C h ap te r-5shodhganga.inflibnet.ac.in/bitstream/10603/39789/9/09_chapter5.pdf · C h ap te r-5 1 9 2 M. Hranjec et al. have reported the synthesis and in vitro antitumor evaluation

Chapter-5

190

5.1 INTRODUCTION

This chapter deals with the synthesis of new acrylonitrile and propionitrile

derivatives bearing 2-morpholinoquinoline and benzimidazole nuclei in a single

scaffold. Twelve derivatives have been synthesized by Knoevenagel condensation of

2-morpholinoquinoline-3-carbaldehyde and 2-cyanomethylbenzimidazole followed by

reduction with sodiumborohydride.

5.2 Knoevenagel condensation

The synthesis of electrophilic olefins from active methylene and carbonyl

compounds is known as the Knoevenagel condensation1, an important and widely

employed method for effecting carbon–carbon bond formation with elimination of

water in organic synthesis or for the synthesis of alkene compounds having electron-

withdrawing groups such as COR, CN, COOR and NO2.

Knoevenagel condensation has been extensively studied under a variety of

conditions and solvents i.e. different conditions and catalysts were also applied for

this reaction. Generally, this type of reaction is catalyzed by base or Lewis acid in the

liquid-phase system. In recent years, a number of methods have been developed for

this reaction and chemists paid more and more attention for synthesis of alkenes by

Knoevenagel condensations for following advantages: (i) cleaner synthesis, (ii)

shorter time, (iii) higher selectivity, (iv) catalyst free, (v) high yields, (vi) ecofriendly

and (vii) economical. This reaction was widely used in the preparation of natural

products2, functional polymers3, fine chemicals4 and so forth. Knoevenagel

condensation is an excellent method for the preparation of ylidenenitriles.

5.3 Sodium borohydride (NaBH4)

NaBH4 is a frequently used hydride in reduction processes and it is known to

reduce polar carbonyl groups such as aldehydes and ketones5 and esters6. It is also

known to reduce, selectively, carbonyl groups in α,β-unsaturated ketones7 and nitriles

under certain conditions8.

Chapter-5

191

5.4 SYNTHETIC AND BIOLOGICAL ASPECTS OF ACRYLONITRILE

AND PROPIONITRILE DERIVATIVES

P. K. Dubey and coworker have carried out Knoevenagel condensation and

reported the synthesis of acrylonitrile and propionitrile derivatives bearing

benzimidazole nucleus9.

M. Hranjec et al. have reported the synthesis and DNA interaction study of novel

2-(1H-benzimidazol-2-yl)-3-(4-N,N-dimethylamino-phenyl)-acrylonitrile

hydrochloride monohydrate10.

O. V. Khilya and coworkers have reported the reaction of 2-heteroarylacetonitriles

with heterocyclic haloaldehydes11.

Chapter-5

192

M. Hranjec et al. have reported the synthesis and in vitro antitumor evaluation of

benzimidazole substituted acrylonitriles and benzimidazo[1,2-a]quinolines12.

M. Hranjec et al. have reported the synthesis as well as electronic absorption and

fluorescence data of benzimidazolyl-substituted acrylonitriles and amidino-substituted

benzimidazo[1,2-a]quinolines13.

N

HN CN

+

CHOEthanolPiperidine

N

HN CN Ethanol

hv, I2, O2 N

NNC

R

R

R

R H, CN

1. HClg2. R-NH2

N

NH2NOC

R

Ethanol

R H,NH2

NH+ Cl-

NH

NH+ Cl-

N

O

NH

HN

+Cl-

, ,

U. V. Gokhale and S. Seshadri have reported the synthesis and absorption study of

1,2-fused benzimidazole-2-acetonitrile and heterocyclic o-chloroaldehyde14.

Chapter-5

193

5.5 PRESENT WORK

STUDIES OF NEW ACRYLONITRILE AND PROPIONITRILE

DERIVATIVES BEARING 2-MORPHOLINOQUINOLINE MOIETY

Over the past few decades, the problems posed by multi-drug resistant

microorganisms have reached an alarming level in many countries around the world.

