Design, synthesis, bioactivity, and computational studies of some morpholine-clubbed coumarinyl acetamide and cinnamide derivatives

Article abstract of DOI:10.1007/s13738-018-1324-0

Abstract: The novel derivatives of morpholine-clubbed 3-substituted coumarinyl acetamide and cinnamide derivatives 5a–5j and 6a–6j have been synthesized via various 2-chloro-N-phenyl acetamide and cinnamoyl chloride derivatives, respectively. The required motif has been generated through Vilsmeier–Haack reaction on 4-hydroxycoumarin annelation of morpholine followed by imine formation and subsequently condensation with various 2-chloro-N-phenylacetamide and cinnamoyl chloride to furnish the desired molecule. The synthesized molecules were characterized by various spectroscopic methods viz IR, ¹H NMR, ¹³C NMR. Their antimicrobial activities against various strains of bacteria and fungi have been evaluated, and computational studies have also been performed for all the newly synthesized analogs. Graphical Abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s13738-018-1324-0

Journal of the Iranian Chemical Society
https://doi.org/10.1007/s13738-018-1324-0
ORIGINAL PAPER
Design, synthesis, bioactivity, and computational studies of some
morpholine‑clubbed coumarinyl acetamide and cinnamide derivatives
1
1
2
Prakashsingh M. Chauhan · Sandeep N. Thummar · Kishor H. Chikhalia
Received: 1 August 2017 / Accepted: 9 February 2018
©
Iranian Chemical Society 2018
Abstract
The novel derivatives of morpholine-clubbed 3-substituted coumarinyl acetamide and cinnamide derivatives 5a–5j and
6
a–6j have been synthesized via various 2-chloro-N-phenyl acetamide and cinnamoyl chloride derivatives, respectively.
The required motif has been generated through Vilsmeier–Haack reaction on 4-hydroxycoumarin annelation of morpho-
line followed by imine formation and subsequently condensation with various 2-chloro-N-phenylacetamide and cinnamoyl
chloride to furnish the desired molecule. The synthesized molecules were characterized by various spectroscopic methods
1
13
viz IR, H NMR, C NMR. Their antimicrobial activities against various strains of bacteria and fungi have been evaluated,
and computational studies have also been performed for all the newly synthesized analogs.
Graphical Abstract
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s13738-018-1324-0) contains
supplementary material, which is available to authorized users.
Extended author information available on the last page of the article
Vol.:(0
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Journal of the Iranian Chemical Society
Keywords Coumarin · Acetamide · Cinnamide · Bioactivity · Computational study
Introduction
molecular framework. So we have developed novel mor-
pholine-clubbed coumarin-based acetamide and cinnamide
derivatives via exploration of 3rd position of coumarin with
azomethine linkage and examined their antimicrobial and
antifungal activity against various Gram-positive and Gram-
negative bacterial strains. Moreover, pursuant to thumb rule
for physicochemical factor log P estimated as hydrophobic-
ity for a drug molecule, it must be underneath “5” to by-pass
the cell barrier. To explain the uptake, distribution, biotrans-
formation, and excretion of organic chemicals in biologi-
cal systems, partition or distribution coeꢂcient is essential
factor, and hence in this context, the novel molecules with
substantial lipophilic character are oꢃered in order to cre-
ate remarkable bioactivities [31]. Nowadays, computational
studies play an important role in the ꢀeld of medicinal chem-
istry with augmented the drug design process, and molecu-
lar docking studies of drug molecule provides signiꢀcant
information about the interactions between receptor (target)
and drug and becomes helpful in predicting the activity and
aꢂnity of drug molecule to their targets [32].
In the last few decades, infectious diseases have been ema-
nated dramatically by the bacteria and fungi, resulting in
severe threat to health of human being [1]. In spite of avail-
ability of various types antibiotics drugs, multidrug resist-
ance (MDR) have been continuously emerged for these
drugs in most of the pathogenic bacteria [2]. To overcome
such problems, we tempted to design and synthesize some
novel antibacterial agents, which might have better antimi-
crobial potency compare to recent existing drugs. It accentu-
ates the exploitation of novel antimicrobial and antifungal
drugs, which can facilitate treatment and prevents disease
in a better way.
Coumarin, naturally as well as synthetically occur-
ring compound, constitutes a large family of heterocyclic
compounds with a benzo-α-pyrone moiety, and its various
derivatives have acquired great importance in the ꢀeld of
organic and medicinal chemistry due to its excellent phar-
macological properties [3, 4] viz antimicrobial [5], antioxi-
dant [6], antiviral [7], antifungal [8], anti-inꢁammatory [9],
anticancer [10], antiasthmatic [11], and anti-HIV [12, 13]
activities. Its extraordinary broad range of biological pro-
Results and discussion
ꢀ
le and “immense” therapeutic potential encouraged us to
design novel molecule containing coumarin as its core unit
with the aim of exploring and modifying its antimicrobial
proꢀle. The literature survey reveals that coumarin contain-
ing azomethine linkage at C-3 position shows better pharma-
cological activities which are clinically important [14–17].
Likewise, oxygen- and nitrogen-containing heterocyclic ana-
logs such as morpholine- and morpholine-merged aromatic
ring compounds are very vital building blocks in pharma-
ceutical chemistry. So when morpholine is associated with
another heterocyclic or aromatic ring, it stimulates research
activity in the ꢀeld of the medicinal chemistry [18–23].
Furthermore, the signiꢀcance of amide derivatives is well
known due to their biological properties. Amide derivatives
were linked with the wide range of pharmacological activi-
ties and when they are conjugated with other aromatic and
heterocyclic ring exhibits various type of biological activi-
ties. They have been reported to possess antitubercular [24],
antimicrobial [25], anti-inꢁammatory [26], antidepressant
Chemistry
To accomplish the synthesis of desired compound (5a–5j)
and (6a–6j), the tracks outlined in Schemes 1 and 2 were
implemented. It can be observed from the topography of
4-hydroxycoumarin that it has both nucleophilic and elec-
trophilic properties. The most reactive site of 4-hydroxycou-
marin at 3rd position is carbon atom due to its nucleophilic-
ity. So to explore the 3rd position of coumarin nucleus, it is
required that motif 3-formyl-4-chlorocoumarin 2 was gener-
ated through Vilsmeier–Haack reaction from commercially
available 4-hydroxycoumarin [33, 34]. Then compound 2
on treatment with morpholine in dichloromethane as solvent
and few drops of triethylamine as catalyst, aꢃorded com-
pound 3 [35, 36]. Further, imine linkage was introduced on
3rd position by treatment of compound 3 with p-phenylene-
diamine in ethanol and few drops of acetic acid as catalyst to
get compound 4 [37, 38]. Then compound 4 was condensed
with the 2-chloro-N-phenyl acetamide in DMF and with
cinnamoylchloride in pyridine to get desired compounds
(5a–5j) and (6a–6j), respectively. The entire synthesized
[
27], antitumor [28], antiproliferative [29], anticonvulsant,
analgesic, antimalarial, antileukemic, antiviral, and anti-
oxidant activities [30]. The signiꢀcance of heterocyclic
compounds like 4-hydroxycoumarin, morpholine, and ana-
logs which comprise azomethine and amide linkages, in
the ꢀeld of medicinal chemistry and to explore the scope
of these motifs, prompted us to develop novel heterocy-
clic derivatives which comprise all these things in a single
1
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compounds were conꢀrmed by IR, H NMR, C NMR,
mass spectral studies, and elemental analysis.
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Journal of the Iranian Chemical Society
Scheme 1 Synthetic strategy of ꢀnally synthesized compounds 5a–j
1H NMR
Characterization
1
IR spectra
H NMR spectra of all the newly synthesized compound
5
a–5j and 6a–6j showed sharp singlet of (–CH=N) pro-
IR spectra of all the newly synthesized compounds 5a–5j
and 6a–6j showed a very broad peak of amide forma-
ton of imine and proton of (–NH–CO–) amide linkage at
8.50–9.00 δ ppm and 8.00–8.50 δ ppm, respectively. And
the multiplet of aromatic region proton lies in the range of
6.30–7.90 δ ppm and the two set of triplet (4H and 4H) pro-
ton of morpholine appeared in the range 3.20–3.90 δ ppm
and 4.00–4.80 δ ppm, respectively. Further the singlet of
proton (–NH) in acetamide derivatives 5a–5j resonates at
6.30–6.90 δ ppm, and doublet of proton (–CH=CH) in cin-
namide derivatives appeared between range of 6.20–6.60
δ ppm, and another doublet of proton (–CH=CH–) was
inserted into the aromatic region 6.30–7.90 δ ppm.
