Design and Synthesis of Antimicrobial Active (E)-(3-(Substituted-styryl)-7H-furo[2,3-f]chromen-2-yl)(phenyl)methanone Derivatives and Their In Silico Molecular Docking Studies

Article abstract of DOI:10.1002/jhet.3373

Nine new (E)-(3-(substituted-styryl)-7H-furo[2,3-f]chromen-2-yl)(phenyl)methanone derivatives, 7(a–i), with an efficient microwave-assisted synthetic method was achieved by reacting with (E)-3-(aryl)-1-(5-hydroxy-2H-chromen-6-yl)prop-2-en-1-ones and 2-bro

Full text of DOI:10.1002/jhet.3373

Month 2018 Design and Synthesis of Antimicrobial Active (E)-(3-(Substituted-styryl)-
7H-furo[2,3-f]chromen-2-yl)(phenyl)methanone Derivatives and Their
In Silico Molecular Docking Studies
a
b
c
a
*
Srinivas Boddupally, Prashanth Jyothi, Mandava Venkata Basaveswara Rao, and Koya Prabhakara Rao
aNew Generation Materials Lab (NGML), Department of Science and Humanities, Vignan’s Foundation for Science
Technology and Research (VFSTR), Guntur 522 213, Andhra Pradesh, India
bDepartment of Physics, Kakatiya University, Warangal 506009, Telangana, India
cDepartment of Chemistry, Krishna University, Machilipatnam 521001, Andhra Pradesh, India
*E-mail: kprao2005@gmail.com
Dedicated to Prof. C. N. R. Rao on his 84th birthday.
Received July 3, 2018
DOI 10.1002/jhet.3373
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
Nine new (E)-(3-(substituted-styryl)-7H-furo[2,3-f]chromen-2-yl)(phenyl)methanone derivatives, 7(a–i),
with an efficient microwave-assisted synthetic method was achieved by reacting with (E)-3-(aryl)-1-(5-hy-
droxy-2H-chromen-6-yl)prop-2-en-1-ones and 2-bromo-1-(4-bromophenyl)ethanone. The microwave irradi-
ation method was found to be best with high yields and with shorter reaction times compared with the
conventional method. All the new products structural assignments were confirmed by spectral data like
1
FTIR, H NMR, 13C NMR, ESI MS, and analytical data. Moreover, these newly synthesized compounds
were tested in vitro for their antimicrobial activity against various bacterial and fungal strains. Some of these
new chromen derivatives like 7b, 7c, and 7d exhibits good antibacterial and antifungal activities. Further-
more, these biological evolution results were a good correlation with molecular docking studies performed
based on their computational DFT minimized structures exhibited high binding energies.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
antiviral [7], estrogenic [8], anti-inflammatory [9],
antibacterial [10], and TNF-α inhibitor [11]. Another
important aspect is that the lipophilic nature of the
chromene derivatives helps to peeve the cell membrane
effectively [12]. Additionally, benzopyran derivatives
also played imperative performance in organic material
chemistry like fluorescent dyes, pigments, synthetic
fibers, molecular devices [13,14], and electrophotographic.
On the other hand, benzofuran derivatives are also
present in many natural products [15] and exhibit
properties like physiological, pharmacological, and toxic.
They also display many applications like sedatives,
antioxidants [16], pharmaceuticals [17–20], cosmetics
[21], molecular switches [22,23], and also for the building
blocks of optical brighteners [24,25]. In fact, several
benzofuran ring systems bearing various substituents at
the C-2 position are widely distributed in nature. For
example, 2-arylbenzofuran has been isolated from a
Chinese herbal plant and possesses various biological
Heterocyclic compoundscontaining nitrogen and oxygen
atoms play an important role in pharmaceutical,
agrochemical, and materials chemistry [1–14]. Recent
years, by utilizing varieties of heterocyclic moieties, a
large number of drugs and agrochemical products were
reported in the literature. Chromene (benzopyran) is one
of the privileged scaffolds of such heterocyclic moiety,
which appear as a significant structural moiety in
numerous natural products. Moreover, the derivative of
chromene moiety leads to a wide range of biological
activities due to their interactive nature with various
protein moieties. In fact, benzopyran moiety is part of
various types of polyphenols [1], and they could found
extensively in alkaloids, flavonoids, anthocyanins, and
tocopherols. In fact, some natural products and also
synthetic benzopyran derivatives exhibit important
biological activities such as anticancer [2], antivascular
[3], antioxidant [4], antimicrobial [5], antifungal [6],
activities [26]. Similarly, ailanthoides,
a neolignan
© 2018 Wiley Periodicals, Inc.

S. Boddupally, P. Jyothi, M. V. B. Rao, and K. P. Rao
Vol 000
derivative, has been reported to have antiviral, antioxidant,
and antifungal activities [27]. Moreover, benzofuran
derivatives also possess various pharmacological and
biological activities such as antibacterial [28], antifungal
[29], anti-inflammatory [30], antitubercular [31],
antidiabetic [32], antidepressant [33], antioxidant [34],
anticonvulsant [35], and analgesic [36] activities.
