Solvent free synthesis, characterization, anticancer, antibacterial, antifungal, antioxidant and SAR studies of novel (E)-3-aryl-1-(3-alkyl-2- pyrazinyl)-2-propenone

Article abstract of DOI:10.1039/c3nj00308f

Two series of novel (E)-3-aryl-1-(3-alkyl-2-pyrazinyl)-2-propenones (3a-3f and 3g-3l) have been synthesized by the Claisen-Schmidt condensation reaction between 2-acetyl-3-alkyl pyrazine (0.005 mol, 1a-1b) and para-substituted aromatic aldehydes (0.005 mol, 2a-2f) under solvent-free K₂CO ₃ solid supported microwave environment, with 90-95% yield. The structures were confirmed by FTIR, ¹H NMR, ¹³C NMR, LCMS (Q-TOF) and elemental analysis. The mean surface roughness values (R _a) of 10.59 and 10.87 nm for 3c and 3i, respectively, were measured with AFM. Compounds were tested for their in vitro anticancer activity against the MCF-7 cell line using sulforhodamine B (SRB) assay protocols to estimate cell growth and compared with adriamycin. Compound 3i containing p-Br on the phenyl ring expressed promising anticancer activity (GI₅₀ ≤ 0.1 μM). The cytotoxicity (LC₅₀) was found in the range of 86 to >100 μM as compared to that of the standard (LC₅₀ = 89 μM). Also, compounds were screened for in vitro antibacterial and antifungal activities, and the most prominent effects were observed with 3a, 3c, 3d and 3e against gram-positive and gram-negative strains. Compounds 3a-3l showed 30-66% antioxidant activities, determined by 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical method. The viscosity as a transport property was studied for their entire composition range at 298.15 K. Data were regressed against concentration for limiting viscosity and noted as 3h > 3g > 3i = 3l > 3k > 3a > 3j > 3f > 3e > 3c > 3d > 3b.

Full text of DOI:10.1039/c3nj00308f

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Solvent free synthesis, characterization, anticancer,
antibacterial, antifungal, antioxidant and SAR studies
of novel (E)-3-aryl-1-(3-alkyl-2-pyrazinyl)-2-propenone†
Cite this: NewJ.Chem., 2013,
37, 2541
Bheru Singh Kitawat,a Man Singh*a and Raosaheb Kathalupant Kaleab
Two series of novel (E)-3-aryl-1-(3-alkyl-2-pyrazinyl)-2-propenones (3a–3f and 3g–3l) have been synthe-
sized by the Claisen–Schmidt condensation reaction between 2-acetyl-3-alkyl pyrazine (0.005 mol, 1a–
1b) and para-substituted aromatic aldehydes (0.005 mol, 2a–2f) under solvent-free K2CO3 solid sup-
ported microwave environment, with 90–95% yield. The structures were confirmed by FTIR, 1H NMR,
13C NMR, LCMS (Q-TOF) and elemental analysis. The mean surface roughness values (Ra) of 10.59 and
10.87 nm for 3c and 3i, respectively, were measured with AFM. Compounds were tested for their
in vitro anticancer activity against the MCF-7 cell line using sulforhodamine B (SRB) assay protocols to
estimate cell growth and compared with adriamycin. Compound 3i containing p-Br on the phenyl ring
expressed promising anticancer activity (GI50 r 0.1 mM). The cytotoxicity (LC50) was found in the range
of 86 to >100 mM as compared to that of the standard (LC50 = 89 mM). Also, compounds were screened
for in vitro antibacterial and antifungal activities, and the most prominent effects were observed with
3a, 3c, 3d and 3e against gram-positive and gram-negative strains. Compounds 3a–3l showed 30–66%
antioxidant activities, determined by 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical method. The visc-
osity as a transport property was studied for their entire composition range at 298.15 K. Data were
regressed against concentration for limiting viscosity and noted as 3h > 3g > 3i = 3l > 3k > 3a > 3j > 3f >
3e > 3c > 3d > 3b.
Received (in Montpellier, France)
24th March 2013,
Accepted 28th May 2013
DOI: 10.1039/c3nj00308f
www.rsc.org/njc
production in human polymorphonuclear leukocytes.7 The
aminopyrazine derivatives were found to inhibit the activity of
Introduction
Pyrazine derivatives comprise an important class of aromatic
fragrances1,2 and are relevant components of the aromas of
many fruits, vegetables, wines and natural products.1,3 Pyrazine
derivatives are known for their uses as versatile synthetic
intermediates, and for their cyclooxygenase enzyme (COX-2)
inhibiting, relaxing cardiovascular, antithrombotic, anti-aggregation,
and analgesic effects.4,5 Some reported imidazo[1,2-a]pyrazine
derivatives are found to decrease the expression of glycoprotein
(GP)Ib in Dami cells while others enhanced that of GPIIb/IIIa
and also inhibited the proliferation of the human erythro-
leukemia (HEL) cell line.6 Tetramethylpyrazine is used for the
treatment of ischemic stroke permeate, blood–brain barrier
and also enrich the brainstem and decrease nitric oxide
Syk kinase and showed inhibition of LAD2 cell degranulation
while some have binding affinity to hepatic cytochrome P450
2E1.8,9 Because of the wider applications of pyrazine and its
derivatives, their synthesis has been a centre of attraction for
researchers over the years, especially in medicinal chemistry for
designing structural analogues of bioactive heterocyclic com-
pounds with a better pharmacological profile. In the search for
novel agents with better pharmacokinetic properties, potency
and lower side effects, a large number of chalcone derivatives
have been synthesized and several of them have shown promising
biological activities. Chalcones are prominent secondary meta-
bolites and precursors of flavonoids.10 The presence of enone
functionality (–C(O)CHQCH–) in the chalcone moiety has shown
an array of biological activities such as antimicrobial,11 anti-
inflammatory,11,12 antiplatelet,13 antimalarial,14 anticancer,15,16
antileishmanial,17 antioxidant,11 antifungal,18 inhibition of
leukotriene B4,19 anti-HIV20 anti-tuberculosis21 and also agro-
chemical22 activities have been reported. Chalcones are signifi-
cant precursors in the synthesis of numerous biologically
a School of Chemical Sciences, Central University of Gujarat, Gandhinagar-382030,
India. E-mail: mansingh50@hotmail.com; Fax: +91-079-232-60076;
Tel: +91-079-232-60210
b School of Life Sciences, Jawaharlal Nehru University, New Delhi-110067, India
† Electronic supplementary information (ESI) available: Copies of 1H and 13C
NMR spectra are given in ESI. See DOI: 10.1039/c3nj00308f
c
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important pyrimidines, isoxazolines, pyrazolines, flavonoids and
other heterocycles.23–25
Conventionally, chalcones are synthesized by the Claisen–
Schmidt condensation reaction of substituted aldehydes and
ketones using strong acid or base or high cost catalysts like
LiNO3/natural phosphate, Amberlyst-15, bamboo char sulfonic
acid, SOCl2/EtOH, Cu3(BTC)2(H2O)3, zinc oxide, and Zn–Al
hydrotalcite adhere ionic liquid in organic solvents, which
not only required longer time, high temperature, inert environ-
ment but also involve typical workup procedures with lesser
yield.26–32
Scheme 1 Synthesis of (E)-3-aryl-1-(3-alkyl-2-pyrazinyl)-2-propenones (3a–3l).