−
1
tion between 3400 and 3500 cm for (–NH) stretching,
−
1
1
625–1700 cm for carbonyl (–C=O) stretching vibra-
−
1
tions in pyran nucleus, and 1715–1730 cm for car-
bonyl (–C=O) stretching vibrations in amide. The strong
bands for (–C=N) and (–C–O–C–)stretching vibrations
were observed between 1690 and 1915 and between 1280
−
1
and 1380 cm in morpholine, respectively. The aro-
matic C–H stretching vibrations were observed among
060–3170 cm− in the form of a medium band.
1
3
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Journal of the Iranian Chemical Society
Scheme 2 Synthetic strategy
for ꢀnally synthesized com-
pounds 6a–j
Where R =various substituent.
13C NMR
Antibacterial activity
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3
C NMR spectra of all the newly synthesized compound
The antimicrobial potency in terms of MIC values is summa-
rized in Table 1. It reveals that in general the values of com-
pounds are observed in the varied range (62.5–500 µg/ml)
for antibacterial activities against Gram-positive bacterial
strain Staphylococcus aureus and Streptococcus pyogenes
and (31.25–500 µg/ml) for antibacterial activities against
Gram-negative bacterial strain Pseudomonas aeruginosa
and Escherichia coli, respectively. All the newly synthe-
sized coumarinyl amide derivatives with weakly electron-
withdrawing halogen substitution and electron-donating
substitution on 4th position of phenyl nucleus were found to
be more potent than the remaining ultimate analogs against
all the bacterial strains. Compound 5g and 5j with 4-chloro
and 4-methoxy substituents at the phenyl nucleus of entire
coumarin core showed good potency against all the bacte-
rial strains, but among these strains speciꢀcally they were
more potent against S. aureus and S. pyogenes with 62.5 and
31.25 µg/ml of MIC, respectively. It can be evidently seen
that the compound 5g (Log P = 2.78) and 5j (Log P = 2.00)
with lipophilicity displayed higher activity. In addition to
this, the compound 5d (Log P = 2.21) and 5f (Log P = 2.76)
substituted with electron-withdrawing nitro group at the 4th
position of phenyl nucleus and weakly electron-donating
5
a–5j and 6a–6j showed around 163–170 δ ppm due to the
carbonyl (–C=O) carbon of lactone in coumarin, amide
group, and (–C–O–) of pyran ring which is attached with
morpholine ring and around 150–155 δ ppm which is due to
the (–CH=N) imine carbon, while the signals around range
between 115 and 155 δ ppm due to the aromatic region
carbon and (–C=C–) of cinnamide derivatives. Further the
most higher ꢀeld signal at around 44, 48, and 66 δ ppm can
be attributed to methylene group of acetamide derivative
carbon (–C–N–C–) and (–C–O–C–) of morpholine ring,
respectively.
Biological evaluation
All the newly synthesized morpholine-clubbed 3-substituted
coumarinyl acetamide (5a–5j) and cinnamide derivatives
(
6a–6j) were examined for their antibacterial and antifun-
gal activity against diꢃerent bacterial strains by employing
broth microdilution method. The minimum inhibitory con-
centration (MIC) was determined for each compound along
with ciproꢁoxacin for antibacterial activity and nystatin for
antifungal as standard drugs.
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Journal of the Iranian Chemical Society
Table 1 In vitro antibacterial and antifungal activities of ꢀnally synthesized compounds (5a–j) and (6a–j)
Comp. No.
Antibacterial activity
Antifungal activity
Minimum inhibitory concentration in µg/ml
R
Log P
Gram positive
Gram negative
Fungi
S. aureus
S. pyogenes
P. aeruginosa
E. coli
C. albicans
A. niger
A. clavatus
5
5
5
5
5
5
5
5
5
5
6
6
6
6
6
6
6
6
6
6
a
b
c
d
e
f
–H
2.25
2.21
2.22
2.21
2.77
2.76
2.78
2.72
2.00
2.01
3.49
3.43
3.46
3.45
3.96
3.97
3.24
3.22
3.25
2.73
–
250
500
500
200
250
200
62.5
200
250
100
250
500
500
200
100
200
250
200
125
62.5
50
250
500
500
250
250
250
100
250
200
100
250
500
500
250
125
250
500
250
125
100
50
500
250
200
500
500
125
100
125
250
31.25
500
250
500
200
500
250
200
250
31.25
125
25
500
250
200
100
500
200
100
100
250
250
500
250
250
250
500
250
250
200
100
125
25
500
1000
> 1000
500
250
200
100
500
500
250
500
250
500
500
1000
1000
250
250
250
100
–
1000
> 1000
500
> 1000
500
250
500
> 1000
500
500
250
100
500
500
500
250
> 1000
> 1000
500
> 1000
–
500
2-NO2
3-NO2
4-NO2
2-Cl
3-Cl
4-Cl
2-CH3
2-OCH3
4-OCH3
–H
2-NO2
3-NO2
4-NO2
2-CH3
4-CH3
2-OCH3
3-OCH3
4-OCH3
3,4,5-OCH3
Ciproꢁoxacin
Nystatin
1000
1000
500
1000
500
> 1000
> 1000
500
500
100
1000
1000
500
1000
500
g
h
i
j
a
b
c
d
e
f
g
h
i
> 1000
> 1000
500
250
–
j
Standard drug
–
–
–
–
100
100
100
S. aureus, Staphylococcus aureus; S. pyogenes, Streptococcus pyogenes; P. aeruginosa, Pseudomonas aeruginosa; E. coli, Escherichia coli; C.
albicans, Candida albicans; A. niger, Aspergillus niger; A. clavatus, Aspergillus clavatus
chloro group at the 3rd position of phenyl nucleus of aceta-
mide derivatives showed better activity to some extent
against Gram-negative bacteria E. coli and P. aeruginosa,
respectively. Other analogs of acetamide 5h (Log P = 2.72)
with methyl substituent at the 2nd position of phenyl ring
showed good lipophilic value and better activity to some
extent against both the Gram-negative bacilli. Rest of the
compounds appeared with moderate-to-good activity pro-
62.5 µg/ml of MIC, while the compound 6e (Log P = 3.96)
substituted at 2nd position with methyl group and with
higher lipophilic parameter showed good activity against
Gram-positive bacteria compared to other compounds. Rest
of other coumarinyl cinnamide derivatives appeared with
moderate-to-good activity proꢀle. None of the compound
has reached up to the level of standard drug ciproꢁoxacin.
ꢀle. Furthermore, the coumarinyl cinnamide derivatives also
Antifungal Activity
showed diversiꢀed activity against diꢃerent bacterial strains.
Final compound 6i (Log P = 3.25) substituted with electron-
donating methoxy group at 4th position of phenyl ring of
coumarinyl cinnamide derivatives showed good activity
against all the Bacillus, but among these particularly against
Gram-negative P. aeruginosa, it showed most prominent
activity with 31.25 µg/ml of MIC with higher value of lipo-
philicity. Another analogs of cinnamide 6j (Log P = 2.73)
tri-substituted with electron-donating methoxy group exhib-
ited good activity against both the bacterial strains, but spe-
ciꢀcally against S. aureus it showed promising activity with
All the synthesized novel derivatives were screened for
their in vitro antifungal activity using nystatin as refer-
ence drug. The antifungal potency in terms of MIC val-
ues is summarized in Table 1. Results of the MIC values
of the coumarinyl acetamide derivatives are found in
the range (100 to > 1000 µg/ml) against studied fungal
strains. Final analogs of coumarinyl acetamide derivative
5g (Log P = 2.78) with electron-donating chloro sub-
stituent at the 4th position of phenyl nucleus exhibited
better inhibition against Candida albicans with 100 µg/
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Journal of the Iranian Chemical Society
Graphical representation of anti-
bacterial activity of synthesized
compounds (5a–5j) and (6a–6j)
600
5
4
3
2
1
00
00
00
00
00
0
S.aureus
S.pyogenus
P.aeruginosa
E.coli
Graphical representation of anti-
fungal activity of synthesized
compounds (5a–5j) and (6a–6j)
1200
1
000
8
6
4
2
00
00
00
00
0
C.albicans
A.niger
A.clavatus
ml MIC value equivalent to nystatin drug, while none of
the acetamide derivatives were reached at the level of
standard drug. On the other hand, unsubstituted coumari-
nyl cinnamide derivatives 6a (Log P = 3.49) with higher
lipophilicity showed the best activity against Aspergil-
lus clavatus with 100 µg/ml MIC value, while compound
Structure–activity relationship studies (SAR)
It was examined from the biological evaluation of deriva-
tives (5a–5j) and (6a–6j) is that weakly electron-withdraw-
ing and electron-donating groups provided diverse electronic
surroundings on the molecules and demonstrated a great
inꢁuence on their various biological properties. It is abso-
lutely clear from above-mentioned biological activities in
Table 1 that the molecule which possesses electron-donat-
ing substituent like (4-OCH ) (3, 4, 5-OCH ) and weakly
6
b (Log P = 3.43) substituted on 2nd position of phenyl
nucleus with electron-withdrawing nitro group exhibited
potent activity against Aspergillus niger with 100 µg/ml
MIC value, and 6j (Log P = 2.73) substituted on 3, 4, 5
position of phenyl ring of cinnamide with methoxy group
also proved better against C. albicans with 100 µg/ml
MIC value. Rest of the compounds were not reached up
to the level of standard drug nystatin.
