An efficient synthesis of flavanones and their docking studies with aldose reductase

Article abstract of DOI:10.1007/s00044-017-1813-1

A series of flavanone derivatives have been synthesized from 2-hydroxy acetophenone and benzaldehyde using fused calcium chloride in good to moderate yields, and their in vitro aldose reductase inhibitory activity has been tested on aldose reductase purified enzyme from Bovine lens. Most of the synthesized compounds exhibited potent aldose reductase inhibitory activity, and the obtained results are supported by the docking studies. Among the tested derivatives, 2, 3, 4-methoxy derivative 19 (IC₅₀ 5.88 ± 0.03 μM) exhibited the highest inhibitory activity whereas 2-methoxy derivative 12 showed the lowest, and the remaining compounds exhibited moderate activity with IC₅₀ in the range of 6.09–7.89 μM. The spatial configuration of the most active derivative 19 was compared with pharmacophore requirements of the aldose reductase inhibitor site using a molecular modeling system.

Full text of DOI:10.1007/s00044-017-1813-1

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-017-1813-1
ORIGINAL RESEARCH
An efficient synthesis of flavanones and their docking studies with
aldose reductase
D. D. Kondhare1 G. Gyananath2 Yasinalli Tamboli1 Santosh S. Kumbhar3
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Prafulla B. Choudhari3 Manish S. Bhatia3 P. K. Zubaidha1
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Received: 2 October 2016 / Accepted: 16 February 2017
© Springer Science+Business Media New York 2017
Abstract A series of flavanone derivatives have been
synthesized from 2-hydroxy acetophenone and benzalde-
hyde using fused calcium chloride in good to moderate
yields, and their in vitro aldose reductase inhibitory activity
has been tested on aldose reductase purified enzyme from
Bovine lens. Most of the synthesized compounds exhibited
potent aldose reductase inhibitory activity, and the obtained
results are supported by the docking studies. Among the
tested derivatives, 2, 3, 4-methoxy derivative 19 (IC50 5.88
0.03 µM) exhibited the highest inhibitory activity whereas
2-methoxy derivative 12 showed the lowest, and the
remaining compounds exhibited moderate activity with IC50
in the range of 6.09–7.89 µM. The spatial configuration of
the most active derivative 19 was compared with pharma-
cophore requirements of the aldose reductase inhibitor site
using a molecular modeling system.
Introduction
Hyperglycemia leads to several diabetic complications such
as retinopathy, neuropathy, cataracts, nephropathy and
cardiovascular complication. In 2010, 285 million people
were suffering from diabetes, and this number is estimated
to increase to 439 million by 2030. However, the available
oral antidiabetic drugs are ineffective in preventing com-
plications associated with diabetics. Aldose reductase (AR;
EC: 1.1.1.21) is the key rate limiting enzyme of the polyol
pathway involved in the conversion of glucose to sorbitol
utilizing NADPH as the cofactor (Chen et al. 2011). The
activity of the enzyme is found to be enhanced in diabetic
patients (Gabbay et al. 1996). It is a major risk factor
leading to cataract, a major cause of blindness over the
world. Various pharmacological strategies have been used
to prevent the cataract formation, among them AR inhibi-
tors (ARIs) have received much attention because of its
involvement in the pathophysiology of diabetic complica-
tions including cataract (Ghahary et al. 1991, Wild et al.
2004). Inhibition of this crucial enzyme would therefore
constitute a vital strategy in control of secondary complica-
tions associated with diabetes. Studies directed towards the
development of ARIs to prevent these complications have
yielded many structurally diverse ARIs such as tolrestat,
sorbinil, zopolrestat, and from other sources (Obrosova et al.
2010; Costantino et al. 2000; Miyamoto 2002; Soni et al.
2008; Jung et al. 2011; Hamada et al. 2000). Flavonoids are
credited with a number of biological activities (Aherne and
O’Brien 2002; Middleton et al. 2000), and possess significant
health-promoting activities, such as inhibition of AR and
sorbitol accumulation (Haraguchi et al. 1996a, 1996b; Wir-
asathien et al. 2007), lipid-lowering effect (Kigarashi et al.
1996), and antioxidant activity (Haraguchi et al. 1996a).
Keeping in view of the diverse biological effects displayed
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Keywords Aldose reductase inhibitor Flavanone
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Calcium chloride Bovine lens Molecular docking
* P. K. Zubaidha
pzubaidha20001@yahoo.co.in
1
School of Chemical Sciences, Swami Ramanand Teerth
Marathwada University, Nanded, Maharashtra 431606, India
2
School of Life Sciences, Swami Ramanand Teerth Marathwada
University, Nanded, Maharashtra 431606, India
3
Department of Pharmaceutical Chemistry, Bharati Vidyapeeth
College of Pharmacy, Kolhapur, Maharashtra 416013, India

Med Chem Res
Scheme 1 Synthesis of flavanone derivatives
Table 1 Synthesis of flavanone derivatives
by flavanones, a simple cost-effective one-pot method has
been developed for flavanones from easily available raw
materials (Scheme 1), and their in vitro ARI studies have
been carried out.
Compounds R1
R2
R3
R4
Time in h % yield
1
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
10
8
92
91
88
89
90
85
86
82
76
80
70
74
80
83
79
78
75
80
78
80
2
H
H
Cl
Me
OMe
Br
NO2
F
A number of methods exist in literature for synthesis of
flavanones from substituted 2-hydroxychalcones using acid
catalysts (Monserrat et al. 2010; Kumar et al. 2008; Kagawa
et al. 2005), bases (Akcok and Çağır 2010; Chandrasekhar
et al. 2005), thermal, photochemical methods and electro-
chemical transformations (Maki et al. 1988; Pandey et al.
1987; Sanicanin and Tabakovic 1986; Matsushima and
Kageyama 1985). Other alternate procedures for flavanones
include oxidation of flavan-4-ols (Sing 1993; Izumi et al.
1992) reaction of aldehydes with 1,3-diones in basic med-
ium (Bhatia et al. 1968), transformation of phenyl alkenyl
aryl ethers in the presence of Hg(OCOCF3)2 (Joglekar and
Samant 1988), intramolecular Oxa Michael addition of
activated α, β-unsaturated ketones (Subramanian and
Balasubramanian 1990), Juliae Kocienski olefination of 2-
3
H
H
11
8
4
H
H
5
H
H
10
6
H
H
7.5
7
H
H
9
12
12
8
OMe
F
H
H
9
H
H
10
11
12
13
14
15
16
17
18
19
20
NO2
Cl
H
H
H
7.5
H
H
10
13
OMe
NO2
H
H
H
H
7.5
Cl
Me
H
Cl
Me
Me
H
9
11
11
H
Me
H
(Benzo[d]thiazol-2-ylsulfonyl)-1-phenylethanones
with
OMe
H
OMe 10
OMe 12
aldehydes in the presence of base, and intermolecular C–O
addition of carboxylic acids to arynes (Kumar et al. 2010;
Wang et al. 2008) and from 3-hydroxy-1-(2-hydro-
xylphenyl)-3-arylpropan-1-ones. (Dubrovskiy and Larock
2010) Herein, we have employed one-pot synthesis of fla-
vanones using anhydrous calcium chloride from O-
hydroxyacetophenone and substituted benzaldehyde.