Table 1 Various substituents used in the synthesis and comparison between
On the other hand, for benign synthesis, modern research conventional and MW methods
and trends require advanced techniques for synthesis of various
biologically potent compounds with limited resources.33–35
Thereby, microwave assisted organic synthesis (MAOS) has
gained the consideration of chemists due to its inimitable
Method A
Onset
advantages, such as shorter reaction times, cleaner products,
higher yields, simplicity in operation and being a potential
alternative to accomplish efficient synthesis.33–35 Further, solvent-
free reactions are of great importance in organic synthesis as it
time (h)/yield Method B time m.p. pointa
(%)
Entry R
X
(min)/yield (%) (1C) (1C)
3a
–CH3 –F
6.0/84
6.0/91
8.0/95
9.5/91
6.5/90
8.5/93
10/91
113– 113.71
115
128– 128.67
130
135– 136.92
137
191– 192.22
193
113– 113.34
115
140– 139.41
142
105– 105.27
107
114– 115.05
116
95– 95.70
97
199– 199.59
201
105– 105.88
107
118– 118.20
120
bring down the experimental costs due to simplification of the 3b
–CH3 –Cl
–CH3 –Br
–CH3 –NO2
5.5/87
5.5/85
6.0/88
work-up and reduction of environmental pollution.33,34 The
3c
MAOS is termed as e-synthesis, because it is easy, effective,
economical, efficient and environment friendly.23–25
3d
3e
Thus, keeping in view the high degree of biomedical activ-
ities expressed by pyrazine and chalcone derivatives, in the
–CH3 –N(CH3)2 7.0/86
–CH3 –OCH2Ph 7.0/88
present work, the focus has been drawn on designing new 3f
structural entities of chalcones by incorporating pyrazine and
aromatic para-substituted aldehydes into chalcone scaffolds to
evaluate the potential effects on biological activity, particularly 3h
for anticancer, antimicrobial and antioxidant activities. Synth-
esis of the title compounds for developing an easily reproducible
methodology under solvent free K2CO3 solid supported micro- 3j
3g
–C2H5 –F
5.5/87
5.0/86
6.5/83
6.5/86
7.5/92
9.5/91
6.5/94
8.5/92
6.5/92
8.0/94
–C2H5 –Cl
–C2H5 –Br
–C2H5 –NO2
3i
wave environment has been adopted. The easy work-up of the
products, rapid reaction, and mild conditions are notable
features of this method. Further, to extend the scope of the 3l
3k
–C2H5 –N(CH3)2 5.0/83
–C2H5 –OCH2Ph 5.0/88
reaction, the synthesis of other alkyl substitute pyrazines for
chalcone synthesis and their chemical reactions for pyrazoline,
pyrimidine and isoxazoline synthesis along with anticancer
and antimicrobial activities are under consideration in our
laboratory.
a
Onset point measured with differential scanning calorimeter and
compared with m.p., which are in similar range.
The FTIR absorption peaks of compounds 3a–3l at 3103–
To the best of our knowledge, no one has yet considered 3000 cmÀ1 are attributed to –CH stretching of aromatic ring.
pyrazines as potential molecules for chalcone synthesis with their The peaks at 2920, 2982 and 2822–2932 cmÀ1 are due to –CH
anticancer, antibacterial, antifungal and antioxidant activities.
stretching of methyl and ethyl chains of the pyrazine ring and
–N(CH3)2 of 3e and 3k. The sharp shoulder at 1655 to 1692 cmÀ1
confirmed the –CQO stretching vibration of the chalcone back-
bone chain in 3a–3l. The peaks in the 1590 to 1664 cmÀ1 region
are the –CQN stretching vibrations of the pyrazine ring. The
Results and discussion
Chemistry
Two novel series of (E)-3-aryl-1-(3-alkyl-2-pyrazinyl)-2-propenone peaks at 1557, 1593, 1508 and 1533 cmÀ1 are due to –CQC–
(3a–3l) have been synthesized by Claisen–Schmidt condensation stretching and bending vibrations of the aromatic ring, respec-
reaction between an equimolar ratio (0.005 mol) of 2-acetyl-3- tively. Peaks at 1516 and 1344 cmÀ1 due to Ar–NO2, 1373 and
alkyl pyrazine (1a–1b) and para-substituted aldehydes (2a–2f) by 1332 cmÀ1 due to Ar–N(CH3)2, and 1247 and 1177 cmÀ1 due to
conventional and MAOS methodologies, as shown in Scheme 1. the stretching vibration of the Ar–C–O–C– ester bond linkage are
Comparative data of both methods are given in Table 1. The observed. The peaks at 981 and 1014 cmÀ1 in 3a–3l, due to
authenticity of the products 3a–3l was confirmed by FTIR, stretching of –C(O)CHQCH– linkage, confirm the formation of
1H NMR, 13C NMR and LCMS (Q-TOF) spectral data (see ESI†).
an a,b-unsaturated ketonic bond.
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In the 1H NMR spectra of 3a–3l, Ha and Hb appeared as
Paper
doublets due to olefinic vicinal coupling at d = 7.33–7.89 ppm
and d = 8.22–7.39 ppm, respectively, with coupling constant
values J = 13–17 Hz between them, which agrees with
E-propenones.16 The 13C NMR spectra provided a final struc-
tural elucidation of 3a–3l. Thus, the signals for Ca and Cb were
in the range of d = 118.02–124.20 ppm, the signal for Cb appears
at d = 140.66–145.38 ppm, while –CQO carbon appears at
d = 190.04–191.12 ppm (see ESI†).
The UV-vis absorption properties of 3a–3l at r.t. were
recorded at a molar concentration 3 Â 10À3 in ethanol. The
absorption spectra of each compound exhibits intense absorp-
tion bands which are due to the p - p* transition of the
conjugated backbone.36 The para-substituted effect on the
absorption of electron donating and electron withdrawing
groups is seen from the UV absorption values. The spectral
shapes of the compounds are very similar because these
compounds possess similar structures. Compounds 3a–3l exhibit
two prominent bands appearing at 305, 345 nm (3a), 305, 330 nm
(3b), 315, 375 nm (3c), 315, 390 nm (3d), 310, 510 nm (3e) 310,
415 nm (3f), 310, 365 nm (3g), 315, 375 nm (3h), 305, 375 nm (3i),
295, 380 nm (3j), 295, 510 nm (3k) and 250, 420 nm (3l),
respectively. The maximum absorption band is red-shifted from
310 to 510 nm and from 295 to 510 nm for 3e and 3j, respectively,
due to the lone electron pair donating nature of nitrogen in
–N(CH3)2 to the aromatic ring which makes the conjugated-
system of molecules become larger and band shift towards red
shift is attributed to the n - p* transition. Compounds 3f and 3l,
which have one more phenyl ring in their structures than the rest
of compounds, lead to a bathochromic shift of about 95 and
90 nm (3e versus 3f and 3k versus 3l). This result is in accordance
with the weak donor character of the phenyl ring. The electron
withdrawing groups (4-F, 4-Cl, 4-Br and 4-NO2) at the para-
position lead to a bathochromic shift as compared to 3e, 3f, 3k
and 3l. The first transition is ascribed to a localized aromatic p -
p* transition and the later is an n - p* transition.37 Thus, these
differences might result from the different conjugation degrees
and different electron effects of the compounds.38
Fig. 1 Curve between percentage control growth and concentrations of drugs
on MCF 7 cell line.
which is a chemotherapy drug often used to kill cancer cells,
was used as the standard anticancer drug.40 Reported para-
meters are given in Table 2.
As shown in Table 2, compounds which have less than
0.1 mM GI50 are considered as anticancer active. Compound 3i,
having 4-Br on the phenyl ring, showed promising anticancer
activity against the MCF7 cell line with a GI50 value of less than
0.1 mM. The GI50 values of the other compounds were found to
be more than 10 mM and the trend of GI50 is noted as 3i = ADR >
3h > 3g > 3b > 3j > 3c > 3d > 3k > 3f > 3e. Replacing –CH2CH3 (3i)
by –CH3 (3c) of 4-Br substituted compounds is noted to lower
the activity. The higher GI50 values in both series of 3e (GI50
=
67.5 mM) and 3k (GI50 = 40.7 mM) having –N(CH3)2 at the para-
position on the phenyl ring may be attributed to the two methyl
groups attached with nitrogen that increased the hydrophobicity
leading to a decrease in the anticancer activity as compared
to the halogens at the para-positions of the phenyl ring.