3
3
electron-withdrawing substituent like (4-Cl) exhibit much
better activity than the other derivatives against Gram-
positive and Gram-negative bacteria, while substituent like
(4-NO ), (3-Cl) and (3-CH ) showed to some extent better
2
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Journal of the Iranian Chemical Society
activity against only Gram-negative bacilli, and substituent
understood from the docking pose. Crystal structure of pro-
tein (1KZN) of E. coli and ciproꢁoxacin are represented as
below (Fig. 1).
like (2-CH ) showed in some extent better activity against
3
only Gram-positive bacilli. It was also observed that for
antifungal activity, compound with unsubstituted phenyl
nucleus, (2-NO ), (3, 4, 5-OCH ), and (4-Cl) exhibited
Figure 2 shows the interaction of ciprofloxacin with
receptor protein 1KZN. The docking score of ciproꢁoxacin
was − 6.148, and it was taken as standard for newly synthe-
sized compounds. And the pocket site of ciproꢁoxacin with
receptor included SER-121, ALA-96, VAL-120, and GLU-
50 amino acid residues which formed four hydrogen bonds,
from which SER-121, ALA-96, VAL-120 formed hydrogen
bond with backbone, while GLU-50 formed hydrogen bond
with side chain.
2
3
excellent activity compared to standard drug nystatin. SAR
study leaded toward conclusion that alteration if undertaken
by introducing electron-donating and weakly electron-with-
drawing functional group can help to increase the antimi-
crobial activities of the prepared compounds. From this
study, we concluded that substitution by electron-donating
and weakly electron-withdrawing group on 4th position of
phenyl nucleus of acetamide and cinnamide derivatives are
more beneꢀcial for the betterment of antimicrobial proꢀle.
Figure 3 shows the interaction of 5e with DNA gyrase
protein 1KZN. The docking score of 5e was − 5.108, and the
pocket site of compound 5e with receptor protein included
ALA-96 and ARG-136 amino acid residues which formed
two hydrogen bonds. ALA-96 formed hydrogen bond by
Molecular docking
In biochemical process, DNA gyrase is one of the most
important bacterial protein which is engaged with process
like transcription and replication, and it catalyzes the nega-
tive supercoiling of circular DNA bacteria, and it is also
a very known object for the antibacterial compound since
its blocking causes the death of bacteria [39]. So with a
view to understand the binding mode of the newly synthe-
sized compounds (5a–5j) and (6a–6j) against DNA gyrase
protein receptor (1KZN), docking study was carried out.
All the newly synthesized compounds were docked in the
protein structure of E. coli, which was obtained from the
Protein Data Bank (PDB ID-1KZN), and ciproꢁoxacin was
used as a standard for docking study, and it was docked
with target receptor 1KZ. All the ligands showed negative
docking scores but none of them reached up to the level of
standard ciproꢁoxacin scores. However, the docking scores
of compounds 5e, 5g, 5i, 6i were found to possess highest
negative dock score in all the newly synthesized compounds
electrostatic attraction between N atom of (–NH ) group
2
of backbone and H atom (–NH–CO–) amide linkage, while
ARG-136 formed hydrogen bond by electrostatic attraction
between H atom of (–NH ) group of guanidine side chain
2
and O atom of carbonyl (–CO–) group of pyran nucleus.
Figure 4 shows the interaction of 5g with DNA gyrase
protein 1KZN. The docking score of 5g was − 5.114, and the
pocket site of compound 5g with receptor protein included
ARG-136 amino acid residue which formed 2 hydrogen
bonds via side chain. One hydrogen bond formed by electro-
static attraction between H atom of (–NH ) group of guani-
2
dine and N atom of (–CH=N–) imine linkage, and another
hydrogen bond is formed by electrostatic attraction between
+
H atom of (–NH ) group of side chain and O atom of car-
2
bonyl (–CO–) group of pyran nucleus.
Figure 5 shows the interaction of 5i with DNA gyrase
protein 1KZN. The docking score of compound 5i was
− 5.217, and the pocket site compound 5i with recep-
tor protein included ASP-46 amino acid residue which
formed 2 hydrogen bonds via backbone. Both hydrogen
bond formed by electrostatic attraction between 2H atom
(
Table 2).
And some molecular basis interactions with DNA gyrase
protein target enzymes and synthesized compounds can be
Table 2 Docking score of
Compound No.
Standard
R
Docking score
Compound No.
R
Docking score
synthesized compounds (5a–j)
and (6a–j)
Ciproꢁoxacin
–H
2-NO2
3-NO2
4-NO2
2-Cl
3-Cl
4-Cl
2-CH3
2-OCH3
4-OCH3
− 6.148
− 3.68
Standard
6a
Ciproꢁoxacin
–H
2-NO2
3-NO2
4-NO2
2-CH3
4-CH3
2-OCH3
3-OCH3
4-OCH3
3,4,5-OCH3
− 6.148
− 1.963
− 3.27
− 3.732
− 1.43
− 2.456
− 2.471
− 3.015
− 2.945
− 5.224
− 2.636
5
5
5
5
5
5
5
5
5
5
a
b
c
d
e
f
− 2.476
− 3.441
− 2.792
− 5.108
− 3.272
− 5.114
− 4.311
− 5.217
− 2.391
6b
6c
6d
6e
6f
g
h
i
6g
6h
6i
j
6j
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Journal of the Iranian Chemical Society
Fig. 1 Crystal structure of target receptor (1KZN) of E. coli and standard drug Ciproꢁoxacin
Fig. 2 Binding pose of standard drug ciproꢁoxacin with receptor protein E. coli (1KZN)
of (–NH–CO–NH–) amide linkage and O atom of carbonyl
HOMO–LUMO theory (FMO approach)
(
–CO–) group of pyran nucleus.
Figure 6 shows the interaction of 6i with DNA gyrase
In frontier molecular orbital theory, “highest occupied
molecular orbital” (HOMO) and “lowest unoccupied molec-
ular orbital” (LUMO) are most inꢁuential molecular orbital,
protein 1KZN. The docking score of compound 6i was
−
5.224, and the pocket site of compound 6i with recep-
tor protein included ARG-76 and ARG-136 amino acid
and the value of their energy gap (E
–E
) reꢁects
LUMO
HOMO
residue from which ARG-136 formed hydrogen bond
the reactivity of molecule. So here we can try to correlate
this reactivity with biological activity, and it also reinforces
the biological activity [40, 41]. A molecule which possesses
a small gap between frontier orbitals is highly polarizable
and showed higher chemical reactivity and lower kinetic sta-
bility. Generally, the energy of HOMO is directly associated
+
by electrostatic attraction between H atom of (–NH )
2
group of side chain and O atom of morpholine ring, while
another residue ARG-76 showed (π–π stacking) attractive
non-covalent interaction with π-bonds of aromatic nucleus
which is shown by green line.
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Journal of the Iranian Chemical Society
Fig. 3 Binding pose of compound 5e with the E. coli (1KZN)
Fig. 4 Binding pose of compound 5g with the E. coli (1KZN)
with ionization potential because electrons are weakly held
by HOMO, so it loses electrons easily when the molecule is
energized. In case of LUMO, it is directly associated with
electron aꢂnity because it accepts electrons. The HOMO
and LUMO theory was applied on novel synthesized com-
pounds (5a–5i) and (6a–6j) from these compounds, and
some of the substituted compounds like, 5g, 5j, 6b, 6i, 6j
showed better energy gap when compared to unsubstituted
compounds like 5a and 6a (Fig. 7).
biological activity. On the other hand, unsubstituted compound
6a contains HOMO–LUMO Gap (1.347), while substituents
6b and 6i contain HOMO–LUMO Gap (0.876) and (0.865),
respectively, which were less when compared to unsubstituted
compound 6a and therefore exhibited better biological activity.
It can further be concluded that lower the energy gap better
activity can be generated.
