rare method which

involve direct functionalization of heterocycle C-H bonds.

The 5-amino-2-arylbenzoxazoles can be synthesized by the reaction of 2,4-diaminophenol.2HCl

and various aryl carboxylic acids in polyphosphoric acid (PPA).11

The acylated derivatives of

these compounds had shown broad spectrum antimicrobial activity against various Gram-

positive and Gram-negative bacteria and the different yeasts.

OH

NH2

NH2

N

O

NH2

R+

.2 HCl

RHOOCPPA

2-Cyclicamine benzoxazoles were prepared by the reaction of 2-mercapto benzoxazole or 2-

chlorobenzoxazole with cyclicamine under different reaction conditions.12

Some of the

compounds had shown potential 5-HT receptor agonist activity.

R

R N

O

SH +

1

2

R

R N

O

Cl

1

2

+

NHToluene

RefluxN

N

O

R

R

1

2

NH

Chloroform

N

N

O

R

R

1

2rt

2.1.2 Present work

2.1.2.1 Chemistry

The pharmacological potency of cyclic amines e.g., piperazines, morpholine and piperadine as

well as the biological activity of benzoxazole analogues has drawn our attention to synthesize the

compounds containing both these moieties in a single molecule frame work. The substitution at

O

X

Ar

YO

X

YDMF, 150°C, 1 h

+ Ar Br

Pd(OAc)2 / P(t-Bu)

3

Cs2CO

3 / CuBr

X= N, S


42

second position in benzoxazole skeleton is influential for the biological activity of the molecule.

As our interest in the synthesis of New Chemical Entities (NCEs) of biological importance,

various 2-cyclic amine benzoxazole derivatives were prepared. The compounds were

characterized by spectroscopic techniques like 1H-NMR,

13C-NMR, IR, and Mass. The

synthesized compounds were evaluated for anticancer, antibacterial, antifungal and anti-

inflammatory activities.

The use of microwave irradiation to carry out organic chemical transformations have attracted

much attention in the organic synthesis and today generally referred to as microwave-assisted

organic synthesis (MAOS). MAOS possess many advantages like milder reaction conditions,

shorter reaction time, simple work-up, high yields and enhance product purity by reducing

unwanted side reactions compared to conventional heating methods.13,14

They are

environmentally benign and economical. The advantages of this enabling technology have, more

recently, also been exploited in the context of multi step total synthesis, medicinal

chemistry/drug discovery, and have additionally penetrated related fields such as polymer

synthesis, material sciences, nanotechnology and biochemical processes. After same time of

microwave irradiation and treatment in an oil bath, microwave irradiation raises the temperature

of the whole volume simultaneously (bulk heating) whereas in the oil-heated tube, the reaction

mixture in contact with the vessel wall is heated first (Figure 1).

In recent times, metal and metal-salt catalyzed reactions are extensively studied in organic

synthesis because of their simple work up, activating or catalyzing nature, selectivity and re-

usability. Among them, zinc15

has drawn attention of many researchers because of easy

availability, inexpensiveness and non-toxic nature. Zinc has gained wide acceptance due to the

unique property of surface co-ordination with polar groups. The organozinc halides form halogen

\


43

bridges like Grignard reagents. The C-Zn bond is polarized towards the carbon atom due to the

difference in electronegativity of carbon (2.55) and zinc (1.65). Zinc has found applications in

many organic reactions e.g. Barbier reaction, Diels-Alder reaction, Williamson reaction, Friedel-

Crafts sulfonylation, Fries rearrangement, Reformatsky reaction and the synthesis of Z-amino

acids. Recently, our group has reported Zn-dust promoted alkylation16

and sulfonylation17

of

amines.

In this section, we are reporting the application of zinc dust as a reusable reagent in synthesis of

2-cyclic amine benzoxazoles under microwave irradiation conditions in the absence of a solvent.

The starting material 2-chlorobenzoxazole (4), is commercially available chemical and also

otherwise we prepared starting from 2-nitrophenol (1).18

The 2-nitrophenol (1) was subjected to

hydrogenation under Pd-C in ethanol to obtain 2-aminophenol (2). The formation of 2 was

confirmed by mass spectrum and by comparison with the reported melting point. The 2-

aminophenol (2) was treated with carbon disulfide under basic conditions to obtain 2-mercapto-

1,3-benzoxazole (3). The formation of 3 was confirmed by mass spectral data and by comparison

with the reported melting point. 2-Mercapto-1,3-benzoxazole (3) was reacted with phosphorus

pentachloride (PCl5) to obtain 2-chlorobenzoxazole (4) (Scheme 1). The formation of 4 was

confirmed by 1H NMR, IR and mass spectral data.

OH

NH2

N

O

SH

N

O

Cl

Scheme 1

12 3

(ii) (iii)

Reagents: (i) H2/Pd-C, Ethanol, 24 h; (ii) CS2, KOH, Ethanol, Reflux, 8 h; (iii) PCl5, dry Toluene, 3 h

OH

NO2

(i)

4

The 2-chlorobenzoxazole was treated with various cyclic amines (Table 1) under conventional

and microwave irradiation conditions. In the conventional procedure 2-chlorobenzoxazole was

treated with various cyclic amines in acetonitrile at 0°C-rt to obtain the 2-cyclic amine

benzoxazoles (5a-l) (Scheme 2) for an appropriate time as mentioned in the Table 1 (Method

A).25

The formation of the products were confirmed by 1H NMR,

13C NMR, IR and mass

spectroscopy. The characteristic methylene protons of the cyclic amine and the characteristic

aromatic protons of the benzoxazole were present in the 1H NMR spectra of the products.