Encouraged by these facts about the chromene and
benzofuran moieties, we are interested to design and
synthesize a new series of heterocyclic compounds by
mimicking with the aforementioned two moieties in a
single molecule. In fact, continuation with our main
objective related to the synthesis, spectral studies, and
biological properties of new heterocyclic products,
herein, we reported the synthesis, characterization, and
biological evaluation of nine new styryl furanochromene
compounds, 7(a–i). Moreover, we also report the
computational and molecular docking studies, which
correlate these biological evolution results.
(Scheme 1). As we described in Scheme 2, Claisen–
Schmidt condensation between 1-(5-hydroxy-2H-chromen-
6-yl)ethanone (3) and various substituted aromatic
aldehydes (4a–i) in the presence of KOH under
microwave irradiation conditions for 4–7 min time, yielded
(E)-3-(aryl)-1-(5-hydroxy-2H-chromen-6-yl)prop-2-en-1-
ones (5a–i). In the final step, the compounds (7a–i) achieved
by the chalcones were then cyclized with 2-bromo-1-(4-
bromophenyl)ethanone (6) under conventional heating and
also by microwave irradiation to provide the products in
good yields (Scheme 2) as mentioned in Table 1.
Initially, the synthesis of compounds 7a–i was tried under
conventional heating synthetic method [38,39]. However,
by this method, we achieved the desired products (7a–i)
low yields (54–59%). Alternatively, to improve low yield
problem and also to overcome the long reaction times, the
synthetic method was changed to microwave irradiation
method. In fact, microwave-assisted synthetic provided
good yields for compounds 7a–i, compared with the
conventional synthetic method. The reaction conditions,
reaction time, and yields of the titled compounds of both
microwave irradiation and conventional synthetic methods
were listed in Table 1. Formation of desired (E)-(3-
(substituted-styryl)-7H-furo[2,3-f]chromen-2-yl)(phenyl)
methanones (7a–i) were confirmed by spectral data like
FTIR, 1H NMR, 13C NMR, mass, and elemental analyses.
RESULTS AND DISCUSSION
Synthesis. The synthetic scheme for the synthesis of
(E)-(3-(substituted-styryl)-7H-furo[2,3-f]chromen-2-yl)
(phenyl)methanones (7a–i) is described in Schemes 1 and 2.
For achieving the synthesis of the titled compounds
involved the preliminary preparation of 1-(5-hydroxy-2H-
chromen-6-yl)ethanone (3). In this step, starting from
resacetophenone (1) upon treating with propargylic
bromide in dry acetone solvent in the presence of
anhydrous K2CO3, yielded 1-(2-hydroxy-4-(prop-2-yn-1-
yloxy)phenyl)ethanone (2). Later, the aforementioned
reaction mixture was heated in N,N-dimethyl aniline
solvent at 185°C for 4 h, yielded compound (3) [37]
Biological evaluation (in vitro antimicrobial activity). All
these newly synthesized compounds 7a–i were screened
for their in vitro antimicrobial activity [40] against four
bacteria like Staphylococcus aureus (ATCC 29213)
and Bacillus subtilis (ATCC 6633), as examples of
Gram-positive bacteria and Proteus vulgaris (ATCC
29213) and Escherichia coli (ATCC 11229), as examples
of Gram-negative bacteria, respectively. The results
obtained as minimum inhibitory concentration (MIC) in
Scheme 1. Synthetic conditions for 1-(5-hydroxy-2H-chromen-6-yl)ethanone (3).
HO
OH
O
OH
Propargyl bromide
O
OH
N,N-dimethyl aniline
Reflux
K2CO3, dry acetone
Reflux
O
O
O
1
2
3
Scheme 2. Synthetic conditions for (E)-(3-(substituted-styryl)-7H-furo[2,3-f]chromen-2-yl)(phenyl)methanones (7a–i).
Br
O
Br
O
OH
O
O
O
OH
O
KOH
anhyd.K2CO3
+ Ar-CHO
4a-i
Ar
+
MWI /D
dry acetone
MWI /D
O
O
3
Br
6
Ar
5a-i
7a-i
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Month 2018
Design, Synthesis and Docking Studies of Antimicrobial active Substituted
Chromene Derivative
Table 1
Synthetic reaction conditions for the synthesis of compounds 7a–i, by both microwave irradiation and conventional synthetic methods.