Table 2 In vitro testing expressed as growth inhibition of human cancer cell line
MCF7 of 3a–3la
Biological evaluation
Entry
LC50
TGI
GI50
Anticancer study
3a
3b
3c
3d
3e
ND*
86
ND
ND
53.2
71.8
70.1
>100
>100
54.5
52.9
40.3
79.2
92.5
ND
20.3
33.3
34.3
67.5
64.3
13.1
12.5
o0.1
22.2
40.7
ND
The in vitro anticancer activity of compounds 3a–3l was per-
formed on human malignant cell line MCF-7 at four dose levels
of 0.1, 1.0, 10 and 100 mM mLÀ1 in dimethyl sulfoxide (DMSO)
and the test consisted of a 48 h continuous drug exposure
protocol using sulforhodamine B (SRB) assay to estimate cell
growth.39 Appropriate positive controls were run in each experi-
ment and each experiment was repeated thrice and a graph was
plotted against percentage control growth and concentration
(Fig. 1) to calculate various parameters.
>100
>100
>100
>100
95.9
93.2
92
>100
>100
ND
3f
3g
3h
3i
3j
3k
3l
STD**
89
25.9
o0.1
a
Results are given in terms of GI50 (concentration of drug that
Data are the mean values of three replicates for each concentration
produces 50% inhibition of the cells), TGI (concentration of the (0.1, 1.0, 10, 100 mM mLÀ1). DMSO was used as a vehicle. LC50
=
concentration of drug causing 50% cell kill. TGI = concentration of drug
causing total inhibition of cell growth. GI50 = concentration of drug
causing 50% inhibition of cell growth. STD** = adriamycin, positive
drug that produces total inhibition of the cells) and LC50
(concentration of the drug that kills 50% of the cells) values
that were calculated from the mean graph. Adriamycin (ADR), control drug for MCF7 cell line. ND* = activity not done.
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Table
3
Antioxidant activities of 3a–3l determined by DPPH free radical
Introduction of an ethyl group on the pyrazine ring lowers the
GI50 value as compared to methyl-substituted pyrazine (Table 2).
The TGI values of 3b–3l are higher than the ADR (25.9 mM). The
cytotoxicity (LC50) was also investigated and found to be in good
agreement from 86 to >100 mM as compared to standard drug
adriamycin (LC50 = 89 mM). The LC50 values of 3b, 3g, 3h and 3i
were noted as 86, 95.9, 93.2 and 92 mM, respectively, which fall in
range of ADR. The LC50 values for other compounds were found
to be more than 100 mM (Table 2). Variations in their activities
have been found to be related to the electronic effects of the
substituent groups at the para position of the phenyl rings and
alkyl chains of the pyrazine rings.
methoda
% Antioxidant activity
Concentration (mg mLÀ1
)
Entry
20
40
60
80
100
3a
3b
3c
3d
3e
3f
3g
3h
3i
51.16
36.93
44.09
44.09
16.48
37.39
46.74
46.51
47.21
53.10
38.27
57.49
97.81
51.96
39.32
46.25
45.91
13.86
30.68
46.86
47.09
47.44
55.41
34.87
59.30
98.06
52.51
41.93
46.48
47.50
06.82
29.77
47.09
47.67
47.56
56.26
32.93
59.42
98.18
53.39
42.27
46.70
49.66
01.52
28.30
48.26
49.07
48.26
61.12
27.22
63.55
98.30
54.35
45.45
54.20
54.43
00.11
26.93
49.42
51.51
48.95
62.94
23.57
65.98
98.42
3j
3k
3l
Antioxidant study
In general, antioxidant compounds are capable of scavenging
free radicals and for this purpose, antioxidant therapy is one of
the most recent options.41 Antioxidant activity of 3a–3l was
determined by 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical
method.41 Stock solution of DPPH free radical in ethanol
(2.16 mg/50 mL) was prepared and the absorbance was recorded
at 517 nm. Then, 20, 40, 60, 80, 100 mg mLÀ1 of 3a–3l and
L-ascorbic acid (AA) as standard antioxidant, were prepared in
ethanol by dilution method of 100 mg mLÀ1 stock solution. 1 mL
sample solution and 1 mL of stock solution of DPPH were added
and put into dark conditions for up to 30 min. Then an
absorbance was recorded at 517 nm and the percentage scaven-
ging activity was calculated with the following relation and the
results are plotted in Fig. 2 and given in Table 3.
AA*
a
Data are the mean values of three replicates for each concentration.
AA* = ascorbic acid as standard antioxidant compounds.
antioxidant activity from 57.49 to 66%. Thus, the antioxidant
activity of the compounds is related to their electron or hydro-
gen radical releasing abilities to DPPH so that they become
stable diamagnetic molecules. This might be the reason for the
higher or lower antioxidant activity. The L-ascorbic acid was
used as a standard antioxidant with 97 to 98.50% antioxidant
activity and increased with concentration (Table 3).
In vitro evaluation of antimicrobial activity
Scavenging activity (%) = (Ac À As/Ac) Â 100
The in vitro antibacterial activities of compounds 3a–3l were
carried out using the human pathogenic gram-positive (S. aureus;
ATCC 33591) and gram-negative (E. coli; ATCC 25922) bacterial
strains. The antifungal activities were carried out with C.
albicans; ATCC 14053. The ampicillin, gentamicin, and fluco-
nazole were used as the standard drug for gram-positive, gram-
negative and fungal strains, respectively. The minimum inhi-
bitory concentration (MIC) was evaluated by the broth tube
dilution method42 using Mueller Hinton broth use as a nutrient
medium to grow and to dilute the drug suspension for the test
respectively. Serial dilutions of the test compounds, already
dissolved in DMSO, were prepared to final concentrations of
512, 256, 128, 126, 64 and 32 mg mLÀ1. The MIC which inhibits
the visible growth after 24 h, was determined visually after
incubation for 24 h, at 37 1C and pH 7.4. The lowest concen-
tration, which showed no visible growth, was taken as an end
point for MIC. The MIC level of 3a–3l against these organisms
is given in Table 4.
where Ac = absorbance of DPPH, As = absorbance of test sample.
DPPH radical scavenging activity of the compounds was
found to be good-to-moderate as compared to the standard
AA. The 3a, 3b, 3c, 3d, 3g, 3h, 3i, 3j and 3l showed an increase in
% antioxidant activity within the range of 36 to 66% with an
increase in concentration, while 3e, 3f and 3k showed a
decrease in % antioxidant activity with an increase in concen-
tration. The lowest activity was noted for 3e from 16.48 to
0.11% with an increase in concentration, perhaps due to the
electron lone pair donating nature, while 3l showed the highest
The data revealed that the methylpyrazine chalcones 3a, 3c,
3d showed considerable antibacterial activity with MIC 64, 64
and 32 mg mLÀ1 while ethylpyrazine chalcones showed sensitive
activity up to concentration 256 (3i–3l) and 512 (3f–3h) mg mLÀ1
against gram-positive strains. Further, compound 3b and 3e
showed sensitive activity at MIC 128 mg mLÀ1. On the basis of
MIC results, it was found that compounds having methyl
substitution on pyrazine and electron withdrawing groups such
Fig. 2 Antioxidant activity of 3a–3l determined by DPPH free radical method at
various concentrations.