Similarly the characteristic methylene carbons of the cyclic amine and the characteristic aromatic


44

carbons of the benzoxazole were present in the 13

C NMR spectra of the products. The

characteristic “N-H” stretching of the cyclic amines was absence of in the IR spectra of the

products (except 5i and 5j). The presence of zinc dust did not improve the reaction time and

yield of the product under conventional condition. The product was obtained with less purity in

low yield when the reaction was carried out under microwave irradiation in the absence of zinc

dust. The microwave irradiation experiments were carried out using focused microwave

instrument Discover (CEM) model at 2450 MHz frequency and 450 watts power. Improvement

in yields was not obtained even by increasing the irradiation time and voltage.

On other hand, when the reaction was carried out under microwave conditions in the presence of

activated zinc, the product was obtained in excellent yield with high purity and the reaction time

has decreased from minutes to seconds. This is a remarkable achievement over the existing

conventional method. It was also investigated for the possibility of zinc dust in catalytical or less

than stoichiometric quantities. However high yields of the products with high purity were

obtained with one equivalent of zinc dust (for compound 5f: with 0.25 mmol, 55%; with 0.5

mmol, 67%; with 0.75 mmol, 85%; with 1 mmol, 97%; with 1.5 mmol, 97%). A mixture of 2-

chlorobenzoxazole and cyclic amine was subjected to microwave irradiation in the presence of

zinc dust for an appropriate time as described in Table 1 (Method B) (Scheme 3).

+

N

ON XN

O

Cl NH X

Scheme 2

X = N-methyl, N-ethyl, N-benzyl, N-phenyl, N-pyridyl, N-pyrimidyl, N-(3-chlorophenyl), N-(2-hydroxyethyl), CH2 , O.

entry 9: 2-(3-methylpiperazin-1-yl)-1,3-benzoxazole. entry 10: 2-(1,4-Diazepan-1-yl)-1,3-benzoxazole.

5a-l4

Reagents:(i) Method A: Acetonitrile, 0°C-rt

Cyclic amines

(i)

Method A

+

N

ON XN

O

Cl NH X

Scheme 3

X = N-methyl, N-ethyl, N-benzyl, N-phenyl, N-pyridyl, N-pyrimidyl, N-(3-chlorophenyl), N-(2-hydroxyethyl), CH2 , O.

entry 9: 2-(3-methylpiperazin-1-yl)-1,3-benzoxazole. entry 10: 2-(1,4-Diazepan-1-yl)-1,3-benzoxazole.

5a-l4 Cyclic amines

(i)

Method B

Reagents:(i) Method B: Zinc dust, Microwave, 450 W


45

The reaction is remarkably fast and led to very good yields of the products with high purity.

Comparison of the yields and the reaction time under conventional and microwave condition are

listed in Table 1.

N

ON N

N

ON N

N

ON N

Ph

N

ON N

N

ON

N

ON O

N

ON N

N

N

ON N

N

N

N

ON N

Cl

N

ON NH

CH3

N

ON

NH

N

ON N

OH

NH N

NH N

Ph

NH N

NH

NH O

NH NN

NH NN

N

NH N

Cl

NH NH

CH3

NHNH

NH NOH

Entry cyclic amine

NH N1

2

3

4

5

6

7

8

9

10

11

12

Table 1. Synthesis of 2-cyclic amine benzoxazoles.

2-cyclic amine-benzoxazolea Yield (%)b

70

65

75

80

78

68

78

85

82

69

74

70

Reaction Time

30

45

35

4 0

50

50

30

35

35

50

45

55

Convensional MW Convensional MW

( Min) (Sec)

87

89

92

90

94

96

95

97

96

88

95

85

70

60

55

70

60

60

55

50

75

60

70

65

aAll the products were characterized by 1H NMR, 13C NMR, IR and mass spectroscopy.bIsolated and optimized yields.

5a

5b

5c

5d

5k

5l

5e

5f

5g

5i

5j

5h


46

Under conventional as well as microwave irradiation conditions, when 1 equivalent of 2-

methylpiperazine was reacted with 2-chlorobenzoxazole, only mono alkylated product 5i formed

i.e. alkylation occurred at the less hindered nitrogen. Similarly, when 1 equivalent

homopiperazine reacted with 2-chlorobenzoxazole, only mono alkylated product 5j formed.

Reusability of zinc dust under microwave conditions was also studied for 5c and 5e (Table 2).

The zinc dust was reactivated19

and used for subsequent runs. It has shown nearly same activity

after each use. This makes the process more economical.

Table 2: Recycle studies of Zn-dust for 5c and 5e under microwave conditions.

Number

of Uses

1 2 3 4 5

Time (Sec) 60 65 80 90 120 5c Yield (%) 92 92 90 89 85

Time (Sec) 60 70 75 85 100 5e Yield (%) 95 95 93 90 87

The significant feature of this method is the isolation of the pure product by simple work up in a

short reaction time with high purity.

2.1.2.2 Biology

The synthesized 2-cyclic amine benzoxazoles were evaluated for anticancer, antibacterial,

antifungal and anti-inflammatory activities.

� Anticancer activity

Many of the major classes of anticancer drugs in current use owe their overall therapeutic

effectiveness but lack of selectivity for tumor cells over normal cells can lead to severe side

effects.20

Design and synthesis of novel small molecules which can specifically block some

targets in tumor cells are in perspective direction in modern medicinal chemistry. Therefore

there is an urgent need to establish processes to assess anticancer drug action (i.e., safety,

efficacy and mechanism of action). From the different groups of heterocycles, many synthetic

small molecules with cytotoxic activity have been reported and several of them under gone for

the clinical trials.21

Herein we try to explore the cytotoxic behavior of the 2-cyclic amine substituted benzoxazoles.