Conventional MWI (180 W)
Time (h) Time (min)
Ar═
Yield (%)
Yield (%)
7a
7b
7c
7d
7e
7f
7g
7h
7i
Phenyl
5
7
7
7
6
5
5
6
5
59
54
55
53
55
54
59
56
56
3
5
4
5
3
4
4
5
5
90
85
87
85
89
87
89
91
87
4-bromophenyl
2-chlorophenyl
2,4-dichlorophenyl
4-methylphenyl
4-isopropylphenyl
4-methoxyphenyl
3,4-dimethoxyphenyl
2-thiophenyl
μg/mL and the measurements for all the products 7a–i are
presented in Table 2. For the reference purpose, gentamicin
was employed as a standard antibacterial drug for the
the antifungal study. Compounds 7d and 7h displayed
better antifungal activity with MIC 3.125 μg/mL against
all the fungal strains. Similarly, 7b and 7c exhibited
promising antifungal activity with MIC 3.125 μg/mL
against A. niger and MIC 6.25 μg/mL against C. albicans
fungal strains when compared with the reference drug
fluconazole (MIC 3.125 μg/mL). Thus, we can conclude
that compounds with electronegative groups such as
oxygen, chloro, and bromo oxygen on phenyl ring might
be the reason for showing high antifungal inhibitory
potency similar to antibacterial studies.
antibacterial
study.
The
compound
7b
(Ar = 4-bromophenyl), displayed MIC 3.125 μg/mL against
all the bacteria except S. aureus (1.56 μg/mL). Similar, 7c
(Ar = 2-chlorophenyl) displayed 3.125 μg/mL against
B. subtilis and E. coli, 1.56 μg/mL against S. aureus and
P. vulgaris. The compound 7d (Ar = 2,4-dichlorohenyl)
exhibited MIC 1.56 μg/mL against B. subtilis and S. aureus
and 3.125 μg/mL against E. coli and P. vilgaris bacteria. It
was envisaged from the analysis of antibacterial and
antifungal activity results that, electronegative moieties on
aromatic phenyl ring such as chloro, bromo were found to
be more potent as compared with control drug gentamicin
(1.56 μg/mL). All the other products also exhibited
moderate activity against antibacterial.
Later, all the titled compounds 7a–i, of the present
study, were also screened for their in vitro antifungal
activity against Candida albicans (ATCC 10231) and
Aspergillus niger (ATCC 9029) fungal strains; the results
were listed Table 2. For the reference purpose,
fluconazole was used as a standard antifungal drug for
Molecular modeling and drug designing.
In order to
confirm the relationship between in vitro antimicrobial
findings and binding affinities of the inhibitors, the
docking studies of the compounds 7a–i were carried out
against S. aureus reductases including Bacillus subtilis
and Helicobacter pylori (S. aureus MurB) using Auto
Dock program. It is well-known that the proteins
S. aureus MurB are attractive targets for the development
of antibacterial agents in the design and development of
drug molecules. The noteworthy point is that the
structure of the protein indicates the ambiguous yet
important differences that vent among the comparable
Table 2
Antibacterial and antifungal activity studies of synthesized compounds (7a–i).
Gram-positive bacteria MIC (μg/mL)
Gram-negative bacteria MIC (μg/mL)
Fungal strains MIC (μg/mL)
Compound
B. subtilis
S. aureus
E. coli
P. vulgaris
A. niger
C. albicans
7a
7b
7c
7d
7e
7f
7g
7h
25
3.125
3.125
1.56
12.5
25
12.5
6.25
25
12.5
1.56
1.56
1.56
25
12.25
12.5
12.5
25
12.5
3.125
3.125
3.125
25
12.5
6.25
25
50
3.125
1.56
3.125
12.5
50
12.5
25
50
25
3.125
3.125
3.125
12.5
25
6.25
3.125
50
12.5
6.25
6.25
3.125
25
12.5
12.25
3.125
25
7i
>100
3.125
—
Gentamicin
Fluconazole
1.56
—
1.56
—
1.56
—
—
3.125
—
3.125
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S. Boddupally, P. Jyothi, M. V. B. Rao, and K. P. Rao
Vol 000
Table 3
Docking binding energies of compounds 7a–i, substituted inhibitors against receptor S. aureus MurB.
Binding energies (Kcal molꢀ1
)
S. aureus MurB (PDB ID: I HSK)
S. No
Compound
Binding energy
No. of H bonds
Residues involved in bonding
1
2
3
4
5
6
7
8
9
7a
7b
7c
7d
7e
7f
7g
7h
7i
ꢀ13.01
ꢀ13.03
ꢀ13.22
ꢀ12.84
ꢀ12.78
ꢀ13.57
ꢀ12.95
ꢀ12.39
ꢀ13.01
02
03
02
01
02
03
04
02
03
Arg310, His196
Gly79, Gly81, Val199
Arg310, His196
Val199
Gly81, Val199
Gly79, Gly81, Val199
Arg310, Gly81, Asn80, Val199
Arg310, Val199
Arg310 (2), Val199
proteins of various bacterial species. Moreover, this
structure also determines the emphasis of the conducting
structural and biochemical analysis on the target of the
bacterial species of concern to promote useful drug
discovery [41–43]. The antimicrobial results of the 7a–i
derivatives against the receptor S. aureus MurB along
with their respective binding energy and residues are
reported in Table 3.