The use of most antimicrobial agents is limited, not only by the rapidly developing

drug resistance, but also by the unsatisfactory status of the present treatment of

bacterial and fungal infections15-17. Infections caused by those microorganisms

represent a serious challenge to the medical community; hence, the development of

new antimicrobial agents is an important goal. In pursuit of this goal, our research

efforts are focused on the development of novel structural moieties with promising

antimicrobial properties.

Benzimidazoles and their derivatives are one of the most extensively studied

classes of heterocyclic compounds receiving a lot of attention from chemists

concerned with organic syntheses. It is because these compounds are applied in a

variety of therapeutic areas including antimicrobial18, antioxidant19, antiviral20,

antistaphylococal21. On the other hand, quinoline derivatives possess a high activity

profile due to their wide range of useful biological properties such as antibacterial22,

antifungal23, antimycobacterial24, and antimalarial25.

Moreover, encouraged by the antimicrobial activity of compounds bearing

quinoline and benzimidazole moieties in a single molecule26-27, our efforts were

focused on designing and synthesising heterocyclic systems via a combination of

these moieties in a single framework to obtain more biologically potent compounds.

Chapter-5

194

5.5.1 EXPERIMENTAL

All the reagents were obtained commercially and used with further purification.

Solvents used were of analytical grade. All melting points were taken in open

capillaries and are uncorrected. Thin-layer chromatography (TLC, on aluminum

plates coated with silica gel 60 F254, 0.25 mm thickness, Merck) was used for

monitoring the progress of all reactions, purity and homogeneity of the synthesized

compounds. Elemental analysis (% C, H, N) was carried out by Perkin-Elmer 2400

series-II elemental analyzer at Sophisticated Instrumentation Centre for Applied

Research & Training (SICART), Vallabh Vidhyanagar and all compounds are within

±0.4% of theory specified. The FT-IR spectra were recorded using potassium bromide

disc on a Shimadzu FT-IR 8401 spectrophotometer and only the characteristic peaks

are reported in cm-1. 1H-NMR and 13C-NMR spectra were recorded in DMSO-d6 on a

Bruker Avance 400F (MHz) spectrometer using solvent peak as internal standard at

400 MHz and 100 MHz respectively. Chemical shifts are reported in parts per million

(ppm).

5.5.2 Synthesis of title compounds 5a-f and 6a-f.

The title compounds were synthesized in following steps:

1. Synthesis of 4-substituted acetanilide [1a-c] (Chapter 2.4.2):

2. Synthesis of 6-substituted-2-chloroquinoline-3-carbaldehyde [2a-c] (Chapter 2.4.2):

3. Synthesis of 6-substituted-2-morpholinoquinoline-3-carbaldehyde [3a-c] (Chapter

3.3.2):

4. Synthesis of 2-cyanomethyl benzimidazole [4a-b]28

:

Scheme 5.1 Synthetic pathway for the compounds 4a-b.

o-Phenylenediamine 3a-b (10 mmol, 10.0 g) and ethylcyanoacetate (15 mmol, 17

g) were placed in the reaction tube and heated in boiling aniline for 20 minutes. The

reaction tube was broken up and extracted with ether. The residue was recrystallized

from hot water with the aid of norite and finally from alcohol and water. Physical data

of compounds 4a-b are given hereafter.

Chapter-5

195

Table 5.1 Physical data for compounds 4a-b

Compd R

Mol. Wt.

gm/mole

M.P.

(0C)

Yield

(%)

4a H 157 209-210 70

4b CH3 171 193-194 85

5. Synthesis of 2-(5-R2-1H-benzo[d]imidazole-2-yl)-3-(6-R

1-2-

morpholinoquinolin-3-yl)acrylonitriles [5a-f]:

2-Morpholinoquinoline-3-carbaldehyde 2a-c (10 mmol) and 2-

cyanomethylbenzimidazoles 4a-b (10 mmol), ethanol (10 mL) and 0.5 mmol of

piperidine were charged in 100 mL round bottomed flask. The reaction mixture was

stirred at room temperature for 1 h and on completion of reaction (checked by TLC),

the solid separated was filtered and washed well with ethanol (10 mL) to obtain the

pure compounds 5a-f.