The synthesized compounds (5a-l) were subjected to cytotoxicity study using cancer cells of

various origins. The cytotoxicity studies of the compounds were determined against four human

cancer cell lines using MTT assay as described earlier and the results were presented in the


47

Table 3. Among the compounds (n=9) evaluated for their cytotoxic potential, eight entries

showed dose dependent inhibition of cancer cell proliferation (IC50 values are of less than 100

µM) and the IC50 values for the compounds are given in Table 3. It is evident from the results

that these compounds are comparatively more effective on human breast cancer (MCF-7) and

lung cancer cells (A549) than cervical cancer (HeLa) and colon cancer (SW-480) cells except the

compound 5c (entry 3) which showed maximum activity towards cervical cancer cells (IC50 -

17.31 µM) followed by lung cancer cells (IC50-32.35 µM) and is the most potent among the

compounds screened. It was very interesting to note that the compound 5d (entry 4) showed

almost equal % of inhibition to the growth of lung, breast and colon cancer cells (IC50-51-54 µM)

while almost double the amount was necessary to induce the same cytotoxic effect in cervical

(IC50-102.02 µM) cancer cells. Similarly, the compound 5b (entry 2) induced almost equal

cytotoxicity in breast (IC50-54.55 µM) as well as lung (IC50-52.51 µM) cancer cells while it did

not show any effect in cervical or colon cancer cells .The compounds 5e (entry 5) was cytotoxic

only to breast cancer cells (IC50-52-57 µM) where as the compound 5k (entry 11) induced

cytotoxicity only in lung cancer cells ( IC50-52.51 µM) while they could not induce cytotoxicity

in any of the other cells studied. So from the cytotoxicity results, it is evident that cytotoxicity of

the benzoxazole is increasing when substituted cyclic amine is incorporated at its 2nd

position.

Table 3. IC50 values on different cell lines for the compounds 5a-l.

IC50 values (µM) Compound

HeLa MCF-7 A549 SW-480

Entry-1 (5a) -a - - -

Entry-2 (5b) 212.93±19.18 54.55±3.65 52.51±6.66 NA

Entry-3 (5c) 17.31±6.09 46.21±4.83 32.35±17.6 214.68±21.65

Entry-4 (5d) 102.02±14.97 52.21±5.99 51.59±5.94 54.11±8.31

Entry-5 (5e) NA 52.21±4.82 216.82±32.12 NA

Entry-6 (5f) NA 84.52±3.66 233.61±18.53 159.40±14.63

Entry-7 (5g) NA 132.49±12.0 89.37±9.21 145.07±9.02

Entry-8 (5h) - - - -

Entry-9 (5i) - - - -

Entry-10 (5j) 109.51±19.18 241.44±14.48 229.41±5.94 116.41±11.99

Entry-11 (5k) NA 72.54±5.99 52.51±20.07 NA

Entry-12 (5l) NA 77.36±6.0 77.60±20.98 226.67±16.67

Curcumin 17.31±3.7 21.39±4.99 24.59±5.12 18.13±4.99

NA: not active. a IC50 value was not determined.


48

� Antibacterial activity

The rapidly increasing occurrence of multiple drug-resistant microbial strains is a serious

problem. Since the emergence of anti resistant bacteria is inevitable, there is an urgency for the

discovery of novel active agents, which is of the highest priority.22,23

In the search of new antibacterial agents, all the twelve synthesized compounds 5a-l were

evaluated for antibacterial activity and the results were summarized in Table 4. The minimum

inhibitory concentrations (MIC) of synthesized compounds were tested against three

representative Gram-positive organisms viz. Bacillus subtilis (MTCC 441), Staphylococcus

aureus (MTCC 96), Staphylococcus epidermidis and Gram-negative organisms viz Escherichia

coli (MTCC 443), Pseudomonas aeruginosa (MTCC 741) and Klebsiella pneumoniae (MTCC

618). Among the synthesized compounds 5a-l, only 5h, 5j and 5l showed moderate antibacterial

activity while other compounds were inactive. Among these three compounds, 5h contains N-(2-

hydroxyethyl) group while 5j and 5l contains NH and O respectively at the 4th

position of cyclic

amine. These results indicate that larger groups at 4th

position of cyclic amine have no significant

contribution to the antibacterial activity of these compounds.

Table 4: Minimum Inhibitory Concentration (MIC) values for the compounds 5a-l.

MIC(µg/ml)

Compound B.subtilis S.aureus S.epidermidis E.coli P.aeroginosa K.pneumoniae

5a 150 150 75 150 150 150

5b 150 150 75 150 150 75

5c 150 150 75 150 75 150

5d 150 150 150 75 75 150

5e 150 150 150 150 75 150

5f 150 150 150 150 75 75

5g 150 75 150 150 150 150

5h 150 75 150 150 75 75

5i 150 150 150 75 150 150

5j 150 150 150 75 75 75

5k 150 150 150 150 150 150

5l 150 75 150 150 150 37.5

Penicillin 1.562 1.562 3.125 12.5 12.5 6.25

Streptomycin 6.25 6.25 3.125 6.25 1.562 3.125


49

� Antifungal activity

In the search of new antibacterial agents, all the twelve synthesized compounds 5a-l were

evaluated for antifungal activity and the results are summarized in Table 5. In vitro antifungal

activity of the synthesized compounds was studied against the fungal strains, Candida. albicans

(MTCC 227), Saccharomyces. cereviseae (MTCC 36), Rhizopus oryzae (MTCC 262) and

Aspergillus niger (MTCC 282). Among the synthesized compounds 5a-l, only 5b with N-ethyl

group and 5c with N-benzyl group at the 4th

position of cyclic amine and 5k with piperidine as

cyclic amine showed moderate antifungal activity while other compounds were inactive. So

again the results evidence that larger groups at 4th

position of cyclic amine have no significant

contribution to the antifungal activity of these compounds.