From the docking study, the compounds 7a, 7b, 7c, 7f,
and 7i show strong binding behavior among the
remaining tested derivatives against 1HSK as deduced by
their minimum binding energies ꢀ13.01, ꢀ13.03,
ꢀ13.22, 13.57, and 13.01 Kcal/mol, respectively.
Whereas the compounds 7g, 7d, 7e, and 7h show the
binding affinities as ꢀ12.95, ꢀ12.84, ꢀ12.78, and
ꢀ12.39 Kcal/mol, respectively. For example, the
structural conformation of 7b, which shows good
antimicrobial, with hydrogen bonds and residues with a
cluster into the binding pocket of the receptor is shown in
Figure 1 (see Figure S21–S29 for receptor binding sites
for the other compounds). Molecular docking study
reveals that 7b ligand-receptor complex exhibits totally
three hydrogen bonds with three amino acid residues.
Two hydrogen bonds are between the oxygen atom of the
carbonyl group C¼O of 7b ligand, with Gly79 and
Gly81 amino acid residues with 2.408 and 2.217 Å bond
distances, respectively. Another hydrogen bond of 7b
ligand-receptor is between the oxygen atom of the
chromen ring and with the third Val199 amino acid
residue with a bond distance of 2.034 Å. Similarly, all
other 7a–i ligands also have shown hydrogen bond
interactions with various amino acid residues as shown in
Table 3 (see Supporting Information for other ligand
interaction figures). These hydrogen bonding interactions
clearly indicated that the docking study is in very good
correlation with their antifungal and antibacterial studies.
Figure 1. Showing the binding poses and interactions of 7a–i analogue, 7b to binding sites of target protein: S. aureus MurB (PDB ID: I HSK).
Journal of Heterocyclic Chemistry
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Month 2018
Design, Synthesis and Docking Studies of Antimicrobial active Substituted
Chromene Derivative
EXPERIMENTAL SECTION
(E)-(4-Bromophenyl)(3-styryl-7H-furo[2,3-f]chromen-2-yl)
methanone (7a). Yield 90%, mp 153–155°C. IR spectrum,
1
ν (cmꢀ1): 1632 (C¼O); H NMR (Bruker Avance-400,
General.
All the reagents were purchased from SD
400 MHz, DMSO), δ, ppm (J, Hz): 4.95 (2H, s, O–CH2);
5.90–5.94 (1H, m, O–CH2CH); 6.47 (1H, d, J = 8.49, H
Ar), 6.84 (1H, d, J = 10.07, Ar–CH¼C), 7.16–7.21 (1H,
m, H Ar), 7.29–7.38 (4H, m, H Ar), 7.47–7.51 (4H, m, H
Ar), 7.61 (1H, d, J = 8.49, H Ar), 7.89 (2H, d, J = 7.67,
Ar–H); 13C NMR spectrum (Bruker Avance-400,
100 MHz, DMSO), δ, ppm: 181.2 (C¼O), 154.1, 151.7,
146.8, 135.4, 133.5 131.7, 131.4, 128.7, 128.5, 127.4,
126.7, 125.1, 124.4, 123.1, 121.2, 119.9, 119.6, 115.8,
112.8, 106.1, 66.0 (OCH2); mass spectrum, m/z (Irel, %):
459 (M + H + 2)+. Found, %: C, 68.29; H, 3.75.
C26H17BrO3. Calculated, %: C, 68.27; H, 3.78.
Fine, India, and the reagents were used without further pu-
rification. The microwave irradiation synthetic experiments
were performed on CEM Discover microwave system
(Labindia Analytical Instruments Pvt. Ltd., Thane, India)
by using IR sensor for monitoring the reaction tempera-
tures. Melting points were recorded for all the compounds
on Stuart SMP3 melting-point apparatus (Sigma Aldrich
Chemicals Pvt. Ltd, Bangalore, India), and the values re-
ported are uncorrected. The FTIR spectra in cmꢀ1 (KBr)
were recorded using the transparent disc on Shimadzu FTIR
8400 S spectrometer (SHIMADZU Corporation, Tokyo,
Japan). The 1H NMR and 13C NMR spectra were recorded
on Bruker Avance-400 spectrometer (Bruker India Scien-
tific Pvt. Ltd, Hyderabad, India) at 400 and 100 MHz, re-
spectively. Tetramethylsilane as an internal reference and
DMSO as a solvent were used for all NMR studies. CHN
analysis was carried out using Vario Micro Cube Elementar
instrument, Germany. The mass spectra of electrospray ion-
ization (ESI) were recorded on Finnigan MAT 1020 mass
spectrometer (Scientific Instrument Services Inc, Ringoes,
NJ) with m/z. For monitoring the reactions completion, sil-
ica gel percolated TLC plates of Merck 60 F254 (Merck Life
Science Pvt. Ltd, Mumbai, India) commercially purchased
(E)-(4-Bromophenyl)(3-(4-bromostyryl)-7H-furo[2,3-f]
chromen-2-yl)methanone (7b).