From Table 3, it is observed that unsubstituted compound
5
a contains HOMO–LUMO Gap (3.565) and further enlist-
ing substituents 5g and 5j contain less HOMO–LUMO
Gap (3.510) and (3.508), respectively, and exhibited better
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Journal of the Iranian Chemical Society
Fig. 5 Binding pose of compound 5i with the E. coli (1KZN)
Fig. 6 Binding pose of compound 6i with the E. coli (1KZN)
Materials and methods
all synthesized compounds was checked using thin layer
chromatography (TLC) on silica gel-coated sheets (Merck
1
13
The melting points of all the newly synthesized compounds
were determined in open capillaries on a Veego electronic
apparatus VMP-D (Veego Instrument Corporation, Mum-
Kiesel 60 GF-254, 0.2 mm thickness). H NMR and
C
NMR spectra were recorded on a Varian 400 MHz model
spectrometer (Varian India Pvt. Ltd., Mumbai, India)
using DMSO as a solvent and TMS as internal standard
with 1H resonant frequency of 400 MHz and 13C reso-
1
13
bai, India). H NMR and C NMR spectra were recorded
at 400 MHz on a Bruker AM-400 spectrometer with TMS
−
1
1
13
as internal standard. IR spectra (4000–400 cm ) of newly
synthesized compounds were recorded on a Shimadzu
nant frequency of 100 MHz. The H NMR and C NMR
chemical shifts were reported as parts per million (ppm)
downꢀeld from TMS. Mass of the synthesized compound
was recorded on GC/MS Shimadzu mass spectrometer,
and (M + H) of the compounds was stated in percentage.
8
400-S FTIR spectrophotometer (Shimadzu India Pvt.
Ltd., Mumbai, India) using KBr pellets. The purity of
1
3

Journal of the Iranian Chemical Society
Fig. 7 HOMO–LUMO plot
of synthesized compounds 5a
and 6a
Preparation of 4‑chloro‑2‑oxo‑2H‑chromene‑3‑car‑
baldehyde (2)
was appeared after stirring for 1 h at room temperature.
Then the temperature was gradually raised up to 60 °C and
further stirred for 5–6 h at 60 °C. The progress of reaction
was monitored by TLC using ethyl acetate–hexane (6:4) as
eluent. After the completion of reaction, it was poured into
crushed ice with stirring. The separated solid mass was ꢀl-
tered oꢃ and washed thoroughly with water then aqueous
Na CO (5%). The yellow solid product was obtained. The
POCl (0.18 mol) was added dropwise to a stirring mix-
3
ture of 4-hydroxycoumarin (1) (0.6 mol) in DMF (46.2 ml),
below 0 °C, producing a semisolid mass. A clear solution
2
3
Table 3 HOMO–LUMO energy gap of the compounds 5a, 5g, 5j and
crude product was puriꢀed by crystallization from acetone
6
a, 6b, 6i
to get the title compound (2) M.P. = 143–148 °C, Yield 74%
Compound
EHOMO
ELUMO
HOMO–
LUMO
gap
ꢀ.ꢁ. = 143 − 148, ꢂꢃꢄꢅꢆ 74%.
Preparation of 4‑mor‑
pholino‑2‑oxo‑2H‑chromene‑3‑carbaldehyde (3)
5
5
5
6
6
6
a
g
j
a
b
i
− 5.556
− 5.510
− 5.509
− 5.480
− 5.005
− 4.964
− 1.991
− 2.000
− 2.001
− 4.133
− 4.129
− 4.099
3.565
3.510
3.508
1.347
0.876
0.865
Morpholine (0.004 mol) in dichloromethane (5 ml) was
gradually added with stirring to an ice-cooled mixture of
compound (2), (0.002 mol) in dichloromethane (10 ml), and
stirred for 30 min at 0–5 °C. The progress of reaction was
1
3

Journal of the Iranian Chemical Society
1
monitored by TLC by using chloroform–methanol (9:1) as
eluent. After the completion of reaction, the mixture was
washed with 3 × 10 ml of water in order to remove unre-
acted morpholine and its salt. The organic layer was dried
over anhydrous sodium sulfate, and the solvent was evapo-
rated under reduced pressure. The dry, ꢁake-like residue was
recrystallized from ethanol. The crude product was puriꢀed
by crystallization from acetone to get the title compound (3).
(–C=O). H NMR: (400 MHz, DMSO-d6): δ 8.51 (br s,
1H, –NH), 7.68–7.52 (m, 4H), 4.25 (s, 2H, –CH –Cl).
2
2-Chloro-N-(4-nitrophenyl) acetamide (2d): Yield:
−
1
76%, M.P. 168–170 °C. IR (KBr), cm : 3273 (–NH),
1
1667 (–C=O). H NMR: (400 MHz, DMSO-d6): δ 8.61
(br s, 1H, –NH), 7.63–7.450 (m, 4H), 4.32 (s, 2H,–CH –
2
Cl).
2-Chloro-N-(2-chlorophenyl) acetamide (2e): Yield:
−
1
7
1
8
–
2
8
1
9%, M.P. 151–154 °C. IR (KBr), cm : 3282 (–NH),
1
668 (–C=O). H NMR: (400 MHz, DMSO-d6): δ d
Preparation of 3‑(((4‑aminophenyl)imino)
methyl)‑4‑morpholino‑2H‑chromen‑2‑one (4)
.45 (br s, 1H, –NH), 7.68–7.21 (m, 4H), 4.28 (s, 2H,
CH –Cl).
2
-Chloro-N-(3-chlorophenyl) acetamide (2f): Yield:
A solution of p-phenylenediamine (0.002 mol) in ethanol
−
1
3%, M.P. 140–143 °C. IR (KBr), cm : 3293 (–NH),
(
10 ml) was added to mixture of compound (3) (0.002 mol)
1
675 (–C=O). H NMR: (400 MHz, DMSO-d6): δ d 8.46
in ethanol (10 ml) containing 1–2 drops of acetic acid. The
reaction mixture was reꢁuxed for 3–4 h. The progress of the
reaction was monitored by TLC using ethyl acetate–hexane
(
br s, 1H, –NH), 7.73 (s, 1H), 7.58–7.29 (m, 3H), 4.31 (s,
2
2
8
1
8
–
2
H, –CH –Cl).
2
-Chloro-N-(4-chlorophenyl) acetamide (2g): Yield:
(4:6) as eluent. After the completion of the reaction, mixture
−
1
5%, M.P. 145–147 °C. IR (KBr), cm : 3297 (–NH),
was kept at room temperature for 30 min and then poured
into crushed ice. The precipitate obtained was ꢀltered oꢃ
and washed with water. The crude product was puriꢀed by
crystallization from absolute alcohol to get the title com-
pound (4).
1
681 (–C=O). H NMR: (400 MHz, DMSO-d6): δ d
.51 (br s, 1H, –NH), 7.72–7.25 (m, 4H), 4.27 (s, 2H,
CH –Cl).
2
-Chloro-N-p-tolylacetamide (2h): Yield: 82%, M.P.
−1
1
62–164 °C. IR (KBr), cm : 3294 (–NH), 1675 (–C=O).
1
H NMR (400 MHz, DMSOd6): δ 8.36 (br s, 1H, –NH),
7.53–7.48 (m, 2H), 7.37–7.36 (m, 2H), 4.29 (s, 2H, –
CH –Cl), 2.15 (s, 3H, –CH ).
General synthetic procedure
for 2‑chloro‑N‑(substituted) phenyl acetamides
2
3
(2a–2j)
2-Chloro-N-(2-methoxyphenyl)acetamide (2i): Yield:
−1
8
0%, Limpid. IR (KBr), cm : 3318 (–NH), 1658 (–
1
Chloroacetyl chloride (0.06 mol) was added dropwise to
a mixture of the appropriate amine (0.05 mol) and K CO
C=O). H NMR: (400 MHz, DMSOd6): δ 8.28 (br s,
1H, –NH), 7.66 (d, J = 7.5 Hz, 2H), 7.45 (d, J = 7.1 Hz,
2H), 4.28 (s, 2H, –CH –Cl), 3.79 (s, 3H, –OCH ).
2
3
(
0.06 mol) in acetone (50 ml) at room temperature. The
2
3
reaction mass was reꢁuxed for 4–8 h, and then progress of
reaction was monitored by TLC using ethyl acetate–hexane
2-Chloro-N-(4-methoxyphenyl)acetamide (2j): Yield:
−1
78%, M.P. 121–122 °C. IR (KBr), cm : 3331 (–NH),
1
(
8:2) solvent system as eluent. Then the reaction mixture
1661 (–C=O). H NMR: (400 MHz, DMSOd6): δ
was cooled and poured into 100 ml of ice water. The result-
ing white precipitates were ꢀltered oꢃ and dried under the
vacuum condition and puriꢀed by recrystallization from
alcohol. Similarly, other compounds (5a–5j) were prepared
by using various substituted amines.
8.37 (br s, 1H, –NH), 7.58 (d, J = 7.5 Hz, 2H), 7.38 (d,
J = 7.1 Hz, 2H), 4.21 (s, 2H, –CH –Cl), 3.67 (s, 3H, –
2
OCH ).
3
General synthetic procedure for 2‑((4‑(((4‑mor‑
pholino‑2‑oxo‑2H‑chromene‑3‑yl)methylene)
amino)phenyl)amino)‑N‑phenylacetamide (5a–5j)
2
-Chloro-N-phenyl acetamide (2a): Yield: 81%, M.P.