Table 5. Antifungal activity of the compounds 5a-l.

a not active Concentration used: 100µg/150µg

Negative Control: DMSO (No activity)

Positive Control: Amphotericin-B (50µg)

Zone of Inhibition (mm)

C.albicans S.cerevisiae R.oryzae A.niger

Compound

100

µµµµg

150

µµµµg

100

µµµµg

150

µµµµg

100

µµµµg

150

µµµµg

100

µµµµg

150

µµµµg

5a -a - - - - - - -

5b 8 10 7 9 - - 9 12

5c - 9 12 10 - 9 - 9

5d - 9 - - - - - -

5e 8 10 - - - - - -

5f - - - - 8 10 - -

5g - - - - - - - -

5h - - - - - - - -

5i - - - - - - - -

5j - - - - 8 10 - -

5k 9 12 9 12 8 11 8 10

5l 7 9 - - - - - -

Amphoterici

n-B(50µg)

23.5 22 24 25


50

� Anti-inflammatory activity

Non-steroidal anti-inflammatory drugs (NSAIDs) are a main-stay in the treatment of

inflammation and they owe their therapeutic and side effects in large part to the inhibition of

cyclooxygenase (COX). The separation of the therapeutic effects from the side effects has been a

major challenge in the design and synthesis of these drugs. The discovery of a second isoform of

cyclooxygenase, namely COX-2, has opened a new line of research based on the assumption that

pathological prostaglandins are produced by the inducible isoform COX-2 while physiological

prostaglandins are produced by the constitutive isoform COX-1.24

On this premise several new

inhibitors have been developed and some are now commercially available.25,26

However, an

increased risk of myocardial infarction and cardiovascular thrombotic events associated with the

use of some selective COX-2 inhibitors has been observed.27

These adverse cardiovascular

effects, which are attributed to a decreased level of the vasodilatory PGI2 and an increased level

of the potent platelet aggregator TxA2, were primarily responsible for the recent withdrawal of

rofecoxib (Vioxx@) and valdecoxib (Bextra@) from the market .28

In the search of new anti-inflammatory agents, the synthesized compounds 5a-l were subjected

to carrageenan induced oedema in hind paw of rats as an assay for anti-inflammatory drugs and

the results are listed in Table 6. Among tested compounds, moderate anti-inflammatory activity

was exhibited by 5a with N-methyl group and 5g with N-(3-chlorophenyl) group at the 4th

position of cyclic amine. Other compounds have shown very less or no activity.

Table 6. In vivo anti-inflammatory activity of the compounds 5a-l.

COMPOUND DOSE: 100 mg / Kg STANDARD [INDOMETHACIN]: 10 mg / Kg EXPERIMENT: 1

Group Initial Paw

Volume

Final paw

Volume

Difference in

Paw volume % of inhibition

CONTROL 1.26 2.23 0.99±0.05

STD 1.24 1.71 0.47 56.50±6.01

5b 1.26 2.50 1.24 1.00±1.00

5c 1.13 2.07 0.94 0.0±0.00

5d 1.17 2.30 1.13 1.50±1.50

5e 1.25 2.35 1.10 2.40±1.20

5g 1.27 2.23 0.96 13.30±0.79

5j 1.21 2.50 1.29 0.00±0.00


51

5k 1.22 2.38 1.16 2.40±2.40

5l 1.16 2.44 1.28 0.00±0.00

COMPOUND DOSE: 100 mg / Kg STANDARD [INDOMETHACIN]: 10 mg / Kg EXPERIMENT: 2

CONTROL 1.42 2.72 1.30±0.01

STD 1.50 2.14 0.64 50.00±0.58

5a 1.36 2.48 1.12 14.27±0.90

5f 1.39 2.71 1.32 0.00±0.00

5h 1.42 2.77 1.35 2.03±2.03

5i 1.44 2.79 1.35 2.03±2.03

2.1.2.3 Experimental

Procedure for the preparation of 2-aminophenol (2)18

filtration. The solution was concentrated under vacuum. 2-Aminophenol (2) was obtained as

yellow solid and was crystallized from ethanol (9.9 g, 90 %).

White solid. mp 174-177°C (reported mp 170-175°C).

EI-MS (m/z): 109 (M+).

Procedure for the preparation of 2-mercapto-1,3-benzoxazole (3)18

added to the residue. The organic layer was washed with water (2 X 50 mL), dried over Na2SO4,

and concentrated under vaccum. 2-Mercapto-1,3-benzoxazole (3) was obtained as a yellow

powder and was crystallized from ethanol (11.2 g, 82 %).

OH

NH2

2

N

O

SH

3

2-Nitrophenol (1) (14 g, 0.1 mole) was dissolved in ethanol (150 mL),

and 10% palladium-carbon (1.4 g) was added cautiously to the solution.

The reaction mixture was stirred under a hydrogen atmosphere for 24 h.

After the reaction completes (TLC), palladium- carbon was removed by

2-Aminophenol (2) (9.9 g, 0.09 mole) was refluxed for 8 h with

potassium hydroxide (6.6 g, 0.14 mole) and carbon disulfide (100 mL) in

ethanol (150 mL). The reaction mixture was concentrated under vacuum;

1 N aqueous hydrochloric acid (100 mL) and ethyl acetate (200 mL) were


52

White solid. mp 189-192°C (reported mp 192-195°C).

EI-MS (m/z): 151 (M+).

Procedure for the preparation of 2-chlorobenzoxazole (4)18

under vacuum to obtain pure 2-chlorobenzoxazole (4) (95-95°C/20 mm) (8.7 g, 76 %).