Yield 85%, mp 204–
1
206°C. IR spectrum, ν (cmꢀ1): 1626 (C¼O). H NMR
spectrum (Bruker Avance-400, 400 MHz, DMSO), δ,
ppm (J, Hz): 4.92 (2H, s, O–CH2); 5.92–5.96 (1H, m,
O–CH2CH); 6.55 (1H, d, J = 8.69, H Ar), 6.85 (1H, d,
J = 10.05, Ar–CH¼C), 7.35–7.44 (4H, m, H Ar), 7.63
(2H, d, J = 8.24, H Ar), 7.66 (1H, d, J = 8.69, H Ar),
7.76 (2H, d, J = 8.12, Ar–H), 7.98 (2H, d, J = 8.12, Ar–H);
13C NMR spectrum (Bruker Avance-400, 100 MHz,
DMSO), δ, ppm: 66.9 (OCH2), 107.3, 112.3, 114.7, 118.1,
119.2, 119.5, 121.4, 122.9, 124.6, 124.9, 127.5, 128.7,
129.5, 131.5, 131.8, 132.4, 135.6, 145.2, 150.4, 154.0,
181.0 (C¼O); mass spectrum, m/z (Irel, %): 537
[M + H + 2]+ (100). Found, %: C, 58.24; H, 3.01.
C26H16Br2O3. Calculated, %: C, 58.21; H, 3.04.
were used, and the spots were visualized with UV light.
Synthesis. General synthesis of compounds (7a–i).
Conventional synthetic method.
To a stirred solution of
anhydrous K2CO3 (276 mg, 2 mmol) in dry acetone
(11 mL) and (E)-3-(aryl)-1-(5-hydroxy-2H-chromen-6-yl)
prop-2-en-1-ones (5a–i) (1 mmol), the reagent 2-bromo-
1-(4-bromophenyl)ethanone (6) (1 mmol) was added, and
the whole reaction mixture was refluxed at 70°C for 4–
7 h. The progress of the reaction was observed using
TLC plates. The solvent was evaporated under reduced
pressure after completion of the reaction. The crude solid
residue was purified by column chromatography on silica
gel using hexane/ethyl acetate (8:2, v/v) as an eluent to
afford compounds (7a–i).
Microwave synthetic method. To a mixture of (E)-3-
(aryl)-1-(5-hydroxy-2H-chromen-6-yl)prop-2-en-1-ones
(5a–i) (1 mmol) and 2-bromo-1-(4-bromophenyl)ethanone
(6) (1 mmol) in dry acetone (5 mL), anhydrous K2CO3
(276 mg, 2 mmol) was added and applied to microwave
conditions at 180 W for 3–5 min. The solvent was
evaporated under reduced pressure after completion of
the reaction, as indicated by TLC. The crude solid mass
was purified by silica gel column chromatography using
an eluent of hexane/ethylacetate (8:2, v/v) to afford pale
yellow solids of titled compounds (7a–i). The spectral
data and the yields of all the compounds (7a–i) are as
follows. For spectral data (1H NMR, 13C NMR, and
mass), see Figures S1 to S20.
(E)-(4-Bromophenyl)(3-(2-chlorostyryl)-7H-furo[2,3-f]
chromen-2-yl)methanone (7c). Yield 87%, mp 162–163°C.
1
IR spectrum, ν (cmꢀ1): 1629 (C¼O). H NMR spectrum
(Bruker Avance-400, 400 MHz, DMSO), δ, ppm (J, Hz):
4.98–5.01 (2H, q, O–CH2); 5.94–5.99 (1H, m, O–CH2CH);
6.64 (1H, d, J = 8.53, H Ar), 6.85 (1H, d, J = 10.14,
Ar–CH¼C), 7.37–7.46 (4H, m, H Ar), 7.51–7.64 (1H,
m, H Ar), 7.62 (1H, d, J = 8.53, H Ar), 7.73 (2H, d,
J = 8.31, Ar–H), 7.85 (2H, d, J = 8.31, Ar–H), 7.95–
7.99 (1H, m, H Ar); 13C NMR spectrum (Bruker
Avance-400, 100 MHz, DMSO), δ, ppm: 65.6(OCH2),
107.7, 112.7, 114.9, 119.1, 119.5, 121.1, 122.8, 124.4,
125.0, 127.5, 127.6, 127.8, 131.0, 131.3, 131.5, 132.9,
135.4, 144.6, 149.7, 154.3, 180.7 (C¼O); mass spectrum,
m/z (Irel, %): 491 [M + H]+ (100). Found, %: C, 63.50;
H, 3.28. C26H16BrClO3. Calculated, %: C, 63.47; H, 3.32.