−1
1
10–115 °C. IR (KBr) cm : 3261 (–NH), 1681 (–
1
C=O). H NMR: (400 MHz, DMSO-d6): δ ppm, 8.46 (br
A mixture of compound (4) (0.0014 mol) and K CO
2
3
s, 1H, –NH), 7.56 (m, 2H), 7.40 (m, 2H), 7.24 (m, 1H),
(0.0021 mol) in anhydrous dimethylformamide (10 ml)
was stirred for 1 h at room temperature. Then the solution
of 2-chloro-N-phenyl acetamide (5) (0.0014 mol) in 5 ml
DMF solvent and appropriate catalytic amount of triethyl-
amine was added to this reaction mixture and reꢁuxed for
3–12 h. The progress of reaction was monitored by TLC
using ethyl acetate–hexane (6:4) as eluent. After the com-
pletion of reaction, the reaction mixture was poured into
ice-cold water. The crude product was ꢀltered and washed
4
2
7
1
.34 (s, 2H, –CH –Cl).
2
-Chloro-N-(2-nitrophenyl) acetamide (2b): Yield:
−
1
3%, M.P. 165–170 °C. IR (KBr) cm : 3263 (–NH),
1
679 (–C=O). H NMR: (400 MHz, DMSO-d6): δ 8.43
(
br s, 1H, –NH), 7.63–7.51 (m, 4H), 4.28 (s, 2H, –CH –
2
Cl).
2
-Chloro-N-(3-nitrophenyl) acetamide (2c): Yield:
−1
7
1%, mp 160–165 °C. IR (KBr) cm : 3265 (–NH), 1675
1
3

Journal of the Iranian Chemical Society
thoroughly with cold water for several times and puriꢀed
by absolute alcohol to get the title compound (5). Simi-
larly, other ꢀnal compounds (5a–5j) were prepared from
intermediate (4) with various substituted aryl acetamide.
2‑((4‑(((4‑Morpholino‑2‑oxo‑2H‑chromen‑3‑yl)meth‑
ylene)amino)phenyl)amino)‑N‑(4‑nitrophenyl)aceta‑
−
1
mide‑(5d) Yield: 71%, M.P. 239 °C. IR (KBr), cm :
3411 (–NH), 3058 (–CH), 1716 (–C=O), 1688 (–C=O),
1
618 (–C=N), 1587 (–C=C–Ar), 1559, 1352 (Ar–NO ),
2
1
2
‑((4‑(((4‑Morpholino‑2‑oxo‑2H‑chromen‑3‑yl)
1284 (–C–O–C–morpholine). H NMR: (400 MHz, DMSO-
methylene)amino)phenyl)amino)‑N‑phenyl aceta‑
d ): δ 3.80 (t, 4H J = 3.9 Hz), 4.30 (t, 4H J = 3.9 Hz), 4.65
6
−1
mide‑(5a) Yield: 75%, M.P. 234 °C. IR (KBr), cm : 3413
(s, 2H), 8.21–6.38 (a set of signals 13H, aromatic protons
(
–NH), 3067 (–CH), 1718 (–C=O), 1692 (–C=O), 1625 (–
and Ar–NH–), 8.22 (s, 1H), 8.75 (s, 1H). MS (ESI): m/z
1
13
C=N), 1593 (–C=C–Ar), 1287 (–C–O–C–morphine). H
([M + H] +); 528.2. C NMR: (100 MHz, DMSO-d ): δ
6
NMR: (400 MHz, DMSO-d ): δ 3.33 (t, 4H J = 4.1 Hz),
44.6, 48.5, 66.1, 84.6, 117.3, 117.9, 120.6, 125.1, 125.5,
126.9, 127.9, 130.3, 143.3, 148.1, 145.4, 148.1, 150.6,
151.9, 164.3, 165.5, 167.9. Elemental Analysis: Calcd. for
C H N O : C, 63.75; H, 4.78; N, 13.28. Found: C, 63.72;
6
4
.05 (t, 4H J = 4.1 Hz), 4.34 (s, 2H), 7.60–6.54 (a set of
signals 14H, aromatic protons and Ar–NH–), 8.58 (s, 1H),
1
3
8
.88 (s, 1H). MS (ESI): m/z ([M + H] +); 483.0. C NMR:
2
8
25
5
6
(
100 MHz, DMSO-d ): δ 44.5, 48.5, 66.1, 84.8, 117.3,
H, 4.79; N, 13.31.
6
1
1
17.9, 121.4, 123.7, 125.1, 126.9, 127.9, 129.3, 130.3,
37.7, 143.3, 148.1, 150.6, 151.9, 164.3, 165.5, 167.9, Ele-
N‑(2‑chlorophenyl)‑2‑((4‑(((4‑morpholino‑2‑oxo‑2H‑c
mental Analysis: Calcd. for C H N O : C, 69.70; H, 5.43;
hromen‑3‑yl)methylene)amino)phenyl)amino)aceta‑
28
26
4
4
−1
N, 11.61. Found: C, 69.67; H, 5.39; N, 11.58.
mide‑(5e) Yield: 72%, M.P. 225 °C. IR (KBr),cm : 3411
(
–NH), 3057 (–CH), 1716 (–C=O), 1685 (–C=O), 1616 (–
2
‑((4‑(((4‑Morpholino‑2‑oxo‑2H‑chromen‑3‑yl)meth‑
C=N), 1584 (–C=C–Ar), 1282 (–C–O–C–morpholine). MS
1
ylene)amino)phenyl)amino)‑N‑(2‑nitrophenyl)aceta‑
(ESI): m/z ([M + H] +); 517.0. H NMR:(400 MHz, DMSO-
−
1
mide‑(5b) Yield: 62%, M.P. 248 °C. IR (KBr), cm :
d ): δ 3.82 (t, 4H J = 4.1 Hz) 4.30 (t, 4H J = 4.1 Hz), 4.60 (s,
6
3
1
1
415 (–NH), 3069 (–CH), 1720 (–C=O), 1695 (–C=O),
2H), 7.72–6.30 (a set of signals 13H, aromatic protons and
1
3
627 (–C=N), 1596 (–C=C–Ar), 1538, 1343 (Ar–NO ),
Ar–NH–), 8.22 (s, 1H), 8.80 (s, 1H). C NMR (100 MHz,
2
1
285 (–C–O–C–morphine). H NMR: (400 MHz, DMSO-
DMSO-d ): δ 44.5, 48.5, 66.1, 84.8, 117.3, 117.9, 120.3,
6
d ): δ 3.80 (t, 4H J = 4.1 Hz), 4.35 (t, 4H J = 4.1 Hz), 4.68
120.4, 124.8, 125.1, 126.9, 127.9, 129.9, 130.6, 134.3,
139.5, 143.3, 148.1, 150.6, 151.9, 164.8, 165.5, 167.9. Ele-
mental Analysis: Calcd. for C H ClN O : C, 65.05; H,
6
(
s, 2H), 7.84–6.38 (a set of signals 13H, aromatic protons
and Ar–NH–), 8.28 (s, 1H), 8.78 (s, 1H). MS (ESI): m/z
2
8
25
4
4
1
3
(
[M + H] +); 528.1. C NMR: (100 MHz, DMSO-d ): δ
4.87; N, 10.84. Found: C, 65.08; H, 4.86; N, 10.82.
6
4
1
1
4.5, 48.5, 66.1, 84.8, 117.3, 117.9, 124.0, 125.1, 126.9,
27.9, 133.6, 136.5, 143.3, 148.1, 150.6, 151.9, 164.3,
65.5, 167.7. Elemental Analysis: Calcd. for C H N O :
N‑(3‑chlorophenyl)‑2‑((4‑(((4‑morpholino‑2‑oxo‑2H‑c
hromen‑3‑yl)methylene)amino)phenyl)amino)aceta‑
2
8
25
5
6
−1
C, 63.75; H, 4.78; N, 13.28. Found: C, 63.72; H, 4.76; N,
mide‑(5f) Yield: 73%, M.P. 229 °C. IR (KBr), cm : 3413
1
3.25.