Synthesis of 2-(5-R2-1H-benzo[d]imidazole-2-yl)-3-(6-R

1-2-morpholinoquinolin-

3-yl)propanenitriles [6a-f]:

Mixture of acrylonitrile compounds 5a-f (10 mmol), NaBH4 (10 mmol) and

ethanol (15 mL) was stirred at room temperature for 0.5 h. After the completion of

reaction, monitored by TLC, the reaction mixture was poured into chilled water (20

mL) and extracted into ethyl acetate (2x10 mL). The organic layers were dried with

anhydrous sodium sulphate and evaporated to get compounds 6a-f.

Scheme 5.2 Synthetic pathway for the compounds 5a-f and 6a-f.

Chapter-5

196

5.5.3 RESULTS AND DISCUSSION

2-Chloroquinolin-3-carboxaldehydes 1a-c and 2-cyanomethylbenzimidazoles 3a-b

used in condensation were prepared in accordance with the methods described (Met-

Cohn & Bramha, 1978; Gudasi et al., 2006). The key intermediates, 2-

morpholinoquinoline-3-carboxaldehydes 2a-c were obtained by heating 2-

chloroquinolin-3-carboxaldehydes 1a-c and morpholine in dry DMF under reflux in

the presence of anhydrous potassium carbonate for 2.5 h (Rabong et al., 2008).

In the present study, the condensation reaction of 2-morpholinoquinoline-3-

carboxaldehydes 2a-c and 2-cyanomethylbenzimidazoles 3a-b has been carried out in

the presence of piperidine as a base catalyst in ethanol at room temperature to afford

the acrylonitrile derivatives in a good yield (73–87%). Subsequent regiospecific

reduction of C=C double bond in the acrylonitrile moiety using NaBH4 in ethanol

afforded the propionitrile derivatives in a good yield (78–89 %).

In addition, we also attempted to conduct the condensation reaction in the

presence of different base catalysts (K2CO3, NaOH, NH4OAc). Due to a number of

shortcomings such as longer reaction time, poor yield, incomplete reaction for some

derivatives as well as the sticky form of the products obtained, the purification

process became difficult. Therefore, we employed piperidine as the base catalyst and

then regiospecific reduction using NaBH4, which were found to be more effective for

the preparation of compounds 5a-f and 6a-f, respectively (Fig. 5.2).

The structures of all the synthesized compounds were established by FT-IR, 1H-

NMR and 13C-NMR spectral data. In 1H-NMR (DMSO-d6) spectra of acrylonitrile

derivative 5b, proton of –C=CH appear as a singlet at 8.69 ppm and a singlet peak

exhibited at δ 13.52 ppm is of N-H proton. In case of 13C-NMR (DMSO-d6) spectra,

aromatic carbons exhibited signals in the range from δ 105.58 to 158.66 ppm. The FT-

IR spectrum of compound 5b showed characteristic absorption bands at 3415 cm-1 of

N-H and 2210 cm-1 of C≡N stretching. Whereas, in 1H-NMR (DMSO-d6) spectra of

propionitrile derivative 6a, a singlet peak exhibited at δ 12.76 ppm is of N-H proton.

A triplet of CH of -CH-CH2 is obtained at around δ 5.24 ppm while multiplets of CH2

of -CH-CH2 obtained at 3.63 ppm. Both methylene protons are non-identical because

they are surrounded by different chemical environments. As a result, multiplets are

obtained for CH2 of -CH-CH2 and this data provide evidence of reduction of double

Chapter-5

197

bond. Aromatic carbons exhibited signals in the range from δ 112.08 to 161.06 ppm in

the 13C-NMR spectra. The FT-IR spectrum of compound 6a showed characteristic

absorption bands at 3410 cm-1 of N-H and 2225 cm-1 of C≡N. The physical

characterization values are given in Table 5.2.

