Novel O-Alkylated Chromones as Antimicrobial Agents: Ultrasound Mediated Synthesis, Molecular Docking and ADME Prediction

Article abstract of DOI:10.1002/jhet.2868

In the development of novel antimicrobial agents, we synthesized novel O-alkylated chromones 4a–f by ultrasound-assisted method. The synthesized compounds were characterized by IR, ¹H NMR, ¹³C NMR, MS, and elemental analysis. All com

Full text of DOI:10.1002/jhet.2868

Month 2017
Novel O-Alkylated Chromones as Antimicrobial Agents: Ultrasound
Mediated Synthesis, Molecular Docking and ADME Prediction
Vidya S. Dofe,a Aniket P. Sarkate,b Deepak K. Lokwani,c Devanand B. Shinde,d Santosh H. Kathwate,e and
a
*
Charansing H. Gill
aDepartment of Chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad, Maharashtra 431004, India
bDepartment of Chemical Technology, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad, Maharashtra
431004, India
cY. B. Chavan College of Pharmacy, Aurangabad, Maharashtra 431004, India
dShivaji University, Vidya Nagar, Kolhapur, Maharashtra 416004, India
eDepartment of Biotechnology, Rajarshi Shahu College, Latur, Maharashtra 413512, India
*
E-mail: chgill16@gmail.com
Additional Supporting Information may be found in the online version of this article.
Received September 21, 2016
DOI 10.1002/jhet.2868
Published online 00 Month 2017 in Wiley Online Library (wileyonlinelibrary.com).
In the development of novel antimicrobial agents, we synthesized novel O-alkylated chromones 4a–f by
1
ultrasound-assisted method. The synthesized compounds were characterized by IR, H NMR, 13C NMR,
MS, and elemental analysis. All compounds were assessed in vitro for their efficacy as antimicrobial agents
against four bacteria (Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa)
and three fungi (Candida albicans, Candida glabrata, Candida tropicalis). In particular, compounds 4a, 4b,
4d, 4e, and 4f exhibited potent antimicrobial activity. Molecular docking study was used to rationalize bind-
ing interaction at the active site, and the result showed good binding interaction. The compounds were also
processed for in silico ADME prediction, and the result showed that compounds could be exploited as an
oral drug candidate.
J. Heterocyclic Chem., 00, 00 (2017).
INTRODUCTION
properties of compounds such as metabolic stability,
solubility, bioavailability, and lipophilicity [5,6]. Inherent
electronic properties of fluorine such as small size, high
electronegativity, and strong C─F bond can dramatically
alter the biological response of the compound [7].
Fluorine substitution remains a striking aspect in the
development of more active and selective drug candidate.
Chromone and its analogs are important pharmacophore
in the medicinal chemistry and have featured in some
clinically used drugs. Chromone (benzopyran-4-one)
derivatives have exhibited an interesting biological
activity such as antitumor, anti-diabetes [8], antifungal
[9], anti-HIV [10], antioxidant [11], antiallergic [12],
anti-inflammatory [13], and neuro protective activity [14].
It was reported that the 3-substituted chromone such as
Ipriflavone possesses antiosteoporosis activity [15].
Ultrasound-mediated organic synthesis has attracted
much attention during the past few years. Ultrasound-
assisted synthesis has been considered as a green and
efficient technique used to accelerate organic reactions
proceed via acoustic cavitations. Cavitation induces in a
liquid because of the compression and rarefaction of
cycles of the propagating sound waves [1]. Under
ultrasound irradiation,
a large number of organic
reactions can be carried out with improved yield, shorter
reaction time, and milder reaction condition [2,3].
Infections triggered by the rapid development of
multidrug resistant pathogens have reached an alarming
level and became a complex and challenging health
problem. In order to prevent this serious problem, there is
an urgent need for the development of novel
antimicrobial agents [4]. Therefore, in recent years, the
researchers have been focused on the synthesis of new
antimicrobial agents. Inclusion of fluorine atom into an
organic molecule may enhance biological and physical
Many synthetic methods are reported for the synthesis of
alkylated chromone derivatives [16,17]. The present
method is advantageous with respect to the green
protocol of synthesis (ultrasound method). In our ongoing
research work, focusing on chromone as a scaffold for
© 2017 Wiley Periodicals, Inc.

V. S. Dofe, A. P. Sarkate, D. K. Lokwani, D. B. Shinde, S. H. Kathwate, and C. H. Gill
Vol 000
Scheme 1. Synthesis of 3-hydroxychromones 3a–f.
the development of novel antimicrobial agent [18], we
designed and synthesized fluorine containing O-alkylated
chromone derivatives under ultrasound method and
evaluated for antimicrobial activity. We also investigated
the binding interaction of the synthesized compounds at
the active site of Staphylococcus aureus KAS IIIenzyme
using molecular docking studies and also performed
ADME prediction of the synthesized compounds.
frequency υ at 3075 cmꢀ1 and υ at 1606 cmꢀ1 have
confirmed the (C═C). In the 1H NMR spectrum of
compound 4a, the methylene group attached to oxygen
showed doublet at δ 4.65 ppm, two germinal olefinic
protons shows doublet of doublets at δ 5.16 and
5.28 ppm, and one olefinic proton adjacent to a
methylene group shows doublet of doublet of triplets at δ
5.93 ppm. In the 13C NMR spectrum of compound 4a,
the signal at 73.21 ppm indicates the presence of
methylene group attached to oxygen. The mass spectrum
of 4a showed [M+Na]+ at 319.0. Likewise, 4b–f
derivative were in good conformity with the
spectroscopic data.