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Table 4 MIC values for 3a–3l against S. aureus, E. coli and C. albicans strainsa
roughness parameters like mid-value (average of maximum
and minimum), mean, peak to valley of the line (Rpv, difference
between minimum and maximum), root-mean-squared rough-
ness, ten point average roughness area (Rz, is the arithmetic
average of the five highest and five lowest valleys peaks in the
line calculated by ten point average), skewness (Rsk) and
kurtosis (Rku) values of line are given in Table 5.
Minimum inhibitory concentration (MIC, mg mLÀ1
)
Entry
S. aureus
E. coli
C. albicans
3a
3b
3c
3d
3e
3f
3g
3h
3i
64
128
64
512
>512
128
128
512
512
512
512
512
>512
>512
>512
>512
>512
>512
>512
>512
>512
>512
>512
>512
>32
>128
512
512
512
256
256
256
256
Viscosity
Viscosity is a transport property which plays an important role
in the fluid dynamics of drug and pharmaceutical sciences for
their rheological flow and frictional force.45 Thus, the viscos-
ities of the compounds 3a–3l were measured at 298.15 K from
0.002 to 0.010 molar concentrations with acetonitrile (ACN)
using Borosil Mansingh Survismeter (BMS) whose procedural
details are reported elsewhere46 and calibrated using ACN. The
primary viscosity data of 3a–3l were regressed against concen-
tration and their limiting viscosities (Z0) are plotted in Fig. 4.
The Z0 trend was noted as 3h > 3g > 3i = 3l > 3k > 3a > 3j > 3f >
3e > 3c > 3d > 3b, and from 3b to 3f, the Z0 decreased by
approximately 1.0 time than of the ACN viscosity. The max-
imum viscosity of 3b decreased from 0.345 to 0.343 mPa s. The
effect of electron withdrawing and donating groups at the para
position influenced the viscosity of ACN, depicted with experi-
mental data. On increasing the alkyl chain length (–CH3 verses
–C2H5), hydrophobicity increases which in turn increases the
viscosity as a result of weaker interactions. Based on this
interaction, we proposed an interacting model of compound
3e with ACN (Fig. 5).
3j
3k
3l
>512
>512
>512
a
Data are the mean values of three replicates for each concentration.
The compounds were dissolved in DMSO.
as floro, chloro, bromo and nitro on the para position of the
phenyl ring are more sensitive against gram-positive strains.
Compounds 3c and 3d, having 128 mg mLÀ1 MIC, are
sensitive against E. coli, while the MIC of the rest of the
compounds was found to be 512 mg mLÀ1 or greater. None of
the compounds showed activity below 32 mg mLÀ1. It was noted
that an increase in alkyl chain length at the pyrazine ring lowers
the antibacterial activities (Table 4). The tested compounds
showed no significant effect against C. albicans, whereas they
showed activity against S. aureus. The MIC values against
C. albicans of the compounds were found to be greater than
512 mg mLÀ1
.
In silco pharmacology and structural activity relationship
(SAR) study. To qualify compounds as a drug candidate, drug-
like properties were analysed by the parameters set by Lipinski’s
rule of five (ClogP, solubility, molecular weight, drug likeness and
drug score) using Osiris property explorer47 and compared with
some anticancer drugs listed in Table 6.
The ClogP value is used as an indicator to measure lipophi-
licity and also the ability to irritate the various cell mem-
branes.11 The ClogP values are in the range of 1.5 to 3.2,
which is in close agreement with the standard drugs. The drug
score values are in good agreement with the standard anti-
cancer drug score values. Compounds 3a, 3b, 3c, 3g, 3h, 3i and
3l showed good drug score values, calculated by combining all
parameters. Thus, the compounds could be considered as
potent lead compounds in drug discovery.
Atomic force microscopy study
Microstructure analysis of the compounds is generally impor-
tant to understand their physicochemical role, morphology,
topology and size distribution, which play significant roles in
drug binding studies.43 Topographical images of 3c and 3i were
taken using AFM, with a uniform thin film of 3c and 3i in
acetonitrile on a 10 Â 2.5 cm glass slide. To evaporate excess
solvent, the slide was kept in vacuum at r.t. for 24 h.44 The
sample was scanned using non-contact tapping mode and
obtained 3D topological images (Fig. 3). The vertical and
horizontal line analysis of images for 3c and 3i showed rough-
ness parameters such as minimum and maximum surface
value. Mean roughness (Ra) values which were found to be
10.23 and 10.89 nm, respectively, are the mean values of the
surface relative to the centre plane (Table 5). The other
On the basis of reported biological activities, the structural
activity relationship has been proposed which agreed well with
the effect of substitution at the para position on the phenyl ring
and alkyl substitution on pyrazine rings which seem respon-
sible for lower or higher activities. Groups such as –F, –Cl, Br,
–NO2, –N(CH3)2 and –OCH2Ph were introduced at the para
position on the phenyl ring along with introduction of methyl
and ethyl groups at the 3-position on the pyrazine ring to
introduce structural diversity. Results from the biological assay
showed that, in general, electron-withdrawing groups of the
phenyl ring are better for antibacterial activity, while ethyl
pyrazine-based compounds are more active against anticancer
Fig. 3 Topographical surface roughness images of compound 3c and 3i.
c
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Table 5 AFM topographical mean surface parameters (nm) for 3c and 3i
Entry
Line
Min.
Max.
Mid
Mean
Rpv
Rq
Ra
Rz
Rsk
0.40
0.88
0.29
Rku
3c
Horizontal
Vertical
Horizontal
Vertical
À25.66
À16.52
À31.79
À16.16
17.11
12.06
17.16
19.75
À4.28
À2.23
À6.20
0.50
0.00
0.00
0.00
0.00
42.77
28.59
51.54
33.32
12.45
6.80
12.96
9.90
10.59
5.23
10.87
8.55
24.75
25.05
40.51
6.51
2.01
3.40
2.30
1.79
3i
À0.04
Conclusions
In conclusion, two novel series of pyrazine moieties containing
substituted chalcones have been synthesized by a solvent-free
microwave-assisted method. The solvent-free synthesis is better
than the conventional method with shorter reaction time (h to
min), better yield and simpler work-up. Their characterization
was made using various spectral techniques. Various in vitro
studies were performed which agreed well that 3a, 3c, 3d and 3f
are sensitive against gram-positive strains, while 3a, 3c and 3d
also showed moderate-to-good sensitivity against gram-negative
strains. Compound 3i showed remarkable anticancer activity
against the MCF7 cell line while 3b showed effective efficacy in
comparison to ADR. The compounds showed 35 to 66% anti-
oxidant activity. The AFM study has provided a new outlook for
drug loading, drug delivery, thin film formation, DNA binding or
interactions of drugs and in vivo studies. The relationship
between structural and biological properties has been explored
and could be helpful in designing more potent compounds for
biomedical uses in future.
Fig. 4 Limiting viscosity of 3a–3l in acetonitrile at 298.15 K.
Fig. 5 Viscosity interacting model of compound 3e with acetonitrile.
Experimental
General
Table 6 ClogP, solubility, drug likeness and drug score values of 3a–3l and their
2-Acetyl-3-alkylpyrazine (1a–1b) and aldehydes (2a–2f) were of
synthetic grade and purchased from Sigma Aldrich chemicals
and used as received. The K2CO3, NaOH and solvents were from
Rankem, India. Freshly prepared Milli pore water was used as a
solvent (conductance 1 Â 10À6 mS). The reactions were carried
out with an Anton Paar Synthos 3000 microwave reaction
system at an output power of 300 W, infrared (IR) temperature
70 1C. The reaction progress was monitored with TLC (Merck,
silica GF257) using ethyl acetate/hexane (1 : 2, v/v) solvent
system and spots were visualized under UV light (RICO scien-
tific industries, Model RSUV-5). Melting points were deter-
mined on a Veego apparatus and are uncorrected. Elemental
analysis was performed with Euro Vector CHNS/O analyser.