(E)-(4-Bromophenyl)(3-(2,4-dichlorostyryl)-7H-furo[2,3-f]
chromen-2-yl)methanone
(7d).
Yield 85%, mp
175–177°C. IR spectrum, ν (cmꢀ1): 1625 (C¼O). 1H
NMR spectrum (Bruker Avance-400, 400 MHz, DMSO),
δ, ppm (J, Hz): 5.03 (2H, s, O–CH2); 5.97–6.02 (1H, m,
O–CH2CH); 6.63 (1H, d, J = 8.45, H Ar), 6.86–6.91 (2H,
m, Ar–CH¼C & H Ar), 7.46 (1H, d, J = 14.01, CH
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S. Boddupally, P. Jyothi, M. V. B. Rao, and K. P. Rao
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styryl), 7.52 (1H, d, J = 8.15, H Ar), 7.64 (1H, s, H Ar),
7.71 (1H, d, J = 8.45, H Ar), 7.76 (2H, d, J = 8.27,
Ar–H), 8.04 (2H, d, J = 8.27, Ar–H), 8.18 (1H, d,
J = 8.15, H Ar); 13C NMR spectrum (Bruker Avance-
400, 100 MHz, DMSO), δ, ppm: 65.4 (OCH2), 107.7,
112.7, 114.7, 119.1, 119.3, 120.7, 122.5, 123.6, 124.5,
125.1, 125.9, 127.7, 128.3, 129.1, 130.9, 131.3, 131.5,
134.1, 135.3, 144.9, 150.5, 154.5, 181.0 (C¼O); mass
spectrum, m/z (Irel, %): 525 [M + H]+ (100). Found, %:
C, 59.35; H, 2.87. C26H15BrCl2O3. Calculated, %: C,
59.33; H, 2.90.
NMR spectrum (Bruker Avance-400, 100 MHz, DMSO),
δ, ppm: 56.0 (OCH3), 65.5 (OCH2), 106.9, 111.9, 112.8,
115.5, 119.5, 120.2, 121.4, 123.6, 124.3, 124.8, 127.1,
128.4, 129.2, 130.0, 131.2, 135.4, 146.8, 151.6, 154.1,
159.7, 181.0 (C¼O); Mass spectrum, m/z (Irel, %): 487
(M + H)+. Found, %: C, 66.54; H, 3.93. C27H19BrO3.
Calculated, %: C, 66.51; H, 3.95.
(E)-(4-Bromophenyl)(3-(3,4-dimethoxystyryl)-7H-furo[2,3-f]
chromen-2-yl)methanone (7h).
Yield 91%, mp 145–
1
147°C. IR spectrum, ν (cmꢀ1): 1629 (C¼O); H NMR
spectrum (Bruker Avance-400, 400 MHz, DMSO), δ,
ppm (J, Hz): 3.89, 3.84 (3H, s, 2OCH3), 5.02 (2H, s,
O–CH2); 5.95–5.99 (1H, m, O–CH2CH); 6.42 (1H, d,
J = 8.15, H Ar), 6.87 (1H, d, J = 10.19, Ar–CH¼C),
6.93 (2H, d, J = 8.21, Ar–CH¼C), 7.25 (1H, dd, H Ar),
7.31 (2H, d, J = 14.59, H styryl), 7.59 (1H, s, H Ar),
7.64 (1H, d, J = 8.15, H Ar), 7.81 (2H, d, J = 8.11, H
Ar), 7.99 (2H, d, J = 8.11, H Ar); 13C NMR spectrum
(Bruker Avance-400, 100 MHz, DMSO), δ, ppm: 55.7
(OCH3), 65.4 (OCH2), 107.2, 109.5, 111.2, 112.6, 115.3,
117.6, 119.7, 120.1, 121.3, 123.1, 124.6, 124.9, 127.4,
129.0, 130.9, 131.4, 135.3, 146.1, 151.9, 154.5, 159.5,
159.8, 180.6 (C¼O); mass spectrum, m/z (Irel, %): 519
(M + H)+. Found, %: C, 65.00; H, 4.09. C27H19BrO3.
Calculated, %: C, 64.98; H, 4.12.
(E)-(4-Bromophenyl)(3-(4-methylstyryl)-7H-furo[2,3-f]
chromen-2-yl)methanone (7e).