RESULTS AND DISCUSSION
Chemistry.
We have synthesized novel O-alkylated
chromone derivatives 4a–f under conventional method as
well as ultrasound irradiation method. The key starting
material, 3-hydroxy chromones 3a–f was synthesized in
our previous report [19] (Scheme 1). 3-Hydroxy
chromones 3a–f have been alkylated with allyl bromide
in the presence of K2CO3 in N,N0-DMF at the room
temperature to furnish the desired product 4a–f
(Scheme 2).
Antimicrobial activity. In the screening assay studies,
all the compounds were evaluated for antibacterial
activity
against
Gram-positive
bacteria
viz.
Staphylococcus aureus NCIM 2178, Bacillus subtilis
NCIM 2250, and Gram-negative bacteria viz. Escherichia
coli NCIM 2137, Pseudomonas aeruginosa NCIM 2036,
and antifungal activity against Candida albicans MTCC
277, Candida glabrata NCIM 3236, and Candida
tropicalis NCIM 3110 (Table 2). The minimum
inhibitory concentration (MIC) values were determined
by micro-broth dilution method. The results of
antibacterial screening were compared with the standard
antibacterial drug streptomycin. DMSO was used as
solvent control.
From the antimicrobial screening of newly synthesized
compounds, compound 4d showed equipotent activity
compared with streptomycin MIC 400 μg/mL against
E. coli, and compounds 4b, 4d, and 4e showed
equipotent activity against P. aeruginosa as compared
with standard streptomycin MIC 200 μg/mL. Compounds
Considering the significance of ultrasound irradiation,
we next attempted to investigate the effect of
ultrasonication on this synthesis using optimized reaction
conditions. The results are summarized in (Table 1). It
was observed that ultrasonic irradiation led to relatively
higher yield and reduced reaction time as compared with
the conventional method. Thus, ultrasonic irradiation was
found to be beneficial for the synthesis of O-alkylated
chromone derivatives 4a–f.
1
The compounds 4a–f was confirmed by IR, H NMR,
13C NMR, MS, and elemental analysis. The IR spectrum
of 4a showed the significant alkene CH-stretching
Scheme 2. Synthesis of O-alkylated chromone derivatives 4a–f.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Novel O-Alkylated Chromones as Antimicrobial Agents: Ultrasound Mediated
Synthesis, Molecular Docking and ADME Prediction
Table 1
condensation of acetyl-CoA to malonyl-ACP and plays
an essential role in the biosynthesis of bacterial fatty
acids. The enzyme is characterized by having a Cys-His-
Ultrasound-promoted synthesis of O-alkylated chromone derivatives 4a–f.
Conventional
Asn catalytic triad, located at the bottom of
a
Ultrasound method
method
Melting
point
(°C)
hydrophobic tunnel. The docking pose of compounds for
S. aureus KAS III was compared with the standard
streptomycin.
Time
(min)
Yielda
(%)
Time
(min)
Yielda
(%)
75
Entry
4a
4b
4c
4d
4e
4f
40
30
35
35
32
35
83
90
80
82
86
92
110
95
95
100
95
90
55–57
79–81
80–82
53–55
90–92
The docking studies showed that the primer site of
S. aureus KAS III enzyme is associated with key amino
acid residues Cys112, His238, Asn268, Phe298, Phe157,
Leu190, and Gly300. In spite of the identical sequence
for all amino acids, the sifting of the side chain and the
movement of some key amino acids makes the primer
binding site of S. aureus KAS III enzyme somewhat
larger [20]. Thus, compounds from series 4a–f bind
more perfectly in the primer binding site of S. aureus
KAS III enzyme and showed higher activity against
S. aureus. Compound 4a acquire the binding pose in
the active site of S. aureus KAS III enzyme (Fig. 1).
Chromone group of compound 4a spans near the
catalytic tried and forms hydrogen bond with Gly300. It
is also observed that all the docked compounds are
stabilized in the prime site of S. aureus KAS III
enzymes mainly through hydrophobic interaction with
surrounding amino acid residues.
In silico ADME prediction. The drug achievement is
determined by good efficacy and also through the
pharmacokinetics filters. ADME properties such as
absorption, distribution, metabolism, and excretion are
important to determine the efficacy of the molecule.
Molecular volume, MW, logarithm of partition coefficient
(milogP), number of hydrogen bond acceptors (n-ON),
number of hydrogen bond donors (n-OHNH), topological
polar surface area (TPSA), number of rotatable bonds
(n-ROTB), and Lipinski’s rule of five [21] were calculated
using the Molinspiration online property calculation
78
69
74
80
87
113–115
aIsolated yields.
4a and 4c with MIC 50 μg/mL showed considerable
activity against S. aureus compared with standard
streptomycin MIC 12.5 μg/mL. Compound 4b has a
chloro group on chromone ring with MIC 50 μg/mL
showed potent activity against B. subtilis. Compounds 4a
and 4f with MIC 100 μg/mL exhibited highly potent
activity against E. coli and P. aeruginosa.
Remarkably, allyl derivative of fluorinated chromone
are more susceptible to fungal strains. Compounds 4a,
4d, and 4f showed equipotent activity with miconazole
MIC 12.5 μg/mL against C. albicans. Compound 4a has
no substituent, 4d has methyl substituent, and 4f has
chloro, methyl substituent on chromone ring, with MIC
12.5 μg/mL exhibited highly potent antifungal activity
against C. glabrata and C. tropicalis.
Molecular docking study.