FT-IR spectra were recorded in KBr pellets with a Perkin Elmer
spectrum 65 FTIR spectrophotometer. Characteristic wavenumbers
are given in cmÀ1. 1H and 13C NMR spectra were recorded at r.t.
in 5 mm tube using a Bruker Avance III 500 MHz spectrometer
in deuterated chloroform (CDCl3) and tetramethylsilane (TMS)
as the internal standard. The chemical shifts are given in d ppm
comparison with some standard anti-cancer drugs
Entry
ClogP
Solubility
Drug likeness
Drug score
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
1.94
2.49
2.58
1.75
1.87
3.14
2.29
2.85
2.93
2.10
2.23
3.50
5.69
À0.24
2.24
1.27
2.15
0.94
À2.96
À3.38
À3.48
À3.10
À2.68
À3.98
À3.12
À3.54
À3.64
À3.26
À2.84
À4.14
À4.40
À2.57
À2.54
À1.67
À4.84
À1.82
À0.37
1.44
0.51
0.62
0.49
0.27
0.17
0.38
0.48
0.59
0.46
0.26
0.16
0.36
0.30
0.17
0.12
0.20
0.65
0.90
À1.61
À9.92
À3.54
À7.66
À0.56
1.24
À1.79
À10.09
À3.70
À7.79
6.30
À3.41
À1.21
2.76
2.31
1.97
Tamoxifen
Temozolomide
Lumustine
Carmustine
Trimetrexate
Silibinin
activity. Halogens at the para position showed 50% antioxidant and coupling constants J in Hz. Splitting patterns are described
activity in comparison to other substituents. Methypyrazine- as singlet (s), doublet (d), triplet (t), quartet (q), broad (br) and
based chalcones lower the viscosity in comparison to ethyl- multiplet (m). Mass spectral analysis was accomplished on
pyrazine because the hydrophobicity increases in ACN by Agilent Technologies G6520B LCMS-QTOF mass spectrometry
weakening the interactions.
with +ESI ionization method. The mobile phase 0.02% trifloroacetic
c
2546 New J. Chem., 2013, 37, 2541--2550
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Paper
acid in water and acetonitrile (30 : 70 v/v) was run on an Agilent (–CQO), 1602 (–CQN), 1557, 1508 (–CQC–), 981(–C(O)CHQCH),
zorbax 300 SB-C18 column (3.5 mm, 4.6 Â 50 mm) with flow rate 834 (1,4 substituted Ar ring); +ESIMS: calculated for C14H12FN2O+
of 0.5 mL minÀ1. The absorption transition (lmax) was recorded 243.0855, found 243.0937; 1H NMR (500 MHz, CDCl3, d ppm):
in ethanol at r.t. ranging from 200–600 nm using Analytical UV 2.90 (s, 3H, –CH3), 7.15–7.12 (t, 2H, J = 8.0 Hz, H12,14), 7.72–7.69
spectro 2060 plus.
(t, 2H, J = 7.0 Hz, H11,15), 7.82–7.79 (d, 1H, J = 16.0 Hz, Ha), 7.95–
7.92 (d, 1H, J = 16.0 Hz, Hb), 8.56 (s, 1H, H2), 8.65 (s, 1H, H1); 13
NMR (125 MHz, CDCl3, d ppm): 23.43 (C7, –CH3), 116.19–116.02
C
Chemistry
Two different methods were used for the synthesis of (E)-3-aryl- (C12,14, Ar ring), 122.54–122.52 (Ca, –CHQCH–), 130.73–130.66
1-(3-alkyl-2-pyrazinyl)-2-propenone by Scheme 1.
(C11,15, Ar ring), 131.08–131.06 (C10, Ar ring), 140.69 (Cb,
–CHQCH–), 143.70 (C2, pyrazine ring), 145.67 (C4, pyrazine ring),
147.75 (C1, pyrazine ring), 155.16 (C5, C–CH3), 163.16 (C13, C–F),
190.58 (C8, –CQO).
Method A: general procedure for the synthesis of compounds
3a–3l by conventional method
2-Acetyl-3-alkylpyrazine (1a–1b, 0.005 mol) and substituted
aromatic aldehyde (2a–2f, 0.005 mol) were taken into a 50 mL
round bottom flask and dissolved in 10 mL ethanol. In a clear
(E)-3-(4-Chlorophenyl)-1-(3-methylpyrazin-2-yl)prop-2-en-1-one
(3b)
solution, a 10% solution of NaOH was added dropwise over a Molecular formula: C14H11ClN2O; color: light yellow crystals;
time duration of 10 min, followed by stirring at r.t. Initially the Rf = 0.74; m.p.: 128–130 1C; lmax: 305 and 330 nm; elemental
reaction mass color changed from clear to light yellow with analysis: calculated: C (65%), H (4.29%), N (10.83%), O (6.18%);
precipitate. The reaction progress was monitored by TLC with found: C (65.10%), H (4.22%), N (10.93%), O (6.23%); FTIR
ethyl acetate/hexane (1 : 2, v/v) as eluents. After completion of (KBr, nmax in cmÀ1): 3030 (Ar, –CH str.); 2981, 2924 (–CH str.,
the reaction followed by TLC (Table 1), the reaction mixture was –CH3); 1671 (–CQO), 1602 (–CQN), 1565, 1524 (–CQC–), 981
poured over crushed ice, acidified with dilute HCl and the (–C(O)CHQCH), 818 (1,4 substituted Ar ring); +ESIMS: calcu-
resultant precipitate was left overnight in a refrigerator. The lated for C14H12ClN2O+ 259.0559, found 259.0650; 1H NMR
precipitated was filtered off with a Buckner funnel on Whattman (500 MHz, CDCl3, d ppm): 2.89 (s, 3H, –CH3), 7.40–7.39
filter paper no. 42 and washed with cold water (5 Â 3 mL). The (d, 2H, J = 8.0 Hz, H12,14), 7.62–7.61 (d, 2H, J = 8.0 Hz, H11,15),
wet solid was dried under vacuum and absolute dryness was 7.79–7.75 (d, 1H, J = 16.0 Hz, Ha), 7.987.95 (d, 1H, J = 16.0 Hz,
checked with anhydrous copper sulphate. Compound 3a was Hb), 8.54 (s, 1H, H2), 8.63 (s, 1H, H1); 13C NMR (125 MHz,
subjected to flash column chromatography using ethyl acetate– CDCl3, d ppm): 23.44 (C7, –CH3), 123.12 (Ca, –CHQCH–), 129.12
hexane as eluents at a ratio of 30 : 70 and 50 : 50 (v/v) on 230– (C12,14, Ar ring), 129.83 (C11,15, Ar ring), 133.26 (C10, Ar ring),
400 mesh size silica gel. The overall yields of 3a–3l were obtained 136.49 (C13, C–Cl), 140.66 (Cb, –CHQCH–), 143.26 (C2, pyrazine
as 83–88%. The products were recrystallized in ethanol/methanol/ ring), 145.66 (C4, pyrazine ring), 147.45 (C1, pyrazine ring),
toluene to afford 3a–3l.
155.17 (C5, C–CH3) and 190.30 (C8, –CQO).