(–NH), 3059 (–CH), 1718 (–C=O), 1681 (–C=O), 1611 (–
1
C=N), 1587 (–C=C–Ar), 1286 (–C–O–C–morpholine). H
2
‑((4‑(((4‑Morpholino‑2‑oxo‑2H‑chromen‑3‑yl)meth‑
NMR:(400 MHz, DMSO-d ): δ 3.79 (t, 4H J = 4.2 Hz),
6
ylene)amino)phenyl)amino)‑N‑(3‑nitrophenyl)aceta‑
4.10 (t, 4H J = 4.2 Hz), 4.51 (s, 2H), 7.72–6.40 (a set of
−
1
mide‑(5c) Yield: 64%, M.P. 240 °C. IR (KBr), cm :
signals 13H, aromatic protons and Ar–NH–), 8.21 (s, 1H),
1
3
3
1
1
411 (–NH), 3066 (–CH), 1720 (–C=O), 1691 (–C=O),
8.75 (s, 1H). MS (ESI): m/z ([M + H] +); 517.2. C NMR:
622 (–C=N), 1592 (–C=C–Ar), 1551, 1338 (Ar–NO ),
(100 MHz, DMSO-d ): δ 44.5, 48.5, 66.1, 84.8, 117.3,
2
6
1
283 (–C–O–C–morphine). H NMR: (400 MHz, DMSO-
117.9, 120.2, 124.8, 125.1, 126.9, 127.95, 129.9, 130.3,
134.3, 139.5, 143.3, 148.3, 150.5, 151.9, 164.3, 165.1,
167.6. Elemental Analysis: Calcd. for C H ClN O : C,
d ): δ 3.60 (t, 4H J = 4.2 Hz), 4.31 (t, 4H J = 4.2 Hz), 4.67
6
(
s, 2H), 7.84–6.38 (a set of signals 13H, aromatic protons
2
8
25
4
4
and Ar–NH–)), 8.28 (s, 1H), 8.63 (s, 1H). MS (ESI): m/z
65.05; H, 4.87; N, 10.84. Found: C, 65.03; H, 4.85; N, 10.85.
1
3
(
[M + H] +); 528.0. C NMR: (100 MHz, DMSO-d ): δ
6
4
1
1
4.5, 48.5, 66.1, 84.8, 115.8, 117.3, 117.9, 120.2, 125.1,
26.9, 127.0, 127.9, 129.2, 130.3, 139.6, 143.3, 148.1,
48.7, 150.6, 151.8, 164.3, 165.5, 167.8. Elemental Anal-
N‑(4‑chlorophenyl)‑2‑((4‑(((4‑morpholino‑2‑oxo‑2H‑c
hromen‑3‑yl)methylene amino)phenyl)amino)aceta‑
−1
mide‑(5g) Yield: 76%, M.P. 228 °C. IR (KBr), cm : 3415
ysis: Calcd. for C H N O : C, 63.75; H, 4.78; N, 13.28.
(–NH), 3059 (–CH), 1716 (–C=O), 1683 (–C=O), 1616 (–
2
8
25
5
6
1
Found: C, 63.78; H, 4.77; N, 13.26.
C=N), 1582 (–C=C–Ar), 1283 (–C–O–C–morpholine). H
NMR: (400 MHz, DMSO-d ): δ 3.70 (t, 4H J = 4.1 Hz),
6
4
.09 (t, 4H J = 4.1 Hz), 4.50 (s, 2H), 7.74–6.55 (a set of
1
3

Journal of the Iranian Chemical Society
signals 13H, aromatic protons and Ar–NH–), 8.20 (s, 1H),
C, 67.96; H, 5.51; N, 10.93. Found: C, 67.99; H, 5.49; N,
10.90.
1
3
8
.73 (s, 1H). MS (ESI): m/z ([M + H] +); 517.1. C NMR:
(
100 MHz, DMSO-d ): δ 44.5, 48.5, 66.1, 84.7, 117.3,
6
1
1
1
6
17.9, 122.2, 125.1, 126.9, 127.9, 128.6, 129.2, 130.3,
34.5, 139.5, 143.3, 148.1, 150.6, 151.9, 164.3, 165.5,
67.9. Elemental Analysis: Calcd. for C H ClN O : C,
General synthetic procedure for 3‑phenyl acryloyl‑
chloride (4a–4j)
2
8
25
4
4
5.05; H, 4.87; N, 10.84. Found: C, 65.07; H, 4.88; N, 10.83.
A mixture of various substituted cinnamic acid (0.01 mol)
and thionylchloride (10.0 ml) was heated under reꢁux condi-
tion and stirred for 4–5 h. The progress of the reaction was
monitored by TLC. After the completion of the reaction,
the unreacted thionylchloride was removed under reduced
pressure by distillation, and then remaining residue was used
for further step without recrystallization. Similarly, other
compounds were also prepared.
2
‑((4‑(((4‑Morpholino‑2‑oxo‑2H‑chromen‑3‑yl)
methylene)amino)phenyl)amino)‑N‑(o‑tolyl)aceta‑
−1
mide‑(5h) Yield: 69%, M.P. 274 °C. IR (KBr), cm : 3418
(
–NH), 3053 (–CH), 1714 (–C=O), 1689 (–C=O), 1618 (–
1
C=N), 1586 (–C=C–Ar), 1282 (–C–O–C–morpholine). H
NMR: (400 MHz, DMSO-d ): δ 2.42 (s, 3H), 3.70 (t, 4H
6
J = 4.1 Hz), 4.09 (t, 4H J = 4.1 Hz), 4.31 (s, 2H), 7.69–6.33
(
(
a set of signals 13H, aromatic protons and Ar–NH–), 8.21
General synthetic procedure for N‑(4‑(((‑mor‑
pholino‑2‑oxo‑2H‑chromene‑3‑yl)methylene)
amino)phenyl)‑3‑(substituted)phenyl acrylamide
(6a–6j)
13
s, 1H), 8.71 (s, 1H). MS (ESI): m/z ([M + H] +); 497.2. C
NMR: (100 MHz, DMSO-d ): δ 44.5, 48.5, 56.7, 66.1, 84.8,
6
1
1
1
7
12.6, 117.3, 117.9, 121.50 122.2, 125.0, 126.9, 130.0,
30.3, 143.3, 147.9, 148.1, 150.6, 151.9, 164.3, 165.5,
67.7. Elemental Analysis: Calcd. for C H N O : C,
A solution of compound (4) (0.003 mol) in 10 ml of pyri-
dine was slowly added to a freshly prepared 3-phenyl acry-
loyl chloride (5) (0.003 mol) at (0–5 °C), and it was further
stirred to 30 min. After addition, the temperature was gradu-
ally raised up to room temperature and further stirred for
15 h. The progress of reaction was monitored by TLC using
hexane–ethylacetate (7:3) as eluent. After the completion
of reaction, it was poured into ice-cold water. The crude
product was ꢀltered oꢃ and washed thoroughly with water in
several times. This crude product was puriꢀed by recrystalli-
zation from absolute alcohol to get title compound (6). Simi-
larly, other compounds (6a–6j) were prepared from interme-
diate (4) with various substituted cinnamoyl chloride.
2
9
28
4
4
0.15; H, 5.68; N, 11.28. Found: C, 70.12; H, 5.70; N, 11.25.
N‑(2‑methoxyphenyl)‑2‑((4‑(((4‑morpholino‑2‑oxo‑2H
chromen‑3‑yl)methylene)amino)phenyl)amino)aceta‑
‑
−
1
mide‑(5i) Yield: 71%, M.P. 240 °C. IR (KBr), cm : 3421
(
–NH), 3053 (–CH), 1711 (–C=O), 1681 (–C=O), 1615 (–
1
C=N), 1591 (–C=C–Ar), 1279 (–C–O–C–morpholine). H
NMR (400 MHz, DMSO-d ): δ 3.77 (t, 4H J = 3.9 Hz),
6
3
6
8
5
6
1
1
.95 (s, 3H), 4.17 (t, 4H J = 3.9 Hz), 4.38 (s, 2H), 7.71–
.34 (a set of signals 13H, aromatic protons and Ar–NH–),
.16 (s, 1H), 8.70 (s, 1H). MS (ESI): m/z ([M + H] +);
1
3
13.0. C NMR (100 MHz, DMSO-d ): δ, 44.5, 48.5, 56.0,
6
6.1, 84.8, 112.6, 117.3, 117.9, 117.9, 122.7, 124.9, 125.1,
26.9, 127.9, 130.3, 131.8, 137.4, 143.3, 148.1, 150.6,
51.9, 164.3, 165.56 167.7. Elemental Analysis: Calcd. for
N‑(4‑(((4‑Morpholino‑2‑oxo‑2H‑chromen‑3‑yl)meth‑
ylene)amino)phenyl)‑3‑phenylacrylamide‑(6a) Yield:
−
1
C H N O : C, 67.96; H, 5.51; N, 10.93. Found: C, 67.98;
67% M.P. 244 °C. IR (KBr), cm : 3457 (–NH), 3167 (–
2
9
28
4
5
H, 5.50; N, 10.90.
CH), 1725 (–C=O), 1696 (–C=O), 1900 (–C=N), 1610
1
(
–C=C–Ar), 1375 (–C–O–C–morpholine). H NMR:
N‑(4‑methoxyphenyl)‑2‑((4‑(((4‑morpholino‑2‑oxo‑2H
(400 MHz, DMSO-d ): δ 3.26 (t, 4H J = 4.1 Hz), 4.18 (t,
6
‑
chromen‑3‑yl)methylene)amino)phenyl)amino)aceta‑
4H J = 4.1 Hz), 6.42 (d, 1H, J = 12.1 Hz, =CH); 7.67–7.24
−1
mide‑(5j) Yield: 78%, M.P.: 239 °C. IR (KBr), cm : 3424
(a set of signals 14H, aromatic protons and =CH–); 8.15
(
–NH), 3053 (–CH), 1719 (–C=O), 1681 (–C=O), 1614 (–
(s, 1H), 8.98 (s, 1H). MS (ESI): m/z ([M + H] +); 480.2.