In order to understand
activity against S. aureus, we performed the docking
study of the most potent compounds to visualize and
compare their binding pose with literature data into the
active site of S. aureus KAS III. β-Ketoacyl-acyl carrier
protein (ACP) synthase III catalyses the initial
Table 2
Antimicrobial screening data of the compounds 4a–f.
Antimicrobial activitya (μg/mL)
Antibacterial activity
Antifungal activity
Entry
Sa
50
100
50
400
100
100
Bs
Ec
Pa
Ca
Cg
Ct
4a
4b
4c
4d
4e
4f
100
50
100
200
800
400
200
100
400
—
100
200
400
200
200
100
200
—
12.5
25
50
12.5
50
12.5
—
12.5
25
50
12.5
25
12.5
—
12.5
25
50
12.5
50
12.5
—
100
800
200
100
400
—
Streptomycin
Miconazole
12.5
—
12.5
400
800
Sa, Staphylococcus aureus; Bs, Bacillus subtilis; Ec, Escherichia coli; Pa, Pseudomonas aeruginosa; Ca, Candida albicans; Cg, Candida glabrata; Ct,
Candida tropicalis.
aMinimum inhibitory concentration (μg/mL) against the pathological strains based on micro-broth dilution method.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

V. S. Dofe, A. P. Sarkate, D. K. Lokwani, D. B. Shinde, S. H. Kathwate, and C. H. Gill
Vol 000
Figure 1. Binding pose of compound 4a in the prime site of Staphylococcus aureus KAS III. Pink dotted line indicated hydrogen bonds and light blue
dotted line indicate Pi-Pi stacking between ligand and enzyme. [Color figure can be viewed at wileyonlinelibrary.com]
toolkit [22]. Absorption was calculated by percentage (%)
ABS = 109 – (0.345 × TPSA) [23]. Drug-likeness model
score was computed by MolSoft software [24].
absorption) ranging from 91.60 to 95.39%. Compounds
obey Lipinski’s rule of five except compounds 4b, 4e,
and 4f, which violated the Lipinski’s rule of five
(milogP ≤ 5). The larger the value of the drug-likeness
model score, the higher will be the probability of a
particular molecule to be active. All tested compounds
followed the criteria for orally active drug. As a result,
these compounds may have good potential for eventual
development as oral agents.
Some important chemical descriptors correlate with
ADME properties are such as TPSA, low MW, and
octanol–water partition coefficient (milogP). TPSA
analysis is the primary determinant of fractional
absorption through which bioavailability of compounds
was accessed. It was observed that the passively
absorbed compounds with PSA > 140 Å2 has low oral
bioavailability and low MW has high oral absorption.
The excretion process that eliminates the compound
from the body depends on the MW and octanol–water
partition coefficient (milogP). A molecule likely to be
developed as an orally active drug candidate should be
evidence for no more than one violation of the
CONCLUSIONS
Ultrasound method was used to promote the synthesis
of O-alkylated chromone derivatives 4a–f in good yields
with more purity in short reaction time. The synthesized
compounds were evaluated for antimicrobial activity. It
can be concluded that the compounds 4a, 4b, 4d, 4e,
and 4f were identified as potent antimicrobial agents.
Binding of the most active compound against S. aureus
KAS III was studied using molecular docking studies.
In addition, ADME analysis has shown that compounds
have good drug-like properties and can be developed as
oral drug candidates.
following four criteria: MW
≤ 500, number of
hydrogen bond acceptors ≤10, number of hydrogen
bond donors ≤5, and milogP (octanol–water partition
coefficient) ≤ 5 [25].
A computational study of compounds was performed for
assessment of ADME properties. The obtained values are
presented in (Table 3). From all these parameters, it was
observed that the compounds exhibited good % ABS (%
Table 3
Pharmacokinetic parameters important for good bioavailability.
%
ABS
TPSA
(Å2)
n-
ROTB
n-
ON
n-
OHNH
Lipinski’s
violations
Drug-likeness model
score
Entry
MV
MW
milogP
Rule
4a
4b
4c
4d
4e
4f
—
—
—
4
4
4
4
—
<500
296.30
≤5
<10
<5
0
0
0
0
≤1
0
1
0
0
—
95.39
95.39
95.39
95.39
95.39
95.39
39.45
39.45
39.45
39.45
39.45
39.45
258.44
271.98
275.00
275.00
285.52
288.54
4.53
5.18
4.93
4.95
5.79
5.56
3
3
3
3
3
3
0.89
0.48
0.26
0.41
-0.07
0.28
330.74
310.32
310.32
365.19
344.77
4
4
0
0
1
1
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Novel O-Alkylated Chromones as Antimicrobial Agents: Ultrasound Mediated
Synthesis, Molecular Docking and ADME Prediction
EXPERIMENTAL
one (2b) as yellow solid, yield 77%, mp: 213–215°C, IR
(KBr, cmꢀ1): 3303, 3028, 1622, 1575; 1H NMR
(400 MHz, DMSO): δ 7.08–7.25 (m, 2H, ArH), 7.68–
7.82 (m, 2H, ArH), 8.12–8.23 (m, 2H, ArH), 8.51 (s,
1H, ArH), 9.08 (brs, 1H, OH); 13C NMR (100 MHz,
DMSO): δ 114.1, 117.5, 120.6, 125.4, 127.4, 128.4,
129.7, 130.2, 133.6, 148.5, 155.4, 157.6, 160.8, 162.5,
172.9; LCMS calculated for C15H8ClFO3 [M+H]+:
291.0224, found: 291.2223. Anal. Calcd for
All the solvents and reagents used in synthesis were
obtained from commercial sources and were used without
further purification. Melting points were recorded by the
open tube capillary method and are uncorrected. The
purity of compounds and completion of the reaction was
checked by TLC. Infrared spectra were recorded on Carry
600 Series FT-IR spectrophotometer using KBr pellets. 1H
NMR (400 MHz) and 13C NMR (100 MHz) spectra were
recorded on Bruker AVANCE II 400 NMR spectrometer
in CDCl3/DMSO-d6 solution. Tetramethylsilane was used
as an internal standard. Chemical shift values are given in
ppm relative to TMS as internal reference and the
coupling constant (J) in Hertz. The splitting pattern
abbreviations are assigned as singlet (s), doublet (d),
triplet (t), broad singlet (brs), doublet of doublets (dd),
doublet of doublet of doublets (ddd), doublet of doublet of
triplets (ddt), and multiplet (m). Mass spectra were
recorded on an WATERS, Q-TOF micro mass equipped
with an electron spin impact source. Elemental analysis
was performed on a Perkin-Elmer EAL-240 elemental
analyzer. For ultrasonic irradiation, Bandelin Sonorex
(frequency 40 MHz, power 100 W) ultrasound bath was
used, and the reaction flask was located in the ultrasonic
bath containing water.