Method B: general procedure for the synthesis of compounds
3a–3l using microwave-assisted method
(E)-3-(4-Bromophenyl)-1-(3-methylpyrazin-2-yl)prop-2-en-1-one
(3c)
2-Acetyl-3-alkylpyrazine (1a–1b, 0.005 mol), substituted aromatic Molecular formula: C14H11BrN2O; color: yellow crystals; Rf:
aldehyde (2a–2f, 0.005 mol) and K2CO3 (2.5 g) were taken in 0.70; m.p.: 135–137 1C; lmax: 315 and 375 nm; elemental
teflon reaction vessels, mixed properly in ethyl acetate (5 mL), analysis: calculated: C (55.47%), H (3.66%), N (9.24%), O
dried in air and irradiated at 300 W, with an IR temperature of (5.28%); found: C (55.52%), H (3.71%), N (9.23%), O (5.22%);
70 1C and a maximum pressure of 20 bar inside the vessels for FTIR (KBr, nmax in cmÀ1): 3038 (Ar, –CH str.); 2969, 2924 (–CH
completion of reactions, as given in Table 1. The progress of the str., –CH3); 1671 (–CQO), 1602 (–CQN), 1561, 1528 (–CQC–),
reaction was followed by TLC within ethyl acetate/hexane (1 : 2, v/v) 981 (–C(O)CHQCH), 814 (1,4 substituted Ar ring); +ESIMS:
as eluents. The reaction mixture was cooled to ambient temper- calculated for C14H12BrN2O+ 303.0054, found 303.0133;
ature and the product was extracted with ethyl acetate and 1H NMR (500 MHz, CDCl3, d ppm): 2.91 (s, 3H, –CH3), 7.57
concentrated under vacuum using a Buchi rotary evaporator. The (s, 4H, H11,12,14,15), 7.79–7.76 (d, 1H, J = 16.5 Hz, Ha), 8.02–7.99
overall yields of synthesized compounds were obtained as 90–95%. (d, 1H, J = 16.0 Hz, Hb), 8.56 (s, 1H, H2), 8.65 (s, 1H, H1); 13C
The compounds were recrystallized in ethanol/methanol/toluene NMR (125 MHz, CDCl3, d ppm): 23.49 (C7, –CH3), 123.27 (Ca,
to afford 3a–3l.
–CHQCH–), 125.03 (C13, C–Br), 130.08 (C11,15, Ar ring), 132.16
(C12,14, Ar ring), 133.72 (C10, Ar ring), 140.70 (Cb, –CHQCH–),
143.46 (C2, pyrazine ring), 145.75 (C4, pyrazine ring), 147.54 (C1,
pyrazine ring), 155.25 (C5, C–CH3) and 190.45 (C8, –CQO).
(E)-3-(4-Fluorophenyl)-1-(3-methylpyrazine-2-yl)prop-2-en-1-one
(3a)
Molecular formula: C14H11FN2O; color: yellow crystals; Rf: 0.75;
m.p.: 113–115 1C; lmax: 305, 345; elemental analysis: calculated:
C (69.41%), H (4.58%), N (11.56%), O (6.60%); found: C
(E)-3-(4-Nitrophenyl)-1-(3-methylpyrazin-2-yl)prop-2-en-1-one
(3d)
(69.35%), H (4.62%), N (11.50%), O (6.65%); FTIR (KBr, nmax Molecular formula: C14H11N3O3; color: yellow crystals; Rf: 0.69;
in cmÀ1): 3047 (Ar, –CH str.), 2977, 2932 (–CH str., –CH3), 1671 m.p.: 191–193 1C; lmax: 315 and 390 nm; elemental analysis:
c
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calculated: C (62.45%), H (4.12%), N (15.61%), O (17.83%); 127.80 (C10, Ar ring), 128.20 (C20, Ar ring), 128.69 (C19,21, Ar
found: C (62.39%), H (4.17%), N (15.69%), O (17.89%); FTIR ring), 130.65 (C11,15, Ar ring), 136.38 (C17, Ar ring), 140.67 (Cb,
(KBr, nmax in cmÀ1): 3063 (Ar, –CH str.); 2973, 2921 (–CH str., –CHQCH–), 145.13 (C2, pyrazine), 145.42 (C4, pyrazine), 148.41
–CH3); 1679 (–CQO), 1614 (–CQN), 1593, 1516 (–CQC), 1516, (C1, pyrazine), 154.88 (C5, pyrazine), 161.08 (C13, Ar ring) and
1344 (Ar–NO2), 981 (–C(O)CHQCH), 838 (1,4-substituted Ar ring); 190.93 (C8, –CQO).
+
+ESIMS: calculated for C14H12N3O3 270.0800, found 270.0892;
1H NMR (500 MHz, CDCl3, d ppm): 2.95 (s, 3H, –CH3), 7.89–7.85
(E)-1-(3-Ethylpyrazin-2-yl)-3-(4-fluorophenyl)prop-2-en-1-one
(3g)
(d, 1H, J = 17.0 Hz, Ha), 7.89–7.87 (d, 2H, J = 9.0 Hz, H11,15), 8.22–
8.19 (d, 1H, J = 16.0 Hz, Hb), 8.32–8.30 (d, 2H, J = 8.5 Hz, H12,14), Molecular formula: C15H13FN2O; color: yellow crystal; Rf: 0.70;
8.59 (s, 1H, H2), 8.69 (s, 1H, H1); 13C NMR (125 MHz, CDCl3, m.p.: 105–107 1C; lmax: 310 and 365 nm; elemental analysis:
d ppm): 23.58 (C7, –CH3), 124.20 (Ca, –CHQCH–), 126.46 (C12,14 Ar calculated: C (70.30%), H (5.11%), N (10.93%), O (6.24%);
ring), 129.23 (C11,15, Ar ring), 140.82 (C10, Ar ring), 141.03 found: C (70.34%), H (5.20%), N (10.88%), O (6.29%); FTIR
(Cb, –CHQCH–), 141.44 (C2, pyrazine ring), 146.13 (C13, C–NO2), (KBr, nmax in cmÀ1): 3071, 2981 (Ar, –CH str.); 2932, 2879 (–CH
146.98 (C4, pyrazine ring), 148.65 (C1, pyrazine ring), 155.69 str., –CH2CH3), 1675 (–CQO), 1610 (–CQN), 1585, 1504
(C5, pyrazine ring) and 190.04 (C8, –CQO).
(–CQC–), 1014 (–C(O)CHQCH), 830, 802 (1,4-substituted Ar
ring); +ESIMS: calculated for C15H13FN2O+ 257.1012, found
257.1128; 1H NMR (500 MHz, CDCl3, d ppm): 1.39–1.36
(t, 3H, J = 7.5 Hz, –CH3), 3.24–3.20 (q, 2H, J = 7.5 Hz, –CH2),
(E)-3-[4-(Dimethylamino)phenyl]-1-(3-methylpyrazin-2-yl)prop-
2-en-1-one (3e)
Molecular formula: C16H17N3O; color: saffron; Rf: 0.83; m.p.: 7.15–7.12 (t, 2H, J = 8.5 Hz, H12,16, Ar ring), 7.70–7.68 (m, 2H,
113–115 1C; lmax: 310 and 510 nm; elemental analysis: calcu- 13,15, Ar ring), 7.86–7.76 (dd, 2H, JH = 16.0 Hz, JH = 16.5 Hz,
H
b
a
lated: C (71.89%), H (6.41%), N (15.72%), O (5.98%); found: C Ha and Hb, –CHQCH–), 8.55–8.54 (d, 1H, J = 2.5 Hz, pyrazine-
(71.92%), H (6.38%), N (15.68%), O (6.02%); FTIR (KBr, nmax H2), 8.69–8.68 (d, 1H, J = 2.5 Hz, pyrazine-H1); 13C NMR
in cmÀ1): 3034 (Ar, –CH str.); 2912, 2822 (–CH str., –CH3), 1655 (125 MHz, CDCl3, d ppm): 13.35 (C8, –CH3), 28.79 (C7, –CH2),
(–CQO), 1618 (–CQN), 1581, 1528 (–CQC), 1373, 1332 (C–N), 116.22–116.05 (C13,15, Ar ring), 123.05–123.03 (Ca, –CHQCH),
989 (–C(O)CHQCH), 842 (1,4-substituted Ar ring); +ESIMS: 130.74–130.67 (C12,16, Ar ring), 131.05–131.03 (C11, Ar ring),
1
calculated for C16H18N3O+ 268.1371, found 268.1470; H NMR 140.55 (C2, pyrazine), 143.94 (Cb, –CHQCH–), 145.74 (C4,
(500 MHz, CDCl3, d ppm): 2.86 (s, 3H, –CH3), 3.08 (s, 6H, pyrazine), 148.01 (C1, pyrazine), 159.59 (C5, pyrazine), 163.21
–N(CH3)2), 6.72–6.70 (d, 2H, J = 9.0 Hz, H12,14), 7.60–7.58 (d, 2H, (C14, Ar ring), and 190.84 (C9, –CQO).