OMe
H
H
OMe OMe OMe 11
12
Naphthyl flavanone
moderate yield. Aldehydes bearing substituent at ortho posi-
tion required more time for completion and suffered in terms
of yield. Aldehydes bearing electron withdrawing group like
nitro underwent smooth reaction in short time as compared to
unsubstitued aldehyde (6, 10 and 13). The nature of sub-
stituent and its position on the aromatic ring of the aldehyde
had effect on the reaction yield and time. Aldehydes bearing
substituents at para position underwent smooth reaction to
afford the corresponding flavanone in good yield, and also
naphthaldehyde underwent smooth transformation to afford
the corresponding flavanone in high yield.
As far as mechanism is concerned, we speculate that the
reaction proceeds via Schiff’s base formed with benzalde-
hyde in line with literature reports using iodine as catalyst
for the same one-pot reaction (Kavala et al. 2012). It seems
cyclization involving knocking off amino moiety from the
Mannich intermediate may play crucial role in determining
the rate and yield. Calcium chloride being very mild and
Results and discussion
Chemistry
The three-component Mannich reaction of aldehyde, amine
and acetophenone, an enolisable ketone, yields β-amino car-
bonyl compounds, and this transformation has been effected
by calcium chloride (Kulkarni et al. 2012), and we extend this
strategy to furnish flavanone under mild conditions. The fla-
vanone analogs 1–20 were synthesized by treating 2-acetyl
phenol, appropriate aldehyde and aniline with fused calcium
chloride in ethanol under reflux condition (Scheme 1).
As presented in Table 1, the reaction proceeded well with a
variety of substrates to yield the corresponding flavanones in

Med Chem Res
inexpensive makes this protocol attractive from synthetic
point of view, and also the protocol can be extended to acid/
base sensitive molecules of biological importance.
molecules with Quercetin in different concentrations (10,
25, 50 and 100 µM) are depicted in Fig. 2.
The results revealed that almost all flavanones exhibit
moderate to good activity in the potency range of 5.88–9.07
µM, as compared to Quercetin (5.01 0.02 µM). In parti-
cular, the trisubstituted 2, 3, 4-methoxy derivative 19 (5.88
0.03 µM) showed highest AR inhibition followed by
compound 2 (IC50 5.93 0.04 µM) whereas 2-methoxy
derivative 12 (9.07 02 µM) showed the lowest inhibitory
activity while the remaining flavanone derivatives showed
moderate AR inhibitory activity in the IC50 range of
6.09–7.89 µM concentration.
The drug likeness study
The drug likeness of the designed molecules have been
studied using quantitative structure activity relationship
module of the VLife MDS 4.3 and the major five properties
including molecular weight (MW), hydrogen-bond acceptor
atoms (HBA), hydrogen-bond donor atoms (HBD), rota-
table bond count (RBC), Clog P were calculated for the
synthesized molecules. It is obvious from the Table 2; the
designed molecules displayed acceptable Lipinski para-
meters with good drug likeness.
Docking analysis
In order to gain some insight about the binding mode of the
designed inhibitors, the docking analysis of newly synthe-
sized analogs in the active site of aldoreductase enzyme
were carried out using the enzyme AR (protein data base
(PDB): 1AH0). Docking of the flavones derivatives with the
active site of the enzyme AR was performed using grip-
based docking simulation in biopredicta module of Vlife
MDS 4.3, wherein rigid docking is carried out by keeping
protein structure rigid with flexible ligand. All the designed
molecules were docked into the active site of the enzyme
AR, and the results indicated that all the molecules fit well
into the active site of the enzyme with multiple interactions
as shown in (Table 4). Among the flavanones studied, 19
Inhibition of AR
All compounds were tested for their ability to inhibit AR by
measuring the decrease in NADPH absorption at 340 nm
over a 4-min period on an Ultrospec_2100pro UV/Visible
spectrophotometer with Quercetin (well known ARI) as
reference, and the results are summarized in Table 3 and
Fig. 1, and comparative dose response curve of all
Table 2 Physical properties (Lipinski parameters) of compounds 1–
20
Compounds
MW
HBA
HBD
RBC
Clogp
(2-(3,4,5-trimethoxyphenyl) chroman-4-one),
2
(2-(4-
1
224.259
258.704
238.286
254.285
303.155
269.257
242.25
1
1
1
2
1
4
2
2
2
4
1
2
4
1
1
1
3
3
4
1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1
1
2
3
1
2
1
3
1
2
1
3
2
1
3
3
5
5
7
1
3.19
chlorophenyl) chroman-4-one), 4 (2-(4-methoxyphenyl)
chroman-4-one) with potent ARI inhibition in the range of
98% under in vitro studies displayed high affinity binding
with the enzyme as shown in (Table 4). 2-(3,4,5-tri-
methoxyphenyl) chroman-4-one (19) showed significant
interactions with the AR enzymes via the formation of
2
3.809
3.471
3.153
3.986
3.062
3.292
3.153
3.292
3.062
3.809
3.153
3.062
4.428
3.752
3.752
3.116
3.116
3.079
4.476
3
4
5
6
7
Table 3 In vitro ARI activity of flavanone derivatives
8
254.285
242.25
IC50 (µM)a
Compound
IC50 (µM)a
9
Compound
10
11
12
13
14
15
16
17
18
19
20
269.257
258.704
254.285
269.257
293.149
252.313
252.313
284.312
284.312
314.338
274.319
1
6.67 0.02
5.93 0.04
6.12 0.02
6.09 0.01
6.37 0.01
8.73 0.05
7.89 0.04
6.94 0.02
7.23 0.03
8.23 0.03
5.01 0.02
11
12
13
14
15
16
17
18
19
20
6.24 0.04
9.07 0.03
7.36 0.01
7.86 0.01
6.56 0.04
6.22 0.02
6.76 0.02
6.84 0.03
5.88 0.03
7.12 0.02
2
3
4
5
6
7
8
9
10
Quercetinb
MW molecular weight, Clog P calculated logarithm of the octanole:
water partition coefficient, HBA hydrogen-bond acceptor atoms, HBD
hydrogen-bond donor atoms, RBC rotatable bond count
a
IC50 values are expressed as mean SD for three determinations
Quercetin used as positive control
b

Med Chem Res
Fig. 1 Inhibition of AR against bovine lens AR by compounds (1–20) comparing with those of Quercetin. The results are expressed as mean SD
values from three independent experiments
120
100
80
60
40
20
0
Compound 10µM
Compound 25µM
Compound 50µM
Compound 100µM
Molecule Code
Fig. 2 Concentration-dependent AR inhibitory activity of synthesized derivatives
hydrogen bond interaction between CH2 and NH of Trp20
with a distance of 2.6 Å, while 3,4,5-trimethoxyphenyl ring
showed aromatic interaction with Trp219, Trp20 with dis-
tance of 4.4 Å and 4.6 Å, and hydrophobic interaction with
Leu 300. 2-(4-chlorophenyl) chroman-4-one showed
hydrogen bond interaction between C=O and NH of
Trp111 with distance of 1.8 Å and aromatic interaction
between phenyl ring of benzpyran with His110 (5.4 Å), Trp
20(5 Å), Trp 79(4.9 Å) and 4-chlorophenyl ring sowed
aromatic interaction with Trp219(5.4 Å) and Phe 322 (4.3
Å) and hydrophobic interaction with Leu 300. 2-(4-meth-
oxyphenyl) chroman-4-one showed hydrogen bond inter-
action between O of chroman-4-one and NH of with Trp20
with distance of 2.2 Å and 4-methoxyphenyl ring showed
aromatic interactions with Trp20(4.3 Å), Trp219 (4.6 Å),
hydrophobic interaction with Leu 300 (Fig. 3). It is worth
mentioning that the binding pocket can accommodate fla-
vones bearing different substituent with ease (Table 4) and
hence allow modification of substituent to enhance potency.