C15H8ClFO3: C, 61.98; H, 2.77; found: C, 61.72; H, 2.94.
2-(4-Fluorophenyl)-3-hydroxy-8-methyl-4H-chromen-4-one
(3c).
The compound was obtained from (E)-3-(4-
fluorophenyl)-1-(2-hydroxy-3-methylphenyl)prop-2-en-1-
one (2c) as yellow solid, yield 69%, mp: 160–162°C, IR
(KBr, cmꢀ1): 3218, 2915, 1604, 1562; 1H NMR
(400 MHz, DMSO): δ 2.54 (s, 3H, CH3), 7.24–7.29 (m,
3H, ArH), 7.53 (d, 1H, J = 7.0 Hz, ArH), 7.93 (d, 1H,
J = 7.7 Hz, ArH), 8.26 (dd, 2H, J = 8.1, 5.5 Hz, ArH),
9.38 (s, 1H, OH); 13C NMR (100 MHz, DMSO): δ 15.3,
115.1, 115.3, 120, 122.3, 123.6, 127.1, 127.9, 129.6,
133.7, 138.7, 143.5, 152.8, 161.3, 163.7, 173; LCMS
calculated for C16H11FO3 [M+H]+: 271.077, found:
271.2154. Anal. Calcd for C16H11FO3: C, 71.11; H, 4.10;
found: C, 71.23; H, 4.16.
2-(4-Fluorophenyl)-3-hydroxy-6-methyl-4H-chromen-4-one
(3d).
The compound was obtained from (E)-3-(4-
fluorophenyl)-1-(2-hydroxy-5-methylphenyl)prop-2-en-1-
one (2d) as yellow solid, yield 73%, mp: 171–173°C, IR
(KBr, cmꢀ1): 3239, 2983, 1628, 1504; 1H NMR
(400 MHz, DMSO): δ 2.46 (s, 3H, CH3), 7.27 (t, 2H,
J = 8.6 Hz, ArH), 7.54 (s, 2H, ArH), 7.91 (s, 1H, ArH),
8.27–8.30 (m, 2H, ArH), 9.31 (s, 1H, OH); 13C NMR
(100 MHz, DMSO): δ 20.5, 115, 115.2, 117.7, 120.9,
123.8, 127.7, 129.8, 130.6, 134.5, 138.7, 143.9, 152.8,
161.3, 163.8, 172.8; LCMS calculated for C16H11FO3 [M
General procedure for the synthesis of compounds 3a–f. The
mixture of (E)-3-(4-fluorophenyl)-1-(2-hydroxyphenyl)prop-2-
en-1-one 2a–f (1 mmol), ethanol (15 mL), NaOH (10%,
5 mL), and hydrogen peroxide (30%, 1.5 mL) was stirred
vigorously for 30 min and kept for 2–3 h at ice cold
condition. The progress of reaction was observed by TLC
using ethyl acetate:hexane as a solvent system. After
completion of the reaction, the reaction mixture was poured
into ice cold water and acidified with 1 M HCl. The
precipitate was collected by filtration, washed with water and
crystallized from chloroform-ethanol to afford the pure product.
+H]+: 271.077, found: 271.2234. Anal. Calcd for
C16H11FO3: C, 71.11; H, 4.10; found: C, 71.24; H, 4.11.
6,8-Dichloro-2-(4-fluorophenyl)-3-hydroxy-4H-chromen-4-
2-(4-Fluorophenyl)-3-hydroxy-4H-chromen-4-one (3a).
The
one (3e).