Table 5.2 Physical characterization of compounds 5a-f and 6a-f

Compd R1 R2 Yield

(%)

M.P.

(°C)

Elemental analysis (%)

Cald. (Found)

C H N

5a H H 74 190-192 72.42

(72.63)

5.02

(5.28)

18.36

(18.12)

5b CH3 H 87 206-208 72.89

(73.10)

5.35

(5.12)

17.71

(17.43)

5c OCH3 H 79 242-244 70.06

(69.87)

5.14

(5.37)

17.02

(17.38)

5d H CH3 82 212-214 72.89

(73.07)

5.35

(5.15)

17.71

(17.39)

5e CH3 CH3 73 218-220 73.33

(73.04)

5.66

(5.32)

17.10

(17.42)

5f OCH3 CH3 78 258-260 70.57

(70.93)

5.45

(5.79)

16.46

(16.29)

6a H H 80 220-222 72.04

(72.33)

5.52

(5.24)

18.26

(18.57)

6b CH3 H 82 214-216 72.52

(72.24)

5.83

(6.08)

17.62

(17.97)

5c OCH3 H 79 232-234 69.72

(69.43)

5.61

(5.86)

16.94

(16.68)

6d H CH3 85 202-204 72.52

(72.29)

5.83

(6.03)

17.62

(17.89)

6e CH3 CH3 89 224-226 73.33

(73.69)

5.66

(5.43)

17.10

(17.47)

6f OCH3 CH3 78 248-250 70.57

(70.23)

5.45

(5.80)

16.46

(16.20)

Chapter-5

198

Spectroscopic characterization of compounds 5a-f and 6a-f:

2-(1H-benzo[d]imidazole-2-yl)-3-(2-morpholinoquinolin-3-yl)acrylonitrile (5a):

Mol. Formula C23H19N5O

Mol. Wt. 381.43 g/mole

IR (KBr) 3411 (-NH- stretching), 2221 (-C≡N

stretching), 1612 (olifinic C=C str.) cm-1.

1H-NMR

(DMSO-d6)

δ 3.38 (t, 4H, CH2-N-CH2), 3.83 (t, 4H, CH2-O-CH2), 7.29-8.80

(m, 10H, Ar-H + -C=CH), 13.27 (s, 1H, NH).

13C-NMR

(DMSO-d6)

51.24 (CH2-N-CH2), 66.41 (CH2-O-CH2), 105.61, 116.21,

120.93, 121.27, 122.94, 124.50, 125.41, 126.81, 127.15, 127.54,

128.00, 128.52, 129.04, 131.93, 139.36, 142.62, 147.59, 149.26,

159.07 (Ar-C).

1H-NMR spectrum of compound 5a

Chapter-5

199

13C-NMR spectrum of compound 5a

FT-IR spectrum of compounds 5a

NN

NC

HN N

O

Chapter-5

200

2-(1H-benzo[d]imidazole-2-yl)-3-(6-methyl-2-morpholinoquinolin-3-

yl)acrylonitrile (5b):




stretching), 1614 (olifinic C=C str.) cm-1.

1H-NMR

(DMSO-d6)

δ 2.48 (s, 3H, CH3), 3.33 (t, 4H, CH2-N-CH2), 3.83 (t, 4H, CH2-

O-CH2), 7.28-8.69 (m, 9H, Ar-H + -C=CH), 13.52 (s, 1H, NH).

13C-NMR

(DMSO-d6)

21.29 (CH3), 51.30 (CH2-N-CH2), 66.38 (CH2-O-CH2),

105.58, 116.27, 118.73, 120.94, 123.54, 124.42, 127.37, 127.77,

133.90, 134.72, 135.02, 137.90, 138.58, 142.87, 144.99, 146.03,

147.65, 150.54, 158.66 (Ar-C).

2-(1H-benzo[d]imidazole-2-yl)-3-(6-methoxy-2-morpholinoquinolin-3-

yl)acrylonitrile (5c):

Mol. Formula C24H21N5O2

NN

NC

HN N

O

H3CO



stretching), 1615 (olefinic C=C str.), 1125 (-

OCH3 str.) cm-1.