Pharmacophore Modeling studies
Pharmacophore modeling of the designed set of the inhi-
bitors were carried out to identify the basic framework of
the molecules that regulate their pharmacodynamic poten-
tial. Pharmacophore identification studies showed involve-
ment of two aromatic features and one hydrogen bond
accepter as three important features. The two aromatic
features are separated by the 6.741 Å, while hydrogen bond
acceptor is separated from the aromatic features by 3.9 and
5.5 Å, respectively, as shown in Figs. 4 and 5. The two
aromatic features play vital role in the observed biological
activity of the molecules as the hydrophobic pocket of
enzyme comprising of Trp111, Leu300 and Phe122 attri-
bute to significant binding and hence higher activity. The
proposed pharmacophore hypothesis would be useful
for the design of new ARIs of therapeutic significance.
(Figs. 4 and 5).

Med Chem Res
Table 4 Key interactions of the best docked conformations of the designed derivatives in the active site of aldose reducatse
Mol. No.
1
Type of interaction
Amino acid
Binding energy
Hydrogen bond interaction
Aromatic interaction
TRP111
−47.33
PHE122, TRP20, TRP 79
2
3
4
5
Hydrogen bond interaction
Aromatic interaction
TRP111
−47.50
−50.91
−55.57
−54.03
HIS110,PHE122, TRP20, TRP 79
Hydrophobic interaction
Hydrogen bond interaction
Aromatic interaction
LEU300
TRP111
HIS110,PHE122, TRP20, TRP 79
Hydrophobic interaction
Hydrogen bond interaction
Aromatic interaction
LEU300
TRP111
HIS110,PHE122, TRP20, TRP 79, TRP219
Hydrophobic interaction
Hydrogen bond interaction
Aromatic interaction
LEU300
TRP111
HIS110,PHE122, TRP20, TRP79, TRP219
Hydrophobic interaction
Hydrogen bond interaction
Aromatic interaction
LEU300
6
7
TRP20
−48.80
−48.21
TRP20, TRP219
Hydrogen bond interaction
Aromatic interaction
TRP20
TRP20, TRP219
Hydrophobic interaction
Hydrogen bond interaction
Aromatic interaction
LEU300, CYS298
8
TRP111
−55.13
−60.51
−53.59
−55.68
−50
HIS110, PHE122, TRP20, TRP79, TRP219
Hydrophobic interaction
Hydrogen bond interaction
Aromatic interaction
LEU300, SER302
9
TRP20
TRP20
Hydrophobic interaction
Hydrogen bond interaction
Aromatic interaction
LEU300, VAL47, TRP20
10
11
12
13
14
15
TRP20
TRP20
Hydrophobic interaction
Hydrogen bond interaction
Aromatic interaction
LEU300, VAL47, TRP20
TRP20
TRP20
Hydrophobic interaction
Hydrogen bond interaction
Aromatic interaction
LEU300, VAL47, TRP20, CYS298
TRP111
HIS110,PHE122, TRP20, TRP 79, TRP219
Hydrophobic interaction
Hydrogen bond interaction
Aromatic interaction
LEU300
TRP111
−55.13
−53.51
−51.11
HIS110,PHE122, TRP20, TRP 79, TRP219
Hydrophobic interaction
Hydrogen bond interaction
Aromatic interaction
LEU300
TRP111
PHE122, TRP219
LEU300, SER302
TRP20
Hydrophobic interaction
Hydrogen bond interaction
Aromatic interaction
TRP20
Hydrophobic interaction
Aromatic interaction
LEU300,CYS298
TRP20
16
17
−36.47
−50.21
Hydrogen bond interaction
Aromatic interaction
TRP111, SER302
PHE122, TRP219, TYR48, TRP20
LEU300, SER302
Hydrophobic interaction

Med Chem Res
Table 4 continued
Mol. No.
Type of interaction
Amino acid
Binding energy
18
19
20
Hydrogen bond interaction
Aromatic interaction
TRP111
−53.13
PHE122, TRP219, TYR48, TRP20
Hydrophobic interaction
Hydrogen bond interaction
Aromatic interaction
LEU300
TRP20
−50.46
−48.68
TRP219, TRP20
LEU300
Hydrophobic interaction
Hydrogen bond interaction
Aromatic interaction
TRP111
TRP219, TRP20, HIS110
LEU300
Hydrophobic interaction
Fig. 3 Docking poses for some most active compounds (inhibitors
having interactions with amino acids are colored in pink. Hydrogen
bond interactions: green color, aromatic interaction: yellow color).
a Figure showing binding mode of molecule 2 with AR. b Figure
showing binding mode of molecule 2 with AR. c Figure showing
binding mode of molecule 19 with AR
●
Conclusion
The IC50 values of flavanones 2, 4 and 19 were found to
be comparable to that of standard quercetin.
●
●
Molecular docking and biological activity of developed
The present work describes a facile route to flavanones
inhibitors indicated electron withdrawing substitutions
on phenyl ring might infusing AR inhibition potential.
from readily available starting materials and their
development as ARIs.

Med Chem Res
Fig. 4 Selected pharmacophoric
hypotheses of flavones for
aldoreductase inhibitory activity
E. Merck silica gel 60F glass plates, and E. Merck silica gel
(230–400 mesh) was used in flash chromatography separa-
tions. Chemical shifts were reported in parts per million (δ)
using trimethyl silane as internal standard, and coupling
constants were expressed in hertz. The melting points were
determined in open capillaries.