Yield 89%, mp 165–
1
167°C. IR spectrum, ν (cmꢀ1): 1632 (C¼O); H NMR
spectrum (Bruker Avance-400, 400 MHz, DMSO), δ,
ppm (J, Hz): 2.39 (3H, s, Ar–CH3), 4.98 (2H, s, O–CH2);
5.91–5.94 (1H, m, O–CH2CH); 6.50 (1H, d, J = 8.19, H
Ar), 6.84 (1H, d, J = 10.07, Ar–CH¼C), 7.24–7.32 (4H,
m, H Ar), 7.50 (2H, d, J = 8.01, H Ar), 7.66 (1H, d,
J = 8.19, H Ar), 7.76 (2H, d, J = 8.05, Ar–H), 7.92 (2H, d,
J = 8.05, Ar–H); 13C NMR spectrum (Bruker Avance-400,
100 MHz, DMSO), δ, ppm: 22.8 (CH3), 65.9 (OCH2),
107.2, 112.7, 115.1, 119.4, 119.9, 121.0, 123.4, 124.2,
125.0, 127.7, 128.2, 128.4, 131.4, 131.6, 132.7, 134.0,
135.1, 146.2, 152.0, 154.7, 180.1 (C¼O); mass spectrum,
m/z (Irel, %): 471 (M + H)+. Found, %: C, 68.80; H, 4.06.
C27H19BrO3. Calculated, %: C, 68.83; H, 4.04.
(E)-(4-Bromophenyl)(3-(2-(thiophen-2-yl)vinyl)-7H-
furo[2,3-f]chromen-2-yl)methanone (7i).
Yield 87%, mp
160–162°C. IR spectrum, ν (cmꢀ1): 1633 (C¼O); 1H
NMR spectrum (Bruker Avance-400, 400 MHz, DMSO),
δ, ppm (J, Hz): 4.97 (2H, s, O–CH2); 5.91–5.95 (1H, m,
OCH2CH); 6.49 (1H, d, J = 8.53, H Ar), 6.83–6.90 (2H,
m, Ar–CH¼C & H styryl), 7.03–7.06 (1H, m, H Ar),
7.24–7.36 (3H, m, H Ar), 7.51 (2H, d, J = 8.27, Ar–H);
7.60 (1H, d, J = 8.53, H Ar), 7.90 (2H, d, J = 8.27, Ar-
H); 13C NMR spectrum (Bruker Avance-400, 100 MHz,
DMSO), δ, ppm: 65.7 (OCH2); 106.7, 112.3, 115.1,
119.1, 119.8, 121.5, 123.2, 124.5, 125.2, 125.9, 128.1,
128.8, 130.4, 131.2, 131.6, 135.3, 136.1, 146.3, 149.7,
153.6, 181.7(C¼O); mass spectrum, m/z (Irel, %): 463
(M + H)+. Found, %: C, 62.21; H, 3.26. C24H15BrO3S.
Calculated, %: C, 62.23; H, 3.23.
In vitro antimicrobial assay study. As we designed for
biological activity of all the titled compounds,
antimicrobial activity was performed using agar well
diffusion method against test organisms [37,44]. The
nutrient broth plates were swabbed using 100 mL
capacity and 24 h old broth culture for testing the
bacteria. Wells (6 mm) were made into each petridish
using the sterile cork-borer. The test samples of various
concentrations dissolved in DMSO solvent were added
into the wells using sterile pipettes. Similar antimicrobial
conditions were applied for the reference antibiotic,
gentamicin drug for antibacterial activity study, and
fluconazole drug for antifungal activity study. The plates
(E)-(4-Bromophenyl)(3-(4-isopropylstyryl)-7H-furo[2,3-f]
chromen-2-yl)methanone (7f). Yield 87%, mp 184–186°C.
1
IR spectrum, ν (cmꢀ1): 1633 (C¼O); H NMR spectrum
(Bruker Avance-400, 400 MHz, DMSO), δ, ppm (J, Hz):
1.25 (6H, d, 2CH3), 2.95 (1H, d, CH), 4.99–5.01 (2H, q,
O–CH2); 5.90–5.94 (1H, m, O–CH2CH); 6.52 (1H, d,
J = 8.23, H Ar), 6.85 (1H, d, J = 10.09, Ar–CH¼C),
7.37–7.46 (4H, m, H Ar), 7.61 (2H, d, J = 8.23, H Ar),
7.71 (1H, d, J = 8.14, H Ar), 7.78 (2H, d, J = 8.14, H
Ar), 7.93 (2H, d, J = 8.14, H Ar); 13C NMR spectrum
(Bruker Avance-400, 100 MHz, DMSO), δ, ppm: 23.7
(CH3), 32.9 (CH), 66.1 (OCH2), 107.1, 112.6, 115.4,
119.6, 120.1, 121.5, 123.3, 124.2, 125.0, 125.5, 127.3,
127.7, 131.3, 131.7, 132.1, 134.9, 146.1, 149.2, 151.9,
154.5, 180.2 (C¼O); mass spectrum, m/z (Irel, %): 499
(M + H)+. Found, %: C, 69.75; H, 4.64. C29H23BrO3.
Calculated, %: C, 69.72; H, 4.66.
(E)-(4-Bromophenyl)(3-(4-methoxystyryl)-7H-furo[2,3-f]
chromen-2-yl)methanone (7g).