1
13
C=N), 1586 (–C=C–Ar), 1277 (–C–O–C–morpholine). H
C NMR: (100 MHz, DMSO-d ): δ 48.6, 66.5, 84.8,
6
NMR: (400 MHz, DMSO-d ): δ 3.50 (t, 4H J = 4.2 Hz),
117.3, 117.9, 123.6, 125.1, 126.4, 127.9, 128.0, 129.0,
129.4, 130.3, 131.8, 135.8, 135.9, 142.0, 144.7, 150.6,
151.9, 164.6, 165.5, 166.6. Elemental Analysis: Calcd. for
C H N O : C, 72.64; H, 5.25; N, 8.76. Found: C, 72.61;
6
3
.97 (s, 3H), 4.09 (t, 4H J = 4.2 Hz), 4.33 (s, 2H), 7.66–6.33
(
(
a set of signals 13H, aromatic protons and Ar–NH–), 8.27
13
s, 1H), 8.70 (s, 1H). MS (ESI).: m/z ([M + H] +); 513.2. C
2
9
25
3
4
NMR: (100 MHz, DMSO-d ): δ 44.5, 48.5, 56.0, 66.2, 84.8,
H, 5.23; N, 8.73.
6
1
1
1
14.5, 117.3, 117.9, 122.0, 125.1, 126.9, 127.9, 130.0,
31.2, 131.8, 143.3, 148.1, 150.6, 151.9, 156.4, 164.3,
65.5, 167.9. Elemental Analysis: Calcd. for C H N O :
N‑(4‑(((4‑Morpholino‑2‑oxo‑2H‑chromen‑3‑yl)
methylene)amino)phenyl)‑3‑(2‑nitrophenyl)acryla‑
2
9
28
4
5
−1
mide‑(6b) Yield: 59% M.P. 255 °C. IR (KBr), cm : 3461
1
3

Journal of the Iranian Chemical Society
(
(
(
–NH), 3169 (–CH), 1732 (–C=O), 1692 (–C=O), 1905
J = 12.0 Hz, =CH), 7.56–7.07 (a set of signals 13H, aro-
matic protons and =CH–), 8.19 (s, 1H), 8.79 (s, 1H). MS
–C=N), 1614 (–C=C–Ar), 1545, 1335 (Ar–NO ), 1378
2
1
13
–C–O–C–morpholine). H NMR: (400 MHz, DMSO-d ):
(ESI): m/z ([M + H] +); 494.2. C NMR: (100 MHz,
6
δ 3.70 (t, 4H J = 4.0 Hz), 4.15 (t, 4H J = 4.0 Hz), 6.50 (d,
DMSO-d ): δ 48.5, 66.2, 84.7, 117.3, 117.9, 123.6, 125.1,
6
1
H, J = 12.0 Hz, =CH); 7.50–6.68 (a set of signals 13H,
126.4, 127.6, 127.9, 128.3, 129.4, 130.0, 130.3, 131.8,
135.2, 135.9, 136.0, 139.1, 144.7, 150.6, 151.9, 164.3,
165.5, 166.6. Elemental Analysis: Calcd. for C H N O :
aromatic protons and =CH–); 8.28 (s, 1H), 8.75 (s, 1H).
1
3
MS (ESI): m/z ([M + H] +); 525.1. C NMR: (100 MHz,
3
0
27
3
4
DMSO-d ): δ 48.5, 66.6, 84.8, 117.3, 117.9, 123.6, 125.0,
C, 73.01; H, 5.51; N, 8.51. Found: C, 73.03; H, 5.50; N,
6
1
1
25.1, 126.4, 127.9, 130.3, 130.4, 131.8, 133.2, 135.9,
8.49.
41.0, 147.7, 147.9, 150.6, 151.9, 164.3, 165.5, 166.6. Ele-
mental Analysis: Calcd. for C H N O : C, 66.41; H, 4.61;
N‑(4‑(((4‑Morpholino‑2‑oxo‑2H‑chromen‑3‑yl)methyl‑
ene)amino)phenyl)‑3‑(p‑tolyl)acrylamide‑(6f) Yield:
29
24
4
6
N, 10.68. Found: C, 66.38; H, 4.62; N, 10.65.
−
1
6
5%, M.P. 268 °C. IR (KBr), cm : 3461 (–NH), 3149
N‑(4‑(((4‑Morpholino‑2‑oxo‑2H‑chromen‑3‑yl)
methylene)amino)phenyl)‑3‑(3‑nitrophenyl)acryla‑
mide‑(6c) Yield: 56% M.P. 252 °C. IR (KBr), cm : 3454
(–CH), 1718 (–C=O), 1688 (–C=O), 1901 (–C=N),
1
1621 (–C=C–Ar), 1382 (–C–O–C–morpholine).
H
−
1
NMR: (400 MHz, DMSO-d ): δ 2.31 (s, 3H), 3.72 (t,
6
(
(
(
–NH), 3163 (–CH), 1718 (–C=O), 1691 (–C=O), 1898
4H J = 4.0 Hz), 4.17 (t, 4H J = 4.0 Hz), 6.48 (d, 1H,
J = 12.0 Hz, =CH), 7.61–6.82 (a set of signals 13H, aro-
matic protons and =CH–), 8.09 (s, 1H), 8.75 (s, 1H). MS
–C=N), 1612 (–C=C–Ar), 1532, 1331 (Ar–NO ), 1378
2
1
–C–O–C–morpholine). H NMR: (400 MHz, DMSO-d ):
6
1
3
δ 3.60 (t, 4H J = 4.1 Hz), 4.45 (t, 4H J = 4.1 Hz), 6.40 (d,
(ESI): m/z ([M + H] +); 494.1. C NMR: (100 MHz,
1
H, J = 12.1 Hz, =CH), 7.73–6.90 (a set of signals 13H,
DMSO-d ): δ 48.5, 66.3, 84.8, 117.4, 117.9, 123.6, 125.1,
6
aromatic protons and =CH–), 8.28 (s, 1H), 8.75 (s, 1H).
126.4, 127.9, 128.1, 129.1, 130.3, 131.8, 133.9, 135.9,
139.3, 142.0, 144.7, 150.6, 151.9, 164.3, 165.5, 166.6. Ele-
mental Analysis: Calcd. for C H N O : C, 73.01; H, 5.51;
1
3
MS (ESI): m/z ([M + H] +); 525.0. C NMR: (100 MHz,
DMSO-d ): δ 48.5, 66.4, 84.7, 117.3, 117.9, 123.6, 123.9,
6
30 27
3
4
1
1
1
25.1, 125.5, 126.4, 127.9, 129.2, 130.3, 131.8, 135.4,
35.9, 137.9, 141.8, 144.7, 148.1, 150.6, 151.9, 164.3,
65.4, 166.6. Elemental Analysis: Calcd. for C H N O :
N, 8.51. Found: C, 73.04; H, 5.53; N, 8.52.
3‑(2‑Methoxyphenyl)‑N‑(4‑(((4‑morpholino‑2‑oxo‑
2H‑chromen‑3‑yl)methylene)amino)phenyl)acryla‑
2
9
24
4
6
C, 66.41; H, 4.61; N, 10.68. Found: C, 66.39; H, 4.60; N,
−
1
1
0.66.
mide‑(6g) Yield: 69%, M.P. 244 °C. IR (KBr), cm :
3
451 (–NH), 3152 (–CH), 1721 (–C=O), 1684 (–C=O),
N‑(4‑(((4‑Morpholino‑2‑oxo‑2H‑chromen‑3‑yl)
methylene)amino)phenyl)‑3‑(4‑nitrophenyl)acryla‑
mide‑(6d) Yield: 61% M.P. 259 °C. IR (KBr), cm : 3459
1904 (–C=N), 1623 (–C=C–Ar), 1386 (–C–O–C–mor-
1
pholine). H NMR: (400 MHz, DMSO-d ): δ 3.65 (t, 4H
6
−1
J = 4.1 Hz), 3.91 (s, 3H), 4.15 (t, 4H J = 4.1 Hz), 6.47 (d,
1H, J = 12.2 Hz, =CH), 7.52–6.93 (a set of signals 13H,
aromatic protons and =CH–), 8.13 (s, 1H), 8.75 (s, 1H). MS
(
(
(
–NH), 3163 (–CH), 1712 (–C=O), 1693 (–C=O), 1891
–C=N), 1616 (–C=C–Ar), 1550, 1342 (Ar–NO ), 1372
2
1
13
–C–O–C–morpholine). H NMR: (400 MHz, DMSO-d ):
(ESI) m/z: 510.1 (M + H). C NMR: (100 MHz, DMSO-
6
δ 3.72 (t, 4H J = 4.0 Hz), 4.20 (t, 4H J = 4.0 Hz), 6.29 (d,
d ): δ 48.56, 56.79, 66.13, 84.71, 113.51, 117.36, 117.93,
6
1
H, J = 12.2 Hz, =CH), 7.73–6.90 (a set of signals 13H,
120.84, 123.67, 125.11, 126.47, 127.84, 127.95, 129.59,
130.36, 130.57, 131.86, 135.99, 142.57, 147.21, 151.91,
155.81, 157.36, 164.37, 165.50, 166.67. Elemental Anal-
ysis: Calcd. for C H N O : C, 70.71; H, 5.34; N, 8.25.
aromatic protons and =CH–), 8.23 (s, 1H), 8.74 (s, 1H).