General procedure for the synthesis of compounds 1–20
To a mixture of substituted benzaldehyde (1.0 mmol), ani-
line (1.5 mmol), 2-hydroxyacetophenone (1.2 mmol) in
ethanol (1.0 mL), fused calcium chloride (CaCl2 2 mmol)
was added, and the reaction mixture was subjected to reflux
for 7–12 h. The progress of the reaction was monitored by
TLC. After completion of the reaction (monitored by TLC),
water work-up followed by extraction with methylene
chloride and concentration of the extracts dried over sodium
sulphate afforded the crude product. The products were
purified either by recrystallization from hexane:ethyl acetate
or by short flash chromatography on silica gel using pet-
roleum ether: ethyl acetate (9:1) as eluent.
Fig. 5 Pharmacophoric feature of the synthesized inhibitor 19
●
Pharmacophore modeling-indicated derivatives with two
aromatic features and one hydrogen bond accepter will
act as ARIs.
●
Molecular docking studies reveal the mode of interac-
tions as well as binding with the enzyme. The proposed
pharmacophore model would facilitate design of new
ARIs of therapeutic significance.
2, 3-Dihydro-2-phenyl-4H-1-benzopyran-4-one (1)
White solid; yield: 92%; mp: 75–76 °C (Kigarashi et al.
1996); IR (KBr, cm−1): 3358, 3041, 1689 (C=O), 1453,
1294, 1167; H NMR (400 MHz, CDCl3): δ 2.90 (dd, J =
16.8, 2.8 Hz, 1H, Ha-3), 3.10 (dd, J = 16.8, 13.2 Hz, 1H,
Hb-3), 5.49 (dd, J = 13.2, 2.8 Hz, 1H, H-2), 7.06 (m, 2H,
ArH), 7.47 (m, 5H, ArH), 7.94 (dd, J = 8.4, 2.0 Hz, 1H,
ArH); 13C NMR (CDCl3, 100 MHz): δ 44.7 (C-3), 79.6 (C-
2), 118.1, 120.9, 121.6, 126.1, 127.0, 128.8, 128.9, 136.2,
138.7, 161.5 (Ar–C), 192.0 (C=O); EIMS (70 eV) m/z (rel
Experimental section
Chemistry
1
Solvents for extraction and chromatography were distilled
before use. All chemicals were purchased from Merck and
Sigma Aldrich, and used directly without any purification.
Analytical thin-layer chromatography was performed using

Med Chem Res
intensity, %): 224 (M+, 56), 223 (100), 147 (62), 120 (47),
104 (26), 92 (78), 78 (29), 63 (22); anal. calcd for
C15H12O2: C, 80.34; H, 5.39. Found: C, 80.02; H, 5.47.
(16), 77 (5), 57 (8); anal. calcd for C16H14O3: C, 75.57; H,
5.55 found: C, 75.60; H, 5.58.
2, 3-Dihydro-2-(4-bromophenyl)-4H-1-benzopyran-4-one (5)
2, 3-Dihydro-2-(4-chlorophenyl)-4H-1-benzopyran-4-one (2)
Pale yellow solid; yield: 90%; mp: 116–117 °C, (Choudary
et al. 2005); IR (KBr, cm−1): 3358, 3065, 2898, 1917, 1687
(C=O), 1597, 1462, 1410, 1367, 1300, 1222, 1151, 1066,
1013; 1HNMR (400 MHz, CDCl3): δ 2.84(dd, J = 16.8, 3.2
Hz, 1H, Ha-3), 3.03 (dd, J = 16.8, 13.2 Hz, 1H, Hb-3), 5.45
(dd, J = 13.2, 2.8 Hz, 1H, H-2), 7.05 (m, 2H, ArH), 7.35
(dd, J = 8.4, 1.6 Hz, 2H, ArH), 7.55 (td, J = 8.4, 1.6 Hz,
1H, ArH), 7.56 (dd, J = 8.4, 2.0 Hz, 2H, ArH), 7.95 (dd, J
= 8.0, 2.0 Hz, 1H, ArH); 13C NMR (100 MHz, CDCl3): δ
44.6 (C-3), 78.5 (C-2), 118.2, 120.8, 121.7, 122.6, 127.3,
127.6, 132.2, 136.1, 137.4, 161.2 (Ar–C), 191.3 (C=O);
EIMS (70 eV) m/z (rel intensity, %): 303 (M+, 45), 302
(26), 301 (39), 223 (49), 147 (88), 120 (62), 103 (72), 93
(100); anal.calcd for C15H11BrO2: C, 59.43; H, 3.66.
Found: C, 59.39; H, 3.69.
White solid; yield: 91%; mp: 85–86 °C (Chimenti et al.
2010); IR (KBr, cm−1): 3366, 3068, 2958, 2899, 1945,
1
1694(C=O), 1599, 1462, 1300, 1221; H NMR (400 MHz,
CDCl3): δ 2.87 (dd, J = 17.2, 3.2 Hz, 1H, Ha-3), 3.03 (dd, J
= 17.2, 13.2 Hz, 1H, Hb-3), 5.45 (dd, J = 13.2, 3.2 Hz, 1H,
H-2), 7.05 (m, 2H, ArH), 7.45 (m, 4H, ArH), 7.55 (td, J =
8.4, 1.6 Hz, 1H, ArH), 7.95 (dd, J = 8.0, 2.0 Hz, 1H, ArH);
13C NMR (CDCl3, 100 MHz): δ 44.5 (C-3), 78.7 (C-2),
118.3, 121.0, 121.6, 127.3, 127.6, 129.3, 134.4, 136.5,
137.3, 161.2 (Ar–C), 191.4 (C=O); EIMS (70 eV) m/z (rel
intensity, %): 258 (M+, 71), 257 (100), 223 (29), 147 (66),
138 (37), 120 (67), 103 (37), 92 (75); anal. calcd for
C15H11ClO2: C, 69.64; H, 4.29. Found: C, 69.55; H, 4.32.
2, 3-Dihydro-2-(4-methylphenyl)-4H-1-benzopyran-4-one (3)
2, 3-Dihydro-2-(4-nitrophenyl)-4H-1-benzopyran-4-one (6)
White solid; yield: 88%; mp: 81–83 °C (Lee et al. 2007); IR
(KBr, cm−1): 3362, 3034, 2974, 2892, 1955, 1691(C=O),
1603, 1514, 1460, 1301, 1232, 1147, 1067; H NMR (400
White solid; yield: 85%; mp: 120–121 °C, (Bhatia et al.