1H NMR (200 MHz, CDCl3) δ: 7.68-7.60 (m, 1H, Ar-H); 7.50-7.40 (m, 1H, Ar-H); 7.36-7.27 (m,

2H, 2XAr-H).

IR (KBr, cm-1

): 3068 (=C-H), 2927 (-C-H), 1585 (-C=C), 1445 (-C-H ben), 1378 (-C-N), 1258,

1032 (-C-O), 756 (=C-H ben).

EI-MS (m/z): 154 (M+).

Typical procedure for the preparation of 2-(4-methylpiperazin-1-yl)-1,3-benzoxazole (5a)

room temperature for 30 minutes, quenched in ice water (30 mL), extracted with ethyl acetate (3

X 20 mL) and dried over Na2SO4. After concentration, the residue was purified by flash

chromatography to obtain the pure product and was crystallized from methanol.

Method B: Microwave procedure

The 2-chlorobenzoxazole (2.6 mmol, 400 mg) was added to a mixture of 1-methyl piperazine

(2.6 mmol, 260 mg) and activated zinc dust (2.6 mmol, 169 mg). The mixture was subjected to

microwave irradiation at 450 W for 65 seconds. The experiment was performed in 10 mL

pressure tube. After the reaction was completed in a stipulated time (see Table 1), ethyl acetate

was added to the reaction mixture, the zinc dust was filtered off and washed with ethyl acetate.

Combined organic layer was concentrated and the residue was purified by flash chromatography

and was crystallized from methanol to obtain pure product.

N

O

Cl

4

N

O

N N

5a

Phosphorus pentachloride (18.5 g, 0.09 mole) was added slowly to the

solution of 5-chloro-2-mercapto-1,3-benzoxazole (3) (11.2 g, 0.074 mmol)

in dry toluene (300 mL) at 20°C. The reaction mixture was stirred at

120°C for 3 h. The reaction mixture was subjected to fractional distillation

Method A: Conventional procedure18

The 2-chlorobenzoxazole (4) (2.6 mmol, 400 mg) was added to a

solution of 1-methyl piperazine (2.6 mmol, 260 mg) in dry

acetonitrile (30 mL) at 0°C. The mixture was stirred at 0°C –


53

White solid. mp 36-38°C (reported mp 37-38°C).18

1H NMR (200 MHz, CDCl3) δ: 7.22 (t, J= 7.3 Hz, 2H, 2XAr-H); 7.09 (t, J= 7.3 Hz, 1H, Ar-H);

6.95 (t, J= 7.3 Hz, 1H, Ar-H); 3.67 (t, J= 5.1 Hz, 4H, 2XN-CH2); 2.48 (t, J= 5.1 Hz, 4H, 2XN-

CH2); 2.30 (s, 3H, N-CH3).

13C NMR (75 MHz, CDCl3) δ: 162.0, 148.7, 142.8, 124.0, 120.8, 116.3, 108.7, 54.0, 45.9, 45.2.

IR (KBr, cm-1

): 3057 (=C-H), 2933, 2854 (-C-H), 1639, 1578 (-C=C), 1456 (-C-H ben), 1363 (-

C-N), 1285, 1002 (-C-O), 746 (=C-H ben).

EI-MS (m/z): 218 (M+1)+.

Anal. calcd for C12H15N3O (217): C, 66.34; H, 6.96; N, 19.34. Found: C, 66.36; H, 6.94; N,

19.37.

Below listed compounds were prepared under the same conventional and microwave procedures

as mentioned above for 5a.

2-(4-ethylpiperazin-1-yl)-1,3-benzoxazole (5b)

2.54 (t, J= 4.9 Hz, 4H, 2XN-CH2); 2.45 (q, J= 7.2 Hz, 2H, CH3CH2); 1.11 (t, J= 7.2 Hz, 3H,

CH3CH2).

13C NMR (75 MHz, CDCl3) δ: 162.0, 148.6, 142.9, 123.9, 120.6, 116.1, 108.6, 52.2, 51.9, 45.4,

11.7.

IR (KBr, cm-1

): 3052 (=C-H), 2970 (-C-H), 1638, 1578, 1525 (-C=C), 1459 (-C-H ben), 1399 (-

C-N), 1243 (-C-O), 746 (=C-H ben).

EI-MS (m/z): 231 (M+).


18.15.

2-(4-benzylpiperazin-1-yl)-1,3-benzoxazole (5c)

N

O

N N

5b

White solid. mp 78-80°C.

1H NMR (200 MHz, CDCl3) δ: 7.30 (d, J= 7.7 Hz, 1H, Ar-H);

7.20 (d, J= 7.7 Hz, 1H, Ar-H); 7.11 (t, J= 7.7 Hz, 1H, Ar-H);

6.96 (t, J= 7.7 Hz, 1H, Ar-H); 3.70 (t, J= 4.9 Hz, 4H, 2XN-CH2);


54

(s, 2H, Ph-CH2); 2.56 (t, J= 4.7 Hz, 4H, 2XN-CH2).

13C NMR (75 MHz, CDCl3) δ: 162.1, 148.7, 143.0, 136.9, 129.2, 128.4, 127.4, 123.9, 120.6,

116.2, 108.7, 62.9, 52.1, 45.4.

IR (KBr, cm-1

): 3028 (=C-H), 2917, 2860 (-C-H), 1640, 1578, 1494 (-C=C), 1455 (-C-H ben),

1395 (-C-N), 1245 (-C-O), 739 (=C-H ben).

EI-MS (m/z): 293 (M+).


14.33.

2-(4-phenylpiperazin-1-yl)-1,3-benzoxazole (5d)

6.92 (d, J= 6.8 Hz, 2H, 2XAr-H); 6.88 (t, J= 7.6 Hz, 1H, Ar-H); 3.85 (t, J= 5.3 Hz, 4H, 2XN-

CH2); 3.29 (t, J= 5.3 Hz, 4H, 2XN-CH2).