J = 9.0 Hz, H11,15), 7.64–7.61 (d, 1H, J = 16.0 Hz, Ha), 7.79–7.76
(d, 1H, J = 16.0 Hz, Hb), 8.53 (s, 1H, H2), 8.60 (s, 1H, H1); 13C
(E)-3-(4-Chlorophenyl)-1-(3-ethylpyrazin-2-yl)prop-2-en-1-one
(3h)
NMR (125 MHz, CDCl3, d ppm): 23.12 (C7, –CH3), 40.11
(–N(CH3)2), 111.97–111.75 (C11,14 Ar ring), 118.02 (Ca, Molecular formula: C15H13ClN2O; color: yellow crystals; Rf: 0.78;
–CHQCH–), 122.50 (C10, Ar ring), 130.91 (C11,15, Ar ring), m.p.: 114–116 1C; lmax: 315 and 375 nm; elemental analysis:
140.60 (Cb, –CHQCH–), 144.97 (C2, pyrazine ring), 146.80 (C4, calculated: C (66.06%), H (4.80%), N (10.27%), O (5.87%);
pyrazine ring), 149.43 (C1, pyrazine ring), 152.27 (C5, pyrazine found: C (66.04%), H (4.77%), N (10.20%), O (5.94%); FTIR
ring), 154.41 (C13, C–N(CH3)2) and 191.12 (C8, –CQO).
(KBr, nmax in cmÀ1): 3081, 2980 (Ar C–H str.); 2928, 2880 (–CH
str., –CH2CH3), 1672 (–CQO), 1605 (–CQN), 1564, 1486
(–CQC–), 1009 (–C(O)CHQCH), 830, 804 (1,4-substituted Ar
(E)-3-[4-(Benzyloxy)phenyl]-1-(3-methylpyrazin-2-yl)prop-2-en-1-
one (3f)
ring); +ESIMS: calculated for C15H13ClN2O+ 273.0716, found
1
Molecular formula: C21H18N2O2; color: yellow crystal; Rf: 0.77; 273.0831; H NMR (500 MHz, CDCl3, d ppm): 1.39–1.36 (t, 3H,
m.p.: 140–142 1C; lmax: 310 and 415 nm; elemental analysis: J = 7.5 Hz, –CH3), 3.24–3.20 (q, 2H, J = 7.5 Hz, –CH2), 7.42–7.41
calculated: C (76.34%), H (5.49%), N (8.48%), O (9.69%); found: (d, 2H, J = 8.5 Hz, H12,16, Ar ring), 7.64–7.62 (d, 2H, J = 8.5 Hz,
C (76.39%), H (5.55%), N (8.54%), O (9.62%); FTIR (KBr, nmax in
H13,15, Ar ring), 7.78–7.75 (d, 1H, J = 16.0 Hz, Ha, –CHQCH–),
cmÀ1): 3034 (Ar, –CH str.); 2922, 2871 (–CH str., –CH3), 1691 7.92–7.88 (d, 1H, J = 16.0 Hz, Hb, –CHQCH–), 8.55–8.55 (d, 1H,
(–CQO), 1663 (ÀCQN), 1585, 1565, 1512 (–CQC–), 1247–1177 J = 2.0 Hz, pyrazine-H2), 8.69–8.69 (d, 1H, J = 2.0 Hz, pyrazine-
(–C–O–C bond linkage of Ar rings) 1002 (–C(O)CHQCH), 838 H1); 13C NMR (125 MHz, CDCl3, d ppm): 13.33 (C8, –CH3), 28.81
(1,4 substituted Ar ring), 736-610 (terminal mono-substituted (C7, –CH2), 123.70 (Ca, –CHQCH), 129.24 (C12,16, Ar ring),
+
Ar ring); +ESIMS: calculated for C21H19N2O2 331.1368, found 129.90 (C13,15, Ar ring), 133.28 (C11, Ar ring), 136.68 (C14, Ar
331.1472; 1H NMR (500 MHz, CDCl3, d ppm): 2.86 (s, 3H, –CH3), ring), 140.56 (C2, pyrazine), 143.66 (Cb, –CHQCH–), 145.81 (C4,
5.12 (s, 2H, –OCH2), 7.01–6.99 (d, 2H, J = 9.0 Hz, H12,14, Ar ring), pyrazine), 147.84 (C1, pyrazine), 159.69 (C5, pyrazine), and
7.36–7.33 (d, 1H, J = 13.5 Hz, Ha, –CHQCH–), 7.44–7.39 (m, 4H, 190.74 (C9, –CQO).
H
19,20,21, Ar ring and Hb, –CHQCH–), 7.64–7.62 (d, 2H, J =
(E)-3-(4-Bromophenyl)-1-(3-ethylpyrazin-2-yl)prop-2-en-1-one
(3i)
9.0 Hz, H18,22, Ar ring), 7.79–7.78 (d, 2H, J = 3 Hz, H11,15), 8.52 (s,
1H, pyrazine-H2), 8.60 (s, 1H, pyrazine-H1); 13C NMR (125 MHz,
CDCl3, d ppm): 23.33 (C7, –CH3), 70.13 (C16, –O–CH2–), 115.30 Molecular formula: C15H13BrN2O; color: yellow crystals; Rf:
(C12,14, Ar ring), 120.87 (Ca, –CHQCH–), 127.51 (C18,22, Ar ring), 0.81; m.p.: 95–97 1C; lmax: 305 and 375 nm; elemental analysis:
c
2548 New J. Chem., 2013, 37, 2541--2550
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calculated: C (56.80%), H (4.13%), N (8.83%), O (5.04%); found: –CHQCH–), 8.52–8.52 (d, 1H, J = 2.0 Hz, pyrazine-H2), 8.64–
C (56.84%), H (4.19%), N (8.78%), O (5.09%); FTIR (KBr, nmax in 8.63 (d, 1H, J = 2.0 Hz, pyrazine-H1); 13C NMR (125 MHz, CDCl3,
cmÀ1): 3077, 2977 (Ar, –CH str.); 2932, 2872 (–CH str., d ppm): 13.47 (C8, –CH3), 28.59 (C7, –CH2), 40.10 N(CH3)2,
–CH2CH3), 1672 (–CQO), 1601 (–CQN), 1583, 1531 (–CQC–), 111.74 (C13,15, Ar ring), 118.51 (Ca, –CHQCH), 122.37 (C11, Ar
1005 (–C(O)CHQCH), 856, 800 (1,4-substituted Ar ring); ring), 130.91 (C12,16, Ar ring), 140.50 (C2, pyrazine), 145.02 (Cb,
+ESIMS: calculated for C15H13BrN2O+ 317.0211, found –CHQCH–), 147.06 (C4, pyrazine), 149.71 (C1, pyrazine), 152.28
1
317.0324; H NMR (500 MHz, CDCl3, d ppm): 1.39–1.36 (t, 3H, (C14, Ar ring), 158.75 (C5, pyrazine), and 191.42 (C9, –CQO).