1
3
MS (ESI): m/z ([M + H] +); 525.2. C NMR: (100 MHz,
DMSO-d ): δ 48.6, 66.4, 84.8, 117.3, 117.9, 123.6, 124.4,
6
30 27
3
5
1
1
25.1, 126.4, 127.9, 129.1, 130.3, 131.8, 135.9, 142.0,
Found:: C, 70.69; H, 5.36; N, 8.23.
42.4, 144.7, 147.8, 150.6, 151.9, 164.3, 165.5, 166.6. Ele-
mental Analysis: Calcd. for C H N O : C, 66.41; H, 4.61;
3‑(3‑Methoxyphenyl)‑N‑(4‑(((4‑morpholino‑2‑oxo‑
2H‑chromen‑3‑yl)methylene)amino)phenyl)acryla‑
29
24
4
6
N, 10.68. Found: C, 66.37; H, 4.63; N, 10.66.
−
1
mide‑(6h) Yield:71%, M.P. 240 °C. IR (KBr), cm :
N‑(4‑(((4‑Morpholino‑2‑oxo‑2H‑chromen‑3‑yl)methyl‑
ene)amino)phenyl)‑3‑(o‑tolyl)acrylamide‑(6e) Yield:
3459 (–NH), 3161 (–CH), 1728 (–C=O), 1690–(C=O),
1906 (–C=N), 1619 (–C=C–Ar), 1389 (–C–O–C–mor-
−
1
1
6
2%, M.P. 271 °C. IR (KBr), cm : 3451 (–NH), 3158
pholine). H NMR: (400 MHz, DMSO-d ): δ 3.68 (t, 4H
6
(
–CH), 1716 (–C=O), 1696 (–C=O), 1886 (–C=N),
J = 4.0 Hz), 3.81 (s, 3H), 4.11 (t, 4H J = 4.0 Hz), 6.55 (d,
1H, J = 12.1 Hz, =CH), 7.48–6.94 (a set of signals 13H,
aromatic protons and =CH–); 8.05 (s, 1H), 8.81 (s, 1H)
1
1
612 (–C=C–Ar), 1379 (–C–O–C–morpholine).
H
NMR: (400 MHz, DMSO-d ): δ 2.22 (s, 3H), 3.77 (t,
6
1
3
4
H J = 4.2 Hz), 4.16 (t, 4H J = 4.2 Hz), 6.57 (d, 1H,
MS (ESI): m/z ([M + H] +); 510.0. C NMR: (100 MHz,
1
3

Journal of the Iranian Chemical Society
DMSO-d ): δ 48.5, 56.0, 66.1, 84.7, 113.5, 115.6, 117.3,
antibacterial activity. While in case of antifungal activity,
there are no speciꢀc positions which were more beneꢀcial
for antifungal activity. Compounds 5g (4-Cl), 6a (unsubsti-
tuted), 6b (2-NO ), and 6j (3, 4, 5-OCH ) exhibited much
6
1
1
1
17.9, 121.0, 123.6, 125.1, 126.4, 127.9, 129.1, 130.3,
30.5, 131.8, 135.9, 137.9, 141.8, 147.2, 151.9, 155.8,
60.7, 164.3, 165.5, 166.6. Elemental Analysis: Calcd. for
2
3
C H N O : C, 70.71; H, 5.34; N, 8.25. Found: C, 70.68;
better antifungal activity. No signiꢀcant conclusion in con-
text to the electronic eꢃect of substituents is derived oꢃ, but
deviation of biological proꢀle shows that basic pharmacoph-
ore is responsible for activities. It is worth to pursue further
incorporation of more substituents of both electron-donating
and electron-withdrawing groups, which may lead to proper
conclusion. Molecular docking studies showed that com-
pounds 5g, 5e, 5i, and 6i showed better docking score, but
none of the compounds reached up to the level of standard
ciproꢁoxacin docking score. This study also favoured that
4th position of synthesized compound is the most active
on biological point of view, and 5g and 6i also showed bet-
ter dock score, and FMO theory also reinforced this things;
compound 5g, 5j, 6b, and 6i possess better energy gap in
compare to unsubstituted compounds like 5a and 6a and
exhibited better antimicrobial activity correlation with
HOMO–LUMO and bioactivity.
3
0
27
3
5
H, 5.32; N, 8.28.
3
2
‑(4‑Methoxyphenyl)‑N‑(4‑(((4‑morpholino‑2‑oxo‑
H‑chromen‑3‑yl)methylene)amino)phenyl)acryla‑
−
1
mide‑(6i) Yield: 69%, M.P. 238 °C. IR (KBr), cm :
3
1
450 (–NH), 3152 (–CH), 1719 (–C=O), 1687–(C=O),
901 (–C=N), 1620 (–C=C–Ar), 1392 (–C–O–C–mor-
1
pholine); H NMR: (400 MHz, DMSO-d ): δ 3.56 (t, 4H
6
J = 4.0 Hz), 3.83 (s, 3H), 4.15 (t, 4H J = 4.0 Hz), 6.50 (d,
1
H, J = 12.0 Hz, =CH); 7.53–7.03 (a set of signals 14H,
aromatic protons and =CH–); 8.07 (s, 1H), 8.72 (s, 1H).
1
3
MS (ESI): m/z ([M + H] +); 510.2. C NMR: (100 MHz,
DMSO-d ): δ 48.5, 56.0, 66.2, 84.8, 114.5, 117.3, 117.9,
6
1
23.6, 125.1, 126.4, 127.9, 128.7 129.3, 130.3, 131.8, 135.9,
1
42.0, 144.7, 150.6, 151.9, 160.8, 164.3, 165.5, 166.6. Ele-
mental Analysis: Calcd. for C H N O : C, 70.71; H, 5.34;
30
27
3
5
N, 8.25. Found:: C, 70.69; H, 5.36; N, 8.27.
Acknowledgements I am very thankful to Prof. N. K. Shah, Head of
the chemistry Department, School of sciences, Gujarat University, for
giving support and facilities. The authors also express their sincere
thanks to the Centre of Excellence, Department of Chemistry, Sau-
rashtra University, Rajkot, for spectral analysis. The authors wish to
oꢃer their deep gratitude to Department of Microbiology, School of
Sciences, Gujarat University, Ahmedabad, for carrying out the biologi-
cal screenings. Authors are also thankful to GUJCOST, Ghandhinagar,
for ꢀnancial support.
N‑(4‑(((4‑Morpholino‑2‑oxo‑2H‑chromen‑3‑yl)meth‑
ylene)amino)phenyl)‑3‑(3, 4, 5‑trimethoxyphenyl)
acrylamide‑(6j) Yield: 73%, M.P. 248 °C. IR (KBr),
−
1
cm : 3445 (–NH), 3148 (–CH), 1722 (–C=O), 1681 (–
C=O), 1911 (–C=N), 1613 (–C=C–Ar), 1388 (–C–O–C–
1
morpholine). H NMR: (400 MHz, DMSO-d ): δ 3.71 (t,
6
4
H J = 4.0 Hz), 3.82 (s, 9H), 4.25 (t, 4H J = 4.0 Hz), 6.55
(
d, 1H, J = 12.1 Hz, =CH), 7.41–6.85 (a set of signals 11H,
aromatic protons and =CH–), 8.04 (s, 1H), 8.81 (s, 1H).
1
3
MS (ESI): m/z ([M + H] +); 570.1. C NMR: (100 MHz,
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31
3
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N, 7.38. Found: C, 67.45; H, 5.48; N, 7.35.
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Aꢀliations
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Prakashsingh M. Chauhan · Sandeep N. Thummar · Kishor H. Chikhalia
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Kishor H. Chikhalia
Department of Chemistry, Veer Narmad South Gujarat
University, Surat, Gujarat 395007, India
Chikhalia_kh@yahoo.com
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Department of Chemistry, School of Science, Gujarat
University, Ahmadabad, Gujarat 380009, India
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