13C NMR (75 MHz, CDCl3) δ: 161.8, 150.8, 148.6, 142.6, 129.2, 124.1, 120.9, 120.8, 116.9,

116.3, 108.8, 49.2, 45.5.

IR (KBr, cm-1

): 2980, 2914, 2822 (-C-H), 1629, 1575, 1497(-C=C), 1455 (-C-H ben), 1237 (-C-

O), 735 (=C-H ben).

EI-MS (m/z): 280 (M+1)+.


15.05.

2-[4-(pyridin-2-yl)piperazin-1-yl]-1,3-benzoxazole (5e)

N

O

N N

5c

N

O

N N

5d


1H NMR (300 MHz, CDCl3) δ: 7.34-7.25 (m, 6H, 6XAr-H); 7.19

(d, J= 7.8 Hz, 1H, Ar-H); 7.11 (t, J= 7.8 Hz, 1H, Ar-H); 6.96 (t,

J= 7.8 Hz, 1H, Ar-H); 3.70 (t, J= 4.7 Hz, 4H, 2XN-CH2 ); 3.54

White solid. mp 147-148°C (reported mp 150-151°C).18


7.26 (d, J= 7.6 Hz, 1H, Ar-H); 7.23 (d, J= 6.8 Hz, 2H, 2Ar-H);

7.14 (t, J= 6.8 Hz, 1H, Ar-H); 6.99 (t, J= 7.6 Hz, 1H, Ar-H);


55

6.99 (dt, J= 6.6, 1.3 Hz, 1H, Ar-H); 6.68-6.61 (m, 2H, 2XAr-H); 3.88-3.77 (m, 4H, 2XN-CH2);

3.74-3.67 (m, 4H, 2XN-CH2).

13C NMR (75 MHz, CDCl3) δ: 161.9, 158.2, 148.7, 146.8, 142.8, 138.4, 124.0, 120.9, 116.4,

113.8, 108.8, 107.8, 45.2, 44.9.

IR (KBr, cm-1

): 3053 (=C-H), 2993, 2917 (-C-H), 1635, 1576, 1480 (-C=C), 1459 (-C-H ben),

1435 (-C-N), 1242 (-C-O), 744 (=C-H ben).

EI-MS (m/z): 280 (M+).


19.96.

2-[4-(pyrimidin-2-yl)piperazin-1-yl]-1,3-benzoxazole (5f)

6.51 (t, J= 5.0 Hz, 1H, Ar-H); 4.04-3.94 (m, 4H, 2XN-CH2); 3.81-3.72 (m, 4H, 2XN-CH2).

13C NMR (75 MHz, CDCl3) δ: 166.6, 161.4, 157.8, 148.6, 144.4, 124.3, 121.1, 116.3, 110.6,

108.9, 45.5, 43.2.

IR (KBr, cm-1

): 2911, 2860 (-C-H), 1651, 1581, 1490 (-C=C), 1451 (-C-H ben), 1393 (-C-N),

1251 (-C-O), 733 (=C-H ben).

EI-MS (m/z): 281 (M+).


24.94.

2-[4-(3-chlorophenyl)piperazin-1-yl]-1,3-benzoxazole (5g)

N

O

N N

N

5e

N

ON N

N

N

5f


1H NMR (200 MHz, CDCl3) δ: 8.30 (d, J= 5.0 Hz, 2H, 2XArH);

7.33 (d, J= 7.6 Hz, 1H, Ar-H); 7.23 (d, J= 7.6 Hz, 1H, Ar-H);



1H NMR (200 MHz, CDCl3) δ: 8.19-8.15 (m, 1H, Ar-H);

7.51-7.44 (m, 1H, Ar-H); 7.33 (d, J= 7.7 Hz, 1H, Ar-H); 7.23

(d, J= 7.7 Hz, 1H, Ar-H); 7.13 (dt, J= 6.6, 1.1 Hz, 1H, Ar-H);


56

6.90 (t, J= 2.3 Hz, 1H, Ar-H); 6.85 (d, J= 7.6 Hz, 1H, Ar-H); 6.79 (d, J= 7.6 Hz, 1H, Ar-H); 3.84

(t, J= 5.3 Hz, 4H, 2XN-CH2); 3.31 (t, J= 5.3 Hz, 4H, 2XN-CH2).

13C NMR (75 MHz, CDCl3) δ: 161.9, 151.9, 150.9, 142.8, 135.0, 130.1, 124.1, 120.9, 120.3,

116.6, 116.4, 114.7, 108.8, 48.6, 45.3.

IR (KBr, cm-1

): 3015 (=C-H), 2913 (-C-H), 1625, 1593, 1478 (-C=C), 1397 (-C-N), 1253 (-C-O),

695 (=C-H ben).

EI-MS (m/z): 314 (M+1)+.

Anal. calcd for C17H16ClN3O (313): C, 65.07; H, 5.14; N, 13.39. Found: C, 65.09; H, 5.14; N,

13.36.

2-[4-(1,3-benzoxazol-2-yl)piperazino]-1-ethanol (5h)

7.11 (t, J= 7.6 Hz, 1H, Ar-H); 4.64 (t, J= 6.0 Hz, 2H, O-CH2); 2.82 (t, J= 6.0 Hz, 2H, N-CH2);

2.52 (t, J= 5.2 Hz, 4H, 2XN-CH2); 1.60 (t, J= 5.2 Hz, 4H, 2XN-CH2); 1.49-1.38 (m, 1H, OH).

IR (KBr, cm-1

): 3423 (-O-H), 2936, 2855 (-C-H), 1631, 1578, 1483 (-C=C), 1458 (-C-H ben).