Yield 89%, mp 148–
149°C. IR spectrum, ν (cmꢀ1): 1630 (C¼O); H NMR
spectrum (Bruker Avance-400, 400 MHz, DMSO), δ,
ppm (J, Hz): 3.84 (3H, s, 2OCH3), 4.99 (2H, s, O–CH2);
5.92–5.97 (1H, m, O–CH2CH); 6.47 (1H, d, J = 8.33, H
Ar), 6.87 (1H, d, J = 10.17, Ar–CH¼C), 7.21–7.25 (2H,
m, H Ar), 7.29 (2H, d, J = 14.27, H styryl), 7.57 (2H, d,
J = 8.19, H Ar), 7.63 (1H, d, J = 8.33, H Ar), 7.79 (2H,
d, J = 8.02, H Ar), 7.97 (2H, d, J = 8.02, H Ar); 13C
1
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Design, Synthesis and Docking Studies of Antimicrobial active Substituted
Chromene Derivative
were incubated at 37°C for 24 h and 28°C for 48 h,
respectively, for bacteria and fungi. The diameter of
zone of inhibition for each well was measured after
appropriate incubation period. Three duplicates were
maintained for each sample, and the average values were
calculated for more accurate antibacterial activity value.
The MICs were performed using freshly prepared broth
dilution test for the aforementioned samples [45]. The
test bacteria B. subtilis, S. aureus, and E. coli of 24 h
old and fungi P. vulgaris of 24 h old, and the test fungi
A. niger and C. albicans were diluted 100 times in
nutrient broth. The test samples of rising concentrations
were added to the test tubes containing bacterial and
fungal cultures. Using nutrient broth as control, the
tubes were examined for visible turbidity. Among the
test samples of various concentrations, the lowest
concentration that inhibited visible growth of the tested
organisms was reported as the MIC value of the
compounds (7a–i).
[47]. The output of the docking studies of 7a–i analogues
including binding energies of receptor–ligand complexes
are listed in Table 3.
CONCLUSION
In summary, we accomplished a new series of nine
heterocyclic compounds (E)-(3-(substituted-styryl)-7H-
furo[2,3-f]chromen-2-yl)(phenyl)methanones (7a–i) by
reacting (E)-3-(aryl)-1-(5-hydroxy-2H-chromen-6-yl)prop-
2-en-1-ones with 2-bromo-1-(4-bromophenyl)ethanones
under the microwave and conventional methods. The
microwave irradiation method was found to be best with
high yields and with shorter reaction times compared
with conventional method. All these newly synthesized
compounds were screened for their in vitro antimicrobial
activity study. Some of these compounds exhibited better
microbial inhibition against selected microorganisms
compared with the standard drugs. Among the many
substituents on the benzene ring, electronegative
substituents like chlorine and bromine showed significant
role in evaluating the antimicrobial activity. Moreover,
these biological evolution results were a good correlation
with molecular docking studies too. We are confident that
this study provides a road map for design and synthesis
of new heterocyclic compounds for desired applications
as drugs.
Docking studies.
Molecular docking studies were
carried out to understand the interactive mechanism of
7a–i derivatives with most active sites of the receptor.
The 3D structures of all the ligand compounds were
achieved by using Gauss view molecular visualization
program 5.0. The molecular geometries of the ligands
were optimized by using the standard density functional
triply-parameter hybrid model DFT/B3LYP employing
3-21G++ basis set with Gaussian 09w [46]. The
crystallographic 3D structure of S. aureus MurB protein
was brought out from RCSB Protein Data Bank (www.
rscb.org) with PDB ID: 1HSK for S. aureus MurB. The
previously associated ligands and water molecules are
eliminated from downloaded proteins from RCSB
employing UCSF chimera 1.10.1 software. The molecular
docking studies have been accomplished by using Auto
Dock Tools (ADT) (http://mgltools.scripps.edu) version
1.5.6 and Auto Dock 4.2 package suite. The docking
process was accomplished in between the flexible 7a–i
analogues with rigid protein receptor S. aureus MurB.
Moreover, we also performed ADT program to merge
non-polar hydrogens into associated carbon atoms of the
receptor S. aureus MurB to assign Gasteiger charges,
non-polar hydrogens, and torsions degrees of freedom.
The distance between acceptor and donor atoms
displaying the hydrogen bonding interactions was
stabilized to be 1.9 Å. The energy calculations were
achieved by using genetic algorithms. The grid box was
built with dimensions of 60 × 60 × 60 Å3 on the receptor
S. aureus MurB with the aid of ADT program with grid
point spacing of 0.3750 Å. In this molecular docking
studies, population size (150), and the maximum number
of evaluations (2.5 × 106) were used to minimize the
binding mode of ligands. The output results were
graphically examined by Discovery Studio 4.1.0 software
Acknowledgments. Srinivas Boddupally (S. B.) thanks VFSTR
University for the research avenues and funding. Koya Prabhakara
Rao (K. P. R.) thanks Department of Science & Technology/
Science and Engineering Research Board for financial support,
project for early career, project no. EMR/2014/001114.
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SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of the
article.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet