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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):
Mol. Formula C24H21N5O
Mol. Wt. 395.17 g/mole
IR (KBr) 3415 (-NH- stretching), 2210 (-C≡N
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
Mol. Wt. 411.46 g/mole
IR (KBr) 3424 (-NH- stretching), 2237 (-C≡N
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):
Mol. Formula C24H21N5O
Mol. Wt. 395.17 g/mole
IR (KBr) 3418 (-NH- stretching), 2216 (-C≡N
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):
Mol. Formula C25H23N5O
Mol. Wt. 409.48 g/mole
IR (KBr) 3420 (-NH- stretching), 2229 (-C≡N
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):
Mol. Formula C25H23N5O2
NN
NC
HN N
O
CH3
H3CO
Mol. Wt. 425.48 g/mole
IR (KBr) 3427 (-NH- stretching), 2228 (-C≡N
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):
Mol. Formula C23H21N5O
Mol. Wt. 383.45 g/mole
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):
Mol. Formula C24H23N5O
Mol. Wt. 397.47 g/mole
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):
Mol. Formula C24H23N5O2
NN
NC
HN N
O
H3CO
Mol. Wt. 413.47 g/mole
IR (KBr) 3420 (-NH- stretching), 2236 (-C≡N
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, -
CH-CH2-), 3.68 (t, 4H, CH2-O-CH2), 5.24 (t, 1H, -CH-CH2-),
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):
Mol. Formula C24H23N5O
Mol. Wt. 397.47 g/mole
IR (KBr) 3415 (-NH- stretching), 2216 (-C≡N
stretching) cm-1.
1H-NMR
(DMSO-d6)
δ 2.46 (s, 3H, CH3), 3.12 (t, 4H, CH2-N-CH2), 3.61 (m, 2H, -
CH-CH2-), 3.68 (t, 4H, CH2-O-CH2), 5.23 (t, 1H, -CH-CH2-),
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):
Mol. Formula C25H25N5O
Mol. Wt. 409.48 g/mole
IR (KBr) 3412 (-NH- stretching), 2228 (-C≡N
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):
Mol. Formula C25H25N5O2
NN
NC
HN N
O
CH3
H3CO
Mol. Wt. 425.48 g/mole
IR (KBr) 3424 (-NH- stretching), 2225 (-C≡N
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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