1968); IR (KBr, cm−1): 3433, 2894, 1694 (C=O), 1603,
1530, 1462, 1333, 1223, 1118, 1067; H NMR (400 MHz,
1
1
MHz, CDCl3): δ 2.36 (s, 3H, CH3), 2.85 (dd, J = 16.84,
2.80 Hz, 1H, Ha-3), 3.07 (dd, J = 16.84, 13.32 Hz, 1H, Hb-
3), 5.45 (dd, J = 13.32, 2.80 Hz, 1H, H-2), 7.00–7.06 (m,
2H, ArH), 7.25 (d, 2H, J = 7.81 Hz, ArH), 7.37 (d, 2H, J =
7.81 Hz, ArH), 7.50 (m, 1H, ArH), 7.92 (dd, 1H, J = 8.08,
1.76 Hz, ArH); 13C NMR (100 MHz, CDCl3): δ 21.13
(CH3), 44.50 (C-3), 79.47 (C-2), 118.10, 120.90, 121.45,
126.15, 127.02, 129.45, 135.72, 136.10, 138.65, 161.60
(Ar–C), 192.04 (C=O); EIMS m/z (relative intensity): 238
(M+, 29), 181 (19), 141 (33), 139 (100), 118 (27); Anal.
calcd for C16H14O2: C, 80.65; H, 5.92 found: C, 80.67; H,
5.95.
CDCl3): δ 2.98 (dd, J = 16.8, 3.6 Hz, 1H, Ha-3), 3.06 (dd, J
= 16.8, 12.4Hz, 1H, Hb-3), 5.65 (dd, J = 12.4, 3.6 Hz, 1H,
H-2), 7.12 (m, 2H, ArH), 7.55 (td, J = 8.4, 1.6 Hz, 1H,
ArH), 7.68 (dd, J = 8.4, 2.0 Hz, 2H, ArH), 7.94 (dd, J =
8.0, 2.0 Hz, 1H, ArH), 8.33 (dd, J = 8.8, 2.0 Hz, 2H, ArH);
13C NMR (100 MHz, CDCl3): δ 44.5 (C-3), 78.4 (C-2),
118.1, 120.8, 122.3, 124.2, 126.7, 127.3, 136.4, 136.2,
148.6, 160.7 (Ar–C), 190.6 (C=O); EIMS (70 eV) m/z (rel
intensity, %): 269 (M+, 33), 268 (49), 252 (18), 147 (91),
121 (20), 120 (53), 93 (100), 64 (13); anal. calcd for
C15H11NO4: C, 66.91; H, 4.12; N, 5.20. Found: C, 66.83;
H, 4.15; N, 5.13.
2, 3-Dihydro-2-(4-methoxyphenyl)-4H-1-benzopyran-4-one (4)
2, 3-Dihydro-2-(4-flurophenyl)-4H-1-benzopyran-4-one (7)
Pale yellow solid; yield: 89%; mp: 87–88 °C, (Akcok and
Çağır 2010); IR (KBr, cm−1): 3007, 2930, 2836, 1939,
1692(C=O), 1605, 1507, 1474, 1304, 1251, 1166; 1H NMR
(400 MHz, CDCl3): δ 2.85 (dd, J = 16.84, 2.80 Hz, 1H, Ha-
3), 3.10 (dd, J = 16.84, 13.32 Hz, 1H, Hb-3), 3.83 (s, 3H,
OCH3), 5.43 (dd, J = 13.32, 2.80 Hz, 1H, H-2), 6.96 (d, J
= 6.88 Hz, 2H, ArH), 7.03–7.07 (m, 2H, ArH), 7.41 (d, J =
6.88 Hz, 2H, ArH), 7.48–7.50 (m, 1H, ArH), 7.92 (dd, J =
8.44, 1.64 Hz, 1H, ArH); 13C NMR (100 MHz, CDCl3): δ
44.36 (C-3), 55.29 (OCH3), 79.28 (C-2), 114.15, 118.05,
120.85, 121.43, 126.95, 127.66, 130.74, 136.06, 159.92,
161.56 (Ar–C), 192.15 (C=O); MS m/z (relative intensity):
254 (M+, 63), 139 (13), 134 (100), 121 (28), 119 (23), 91
White solid; yield: 86%; mp: 79–80 °C, (Kigarashi et al.
1996); IR (KBr, cm−1): 3348, 3062, 2889, 1915, 1694
(C=O), 1579, 1448, 1428, 1360, 1308, 1227, 1155, 1067,
1
1012, 904, 865, 749, 639; H NMR (400 MHz, CDCl3): δ
2.87 (dd, J = 16.8, 2.8 Hz, 1H, Ha-3), 3.09 (dd, J = 16.8,
13.2 Hz, 1H, Hb-3), 5.46 (dd, J = 13.2, 2.8 Hz, 1H, H-2),
7.13 (m, 4H, ArH), 7.46 (m, 2H, ArH), 7.53 (td, J = 8.4,
1.6 Hz, 1H, ArH), 7.95 (dd, J = 8.0, 2.0 Hz, 1H, ArH); 13C
NMR (100 MHz, CDCl3): δ 44.8 (C-3), 78.6 (C-2), 115.9,
118.3, 120.5, 121.3, 127.4, 128.6, 134.4, 136.2, 161.3,
162.1 (Ar–C), 192.8(C=O); EIMS (70 eV) m/z
(rel intensity, %): 242 (M+, 56), 241 (87), 147 (43), 122

Med Chem Res
(41), 121 (36), 120 (67), 2 (100), 63 (23); anal. calcd for
C15H11FO2: C, 74.37; H, 4.58. Found: C, 74.35; H, 4.60.
(49), 252(18), 147 (91), 121 (20), 120 (53), 93 (100), 64
(13); anal. calcd for C15H11NO4: C, 66.91; H, 4.12; N, 5.20.
Found: C, 66.87; H, 4.15; N, 5.16.
2, 3-Dihydro-2-(2-methoxyphenyl)-4H-1-benzopyran-4-one (8)
2, 3-Dihydro-2-(2,-chlorophenyl)-4H-1-benzopyran-4-one
White solid; yield: 82%; mp: 113–114 °C, (Haraguchi et al.
(11)
1996a); IR (KBr, cm−1): 3025, 2928, 2846, 1958, 1692
1
(C=O), 1615, 1524, 1470, 1315, 1250, 1165; H NMR
Pale yellow solid; yield: 70%; mp: 97–98 °C; IR (KBr,
cm−1): 3265, 3068, 2958, 2899, 1945, 1693 (C=O), 1599,
1462, 1320, 1300, 1221, 1112, 1066; H NMR (400 MHz,
(400 MHz, CDCl3): δ 2.92–3.00 (m, 2H, Ha-b), 3.84 (s, 3H,
OCH3), 5.87 (dd, J = 13.40, 3.96 Hz, 1H, H-2), 6.94 (d, J
= 8.3 Hz, 1H), 7.08–7.03 (m, 3H, ArH), 7.37–7.32 (m, 1H,
ArH), 7.52–7.48 (m, 1H, ArH), 7.63 (dd, J = 0.8, 7.5 Hz,
1H, ArH), 7.94 (dd, J = 1.36, 7.8 Hz, 1H, ArH); 13C NMR
(100 MHz, CDCl3): δ 43.6 (C-3), 55.7 (OCH3), 74.3 (C-2),
111.3, 118.2, 121.4, 121.5, 121.7, 126.4, 127.8, 129.5,
136.3, 156.2, 162.4 (Ar–C), 192.1(C=O); MS m/z (relative
intensity, %): 254 (M+, 39), 223 (100), 134 (25), 119 (66),
91 (52), 77 (16), 59 (49); anal. calcd for C16H14O3: C,
75.57; H, 5.55. Found: C, 75.60; H, 5.58.