1H-NMR

(DMSO-d6)

δ 3.28 (t, 4H, CH2-N-CH2), 3.82 (t, 4H, CH2-O-CH2), 3.90 (s,

3H, OCH3), 7.26-8.70 (m, 9H, Ar-H + -C=CH), 13.56 (s, 1H,

NH).

13C-NMR

(DMSO-d6)

51.44 (CH2-N-CH2), 56.04 (OCH3), 66.38 (CH2-O-CH2),

105.81, 107.03, 116.35, 118.20, 121.24, 123.36, 123.91, 125.37,

127.08, 129.05, 133.79, 135.62, 137.87, 142.45, 143.24, 148.00,

156.76, 157.84, 166.59 (Ar-C).

Chapter-5

201

2-(5-Methyl-1H-benzo[d]imidazole-2-yl)-3-(2-morpholinoquinolin-3-

yl)acrylonitrile (5d):




stretching), 1610 (olefinic C=C str.) cm-1.

1H-NMR

(DMSO-d6)

δ 2.45 (s, 3H, CH3), 3.31 (t, 4H, CH2-N-CH2), 3.78 (t, 4H, CH2-

O-CH2), 7.24-8.67 (m, 9H, Ar-H + -C=CH), 13.41 (s, 1H, NH).

13C-NMR

(DMSO-d6)

21.36 (CH3), 51.32 (CH2-N-CH2), 66.45 (CH2-O-CH2),

105.46, 116.21, 118.67, 120.15, 123.65, 124.70, 127.43, 128.01,

133.86, 134.18, 135.27, 138.06, 138.87, 142.22, 144.87, 146.03,

147.40, 150.00, 158.43 (Ar-C).

2-(5-Methyl-1H-benzo[d]imidazole-2-yl)-3-(6-methyl-2-morpholinoquinolin-3-

yl)acrylonitrile (5e):




stretching), 1614 (olefinic C=C str.) cm-1.

1H-NMR

(DMSO-d6)

δ 2.44 (s, 3H, CH3), 2.94 (s, 3H, CH3), 3.12 (t, 4H, CH2-N-CH2),

3.75 (t, 4H, CH2-O-CH2), 6.83-8.23 (m, 8H, Ar-H + -C=CH),

13.49 (s, 1H, NH).

13C-NMR

(DMSO-d6)

21.36 (CH3), 21.43 (CH3), 51.33 (CH2-N-CH2), 66.58 (CH2-O-

CH2), 110.67, 111.79, 118.83, 120.21, 123.65, 124.15, 124.99,

125.41, 126.51, 127.31, 130.33, 131.20, 134.53, 138.08, 141.20,

144.73, 147.91, 151.70, 159.83 (Ar-C).

Chapter-5

202

2-(5-Methyl-1H-benzo[d]imidazole-2-yl)-3-(6-methoxy-2-morpholinoquinolin-3-

yl)acrylonitrile (5f):


NN

NC

HN N

O

CH3

H3CO



stretching), 1615 (olefinic C=C str.), 1120 (-

OCH3 str.) cm-1.

1H-NMR

(DMSO-d6)

δ 2.41(s, 3H, CH3), 3.88 (s, 3H, OCH3), 3.14 (t, 4H, CH2-N-

CH2), 3.68 (t, 4H, CH2-O-CH2), 6.98-8.19 (m, 8H, Ar-H + -

C=CH), 12.78 (s, 1H, NH).

13C-NMR

(DMSO-d6)

21.34 (CH3), 56.15 (OCH3), 51.31 (CH2-N-CH2), 66.25 (CH2-

O-CH2), 105.71, 116.31, 111.20, 118.91, 119.09, 121.22,

125.70, 126.70, 127.52, 129.08, 134.15, 135.18, 137.54, 141.34,

144.70, 148.08, 156.71, 159.70, 166.47 (Ar-C).