The compound was obtained from (E)-1-
compound was obtained from (E)-3-(4-fluorophenyl)-1-(2-
hydroxyphenyl)prop-2-en-1-one (2a) as yellow solid, yield
74%, mp: 152–154°C, IR (KBr, cmꢀ1): 3297, 2925, 1618,
(3,5-dichloro-2-hydroxyphenyl)-3-(4-fluorophenyl)prop-2-
en-1-one (2e) as yellow solid, yield 75%, mp: 203–205°C,
IR (KBr, cmꢀ1): 3245, 2916, 1625, 1502; 1H NMR
(400 MHz, DMSO): δ 7.25 (t, 2H, J = 8.8 Hz, ArH), 7.82
(d, 1H, J = 2.6 Hz, ArH), 7.96 (d, 1H, J = 2.2 Hz,
ArH), 8.29 (dd, 2H, J = 8.8, 5.5 Hz, ArH), 9.81 (s,
1H, OH); 13C NMR (100 MHz, DMSO): δ 115.2,
115.4, 122.8, 122, 123.7, 127.1, 128.8, 129.8, 132.6,
139.2, 144.5, 148.4, 161.5, 164, 171.3; LCMS
calculated for C15H7Cl2FO3 [M+H]+: 324.9835, found:
325.1267. Anal. Calcd for C15H7Cl2FO3: C, 55.41; H,
1
1572; H NMR (400 MHz, CDCl3): δ 7.11 (brs, 1H, ArH),
7.22 (t, 2H, J = 8.6 Hz, ArH), 7.42 (ddd, 1H, J = 7.6, 7.5,
1.1 Hz, ArH), 7.58 (d, 1H, J = 8.4 Hz, ArH), 7.71 (ddd, 1H,
J = 8.5, 7.1, 1.7 Hz, ArH), 8.24 (d, 1H, J = 1.8 Hz, ArH),
8.26 (s, 1H, OH), 8.27–8.30 (m, 2H, ArH); 13C NMR
(100 MHz, CDCl3): δ 115.7, 115.9, 118.2, 120.7, 124.6,
125.5, 127.3, 129.9, 133.7, 138.2, 144.1, 155.3, 162.3, 164.8,
173.4; LCMS calculated for C15H9FO3 [M+H]+: 257.0,
found: 257.0. Anal. Calcd for C15H9FO3: C, 70.31; H, 3.54;
found: C, 70.34; H, 3.57.
2.17; found: C, 55.49; H, 2.15.
6-Chloro-2-(4-fluorophenyl)-3-hydroxy-7-methyl-4H-chromen-4-
one (3f). The compound was obtained from (E)-1-(5-chloro-
6-Chloro-2-(4-fluorophenyl)-3-hydroxy-4H-chromen-4-one
(3b).
The compound was obtained from (E)-1-(5-
2-hydroxy-4-methylphenyl)-3-(4-fluorophenyl)prop-2-en-
1-one (2f) as yellow solid, yield 79%, mp: 222–224°C, IR
chloro-2-hydroxyphenyl)-3-(4-fluorophenyl)prop-2-en-1-
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

V. S. Dofe, A. P. Sarkate, D. K. Lokwani, D. B. Shinde, S. H. Kathwate, and C. H. Gill
Vol 000
(KBr, cmꢀ1): 3238, 2919, 1628, 1503; 1H NMR
(400 MHz, DMSO): δ 2.5 (s, 3H, CH3), 7.28 (t, 2H,
J = 8.3 Hz, ArH), 7.64 (brs, 1H, ArH), 8.03 (s, 1H, ArH),
8.27 (brs, 2H, ArH), 9.54 (s, 1H, OH); 13C NMR
(100 MHz, DMSO): δ 20.3, 115.1, 115.3, 120.1, 120.5,
124, 127.5, 129.9, 130.1, 138.8, 141.8, 144.3, 152.8,
161.4, 163.9, 171.8; LCMS calculated for C16H10ClFO3
[M+H]+: 305.0381, found: 305.2251. Anal. Calcd for
C16H10ClFO3: C, 63.07; H, 3.31; found: C, 63.13; H, 3.38.
(d, 2H, J = 5.9 Hz, OCH2), 5.09 (dd, 1H, J = 10.2,
1.1 Hz, olefinic proton), 5.20 (dd, 1H, J = 17.2, 1.5 Hz,
olefinic proton), 5.83 (ddt, 1H, J = 16.9, 10.5, 6.1 Hz,
olefinic proton), 7.13 (t, 2H, J = 8.8 Hz, ArH), 7.42 (d,
1H, J = 9.2 Hz, ArH), 7.54 (d, 1H, J = 8.8 Hz, ArH),
8.06 (dd, 2H, J = 9.0, 5.3 Hz, ArH), 8.14 (d, 1H,
J = 2.6 Hz, ArH); 13C NMR (100 MHz, CDCl3): δ 73.3,
115.6, 115.8, 119, 119.7, 125.2, 126.8, 130.8, 131,
131.1, 133.2, 133.7, 139.7, 153.5, 155.3, 162.8, 165.3,
173.9; LCMS calculated for C18H12ClFO3 [M+H]+:
331.1, found: 331.0. C18H12ClFO3 [M+Na]+: 353.0,
found: 353.0. Anal. Calcd for C18H12ClFO3: C, 65.37; H,
3.66; found: C, 65.39; H, 3.74.
General procedure for synthesis of compounds 4a–f.
Conventional method.
To the stirred solution of
substituted 2-(4-fluorophenyl)-3-hydroxy-4H-chromen-4-
one 3a–f (1 mmol) in DMF, potassium carbonate
(2 mmol) and allyl bromide (1 mmol) were added at room
temperature for the period of time indicated in Table 1.
The progress of reaction was observed by TLC using
ethyl acetate:hexane as a solvent system. After completion
of the reaction, ice cold water was added to it.
Precipitated solid was collected by filtration and
recrystallized from ethanol to afford the pure product.
3-(Allyloxy)-2-(4-fluorophenyl)-8-methyl-4H-chromen-4-one
(4c).