1
CDCl3): δ 2.89 (dd, 1H, J = 16.88, 13.12 Hz, Ha-3), 3.22
(dd, 1H, J = 16.92, 2.56 Hz, Hb-3), 6.05 (dd, 1H, J =
13.12, 2.66 Hz, H-2), 7.03 (d, 1H, J = 8.0 Hz, ArH),
7.12–7.09 (m, 1H, ArH), 7.60–7.51 (m, 1H, ArH), 7.75 (m,
1H, ArH), 7.95 (dd, 1H, J = 7.80, 1.64 Hz, ArH), 8.03 (d,
1H , J = 8.20 Hz, ArH), 8.08 (dd, 1H, J = 8.20 Hz, 1.0 Hz,
ArH); 13C NMR (100 MHz, CDCl3): δ 41.1 (C-3), 76.3 (C-
2), 117.4, 121.4, 121.7, 127.2, 127.6, 128.8, 130.5, 133.1,
133.8, 134.7, 135.7, 160.4 (Ar–C), 191.2 (C=O); MS m/z
(relative intensity): 258.04 (100.0%), 260.04 (32.0%),
259.05 (16.4%), 261.05 (5.4%), 260.05 (1.7%); anal. calcd
for C15H11ClO2: C, 69.64; H, 4.29. Found: C, 69.60; H,
4.32.
2, 3-Dihydro-2-(2-fluorophenyl)-4H-1-benzopyran-4-one (9)
Yellow solid; yield: 76%; mp: 147–148 °C, (Bhatia et al.
1968); IR (KBr, cm−1): 3301, 2989, 2872, 1948, 1692
(C=O), 1584, 1432, 1408, 1378, 1348, 1220, 1187, 1057,
2, 3-Dihydro-2-(3-methoxyphenyl)-4H-1-benzopyran-4-one
(12)
1
1002; H NMR (400 MHz, CDCl3): δ 2.90 (dd, 1H, J =
16.88, 3.08 Hz, Ha-3), 3.06 (dd, 1H, J = 16.88, 13.24 Hz,
Hb-3), 5.78 (dd, 1H, J = 13.24, 2.96 Hz, H-2), 7.13–7.02
(m, 3H, ArH), 7.25–7.22 (m, 1H, ArH), 7.39–7.34 (m, 1H,
ArH), 7.53–7.49 (m, 1H, ArH), 7.72–7.64 (m, 1H, ArH),
7.96 (dd, 1H, J = 8.56, 1.0 Hz, ArH); 13C NMR (100 MHz,
CDCl3): δ 43.71 (C-3), 77.3 (C-2), 115.8, 118.4, 122.3,
122.7, 126.4, 126.3, 127.5, 130.6, 136.3, 159.7, 161.6
(Ar–C), 191.75 (C=O); EIMS (70 eV) m/z (rel intensity,
%): 242 (M+, 56), 241 (87), 147 (43), 122 (41), 121 (36),
120 (67), 92 (100), 63 (23); anal.calcd for C15H11FO2: C,
74.37; H, 4.58. Found: C, 74.39; H, 4.63.
White solid; yield: 74%; mp: 110–112 °C, (Akcok and
Çağır 2010); IR (KBr, cm−1): 3012, 2928, 2815, 1930,
1691 (C=O), 1568, 1470, 1346, 1267, 1156, 978, 852, 738,
1
647; H NMR (400 MHz, CDCl3): δ 2.85 (dd, 1H, J =
16.88, 2.96 Hz, Ha-3), 3.07 (dd, 1H, J = 16.88, 13.28 Hz,
Hb-3), 3.85 (s, 3H, OCH3), 5.46 (dd, 1H, J = 13.28, 2.40
Hz, H-2), 6.95–6.92 (m, 1H, ArH), 7.09–7.06 (m, 4H,
ArH), 7.37 (t, 1H, J = 8.4 Hz, ArH), 7.55–7.51 (m, 1H,
ArH), 7.96 (dd, 1H, J = 8.24, 1.64 Hz, ArH); 13C NMR
(100 MHz, CDCl3): δ 44.36 (C-3), 55.30 (OCH3), 79.29 (C-
2), 114.18, 118.10, 120.84, 121.47, 126.93, 127.64, 130.75,
136.04, 159.94, 161.53 (Ar–C), 192.14 (C=O); MS m/z
(relative intensity): 254 (M+, 63), 147 (35), 134 (100), 91
(16), 77 (5), 57 (8); anal. calcd for C16H14O3: C, 75.57; H,
5.55. Found: C, 75.59; H, 5.62.
2, 3-Dihydro-2-(2-nitrophenyl)-4H-1-benzopyran-4-one (10)
White solid; yield: 80%; mp: 121–122 °C, (Cabrera et al.
2007); IR (KBr, cm−1): 3428, 2889, 1691 (C=O), 1615,
1542, 1460, 1343, 1232, 1181, 1062, 932, 872, 736, 642;
1H NMR (400 MHz, CDCl3): δ 2.91 (dd, 1H, J = 16.88,
13.12 Hz, Ha-3), 3.23 (dd, 1H, J = 16.92, 2.56 Hz, Hb-3),
6.06 (dd, 1H, J = 13.12, 2.66 Hz, H-2), 7.03 (d, 1H, J = 8.0
Hz), 7.12–7.09 (m, 1H, ArH), 7.60–7.51 (m, 1H, ArH),
7.75 (m, 1H, ArH), 7.95 (dd, 1H, J = 7.8, 1.64 Hz, ArH),
8.03 (d, 1H, J = 8.20 Hz, ArH), 8.08 (dd, 1H, J = 8.20 Hz,
1.0 Hz, ArH); 13C NMR (100 MHz, CDCl3): δ 44.8 (C-3),
75.6 (C-2), 118.3, 121.5, 122.4, 125.2, 127.6, 128.3, 129.7,
134.1, 134.7, 136.7, 147.8, 161.4 (Ar–C), 190.7(C=O);
EIMS (70 eV) m/z (rel intensity, %): 269 (M+, 33), 268
2, 3-Dihydro-2-(3-nitrophenyl)-4H-1-benzopyran-4-one (13)
White solid; yield: 80%; mp: 145–146 °C, (Po-Yuan et al.