2-(1H-benzo[d]imidazole-2-yl)-3-(2-morpholinoquinolin-3-yl)propanenitrile (6a):



IR (KBr) 3410 (-NH- stretching), 2225 (-C≡N stretching) cm-1.

1H-NMR

(DMSO-d6)

δ 3.11 (t, 4H, CH2-N-CH2), 3.63 (m, 2H, -CH-CH2-), 3.74 (t, 4H,

CH2-O-CH2), 5.24 (t, 1H, -CH-CH2-), 7.18-8.27 (m, 9H, Ar-H),

12.76 (s, 1H, NH).

13C-NMR

(DMSO-d6)

δ 32.11 (CH2), 34.31 (CH), 51.28 (CH2-N-CH2), 66.56 (CH2-O-

CH2), 112.08, 118.93, 119.41, 122.21, 123.23, 125.26, 125.46,

125.97, 127.75, 127.77, 129.88, 134.94, 139.23, 143.22, 146.31,

148.49, 161.06 (Ar-C).

Chapter-5

203

2-(1H-benzo[d]imidazole-2-yl)-3-(6-methyl-2-morpholinoquinolin-3-yl)

propanenitrile (6b):



IR (KBr) 3416 (-NH- stretching), 2210 (-C≡N stretching) cm-1.

1H-NMR

(DMSO-d6)

δ 2.46 (s, 3H, CH3), 3.10 (t, 4H, CH2-N-CH2), 3.63 (m, 2H, -

CH-CH2-), 3.67 (t, 4H, CH2-O-CH2), 5.24 (t, 1H, -CH-CH2-),

7.21-8.18 (m, 8H, Ar-H), 12.70 (s, 1H, NH).

13C-NMR

(DMSO-d6)

δ 21.42 (CH3), 32.10 (CH2), 34.26 (CH), 51.35 (CH2-N-CH2),

66.59 (CH2-O-CH2), 118.42, 118.87, 122.80, 123.34, 125.22,

125.95, 126.60, 127.53, 128.75, 131.94, 134.80, 136.95, 138.69,

144.51, 148.48, 150.66, 160.47 (Ar-C).

2-(1H-benzo[d]imidazole-2-yl)-3-(6-methoxy-2-morpholinoquinolin-3-

yl)propanenitrile (6c):


NN

NC

HN N

O

H3CO



stretching), 1125 (-OCH3 str.) cm-1.

1H-NMR

(DMSO-d6)

δ 3.87 (s, 3H, -OCH3), 3.12 (t, 4H, CH2-N-CH2), 3.61 (m, 2H, -


7.18-8.18 (m, 8H, Ar-H), 12.77 (s, 1H, NH).

13C-NMR

(DMSO-d6)

δ 32.03 (CH2), 34.33 (CH), 51.44 (CH2-N-CH2), 55.92 (OCH3),

66.64 (CH2-O-CH2), 106.15, 112.07, 118.96, 119.41, 121.76,

122.21, 123.22, 125.66, 126.97, 129.32, 134.92, 138.28, 142.01,

143.21, 148.51, 156.93, 159.41 (Ar-C)

Chapter-5

204

1H-NMR spectrum of compound 6c

13C-NMR spectrum of compound 6c

Chapter-5

205

FT-IR spectrum of compound 6c

2-(5-Methyl-1H-benzo[d]imidazole-2-yl)-3-(2-morpholinoquinolin-3-yl)

propanenitrile (6d):




stretching) cm-1.

1H-NMR

(DMSO-d6)

δ 2.46 (s, 3H, CH3), 3.12 (t, 4H, CH2-N-CH2), 3.61 (m, 2H, -


7.19-8.24 (m, 8H, Ar-H), 12.75 (s, 1H, NH).

13C-NMR

(DMSO-d6)

δ 21.44 (CH3), 32.11 (CH2), 34.31 (CH), 51.38 (CH2-N-CH2),

66.53 (CH2-O-CH2), 118.21, 118.87, 122.76, 123.65, 125.76,

126.08, 126.60, 127.12, 128.09, 131.86, 134.13, 136.95, 138.55,

144.24, 148.91, 150.63, 160.80 (Ar-C).

Chapter-5

206

2-(5-Methyl-1H-benzo[d]imidazole-2-yl)-3-(6-methyl-2-morpholinoquinolin-3-yl)

propanenitrile (6e):




stretching) cm-1.

1H-NMR

(DMSO-d6)

δ 2.45 (s, 3H, CH3), 3.06 (s, 3H, CH3), 3.11 (t, 4H, CH2-N-CH2),

3.61 (m, 2H, -CH-CH2-), 3.69 (t, 4H, CH2-O-CH2), 5.24 (t, 1H, -

CH-CH2-), 6.95-8.15 (m, 7H, Ar-H), 12.65 (s, 1H, NH).

13C-NMR

(DMSO-d6)

δ 21.39 (CH3), 21.75 (CH3), 32.01 (CH2), 34.25 (CH), 51.35

(CH2-N-CH2), 66.61 (CH2-O-CH2), 111.57, 111.74, 118.99,

119.10, 123.72, 124.62, 125.28, 125.97, 126.57, 127.60, 131.86,

134.79, 138.54, 141.33, 144.77, 147.87, 160.49 (Ar-C).

2-(5-Methyl-1H-benzo[d]imidazole-2-yl)-3-(6-methoxy-2-morpholinoquinolin-3-

yl)propanenitrile (6f):


NN

NC

HN N

O

CH3

H3CO



stretching), 1125 (-OCH3 str.) cm-1.

1H-NMR

(DMSO-d6)

δ 2.42 (s, 3H, CH3), 3.85 (s, 3H, OCH3), 3.12 (t, 4H, CH2-N-

CH2), 3.62 (m, 2H, -CH-CH2-), 3.68 (t, 4H, CH2-O-CH2), 5.24

(t, 1H, -CH-CH2-), 6.67-8.17 (m, 7H, Ar-H), 12.75 (s, 1H, NH).

13C-NMR

(DMSO-d6)

21.34 (CH3), 32.06 (CH2), 34.12 (CH), 56.19 (OCH3), 51.37

(CH2-N-CH2), 66.32 (CH2-O-CH2), 105.65, 116.80, 111.03,

118.91, 119.17, 121.31, 125.54, 126.81, 127.18, 129.08, 134.90,

135.23, 137.20, 142.04, 144.34, 148.55, 156.67, 159.22, 166.38

(Ar-C).

Chapter-5

207

5.5.4 ANTIMICROBIAL ACTIVITY

The examination of the data summarized in Table 5.3 reveals that majority of the

compounds showed effective antimicrobial activity.

Comp R1 R2 Comp R1 R2

5a H H 6a H H5b CH3 H 6b CH3 H5c OCH3 H 6c OCH3 H5d H CH3 6d H CH3

5e CH3 CH3 6e CH3 CH3

5f OCH3 CH3 6f OCH3 CH3

Compound 5f was found to have excellent activity (MIC=62.5 µg/ml) against E.

coli, whereas, compounds 5a and 5c have shown excellent activity (MIC=100 µg/ml)

against B. subtilis and C. tetani respectively as compared to ampicillin (MIC=250

µg/ml). Compounds 5a, 5b, 5e, 6b and 6e have possessed better activity (MIC=200

µg/ml) against C. tetani as well as compounds 5b, 5c, 6e and 6f were found to be

more potent against (MIC=200 µg/ml) B. subtilis than ampicillin (MIC=250 µg/ml).

Moreover, an antifungal activity data revealed that the compound 6b showed

excellent activity (MIC=100 µg/ml)as well as compounds 5e, 6c, and 6d found more

potent (MIC=250 µg/ml) against C. albicans compared to griseofulvin (MIC=500

µg/ml). Compound 5c was found to be equipotent (MIC=100 µg/ml) against S.

pneumoniae and C. tetani as compared to ampicillin (MIC=100 µg/ml) and

ciprofloxacin (MIC=100 µg/ml) respectively. Compounds 5d, 5f, 6a and 6f have

shown comparable activity (MIC=250 µg/ml) towards C. tetani as compared to

ampicillin (MIC=250 µg/ml). Compound 5a showed comparable activity (MIC=100

µg/ml) to norfloxacin (MIC=100 µg/ml) against B. subtilis as well as compounds 5e,

Chapter-5

208

5f, 6a, 6b, 6c and 6d found equally potent (MIC=250 µg/ml) to ampicillin (MIC=250

µg/ml).