J = 7.5 Hz, –CH3), 3.24–3.20 (q, 2H, J = 7.5 Hz, –CH2), 7.59–7.54
(q, 4H, J = 8.5 Hz, H12,13,15,16, Ar ring), 7.76–7.73 (d, 1H, J =
16.5 Hz, Ha, –CHQCH–), 7.93–7.90 (d, 1H, J = 16.0 Hz, Hb,
(E)-3-(4-(Benzyloxy)phenyl)-1-(3-ethylpyrazin-2-yl)prop-2-en-1-
one (3l)
–CHQCH–), 8.55–8.55 (d, 1H, J = 2.5 Hz, pyrazine-H2), 8.69–8.69
(d, 1H, J = 2.5 Hz, pyrazine-H1); 13C NMR (125 MHz, CDCl3,
d ppm): 13.33 (C8, –CH3), 28.81 (C7, –CH2), 123.79 (Ca,
–CHQCH), 125.09 (C14, Ar ring), 130.09 (C12,16, Ar ring), 132.20
(C13,15, Ar ring), 133.70 (C11, Ar ring), 140.56 (C2, pyrazine),
143.71 (Cb, –CHQCH–), 145.83 (C4, pyrazine), 147.81 (C1, pyr-
azine), 159.70 (C5, pyrazine), and 190.73 (C9, –CQO).
Molecular formula: C22H20N2O2; color: yellow crystals; Rf: 0.81;
m.p.: 118–120 1C; lmax: 250 and 420 nm; elemental analysis:
calculated: C (76.72%), H (5.85%), N (8.13%), O (9.29%); found:
C (76.66%), H (5.90%), N (8.18%), O (9.26%); FTIR (KBr, nmax in
cmÀ1): 3088, 2977 (Ar, –CH); 2936, 2872 (–CH str., –CH2CH3),
1665 (–CQO), 1590 (–CQN), 1568, 1508 (–CQC–), 1292, 1180
(–C–O–C bond linkage of Ar rings), 1013 (–C(O)CHQCH), 878,
800 (1,4-substituted Ar ring), 729, 610 (terminal mono-substi-
(E)-1-(3-Ethylpyrazin-2-yl)-3-(4-nitrophenyl)prop-2-en-1-one (3j)
+
tuted Ar ring); +ESIMS: calculated for C22H20N2O2 345.1525,
1
Molecular formula: C15H13N3O3; color: yellow crystals; Rf: 0.68;
m.p.: 199–201 1C; lmax: 295 and 380 nm; elemental analysis:
calculated: C (63.60%), H (4.63%), N (14.83%), O (16.94%);
found: C (63.66%), H (4.70%), N (14.77%), O (16.95%); FTIR
(KBr, nmax in cmÀ1): 3103, 2980 (Ar, –CH str.); 2936, 2880 (–CH
str., –CH2CH3), 1676 (–CQO), 1613 (–CQN), 1594, 1516.10
(–CQC–), 1344, 1315 (–C–NO2), 1005 (–C(O)CHQCH), 860,
found 345.1648; H NMR (500 MHz, CDCl3, d ppm): 1.39–1.36
(t, 3H, J = 7.5 Hz, –CH3), 3.22–3.17 (q, 2H, J = 7.5 Hz, –CH2), 5.14
(s, 2H, –OCH2), 7.04–7.02 (d, 2H, J = 9.0 Hz, H13,15, Ar ring),
7.39–7.36 (t, 1H, J = 7.0 Hz, H21, terminal Ar ring), 7.47–7.41
(m, 4H, H19,20,22,23 terminal Ar ring), 7.65–7.64 (d, 2H, J =
8.5 Hz, H12,16 Ar ring), 7.78–7.70 (br, 2H, JH = 16.0 Hz, JH
=
a
b
16.0 Hz, Hb and Ha –CHQCH–), 8.54–8.53 (d, 1H, J = 2.0 Hz,
pyrazine-H2), 8.67–8.66 (d, 1H, J = 2.0 Hz, pyrazine-H1); 13C
NMR (125 MHz, CDCl3, d ppm): 13.42 (C8, –CH3), 28.73 (C7,
–CH2), 70.13 (C17, –OCH2), 115.30 (C13,15, Ar ring), 121.34 (Ca,
–CHQCH), 127.51 (C19,23, terminal Ar ring), 127.72 (C21, term-
inal Ar ring), 128.22 (C12,16, Ar ring), 128.70 (C11, Ar ring),
130.66 (C20,22, terminal Ar ring), 136.36 (C18, Ar ring), 140.54
(C2, pyrazine), 145.38 (Cb, –CHQCH–), 145.47 (C4, pyrazine),
148.66 (C1, pyrazine), 159.27 (C5, pyrazine), 161.10 (C14, Ar
ring), and 191.20 (C9, –CQO).
845 (1,4-substituted Ar ring); +ESIMS: calculated for
+
C
15H13N3O3 284.0957, found 284.1069; 1H NMR (500 MHz,
CDCl3, d ppm): 1.40–1.37 (t, 3H, J = 7.5 Hz, –CH3), 3.29–3.24
(q, 2H, J = 7.5 Hz, –CH2), 7.86–7.83 (br, 3H, JH = 9.0 Hz, JH
=
12,H16
a
16.0 Hz, H12,16, Ar ring and Ha, –CHQCH–), 8.15–8.12 (d, 1H,
J = 16.0 Hz, Hb, –CHQCH–), 8.31–8.29 (d, 2H, J = 9.0 Hz, H13,15
Ar ring), 8.58–8.57 (d, 1H, J = 2.0 Hz, pyrazine-H2), 8.72–8.72
(d, 1H, J = 2.5 Hz, pyrazine-H1); 13C NMR (125 MHz, CDCl3,
d ppm): 13.25 (C8, –CH3), 28.92 (C7, –CH2), 124.20 (Ca,
–CHQCH), 126.84 (C13,15, Ar ring), 129.22 (C12,16, Ar ring),
140.63 (C11, Ar ring), 140.99 (C2, pyrazine), 141.50 (Cb,
–CHQCH–), 146.22 (C4, pyrazine), 147.03 (C14, Ar ring),
148.64 (C1, pyrazine), 160.18 (C5, pyrazine), and 190.12 (C9,
–CQO).
Notes and references
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(E)-3-(4-(Dimethylamino)phenyl)-1-(3-ethylpyrazin-2-yl)prop-2-
en-1-one (3k)
Molecular formula: C17H19N3O; color: light saffron; Rf: 0.82;
m.p.: 105–107 1C; lmax: 295 and 510 nm; elemental analysis:
calculated: C (72.57%), H (6.81%), N (14.94%), O (5.69%);
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(KBr, nmax in cmÀ1): 3081, 2980 (Ar, –CH); 2924, 2816 (–CH str.,
–CH2CH3), 1657 (–CQO), 1613 (–CQN), 1564, 1523 (–CQC),
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1
found 282.1667; H NMR (500 MHz, CDCl3, d ppm): 1.38–1.35
(t, 3H, J = 7.5, –CH3), 3.08 (s, 6H, –N(CH3)2), 3.18–3.13 (q, 2H,
J = 7.5, –CH2), 6.71–6.69 (d, 2H, J = 8.5 Hz, H13,15, Ar ring), 7.53–
7.50 (d, 1H, J = 16.0 Hz, Ha, –CHQCH–), 7.58–7.56 (d, 2H, J =
9.0 Hz, H12,16, Ar ring), 7.73–7.70 (d, 1H, J = 15.5 Hz, Hb,
c
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This journal is The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2013