2011); IR (KBr, cm−1): 3426, 2892, 1693 (C=O), 1626,
1
1548, 1476, 1348, 1235, 1183, 1071; H NMR (400 MHz,
CDCl3): δ 2.95 (dd, 1H, J = 16.8, 3.2 Hz, Ha-3), 3.06 (dd,
1H, J = 16.8, 12.8 Hz, Hb-3), 5.63 (dd, 1H, J = 12.8, 3.2
Hz, H-2), 7.13 (m, 2H, ArH), 7.55 (td, 1H, J = 8.4, 1.6 Hz,
ArH), 7.66 (t, 1H, J = 8.0 Hz, ArH), 7.84 (m, 1H, ArH),
7.92 (dd, 1H, J = 8.0, 1.6 Hz, ArH), 8.22 (m, 1H, ArH),

Med Chem Res
8.45 (t, 1H, J = 2.0 Hz, ArH); 13C NMR (100 MHz,
CDCl3): δ 44.4 (C-3), 78.4 (C-2), 118.3, 120.8, 121.4,
122.7, 123.3, 127.7, 129.4, 131.5, 136.2, 140.3, 148.7,
160.3 (Ar–C), 190.2 (C=O); EIMS (70 eV) m/z (rel inten-
sity, %): 269 (M+, 35), 268 (39), 147 (100), 121 (33), 120
(66), 92 (99), 64 (19), 63 (23); anal. calcd for C15H11NO4:
C, 66.91; H, 4.12; N, 5.20. Found: C, 66.81; H, 4.22; N,
5.18.
5.58 (dd, 1H, J = 13.32 Hz, 2.80 Hz, H-2), 7.05–7.15 (m,
2H, ArH), 7.04–7.08 (d, 2H, ArH), 7.23 (s, 1H, ArH), 7.43
(m, 1H, ArH), 7.88 (dd, 1H, J = 8.05, 1.76 Hz, ArH); 13C
NMR (100 MHz, CDCl3): δ 18.6 (CH3), 19.3 (CH3), 41.7
(C-3), 81.3 (C-2), 117.8, 120.2, 121.3, 122.8, 127.6, 128.9,
131.2, 133.7, 135.4, 135.8, 136.9, 158.7 (Ar–C), 189.2
(C=O); MS m/z (relative intensity, %): 252.12 (100.0),
253.12 (18.6), 254.12 (2.0%). anal. calcd for C17H16O2: C,
80.93; H, 6.39. Found C, 80.90; H, 6.47.
2, 3-Dihydro-2-(2,4-chlorophenyl)-4H-1-benzopyran-4-one
(14)
2, 3-Dihydro-2-(2, 5-dimethoxyphenyl)-4H-1-benzopyran-
4-one (17)
White solid; yield: 83%; mp: 98–99 °C; IR (KBr, cm−1):
3328, 3128, 2970, 2865, 1940, 1692(C=O), 1585, 1460,
White solid; yield: 75%; mp: 127–128 °C; IR (KBr, cm−1):
3020, 2930, 2862, 1960, 1692 (C=O), 1600, 1558, 1465,
1
1300, 1205, 1110, 1048; H NMR (400 MHz, CDCl3): δ
1
2.90 (dd, 1H, J = 16.8, 3.0 Hz, H-3a), 3.10 (dd, 1H, J =
16.8, 13.2 Hz, H-3b), 5.41 (dd, 1H, J = 13.2, 3.0 Hz, H-2),
7.11–7.07 (2H, m, ArH), 7.21 (s, 1H, ArH), 7.42 (d, 1H,
ArH), 7.55 (dd 1H, J = 7.8, 2.4 Hz, ArH), 7.61 (d, 1H,
ArH), 7.96 (d, 1H, J = 8.1, 2.4 Hz, ArH); 13C NMR (100
MHz, CDCl3): δ 41.1 (C-3), 76.3 (C-2), 117.4, 121.4,
121.7, 127.2, 127.6, 128.8, 130.5, 133.1, 133.8, 134.7,
135.7, 160.4 (Ar–C), 191.2 (C=O); MS m/z (relative
intensity, %): 292.01 (100.0), 294.00 (63.9), 293.01 (16.4),
295.01 (10.6), 296.00 (10.2), 297.00 (1.7), 294.01 (1.7),
296.01 (1.1); anal. calcd for C15H10Cl2O2: C, 61.46; H,
3.44. Found: C, 61.43; H, 3.47.
1378, 1260, 1189, 1038; H NMR (400 MHz, CDCl3): δ
3.18 (dd, 1H, J = 16.65, 2.85 Hz, Ha-3), 3.35 (dd, 1H, J =
16.85, 13.33 Hz, Hb-3), 3.78 (s, 6H, 2OMe), 5.48 (dd, 1H,
J = 13.33, 2.85 Hz, H-2), 6.62–6.64 (d, 2H, ArH),
7.02–7.08 (m, 2H, ArH), 7.12 (s, 1H, ArH), 7.38 (m, 1H,
ArH), 7.57 (dd, 1H, J = 8.05, 1.75 Hz, ArH); 13C NMR
(100 MHz, CDCl3): δ 42.7 (C-3), 54.7 (OCH3), 55.2
(OCH3), 79.8 (C-2), 109.7, 111.5, 113.6, 118.7, 122.3,
123.8, 127.6, 128.7, 133.4, 148.3, 152.7, 161.3 (Ar–C),
191.2 (C=O); MS m/z (relative intensity, %): 284.10
(100.0), 285.11 (18.7), 286.11 (2.5); anal. calcd for
C17H16O4: C, 71.82; H, 5.67. Found C, 71.85; H, 5. 70.
2, 3-Dihydro-2-(2,4-dimethylphenyl)-4H-1-benzopyran-4-
2, 3-Dihydro-2-(3, 5-dimethoxyphenyl)-4H-1-benzopyran-
one (15)
4-one (18)
Pale yellow solid; yield: 79%; mp: 137–138 °C; IR (KBr,
cm−1): 3345, 3028, 2895, 2863, 1922, 1691 (C=O), 1601,
1563, 1508, 1479, 1323, 1256, 1145; H NMR (400 MHz,
White solid; yield: 80%; mp: 87–88 °C; IR (KBr, cm−1):
3326, 3078, 2868, 1975, 1691 (C=O), 1598, 1525, 1469,
1
1
1335, 1268, 1192, 1046; H NMR (400 MHz, CDCl3): δ
CDCl3): δ 2.35 (s, 6H, 2CH3), 2.84 (dd, 1H, J = 16.84,
2.80 Hz, Ha-3), 3.05 (dd, 1H, J = 16.84, 13.32 Hz, Hb-3),
5.43 (dd, 1H, J = 13.32, 2.80 Hz, H-2), 7.02–7.05 (m, 2H,
ArH), 7.25 (d, 1H, J = 7.81 Hz, ArH), 7.50 (m, 1H, ArH);
13C NMR (100 MHz, CDCl3): δ 19.8 (CH3), 21.4 (CH3),
43.2 (C-3), 80.7 (C-2), 118.7, 120.2, 121.6, 126.8, 127.8,
131.3, 133.1, 134.6, 136.7, 137.3, 160.3 (Ar–C), 189.2
(C=O); MS m/z (relative intensity, %): 252.12 (100.0),
253.12 (18.6), 254.12 (2.0); anal. calcd for C17H16O2: C,
80.93; H, 6.39. Found C, 80.95; H, 6.42.
3.20 (dd, 1H, J = 16.85, 2.85 Hz, Ha-3), 3.32 (dd, 1H,
J = 16.85, 13.33 Hz, Hb-3), 3.70 (s, 6H, 2OMe), 5.47
(dd, 1H, J = 13.33, 2.85 Hz, H-2), 6.43 (s, 1H, ArH), 6.69
(s, 2H, ArH), 7.01–7.05 (m, 2H, ArH), 7.32 (m, 1H, ArH),
7.55 (dd, 1H, J = 8.05, 1.75 Hz, ArH); 13C NMR (100
MHz, CDCl3): δ 41.7 (C-3), 54.9 (OCH3), 84.3 (C-2),
98.5, 101.6, 117.8, 120.2, 122.3, 127.8, 132.9, 141.6,
159.2, 162.1 (Ar–C), 190.1 (C=O); MS m/z (relative
intensity, %): 284.10 (100.0), 285.11 (18.7), 286.11 (2.5);
anal. calcd for C17H16O4: C, 71.82; H, 5.67. Found C,
71.87; H, 5. 63.
2, 3-Dihydro-2-(3, 4-dimethylphenyl)-4H-1-benzopyran-4-
one (16)
2, 3-Dihydro-2-(3, 4, 5-trimethoxynitrophenyl)-4H-1-
benzopyran-4-one (19)
Pale yellow solid; yield: 78%; mp: 112–113 °C; IR (KBr,
cm−1): 3256, 3178, 2945, 2872, 1950, 1690 (C=O), 1612,
1568, 1463, 1319, 1236, 1148, 1058; H NMR (400 MHz,
CDCl3): δ 2.39 (s, 6H, 2CH3), 3.25 (dd, 1H, J = 16.65,
2.80 Hz, Ha-3), 3.38 (dd, 1H, J = 16.84, 13.32 Hz, Hb-3),
White solid; yield: 78%; mp: 132–134 °C; IR (KBr, cm−1):
3006, 2936, 2832, 1940, 1689 (C=O), 1605, 1538, 1442,
1373, 1268, 1154, 1025; H NMR (400 MHz, CDCl3): δ
2.90 (dd, 1H, J = 16.8, 3.0 Hz, Ha-3), 3.10 (dd, 1H, J =
1
1

Med Chem Res
16.8, 13.2 Hz, Hb-3), 3.85 (s, 3H, 4’-OMe), 3.90 (s, 6H, 3’,
5’-2OMe), 5.43 (dd, 1H, J = 13.2, 3.0 Hz, H-2), 6.73 (s, 2H,
ArH), 7.07–7.11 (m, 2H, ArH), 7.54 (dd, 1H, J = 7.8, 2.4
Hz, ArH), 7.95 (d, 1H, J = 8.1, 2.4 Hz, ArH); 13C NMR
Docking analysis
In order to investigate the binding mode of the flavanone
derivatives, grip-based molecular docking analysis of the
synthesized derivatives was carried out using biopredicta
module of the Vlife MDS 4.3. Docking simulation was
carried out using wild type of AR (PDB: 1AH0) down-
loaded from the www.rcsb.org, which is a free PDB. The
protein structure downloaded was optimized for the struc-
ture and energy refinement using biopredicta module. The
water molecules were removed and hydrogen atoms were
added to the protein structure, and then energy of the
resulting protein was minimized using MMFF gradient of
0.001 kcal mol−1 Å−1 was reached.
(100 MHz, CDCl3):
δ
43.9 (C-3), 56.3 (OCH3),
56.8 (OCH3), 79.8 (C-2), 102.7, 119.7, 121.4, 125.1,
126.1, 130.7, 135.1, 140.2, 152.2, 161.4 (Ar–C), 190.1
(C=O); MS m/z (relative intensity, %): 274 (M+, 90),
154 (100), 153 (45), 128 (24), 92 (18), 77 (5); anal.
calcd for C19 H14 O2: C, 83.19; H, 5.14. Found: C, 83.23;
H, 5.20.
2-(Naphthalen-2-yl) chroman-4-one (20)
White solid; yield: 80%; mp: 122–124 °C; IR (KBr, cm−1):
3375, 3058, 2962, 2884, 1689 (C=O), 1487, 1405, 1375,
Pharmacophore Modeling
1
1289; H NMR (400 MHz, CDCl3): δ 2.93 (m, 1H, Ha-3),
Pharmacophore modeling was also carried out in Vlife
MDS 4.3 using Mol sign module. The minimum number of
pharmacophore features generated for an alignment is 4 and
tolerance is kept to 10 Å.
3.06 (m, 1H, Hb-3), 5.69 (d, 1H, J = 12.8 Hz, H-2), 7.07
(m, 2H, ArH), 7.09–7.11 (m, 2H, ArH), 7.53–7.58 (m, 4H,
ArH), 7.89–7.96 (m, 5H, ArH); 13C NMR (100 MHz,
CDCl3): δ 44.7 (C-3), 79.3 (C-2), 112.3, 114.5, 118.7,
118.7, 121.5, 121.6, 127.5, 130.3, 136.6, 140.7, 161.9
(Ar–C), 192.3 (C=O); MS m/z (relative intensity, %): 274
(M+, 90), 154 (100), 153 (45), 128 (24), 92 (18), 77 (5);
anal. calcd for C19H14O2: C, 83.19; H, 5.14. Found c, 83.23,
H, 5.20.
Acknowledgements We wish to express our sincere gratitude to the
Department of Science and Technology, New Delhi, INDIA for pro-
viding research fellowship to Mr. Dasharath D. Kondhare under
INSPIRE Program for the pursuit of this work.
Compliance with ethical standards
Conflict of interest The authors declare that they have no competing
interest.
AR inhibitory activity
The preparation of AR was conducted according to the
method in a previous publication (Sun et al. 2001). The
enzyme activity was assayed spectrophotometrically mon-
itoring the NADPH oxidation that accompanies the reduc-
tion of DL-glyceraldehyde used as substrate. The inhibition
study was performed by using different concentrations of
each flavanone derivatives. The AR activity was determined
by measuring the decrease in NADPH absorption at 340 nm
over a 4-min period on an Ultrospec_2100pro UV/Visible
spectrophotometer. Quercetin, a well known ARI, was used
as a reference. The inhibition percentage (%) was calculated
as [1−(ΔA sample/min − ΔA blank/min)/(ΔA control/min
− ΔA blank/min)] − 100, where ΔA sample/min represents
the reduction of absorbance for 4 min with the test sample
and substrate, respectively, and ΔA control/min represents
the same, but with 100% DMSO instead of the sample. The
50% inhibition concentration (IC50) is expressed as the
mean SEM. The concentration of inhibitors (µg/0.1 mL
reaction mixture) giving 50% inhibition of enzyme activity
was estimated from the least-squares regression line of the
logarithmic concentrations plot against the remaining
activities.
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