Table 5.3 Antimicrobial activity of compounds 5a-f and 6a-f

Further, towards E. coli, compounds 5b and 6e were found equally active

(MIC=100 µg/ml) as compared to ampicillin (MIC=100 µg/ml). Compounds 5f and

Minimum inhibitory concentration (MIC) expressed in µg/ml

Gram-positive

bacteria

Gram-negative

bacteria

Fungal

species

CompdBs.

MTCC

441

Ct.

MTCC

449

Sp.

MTCC

1936

Ec.

MTCC

443

St.

MTCC

98

Vc.

MTCC

3906

Af.

MTCC

3008

Ca.

MTCC

227

5a 100 200 250 250 250 250 >1000 1000

5b 200 200 200 100 200 200 1000 500

5c 200 100 100 200 250 250 1000 1000

5d 500 250 500 250 250 500 >1000 >1000

5e 250 200 200 200 200 250 500 250

5f 250 250 200 62.5 100 100 1000 500

6a 250 250 250 200 250 250 1000 500

6b 250 200 200 200 100 200 500 100

6c 250 500 250 250 250 100 500 250

6d 250 500 250 200 200 500 500 250

6e 200 200 250 100 200 200 250 1000

6f 200 250 200 200 250 250 250 500

A 250 250 100 100 100 100 - -

B 100 50 10 10 10 10 - -

C 50 100 50 25 25 25 - -

D - - - - - - 100 500

E - - - - - - 100 100

Bs.: Bacillus subtilis; Ct.: Clostridium tetani; Sp.: Streptococcus pneumoniae;

Ec.: Escherichia coli; St.: Salmonella typhi; Vc.: Vibrio cholerae; Af.: Aspergillus

fumigatus; Ca.: Candida albicans; A: Ampicillin; B: Norfloxacin; C:

Ciprofloxacin; D: Greseofulvin; E: Nystatin.

Chapter-5

209

6b were found to be equipotent (MIC=100 µg/ml) as compared to ampicillin

(MIC=100 µg/ml) against S. typhi. Compound 5f and 6c were found to be equally

active (MIC=100 µg/ml) to ampicillin (MIC=100 µg/ml) towards V. cholerae. While,

against C. albicans, compounds 5b, 5f, 6a and 6f were found to be equipotent

(MIC=500 µg/ml) compared to griseofulvin (MIC=500 µg/ml). Compound 6b possess

equal activity (MIC=100 µg/ml) against C. albicans compared to nystatin (MIC=100

µg/ml). Unfortunately, none of the tested compounds were found to be potent against

A. fumigatus.

5.5.5 CONCLUSION

New nitrile derivatives have been synthesized via combination of quinoline,

morpholine and benzimidazole nuclei. This synthetic approach allows the

construction of relatively complicated nitrogen and oxygen containing heterocyclic

scaffold through an easy and proficient reaction in good yield. Reviewing the

biological activity data, it has been conclude that majority of the compounds were

found to be active against B. subtilis and C. tetani as well as against C. albicans as

well as compounds 5b, 5f and 6b are active against most of the species employed as

compared to standard ampicillin. An antifungal activity improved after the reduction

over C=C double bond against C. albicans rather than without reduction as compared

to standard griseofulvin. It is worth to mention that the synthesized nitrile derivatives

have become the vital spot of antimicrobial medicine research.

Chapter-5

210

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C h ap te r-5shodhganga.inflibnet.ac.in/bitstream/10603/39789/9/09_chapter5.pdf · C h ap te r-5 1 9 2 M. Hranjec et al. have reported the synthesis and in vitro antitumor evaluation