The compound was obtained from 2-(4-
fluorophenyl)-3-hydroxy-8-methyl-4H-chromen-4-one
(3c) and allyl bromide as yellow solid, IR (KBr, cmꢀ1):
3073, 2942, 1637, 1605; 1H NMR (400 MHz, CDCl3): δ
2.56 (s, 3H, CH3), 4.66 (d, 2H, J = 5.9 Hz, OCH2), 5.16
(dd, 1H, J = 10.3, 1.5 Hz, olefinic proton), 5.29 (dd, 1H,
J = 17.2, 1.5 Hz, olefinic proton), 5.95 (ddt, 1H,
J = 17.0, 10.5, 6.1 Hz, olefinic proton),7.20 (t, 2H,
J = 8.8 Hz, ArH), 7.27 (t, 1H, J = 7.5 Hz, ArH), 7.50
(d, 1H, J = 6.6 Hz, ArH), 8.08 (dd, 1H, J = 7.9,
1.1 Hz, ArH), 8.17 (dd, 2H, J = 9.0, 5.3 Hz, ArH); 13C
NMR (100 MHz, CDCl3): δ 15.8, 73.2, 115.6, 115.8,
118.7, 123.5, 124, 124.4, 127.4, 127.6, 130.8, 133.5,
134.3, 139.7, 153.7, 154.4, 162.6 165.1, 175.3; ESI-
MS calculated for C19H15FO3 [M+H]+: 311.1083,
found: 311.2619. C19H15FO3 [M+Na]+: 333.0903,
found: 333.2385. Anal. Calcd for C19H15FO3: C,
73.54; H, 4.87; found: C, 73.61; H, 4.92.
Ultrasound method.
To the solution of substituted
2-(4-fluorophenyl)-3-hydroxy-4H-chromen-4-one 3a–f
(1 mmol) in DMF, potassium carbonate (2 mmol) and
allyl bromide (1 mmol) were added into 50-mL round-
bottomed flask. The reaction flask was placed in the
ultrasonic cleaner bath with the surface of reactants
slightly lower than the water level and irradiated at
25–30°C for the period of time indicated in Table 1. The
progress of reaction was observed by TLC using ethyl
acetate:hexane as a solvent system. After completion of
reaction indicated by TLC, ice cold water added to it, and
precipitated solid were collected by filtration and
recrystallized from ethanol to afford pure product.
3-(Allyloxy)-2-(4-fluorophenyl)-6-methyl-4H-chromen-4-one
(4d).
The compound was obtained from 2-(4-
3-(Allyloxy)-2-(4-fluorophenyl)-4H-chromen-4-one (4a).
The
fluorophenyl)-3-hydroxy-6-methyl-4H-chromen-4-one
(3d) and allyl bromide as yellow solid, IR (KBr, cmꢀ1):
3077, 2924, 1638, 1618; 1H NMR (400 MHz, CDCl3): δ
2.46 (s, 3H, CH3), 4.64 (d, 2H, J = 5.9 Hz, OCH2), 5.15
(dd, 1H, J = 10.3, 1.5 Hz, olefinic proton), 5.27 (dd, 1H,
J = 17.2, 1.5 Hz, olefinic proton), 5.93 (ddt, 1H,
J = 17.0, 10.5, 6.1 Hz, olefinic proton), 7.18 (t, 2H,
J = 8.6 Hz, ArH), 7.41 (d, 1H, J = 8.4 Hz, ArH), 7.48
(dd, 1H, J = 8.8, 1.2 Hz, ArH), 8.02 (brs, 1H, ArH),
8.14 (dd, 2H, J = 9.2, 5.5 Hz,ArH); 13C NMR
(100 MHz, CDCl3): δ 20.9, 73.2, 115.4, 115.6, 117.7,
118.7, 123.8, 125, 127.3, 130.9, 133.5, 134.7, 134.8,
139.7, 153.5, 154.8, 162.6, 165.1, 175; ESI-MS
calculated for C19H15FO3 [M+H]+: 311.1083, found:
311.1058. C19H15FO3 [M+Na]+: 333.0903, found:
333.0783. Anal. Calcd for C19H15FO3: C, 73.54; H,
compound was obtained from 2-(4-fluorophenyl)-3-hydroxy-
4H-chromen-4-one (3a) and allyl bromide as yellow solid, IR
1
(KBr, cmꢀ1): 3075, 2945, 1639, 1606; H NMR (400 MHz,
CDCl3): δ 4.65 (d, 2H, J = 5.9 Hz, OCH2), 5.16 (dd, 1H,
J = 10.3, 1.1 Hz, olefinic proton), 5.28 (dd, 1H, J = 17.2,
1.5 Hz, olefinic proton), 5.93 (ddt, 1H, J = 17.0, 10.5, 6.1 Hz,
olefinic proton), 7.20 (t, 2H, J = 8.8 Hz, ArH), 7.38–7.42 (m,
1H, ArH), 7.53 (d, 1H, J = 8.1 Hz, ArH), 7.68 (ddd, 1H,
J = 8.6, 7.0, 1.7 Hz, ArH), 8.15 (dd, 2H, J = 9.0, 5.3 Hz,
ArH), 8.26 (dd, 1H, J = 8.1, 1.5 Hz, ArH); 13C NMR
(100 MHz, CDCl3): δ 73.2, 115.5, 115.7, 117.9, 118.7, 124,
124.7, 125.8, 127.2, 130.9, 131, 133.5, 139.7, 154.9, 155.1,
162.6, 165.2, 175; LCMS calculated for C18H13FO3 [M
+Na]+: 319.0, found: 319.0. Anal. Calcd for C18H13FO3: C,
72.97; H, 4.42; found: C, 72.76; H, 4.58.
3-(Allyloxy)-6-chloro-2-(4-fluorophenyl)-4H-chromen-4-one
(4b). The compound was obtained from 6-chloro-2-(4-
4.87; found: C, 73.33; H, 4.96.