EI-MS (m/z): 247 (M+).

Anal. calcd for C13H17N3O2 (247): C, 63.14; H, 6.93; N, 16.99. Found: C, 63.19; H, 6.88; N,

17.05.

2-(3-methylpiperazin-1-yl)-1,3-benzoxazole (5i)

N

O

N N

Cl

5g

N

O

N N

OH

5h

N

O

N NH

CH3

5i



7.23 (d, J= 7.6 Hz, 1H, Ar-H); 7.17 (d, J= 7.6 Hz, 1H, Ar-H);


Brown solid. mp 35-36°C.






6.95 (t, J= 7.6 Hz, 1H, Ar-H); 4.11 (d, J= 11.3 Hz, 2H, N-CH2);


57

3.07 (m, 2H, N-CH2); 2.91 (m, 2H, N-CH2); 2.71 (m, 1H, N-CH); 1.80 (s, 1H, NH); 1.11 (d, J=

8.3 Hz, 3H, CH-CH3).

13C NMR (75 MHz, CDCl3) δ: 161.5, 148.5, 142.8, 123.6, 120.3, 116.0, 108.3, 51.7, 50.0, 44.9,

44.5, 18.5.

IR (KBr, cm-1

): 3322 (-N-H), 3057 (=C-H), 2958, 2856 (-C-H), 1639, 1578 (-C=C), 1459 (-C-H

ben), 1401, 1357 (-C-N), 1283, 1246 (-C-O), 805, 745 (=C-H ben).

EI-MS (m/z): 217 (M+).


19.29.

2-(1,4-Diazepan-1-yl)-1,3-benzoxazole (5j)

3.07 (t, J= 5.2 Hz, 1H, N-CH); 2.91 (t, J= 5.2 Hz, 1H, N-CH); 2.27 (quintet, J= 6.0 Hz, 1H,

CH2CHCH2); 1.97 (quintet, J= 6.0 Hz, 1H, CH2CHCH2).

13C NMR (75 MHz, CDCl3) δ: 161.6, 148.9, 143.1, 124.0, 120.6, 116.2, 108.7, 49.5, 49.1, 48.4,

47.4, 26.7.

IR (KBr, cm-1

): 3399 (-N-H), 3050 (=C-H), 2934 (-C-H), 1639, 1578 (-C=C), 1459 (-C-H ben),

1402 (-C-N), 1244 (-C-O), 744 (=C-H ben).

EI-MS (m/z): 217 (M+).


19.32.

2-(piperidin-1-yl)-1,3-benzoxazole (5k)

13C NMR (75 MHz, CDCl3) δ: 161.9, 148.4, 142.2, 124.1, 120.7, 115.8, 108.7, 46.8, 25.2, 23.9.

N

O

NNH

5j

N

O

N

5k


1H NMR (200 MHz, CDCl3) δ: 7.31 (d, J= 7.6 Hz, 1H, Ar-H); 7.23 (d,

J= 7.6 Hz, 1H, Ar-H); 7.13 (t, J= 7.6 Hz, 1H, Ar-H); 6.98 (t, J= 7.6 Hz,

1H, Ar-H); 3.96 (s, 2H, N-CH2); 3.76 (t, J= 6.0 Hz, 4H, 2XN-CH2);


1H NMR (300 MHz, CDCl3) δ: 7.33 (d, J= 7.9 Hz, 1H, Ar-H); 7.23

(d, J= 7.9 Hz, 1H, Ar-H); 7.14 (t, J= 7.9 Hz, 1H, Ar-H); 6.99 (t, J=

7.9 Hz, 1H, Ar-H); 3.70 (s, 4H, 2XN-CH2); 1.74 (s, 6H, 3XCH2).


58

IR (KBr, cm-1

): 3057 (=C-H), 2936, 2854 (-C-H), 1638, 1577, 1525 (-C=C), 1455 (-C-H ben),

1394 (-C-N), 1221 (-C-O), 744 (=C-H ben).

EI-MS (m/z): 202 (M+).


13.82.

2-(morpholin-4-yl)-1,3-benzoxazole (5l)

4.5 Hz, 4H, 2XN-CH2).

13C NMR (75 MHz, CDCl3) δ: 161.2, 148.2, 141.1, 124.3, 121.3, 116.0, 108.9, 66.0, 45.8.

IR (KBr, cm-1

): 3057 (=C-H), 2966, 2863 (-C-H), 1637, 1578, 1525 (-C=C), 1454 (-C-H ben),

1398 (-C-N), 1242, 1105 (-C-O), 745 (=C-H ben).

EI-MS (m/z): 204 (M+).

Anal. calcd for C11H12N2O2 (204): C, 64.69; H, 5.92; N, 13.72. Found: C, 64.65; H, 5.94; N,

13.69.

� Biology

� Anticancer activity

Maintenance of the cells

The human cancer cells of various origin (HeLa:Cervix, MCF-7:Breast, A549:Lung, SW 480:

Colon) were procured from National Centre for Cell sciences, Pune and maintained in DMEM

containing 10% FBS with antibiotics and antimycotics at 37°C in

a

CO2 incubator.

MTT assay

This assay helps to measure the toxicity induced by the compounds on the cells. Active

mitochondrial dehydrogenases of living cells convert the water soluble yellow tetrazolium salt to

an insoluble purple formazan. This can be solubilized by 20% SDS dissolved in 50% dimethyl

N

O

N O

5l


1H NMR (200 MHz, CDCl3) δ: 7.32 (d, J= 7.9 Hz, 1H, Ar-H); 7.21

(d, J= 7.9 Hz, 1H, Ar-H); 7.13 (t, J= 7.9 Hz, 1H, Ar-H); 6.98 (t, J=

7.9 Hz, 1H, Ar-H); 3.77 (t, J= 4.5 Hz, 4H, 2XO-CH2); 3.64 (t, J=


59

formamide and the intensity of color developed is an indicator of percentage of viable cells

present. The assay was conducted as described earlier.29

Briefly, cells (5x 10 3/ well) were plated in 96 well plates and kept overnight at 37°C. Next day,

the cells were incubated with and without various concentrations of the compounds (5, 10, 25, 50

µM). Curcumin was used as the positive control. At the end of the incubation, medium was

removed and fresh medium containing 20% MTT solution (5 mg/ ml in PBS) was added to each

well. After 2h, 0.1 ml of the extraction buffer (20% SDS, 50% DMF) was added and the optical

density was measured at 570 nm using a 96 well multiscanner auto reader after 4 h and compared

with that of the untreated control. The percentage of inhibition of cell viability was determined

with reference to the untreated control. The data was subjected to linear regression analysis and

the regression lines were plotted for the best straight-line fit. The IC50 concentrations were

calculated using the respective regression analysis.

� Antibacterial activity

Determination of Minimum Inhibitory Concentration (MIC) of synthetic compounds:

The minimum inhibitory concentrations (MIC) of various synthetic compounds were tested

against three representative Gram-positive organisms viz. Bacillus subtilis (MTCC 441),

Staphylococcus aureus (MTCC 96), Staphylococcus epidermidis and Gram-negative organisms

viz Escherichia coli (MTCC 443), Pseudomonas aeruginosa (MTCC 741), and klebsiella

pneumoniae (MTCC 618) by broth dilution method recommended by National Committee for

Clinical Laboratory (NCCL) standards.30

Test organisms were obtained from the Institute of

Microbial Technology, Chandigarh, India. Cultures of test organisms were maintained on

nutrient agar slants and were sub cultured prior to testing. The minimum inhibitory concentration

(MIC) was measured by broth dilution method.30

A set of sterile test tubes with nutrient broth

media were capped with cotton plugs (1-9). The test compound is dissolved in sterile water and

concentration of 100µg/ml of the test compound is added to the first tube, which is serially

diluted from 1 to 9. A fixed volume of 0.5 ml over night culture is added in all the test tubes and

incubated at 37°C for 24 h. After incubation period the tubes were measured for turbidity with

spectrophotometer. Standard antibacterial agents like Penicillin and Streptomycin were also

screened under identical conditions for comparison. The minimum inhibitory concentration

(MIC) values are presented in Table 4.


60

� Antifungal activity

In vitro antifungal activity of the newly synthesized compounds was studied against the fungal

strains, Candida. albicans (MTCC 227), Saccharomyces. cereviseae (MTCC 36), Rhizopus

oryzae (MTCC 262), Aspergillus niger (MTCC 282) by Agar Well Diffusion Method.31

The

ready-made Potato Dextrose Agar (PDA) medium (Hi-media, 39 g) was suspended in distilled

water (1000 mL) and heated to boiling until it dissolved completely, the medium and Petri dishes

were autoclaved at pressure of 15 lb/inc2 for 20 min. Agar well bioassay was employed for

testing antifungal activity. The medium was poured into sterile Petri dishes under aseptic

conditions in a laminar air flow chamber. When the medium in the plates solidified, 0.5 mL of

(week old) culture of test organism was inoculated and uniformly spread over the agar surface

with a sterile L-shaped rod. Solutions were prepared by dissolving the compound in DMSO and

different concentrations were made. After inoculation, wells were scooped out with 6 mm sterile

cork borer and the lids of the dishes were replaced. To each well different concentrations of test

solutions were added. Controls were maintained. The treated and the controls were kept at 27°C

for 48 h. Inhibition zones were measured and the diameter was calculated in millimeter. Three to

four replicates were maintained for each treatment.

� Anti-inflammatory activity

The anti-inflammatory activity of the test compounds was evaluated in Wistar rats employing the

method of Winter32

et al. and Diwan33

et al. Male Wistar rats were used for the study. Animals

were fasted overnight and were divided into control, standard and different test groups each

consisting of 3 animals. The different test compounds were administered to the animals in the

test group at the dose of 100 mg/kg, by oral route. Animals in the standard group received

Indomethacin at the dose of 10mg/kg, by oral route. All test and standard compounds were

administered as 1% gum acacia suspension. Rats in the control group received the vehicle

solution with out drugs. One hour after test drugs administration, rats in all the groups were

challenged with 0.1% carrageenan in the sub plantar region of left hind paw. A zero hour paw

volume was measured for the rats using digital plethysmometer (Ugo Basile, Italy) before the

administration of the carrageenan for all groups. Paw volumes were again measured 3 h after the

challenge of carrageenan. The percent inhibition of paw volume for each rat in the treated groups

was calculated by comparing with mean paw volume of control group and expressed as mean

(±SE) percent inhibition of paw volume for each test group.

The percent edema inhibition was calculated according to the following equation:


61

Percent edema inhibition = (Vc –Vt/Vc) X 100

where, Vt represents the mean increase in paw volume in rats treated with test compounds and Vc

represents the mean increase in paw volume in control group of rats.

2.1.2.4 Conclusions

In conclusion, the synthesis of 2-cyclic amine benzoxazole derivatives was achieved with high

conversion in a short reaction time using zinc dust under solvent free microwave irradiation. The

advantage of the present method over the conventional methods is the use of zinc dust as a

recyclable catalyst. This is remarkable and makes the method environmentally friendly and

economically valuable. Most of the compounds have shown good anticancer activity, in

particular 5b, 5c and 5d. Selectivity of these compounds for particular cancer cells is an

interesting aspect and opens an area for detail study. While the some compounds have shown

moderate antibacterial, antifungal and anti-inflammatory activity.

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