3-(Allyloxy)-6,8-dichloro-2-(4-fluorophenyl)-4H-chromen-4-
one (4e). The compound was obtained from 6,8-dichloro-
fluorophenyl)-3-hydroxy-4H-chromen-4-one (3b) and
allyl bromide as yellow solid, IR (KBr, cmꢀ1): 3089,
1
2-(4-fluorophenyl)-3-hydroxy-4H-chromen-4-one (3e) and
2937, 1639, 1605; H NMR (400 MHz, CDCl3): δ 4.57
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Novel O-Alkylated Chromones as Antimicrobial Agents: Ultrasound Mediated
Synthesis, Molecular Docking and ADME Prediction
allyl bromide as yellow solid, IR (KBr, cmꢀ1): 3012, 2967,
1634, 1600; H NMR (400 MHz, CDCl3): δ 4.68 (d, 2H,
Molecular docking study.
Glide v6.2 (Schrodinger,
1
LLC) software was used for molecular docking studies.
The procedure was followed as per the literature [27–30].
For the said work, X ray crystal structure of S. aureus
KAS III was procured from PDB entry 1ZOW [31] and
prepared for docking using protein preparation wizard.
The termini were covered with the help of ACE and
NMA residue. From the structure, water molecules were
removed, and to all atoms, hydrogen was added. For the
hetero groups, formal charges and bond orders were
added. Side chains, which were not near to the binding
cavity and do not contribute in salt bridges, were
neutralized. After the preparation, the structures were
refined to optimize the hydrogen bond network using
OPLS_2005 force field. This helps in reorientation of the
side chain hydroxyl group. When the energy converged
or the RMSD reached a maximum cut off of 0.30 A, the
minimization was terminated.
J = 6.2 Hz, OCH2), 5.19 (dd, 1H, J = 10.3, 1.1 Hz,
olefinic proton), 5.30 (dd, 1H, J = 17.1, 1.3 Hz, olefinic
proton), 5.94 (ddt, 1H, J = 17.0, 10.5, 6.1 Hz, olefinic
proton), 7.22 (t, 2H, J = 8.8 Hz, ArH), 7.72 (d, 1H,
J = 2.6 Hz, ArH), 8.11 (d, 1H, J = 2.6 Hz, ArH), 8.26
(dd, 2H, J = 9.0, 5.3 Hz, ArH); 13C NMR (100 MHz,
CDCl3): δ 72.4, 115.7, 115.9, 118.4, 123, 123.7, 125.2,
126.3, 129.4, 130.8, 130.9, 133.2, 139.3, 148.8, 154.1,
162.2, 164.7, 172.2; LCMS calculated for C18H11Cl2FO3
[M+H]+: 365.0, found: 365.1. C18H11Cl2FO3 [M+Na]+:
387.0, found: 387.1. Anal. Calcd for C18H11Cl2FO3: C,
59.20; H, 3.04; found: C, 59.24; H, 3.12.
3-(Allyloxy)-6-chloro-2-(4-fluorophenyl)-7-methyl-4H-chromen-
4-one (4f). The compound was obtained from 6-chloro-2-(4-
fluorophenyl)-3-hydroxy-7-methyl-4H-chromen-4-one
(3f)
and allyl bromide as yellow solid,IR (KBr, cmꢀ1): 3069,
1
2952, 1628, 1600; H NMR (400 MHz, CDCl3): δ 2.5 (s,
3H, CH3), 4.63 (d, 2H, J = 6.2 Hz, OCH2), 5.16 (dd, 1H,
J = 10.3, 1.5 Hz, olefinic proton), 5.26 (dd, 1H, J = 17.2,
1.5 Hz, olefinic proton), 5.91 (ddt, 1H, J = 17.0, 10.5, 6.2 Hz,
olefinic proton), 7.18 (t, 2H, J = 8.6 Hz, ArH), 7.40 (s, 1H,
ArH), 8.11 (dd, 2H, J = 9.0, 5.3 Hz, ArH), 8.17 (s, 1H, ArH);
13C NMR (100 MHz, CDCl3): δ 20.8, 73.3, 115.5, 115.7,
118.8, 119.7, 123.1, 125.4, 127, 130.9, 131.6, 133.3, 139.6,
142.8, 153.4, 154.9, 162.7, 165.2, 173.9; ESI-MS calculated
for C19H14ClFO3 [M+H]+: 345.0694, found: 345.2405.
C19H14ClFO3 [M+Na]+: 367.0513, found: 367.2264. Anal.
Calcd for C19H14ClFO3: C, 66.19; H, 4.09; found: C, 66.31;
H, 4.01.
Acknowledgments. Author V.S.D. is very much grateful to the
Council of Scientific and Industrial Research (CSIR), New Delhi,
India, for providing Senior Research Fellowship and Sophisticated
Analytical Instrumentation Facility (SAIF), Panjab University,
Chandigarh, for providing spectral data. We are thankful to Head,
Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada
University, Aurangabad, Maharashtra, for providing laboratory fa-
cility. We are also thankful to the Rajarshi Shahu College, Latur,
for providing biological activities.
REFERENCES AND NOTES
[1] Deshmukh, R. R.; Rajagopal, R.; Srinivasan, K. V. Chem
Commun 2001, 1, 1544.
[2] Srivastava, R. M.; Filho, R. A. W. N.; Silva, C. A.; Bortoluzzi,
A. Ultrason Sonochem 2009, 16, 737.
EXPERIMENTAL PROTOCOL FOR
BIOLOGICAL ACTIVITY
[3] Bazgir, A.; Ahadi, S.; Ghahremanzadeh, R.; Khavasi, H. R.;
Mirzaei, P. Ultrason Sonochem 2010, 17, 447.
[4] Peet, N. P. Drug Discov Today 2010, 15, 583.
[5] Mueller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881.
[6] Nair, N.; Kudo, W.; Smith, M. A.; Abrol, R.; Goddard, W. A.;
Reddy, V. P. Bioorg Med Chem Lett 2011, 21, 3957.
[7] Desai, N. C.; Rajpara, K. M.; Joshi, V. V. J Fluorine Chem
2012, 145, 102.
[8] Forghieri, M.; Laggner, C.; Paoli, P.; Langer, T.; Manao, G.;
Camici, G.; Bondioli, L.; Prati, F.; Costantino, L. Bioorg Med Chem
2009, 17, 2658.
[9] Prakash, O.; Kumar, R.; Prakash, V. Eur J Org Chem 2008, 43,
435.
[10] Ungwitayatorn, J.; Wiwat, C.; Samee, W.; Nunthanavanit, P.;
Phosrithong, N. J Mol Struct 2011, 1001, 152.
[11] Pandurangan, N.; Bose, C.; Banerji, A. Bioorg Med Chem Lett
2011, 21, 5328.
[12] Kris-Etherton, P. M.; Hecker, K. D.; Bonanome, A.; Coval, S. M.;
Binkoski, A. E.; Hilpert, K. F.; Griel, A. E.; Etherton, T. D. Am J Med
2002, 113, 71.
Antimicrobial activity. In vitro antibacterial activity of
the synthesized compounds was tested against Gram-
positive bacteria viz. Staphylococcus aureus (NCIM
2178), B. subtilis (NCIM 2250), and Gram-negative
bacteria E. coli (NCIM 2137), P. aeruginosa (NCIM
2036). The compounds were also screened for antifungal
activity against C. albicans (MTCC 277), C. glabrata
(NCIM 3236), and C. tropicalis (NCIM 3110).
Compounds were diluted in DMSO with 1 μg/mL
concentrations for bioassay. Micro-broth dilution method
[26] used to determined in vitro MICs of compounds in
96-well micro titre plates. National Committee for
Clinical Laboratory Standards defined the method against
a panel of human pathogenic strains. Test compounds
were serially double diluted in growth medium. Plates
were incubated at 30°C for fungi and 37°C for bacteria
for 24 h. All experiments were carried out in triplicates,
and mean values are represented.
[13] Garcıa-Lafuente, A.; Guillamon, E.; Villares, A.; Rostagno, M. A.;
Martınez, J. A. Inflamm Res 2009, 58, 537.
[14] Chiruta, C.; Schubert, D.; Dargusch, R.; Maher, P. J Med
Chem 2012, 55, 378.
[15] Yamazaki, I. Life Sci 1986, 38, 951.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

V. S. Dofe, A. P. Sarkate, D. K. Lokwani, D. B. Shinde, S. H. Kathwate, and C. H. Gill
Vol 000
[16] Kamboj, R. C.; Sharma, G.; Kumar, D.; Arora, R. C R Chimie
2012, 15, 311.
[17] Gharpure, M.; Choudhary, R.; Ingle, V.; Juneja, H. J Chem Sci
2013, 125, 575.
[18] Chate, A. V.; Nikam, M. D.; Mahajan, P. S.; Mohekar, S. R.;
Gill, C. H. Org Commun 2012, 5, 83.
[19] Dofe, V. S.; Sarkate, A. P.; Lokwani, D. K.; Kathwate, S. H.;
Gill, C. H. Res Chem Intermed 2017, 43, 15.
[20] Qiu, X.; Choudhry, A. E.; Janson, C. A.; Grooms, M.; Daines,
R. A.; Lonsdale, J. T.; Khandekar, S. S. Protein Sci 2005, 14, 2087.
[21] Lipinski, C. A.; Lombardo, L.; Dominy, B. W.; Feeney, P. J
Adv Drug Delivery Rev 2001, 46, 3.
[24] Drug-likeness and molecular property prediction, available
from: http://www.molsoft.com/mprop/
[25] Ertl, P.; Rohde, B.; Selzer, P. J Med Chem 2000, 43, 3714.
[26] Wiegand, I.; Hilpert, K.; Hancock, R. E. W. Nat Protoc 2008,
3, 163.
[27] Sarkate, A. P.; Shinde, D. B. Int J Pharm Pharm Sci 2015, 7,
128.
[28] Sarkate, A. P.; Shinde, D. B. Res J Pharm Bio Chem Sci 2015,
6, 391.
[29] Sarkate, A. P.; Lokwani, D. K.; Bahekar, S. S.; Shinde, D. B.
Int J Pharm Pharm Sci 2015, 7, 197.
[30] Lokwani, D.; Azad, R.; Sarkate, A.; Reddanna, P.; Shinde, D.
Bioorg Med Chem 2015, 23, 4533.
[31] Dongamanti, A.; Aamate, V. K.; Devulapally, M. G.; Gundu,
S.; Kotni, M. K.; Manga, V.; Balasubramanian, S.; Ernala, P. Bioorg
Med Chem Lett 2015, 25, 898.
[22] MolinspirationChemoinformaticsBrastislava, Slovak Republic,
Available from: http://www.molinspiration.com/cgi-bin/properties 2014.
[23] Zhao, Y. H.; Abraham, M. H.; Lee, J.; Hersey, A.; Luscombe,
N. C.; Beck, G.; Sherborne, B.; Cooper, I. Pharm Res 2002, 19, 1446.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet