Design, synthesis, and antidepressant/anticonvulsant activities of 3H-benzo[f]chromen chalcone derivatives

Article abstract of DOI:10.1007/s00044-021-02742-5

In this study, 19 3H-benzo[f]chromen chalcone derivatives (2a–2s) were obtained from 2-hydroxy-1-naphthaldehyde as the starting material, and their structures were confirmed by IR, ¹H NMR, ¹³C NMR, and ESI-MS analyses. The antidepressant activities of the compounds were evaluated in mice after one 30 mg/kg dose by means of forced swimming tests, and 18 of the compounds (2a–2l, 2n–2s) showed antidepressant activity, of which three (2b, 2d, and 2n) showed strong antidepressant activity. Furthermore, all the compounds showed some anticonvulsant activity, with 11 of the compounds (2a–2g, 2k, 2m, 2n, and 2q) inhibiting convulsions in the maximal electroshock seizure (MES) test after one dose of 100 mg/kg, and the other eight inhibiting convulsions in the MES after one dose of 300 mg/kg. In the tail suspension test, all the compounds did not show neurotoxicity at the same dose. This research provides an experimental theoretical basis for finding new antidepressants with high biological activity and few side effects.

Full text of DOI:10.1007/s00044-021-02742-5

MEDICINAL
CHEMISTRY
RESEARCH
Medicinal Chemistry Research
https://doi.org/10.1007/s00044-021-02742-5
ORIGINAL RESEARCH
Design, synthesis, and antidepressant/anticonvulsant activities of
3H-benzo[f]chromen chalcone derivatives
Qiu-Wan Tan1 Li-Ya He Zhi-Wen He Wei-Hua Liu Shan-Shan Zhang Lin Lin Hong-Li Yang
Li-Ping Guan
1 ●
1 ●
1 ●
1 ●
1 ●
1 ●
●
1
Received: 18 December 2020 / Accepted: 12 May 2021
©
The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021
Abstract
In this study, 19 3H-benzo[f]chromen chalcone derivatives (2a–2s) were obtained from 2-hydroxy-1-naphthaldehyde as the
1
13
starting material, and their structures were confirmed by IR, H NMR, C NMR, and ESI-MS analyses. The antidepressant
activities of the compounds were evaluated in mice after one 30 mg/kg dose by means of forced swimming tests, and 18 of
the compounds (2a–2l, 2n–2s) showed antidepressant activity, of which three (2b, 2d, and 2n) showed strong antidepressant
activity. Furthermore, all the compounds showed some anticonvulsant activity, with 11 of the compounds (2a–2g, 2k, 2m,
2
n, and 2q) inhibiting convulsions in the maximal electroshock seizure (MES) test after one dose of 100 mg/kg, and the
other eight inhibiting convulsions in the MES after one dose of 300 mg/kg. In the tail suspension test, all the compounds did
not show neurotoxicity at the same dose. This research provides an experimental theoretical basis for finding new
antidepressants with high biological activity and few side effects.
Introduction
progress in the past several decades [6, 7]. In these studies,
it was found that the active components of anti-depressive
mainly include flavonoids, alkaloids, saponins, and volatile
oils [8–12]. Epilepsy is a brain disease characterized by
recurrent seizures as well as emotional and cognitive dys-
function [13]. The clinical manifestations are characterized
by repeated episodes of transient loss of consciousness,
limb spasms, and convulsions. This disease affects 50
million people worldwide and is therefore one of the most
common neurological diseases [14]. Antiepileptic drugs
(AEDs) act on different molecular targets to selectively
modify the excitability of neurons, thereby blocking the
destabilizing activity without interfering with the non-
epileptic activities of normal signals between neurons
Excitatory discharge [15]. When considering the principle
of action of AEDs, there are mainly the following
mechanisms: (1) the regulation of voltage-dependent ion
channels; (2) the enhancement of synaptic inhibition; (3) the
inhibition of synaptic excitement [16].
Depression is an affective disorder characterized by sig-
nificant and lasting cognitive dysfunction and is one of the
most disabling conditions in the world [1, 2]. Its high
incidence, low cure rate, unclear pathogenesis, long treat-
ment cycle, and repeated occurrence make research into its
treatment all the more important [3]. Coppen et al. were the
first to propose in 1965 that the occurrence of depression is
due to the decline of 5-HT function in the central nervous
system, the decrease of 5-HT release, and the decrease of
synaptic cleft content [4]. Janowsky et al. proposed in 1972
that hyperactivity of Achrgic neurons and hypofunction of
adrenergic neurons, the imbalance between the two lead to
depression [5]. There are more and more published studies
on the pathogenesis of depression, which make our under-
standing of its biological aspects has seen considerable
Chalcones, also known as 1,3-diaryl-2-propen-1-ones
(Fig. 1), are a subclass of flavonoids that exist widely in
These authors contributed equally: Qiu-Wan Tan and Li-Ya He
nature, being mainly distributed in Compositae, Legumi-
nosae, and Gramineae family plants [17]. Natural chalcones
and their synthetic analogs have been demonstrated to have
a wide range of biological effects, including anticancer [18],
antioxidant [19], antibacterial [20], antileishmanial [21],
*
Li-Ping Guan
glp730@163.com
1
Food and Pharmacy College, Zhejiang Ocean University,
Zhejiang, Zhoushan 316022, China

Medicinal Chemistry Research
Fig. 1 The structures of
chalcones, FCS-304 and 3H-
benzo[f]chromen chalcone
derivatives
antimalarial [22], antiangiogenesis [23], antituberculosis
coumarin derivatives have antidepressant activity [40], and
Ariza et al. found that coumarin derivatives showed certain
anticonvulsant activity [41]. Vergel et al. discovered the
compound FCS-304 (1-propyl-3H-benzo[f]chromen-3-one)
(Fig. 1), a coumarin compound, FCS-304 (25–200 mg/kg,
p.o.) significantly reduces the immobility time in the forced
swimming test (FST) and the tail suspension test (TST) in
mice. However, no effect was shown in the rotating rod test,
maximum electroshock seizure test, pentylenetetrazole sei-
zure test, light and dark box test, barbiturate sleep time test,
and cold plate test. In addition, FCS-304 can inhibit
monoamine oxidase, IC50: 2.28 ± 0.15 µM. Its anti-
depressant activity is related to selective monoamine oxi-
dase [42].
Accordingly, in the present study, we adopted the
rational drug design principle and synthesized 19 3H-benzo
[f]chromen chalcone derivatives (Fig. 1) from
β-hydroxynaphthaldehyde and acrolein via the Claisen-
Schmidt reaction (Scheme 1, 2a–2s) and evaluated their
antidepressant and anticonvulsant activities as well as their
neurotoxicities.
[
[
24], antidepressant [25], antihistamine [26], anti-obesity
27], antispasmodic [28], and anti-inflammatory [29]
activities. As a specific flavonoid, chalcone has also been
shown to exhibit anticonvulsant activities [30]. Accord-
ingly, chalcone and its derivatives are of increasing interest
in academia and industry, and pure chalcone isolates from
several plants have been clinically trialed for the treatment
of cancer, viruses, and cardiovascular diseases [31]. Fur-
thermore, the antidepressant activities of numerous flavo-
noids have been recently reported [32–34], with the
mechanism of their antidepressant effects in mice being
attributed to their effect on the gene expression of reverse
monoamine neurotransmitters and receptors [35–37].
Although there are effective methods for the treatment of
depression, about one-third of depression patients are inef-
fective to traditional antidepressant treatment [38], and the
antidepressants that are currently on the market have certain
toxic side effects. Therefore, it is still necessary to develop
new antidepressants with quick effects and low side effects.
Our research group is engaged in the identification and
structural optimization of flavonoid antidepressant and
anticonvulsant lead compounds. We have found that ben-
zochromene compounds have a wide range of pharmaco-
logical activities, and many studies have shown that
chromene derivatives, such as monoamine oxidase, ser-
otonin, dopamine, and acetylcholinesterase inhibitors, act
on central nervous system receptors. These findings indicate
that chromene compounds show promise for the treatment
of depression, schizophrenia, and Alzheimer’s disease [39].
As a major biochemical enzyme, monoamine oxidase
affects the levels of several major neurotransmitters in the
central nervous system, such as serotonin, norepinephrine,
and dopamine. It is also the main enzyme of the earliest
antidepressant drugs. As we all know, coumarin (chromen-
Results and discussion
β-Hydroxynaphthaldehyde was subjected to aldol con-
densation with acrolein to produce the intermediate 3H-
benzo[f]chromene-2-carbaldehyde, which was then reacted
with different acetophenones through Claisen-Schmidt
condensation (Scheme 1). The structures of the target
1
13
compounds 2a–2s were confirmed by H NMR, C NMR,
FT-IR, and ESI-MS analyses.
The 1H NMR spectrum of compound 2b features a
singlet peak at 5.14 ppm, which is due to two methylene
hydrogens (–CH ), and doublet peaks at 6.79 and 7.48 ppm,
2
2
-one) is a natural product active compound with a wide
which are due to the two olefin hydrogens (–CH=CH–).
range of pharmacological effects. Chen et al. reported that
A singlet peak appears at 7.12 ppm, which is due to the

Medicinal Chemistry Research
R:
2
2
2
2
a=2-F
f=4-Cl
k=4-CF
2b=3-F
2g=2,4-Cl
2l=4-NO
2q=4-CH
2c=4-F
2h=2-Br
2m=4-CH
2d=2-Cl
2i=3-Br
2n=4-OCH
2e=3-Cl
2j=4-Br
2o=4-N(CH )
3 2
2
3
2
3
3
p=4-NH
2
2
CH
3
2r=2,4-(CH
3
)
2
3 2
2s=2,4-(OCH )
Scheme 1 Synthetic route of target chemical compounds 2a–2s
4
7
-methine group (=CH). Multiple peaks appear in the range
.14–7.84 ppm due to aromatic hydrogen atoms.
Table 1 The evaluation of the antidepression effects of chemical
compounds 2a–2s in the FST
1
3
Antidepression effectsa
The C NMR spectrum of compound 2d features a
methylene (–CH ) carbon peak at 65.00 ppm. Compound
Chemical compounds
R
DID (%)b
2
Duration of immobility(s)
2
(
b presents two peaks for the carbon–carbon double bond
–CH=CH–) at 128.81 and 143.33 ppm and peaks for
the 4-methine carbon (=CH) at 124.33 ppm, and at
93.40 ppm, the carbon peak of the carbonyl group (C=O)
2
2
2
2
a
b
c
2-F
62.8 ± 4.4**
19.8 ± 5.07***
59.6 ± 5.4***
32.6 ± 9.0***
63.4 ± 8.8**
76.4 ± 4.6**
95.2 ± 3.6*
72.8 ± 9.6**
63.0 ± 8.0**
74.6 ± 6.3**
58.0 ± 6.6***
77.0 ± 4.9**
52.57
85.05
54.98
75.38
52.11
42.30
28.10
45.02
52.42
43.66
56.19
41.84
11.33
67.52
55.59
17.67
30.21
47.13
41.24
74.02
–
3-F
4-F
1
d
2-Cl
is shown at the place.
2e
2f
3-Cl
The IR spectrum of compound 2a shows characteristic
4-Cl
−1
2
2
2
2
2
2
g
h
i
2,4-Cl2
2-Br
C–O and C=O peaks at 1546 and 1653 cm , respectively.
This may be because the electronegativity of oxygen is greater
than that of carbon. Therefore, the electron pair is attracted
toward the oxygen atom, causing the carbon atom to carry
partial positive charge, changing its dipole moment greatly.
The FST is a method that is used to induce depression in
mice that was first described by Porsolt et al. [43]. In the
FST, the depression of a mouse is reflected by its immo-
bility time in the experiment, and this behavior is thought to
be an adequate model of human depression. A wide range
of antidepressants and chemical compounds with potential
antidepressant effects have been shown to reduce immobi-
lity time [44]. Therefore, this model is the most widely used
in the preclinical screening of antidepressants.
3-Br
j
4-Br
k
l
4-CF3
4-NO2
4-CH3
4-OCH3
4-N(CH3)2
4-NH2
4-CH2CH3
2,4-(CH3)2
2m
2n
117.4 ± 3.9
43.0 ± 6.2***
58.8 ± 6.1***
109.0 ± 9.7*
92.4 ± 7.6*
70.0 ± 6.0**
2
2
2
2
2
o
p
q
r
s
2,4-(OCH3)2 77.8 ± 8.6**
34.4 ± 5.2***
Fluoxetine
Control
132.4 ± 16.9
The values are average ± SEM (n = 8)
The effects of the target compounds 2a–2s and the widely
known antidepressant fluoxetine hydrochloride on the dura-
tion of immobilization in the FST are given in Table 1. The
data show that, at a dose of 30 mg/kg, 18 of the compounds
*
0
Obviously different from control (*p < 0.05, **p < 0.01, ***p <
.001)
aFluoxetine and chemical compounds intraperitoneal injection at
3
0 mg/kg
(
(
2a–2l, 2n–2s) show antidepressant activity, of which three
2b, 2d, and 2n) exhibit relatively high activities. Specifi-
bThe percentage of immobility duration decreased
cally, the reductions in immobility time are 85.05, 75.38, and
7.52% for 2b, 2d, and 2n, respectively. The antidepressant
activity of compound 2n is slightly lower than that of
fluoxetine hydrochloride; the antidepressant activity of
compound 2d is similar to that of fluoxetine hydrochloride;
and the antidepressant activity of compound 2b is
6

Medicinal Chemistry Research
antidepressant effects
Table 2 The evaluation of the antidepression effects of chemical
compounds 2b, 2d, and 2n in the FST
1
00
2b
Antidepression effectsa
Chemical
compounds
Dose
(mg/kg)
8
6
4
2
0
0
0
0
0
2d
Flu
2n
Duration of
bDID (%)
2c
immobility (s)
2k
2o
2a
2e
2i
2
h
2r
2
f
2j
2l
2s
2
2
2
b
d
n
5
39.0 ± 8.5**
19.8 ± 5.1***
11.4 ± 6.5***
42.7 ± 6.7**
32.6 ± 9.0***
24.4 ± 6.9***
50.5 ± 9.7**
43.0 ± 6.2**
30.6 ± 10.0***
20.5 ± 7.1***
89.6 ± 10.7
56.47
77.90
87.28
52.34
63.62
72.77
43.64
52.01
65.85
77.12
–
2q
1
0
2g
2p
20
5
2m
1
0
Compounds
20
5
Fig. 2 Chemical compounds’ antidepression effects 2a–2s
1
0
significantly higher than that of fluoxetine hydrochloride.
Indeed, the immobility-reduction rate of compound 2b is the
highest of all the compounds evaluated in this study, being
20
5
fluoxetine
control
–
1
1% higher than that of fluoxetine hydrochloride.
To investigate the antidepressant effects of the target
The values are average ± SEM (n = 8)
*
Obviously different from control (*p < 0.05, **p < 0.01, ***p <
chemical compounds in more detail, the percentage
decrease in the duration of immobilization (% DID) was
calculated using the following formula:
0
.001)
aFluoxetine and chemical compounds intraperitoneal injection
bThe percentage of immobility duration decreased
%
DID ¼ ½ðX À YÞ=XŠ  100;
Table 3 The evaluation of the antidepression effects of chemical
compounds 2b, 2d, and 2n in the TST
where X indicates the duration of immobilization (s) for the
control group and Y indicates the duration of immobiliza-
tion (s) for the test group (Fig. 2).
Compounds 2b, 2d, and 2n exhibit the highest anti-
depressant activities and were thus further evaluated for
their antidepressant effects at three lower doses (5, 10, and
Chemical
Dose
Antidepression effectsa
compounds
(mg/kg)
Duration of
immobility (s)
bDID (%)
2
2
2
b
d
n
5
61.8 ± 9.8*
49.8 ± 9.5**
32.0 ± 4.5***
70.7 ± 8.8*
45.50
56.08
71.78
37.65
55.73
64.73
41.01
55.64
61.11
56.70
–
2
0 mg/kg) (Table 2). These compounds were found to
1
2
5
1
2
5
1
0
0
decrease DID in a dose-dependent manner. Furthermore,
fluoxetine has a DID value of 77.12% at 5 mg/kg per dose,
which is lower than that of compound 2b (87.28%) at
0
0
50.2 ± 5.5**
40.0 ± 7.7***
66.9 ± 8.7*
2
0 mg/kg per dose.
The antidepressant effects of compounds 2b, 2d, and 2n
were further evaluated in TSTs after three low-dose treat-
ments (5, 10, and 20 mg/kg), and the results are shown in
Table 3. Administration of compounds 2b, 2d, and 2n
results in significant decreases in inactivity duration,
revealing antidepressant effects in a dose-dependent manner
from 10 to 20 mg/kg. Compound 2b exhibits antidepressant
activity with a DID value of 71.78% at 20 mg/kg, which is
superior to that of fluoxetine (56.70%) at 5 mg/kg.
0
50.3 ± 7.9**
44.1 ± 6.9***
49.1 ± 5.8***
113.4 ± 11.0
20
5
Fluoxetine
Control
–
The values are average ± S.E.M. (n = 8)
*
*
Obviously different Section from control (*p < 0.05, **p < 0.01,
**p < 0.001)
Examining the structure-activity relationship for the
antidepressant effects of compounds 2a–2s reveals that
compounds with with donor and acceptor group substituents
on the benzene ring demonstrate good antidepressant
activities. Furthermore, for the seven compounds with
electron-donating substituents, i.e., –CH , –CH CH , –
aFluoxetine and chemical compounds intraperitoneal injection
bThe percentage of immobility duration decreased
substituent on the benzene ring, significantly decreases the
immobility time in the FST and thus has high antidepressant
activity.
3
2
3
(
CH ) , –OCH , –(OCH ) , –NH , and –N(CH ) groups,
3 2 3 3 2 2 3 2
the antidepressant activities decrease in the order 2n > 2o >
r > 2s > 2q > 2p > 2m. Compound 2n, which has a –OCH3
In addition, the nine compounds with electron-withdrawing
substituents on the benzene ring, namely F atoms (2a, 2b, and
2

Medicinal Chemistry Research
Table 4 Neurotoxocity and anticonvulsant effects of chemical
compounds 2a–2s
2
c), Cl atoms (2d, 2e, and 2f), and Br atoms (2h, 2i, and 2j),
show extremely good antidepressant effects. Furthermore,
the substitution pattern significantly affects their anti-
depressant activities. For the compounds with an F atom on
the benzene ring, their activities increase in the order o-F <
p-F < m-F, while the corresponding order for Cl substitution
is p-Cl < m-Cl < o-Cl, and that for Br substitution is p-Br <
o-Br < m-Br. However, compound 2g, which has 2,4-
dichloro substitution on the benzine ring, exhibits no anti-
depressant activity. Compounds 2k and 2l, which have
trifluoromethyl (–CF ) and nitro (–NO ) substituents,
respectively, show significant antidepressant effects and
decrease the fixed duration of mice by 56.19% and 41.84%,
respectively. Therefore, it may be important to consider the
relationship between the structure and activity and the
substituent groups attached to the benzene ring.
Chemical compounds Dosage (mg/kg) MESa
Rotarodb
0
.5 h
4 h 0.5 h 4 h
2
2
2
a
b
c
100
100
100
100
100
100
100
300
300
300
100
300
100
100
300
300
100
300
300
1/3 0/3
1/3 0/3
1/3 0/3
1/3 0/3
1/3 0/3
1/3 0/3
2/3 0/3
1/3 0/3
1/3 0/3
1/3 0/3
1/3 0/3
1/3 0/3
2/3 0/3
1/3 0/3
1/3 0/3
1/3 0/3
1/3 0/3
1/3 0/3
1/3 0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
2d
2e
2f
3
2
2g
2h
2i
2
2
2
2
2
2
2
2
2
2
j
k
l
We used the maximal electroshock seizure (MES) test to
study the anticonvulsant activities of the compounds, and the
neurotoxicities of the compounds were evaluated by the
rotating rod experiment. The test results are shown in Table 4.
Of compounds 2a–2s, 11 of the compounds (2a, 2b, 2c, 2d,
m
n
o
p
q
r
2e, 2f, 2g, 2k, 2m, 2n, and 2q) inhibit convulsion at a dose of
100 mg/kg, while eight (2h, 2i, 2j, 2l, 2o, 2p, 2r, and 2s)
inhibit convulsion at a dose of 300 mg/kg.
s
In general, the anticonvulsant activities of the 3H-benzo[f]
chromen chalcone derivatives with electron-withdrawing
groups on the benzene ring are stronger than those with
corresponding electron-donating groups. Additionally, the F-
substituted and Cl-substituted derivatives show antic-
onvulsant activity at 100 mg/kg, which is lower than the dose
required for the Br-substituted derivatives. For the com-
pounds with electron-donating groups on the benzene ring,
the p-OCH , p-CH CH , and p-CH derivatives exhibit
aMaximal electroshock seizure test (number of animals protected/
number of animals tested)
bToxicity: rotarod test (number of animals exhibiting toxicity/number
of animals tested). After the injection, the animals were checked in 0.5
and 4 h respectively
cAt 4.0 h, the chemical compounds are excreted/metabolized
In general, the anticonvulsant activities of the derivatives with
electron-withdrawing groups on the benzene ring were found
to be stronger than those with electron-donating groups on the
benzene ring, and all the F– and Cl-substituted derivatives
were found to be more active than the Br-substituted deri-
vatives. In neurotoxicity experiments, the results showed that
all 3H-benzo[f]chromen chalcone derivatives did not show
any neurotoxicity within 0.5–4 h after administration at the
same dose level.
3
2
3
3
higher anticonvulsant activities than the p-N(CH ) , p-NH ,
3
2
2
2
,4-(OCH ) , and 2,4-(CH ) derivatives.
3 2 3 2
Rotating rod experiments were performed to determine
whether the 3H-benzo[f]chromen chalcone derivatives
cause motor dysfunction. As shown in Table 4, none of the
compounds except 2g and 2m show any neurotoxicity at 0.5
or 4 h after administration at either 100 or 300 mg/kg.
Conclusion
Material and methods
In this study, we synthesized 19 3H-benzo[f]chromen chal-
cone derivatives and evaluated their antidepressant and
anticonvulsant activities as well as their neurotoxicities.
Compounds 2a–2s were shown to decrease immobility time
in FST at a dose of 30 mg/kg, reflecting their antidepressant
effects. Compounds 2b, 2d, and 2n were shown to have
antidepressant effects better than or comparable to that of
fluoxetine hydrochloride. In addition, all the chemical com-
pounds were demonstrated to exhibit anticonvulsant activities.
Materials
Fluoxetine hydrochloride (purity >99%) was purchased from
Sigma-Aldrich (Saint Louis, MO, USA). Melting points
were recorded using a digital melting point measuring
instrument (WRS-1B; Shanghai Precision Scientific Instru-
ments & Equipment, China, Shanghai). An HP1100LC/MS
system (CA, USA, Santa Clara, Agilent Technologies) was

Medicinal Chemistry Research
1
3
used to record the mass spectra. A Fourier transform-infrared
FT-IR) system (1730, Billerica, Bruker, MA, USA) was
used to record IR using KBr disks. An AV-300 system
Bruker) was used to measure the nuclear magnetic reso-
nance ( H-NMR and C-NMR) of the compounds. All
reagents were of analytical grade. The compounds 2a–2s
were synthesized through Claisen-Schmidt condensation
with commercial 2-hydroxy-1-naphthaldehyde and sub-
stituted acetophenone [45, 46].
Ar–H). C-NMR (75 MHz, CDCl ): 65.1, 115.2, 116.4,
3
(
116.7, 117.4, 121.2, 124.0, 124.3, 124.6, 127.4, 127.5,
128.8, 129.0, 129.5, 130.2, 131.0, 131.8, 133.9, 142.1,
153.9, 162.8, 188.51. IR (KBr) cm : 1653 (C=O), 1546
(C–O). HRMS m/z: calcd for C H FO 330.11, found
−
1
(
1
13
2
2
15
2
+
330.10 (M + H ).
(E)-3-(3H-benzo[f]chromen-2-yl)-1-(3-fluorophenyl) propyl-
2-en-1-one (2b)
1
Chemistry
Yield: 44.3%, m.p. 173.5–176.1 °C. H NMR (300 MHz,
CDCl ): δ 5.14 (s, 2H, –CH ), 6.79 (d, J = 15.57 Hz, 1H, =
3
2
Synthesis of 3H-benzo[f]chromene-2-carbaldehyde (1)
CH), 7.12 (s, 1H, = CH), 7.14–7.24 (m, 1H, Ar–H),
.25–7.33 (m, 1H, Ar–H), 7.37–7.46 (m, 1H, Ar–H), 7.48
7
β-hydroxynaphthaldehyde (0.02 mol, 3.444 g) and potas-
sium carbonate (0.023 mol, 3.179 g) were added to a round-
bottom flask and placed in a magnetic stirrer. An appro-
priate amount of 1, 4- dioxane solvent was added to the
flask and heated to 101 °C. The mixture was refluxed,
stirred, and activated for 1 h. Then, acrolein (0.03 mol,
(d, J = 15.57 Hz, 1H, = CH), 7.49–7.62 (m, 3H, Ar–H),
7.63–7.80 (m, 3H, Ar–H), 7.84 (m, J = 1.86, 7.51 Hz, 1H,
1
3
Ar–H). C-NMR (75 MHz, CDCl ): 65.1, 115.1, 115.4,
3
117.4, 119.6, 119.9, 121.2, 124.0, 124.4, 127.2, 127.5,
128.8, 129.3, 129.5, 130.3, 131.9, 140.4, 142.8, 153.9,
−
1
161.3, 164.6, 188.7. IR (KBr) cm : 1654 (C=O), 1548
(C–O). HRMS m/z: calcd for C H FO 330.11, found
2
.002 mL) was added to the system, and the mixture was
2
2
15
2
+
heated to reflux. Next, 50 mL of 1 M NaOH solution was
added to the system and extracted with ether (30 mL × 2)
when the reaction was complete. The washed organic layer
was dried overnight with an appropriate amount of anhy-
drous sodium sulfate. Subsequently, the dried sample was
filtered to remove sodium sulfate, and the solvent was
evaporated using rotary evaporation apparatus to obtain the
intermediate solid 3H-benzo[f]chromene-2-carbaldehyde.
330.18 (M + H ).
(E)-3-(3H-benzo[f]chromen-2-yl)-1-(4-fluorophenyl) propyl-
2-en-1-one (2c)
1
Yield: 45.6%, m.p. 175.4–177.1 °C. H NMR (300 MHz,
CDCl ): δ 5.17 (s, 2H, –CH ), 6.85 (d, J = 2.41, 15.57 Hz,
3
2
1H, = CH), 7.11 (s, 1H, = CH), 7.14–7.25 (m, 1H, Ar–H),
.25–7.33 (m, 1H, Ar–H), 7.38–7.46 (m, 1H, Ar–H),
7
Synthesis of 3H-benzo[f]chromen chalcone derivatives
7.49–7.65 (m, 4H, Ar–H), 7.68 (d, J = 15.57 Hz, 1H, =
CH), 7.72–7.80 (m, 2H, Ar–H), 7.84 (t, J = 1.86, 7.51 Hz,
(
2a–2s)
1
3
1
H, Ar–H). C-NMR (75 MHz, CDCl ): 65.1, 115.2, 115.6,
3
Compound 1 (3 mmol, 0.63 g) and 3.9 mmol of differently
substituted acetophenone was placed into a round-bottom
flask. Consequently, 20 mL absolute ethanol and 6 mL
115.9, 117.4, 119.7, 121.2, 124.3, 127.2, 127.5, 128.7,
128.8, 128.9, 129.5, 130.2, 130.9, 131.0, 131.8, 134.6,
−
1
142.3, 153.8, 188.4. IR(KBr) cm : 1654 (C=O), 1547
(C–O). HRMS m/z: calcd for C H FO 330.11, found
3
.5 M NaOH solution were added to the flask, and the
2
2
15
2
+
system was placed in an ice-water bath and stirred over-
night. The completely reacted solution was diluted with
water and filtered to obtain a yellow or orange precipitate.
The precipitate was dissolved using ethyl acetate and
recrystallized to obtain a series of 3H-benzo[f]chromen
chalcone derivative crystals (2a–2s).
330.06 (M + H ).
(E)-3-(3H-benzo[f]chromen-2-yl)-1-(2-chlorophenyl) propyl-
2-en-1-one (2d)
1
Yield: 46.8%, m.p. 164.5–165.9 °C. H NMR (300 MHz,
CDCl ): δ 5.13 (s, 2H, –CH ), 6.53 (d, J = 15.57 Hz, 1H, =
CH), 7.11 (s, 1H, = CH), 7.34–7.42 (m, 2H, Ar–H), 7.50 (d,
J = 15.57 Hz, 1H, = CH), 7.53 (m, 1H, Ar–H), 7.67 (s, 1H,
3
2
(
2
E)-3-(3H-benzo[f]chromen-2-yl)-1-(2-fluorophenyl) propyl-
-en-1-one (2a)
Ar–H), 7.72–7.82 (m, 3H, Ar–H), 7.91–8.02 (m, 3H,
1
13
Yield: 43.5%, m.p.150.5–151.7 °C. H-N-MR (300 MHz,
CDCl ): δ 5.14 (s, 2H, –CH ), 6.79 (d, 15.57 Hz, 1H, =
Ar–H). C-NMR (75 MHz, CDCl ): 65.0, 115.1, 117.4,
3
121.1, 124.3, 124.6, 126.9, 127.1,127.5, 128.8, 129.2,
129.4, 129.5, 130.2, 130.3, 131.3, 131.4, 132.0, 139.1,
3
2
CH), 7.12 (s, 1H, = CH), 7.14–7.33 (m, 2H, Ar–H),
.37–7.46 (m, 1H, Ar–H), 7.55 (d, J = 15.57 Hz, 1H, =
CH), 7.49–7.62 (m, 3H, Ar–H), 7.63–7.68 (m, 1H, Ar–H),
.72–7.80 (m, 2H, Ar–H), 7.84 (t, J = 1.86, 7.51 Hz, 1H,
−
1
7
143.3, 153.9, 193.4. IR (KBr) cm : 1655 (C=O), 1547
(C–O). HRMS m/z: calcd for C H ClO 346.08, found
2
2
15
2
+
7
346.11 (M + H ).

Medicinal Chemistry Research
(
2
E)-3-(3H-benzo[f]chromen-2-yl)-1-(3-chlorophenyl) propyl-
-en-1-one (2e)
131.4, 132.0, 133.5, 141.2, 143.7, 154.0, 194.3. IR (KBr)
−
1
cm : 1656 (C=O), 1548 (C–O). HRMS m/z: calcd for
+
C H BrO 390.03, found 390.11 (M + H ).
2
2
15
2
1
Yield: 41.8%, m.p. 161.9–164.0 °C. H NMR (300 MHz,
CDCl ): δ 5.16 (s, 2H, –CH ), 6.82 (d, J = 15.57 Hz, 1H, =
(E)-3-(3H-benzo[f]chromen-2-yl)-1-(3-bromophenyl) propyl-
3
2
CH), 7.12 (s, 1H, = CH), 7.38–7.45 (m, 1H, Ar–H), 7.49 (d,
J = 15.57 Hz, 1H, = CH), 7.53–7.64 (m, 2H, Ar–H), 7.69
2-en-1-one (2i)
1
(
m, 1H, Ar–H), 7.72–7.82 (m, 3H, Ar–H), 7.91–8.02 (m, 3H,
Yield: 43.3%, m.p. 161.7–164.3 °C. H-NMR (300 MHz,
1
3
Ar–H). C-NMR (75 MHz, CDCl ): 65.1, 115.1, 117.4,
CDCl ): δ 5.13 (s, 2H, –CH ), 6.91 (d, J = 15.57 Hz, 1H, =
3
3
2
1
1
1
19.5, 121.2, 124.4, 126.4, 127.2,127.6, 128.5, 128.8, 129.4,
29.5, 130.0, 130.2, 132.0, 132.6, 135.0, 139.9, 142.9, 153.9,
CH), 7.03 (s, 1H, = CH), 7.33 (m, J = 8.55 Hz, 2H, Ar–H),
7.47 (d, 1H, J = 15.57 Hz, =CH), 7.57 (m, 1H, Ar–H),
7.61–7.77 (m, 4H, Ar–H), 7.93–8.08 (m, 3H, Ar–H). C-
−1
13
88.6. IR (KBr) cm : 1653 (C=O), 1545 (C–O). HRMS
+
m/z: calcd for C H ClO 346.08, found 346.15 (M + H ).
NMR (75 MHz, CDCl ): 65.1, 115.2, 117.4, 119.9, 121.4,
2
2
15
2
3
122.9, 124.4, 127.1, 127.5,127.6, 128.8, 129.1, 129.4,
(
2
E)-3-(3H-benzo[f]chromen-2-yl)-1-(4-chlorophenyl) propyl-
-en-1-one (2f)
130.2, 130.4, 131.3, 131.8, 135.5, 140.0, 142.6, 153.9,
−
1
188.1. IR (KBr) cm : 1655 (C=O), 1547 (C–O). HRMS
+
m/z: calcd for C H BrO 390.03, found 390.07 (M + H ).
2
2
15
2
1
Yield: 45.4%, m.p. 191.0–193.4 °C. H NMR (300 MHz,
CDCl ): δ 5.16 (s, 2H, –CH ), 6.84 (d, J = 15.57 Hz, 1H, =
(E)-3-(3H-benzo[f]chromen-2-yl)-1-(4-bromophenyl) propyl-
3
2
CH), 7.12 (s, 1H, = CH), 7.37–7.45 (m, 1H, Ar–H), 7.49 (d,
J = 15.57 Hz, 1H, = CH), 7.50–7.64 (m, 2H, Ar–H), 7.67
2-en-1-one (2j)
1
(
m, 1H, Ar–H),7.72–7.82 (m, 3H, Ar–H), 7.91–8.02 (m,
Yield: 42.5%, m.p. 193.8–194.8 °C. H-NMR (300 MHz,
1
3
3
1
1
1
1
H, Ar–H). C-NMR (75 MHz, CDCl ): 65.1, 115.1,
CDCl ): δ 5.17 (s, 2H, –CH ), 6.84 (d, J = 15.57 Hz, 1H, =
3
3
2
17.4, 119.6, 121.2, 124.3, 127.2, 127.5,128.8, 129.0,
29.1, 129.5, 129.8, 130.2, 130.9, 131.9, 134.6, 136.6,
CH), 7.13 (s, 1H, = CH), 7.37–7.58 (m, 3H, Ar–H),
7.64–7.70 (m, 2H, Ar–H), 7.73(d, J = 15.57 Hz, 1H, =
CH), 7.76–7.82 (m, 2H, Ar–H), 7.87–8.00 (m, J = 8.55 Hz,
−
1
39.2, 142.6, 153.9, 188.7. IR (KBr) cm : 1654 (C=O),
546 (C–O). HRMS m/z: calcd for C H ClO 346.08,
1
3
3H, Ar–H). C-NMR (75 MHz, CDCl ): 65.1, 115.2,
22
15
2
3
+
found 346.04 (M + H ).
117.4, 119.9, 121.4, 122.9, 124.4, 127.1, 127.5,127.6,
1
28.8, 129.1, 129.4, 130.2, 130.4, 131.3, 131.8, 135.5,
−
1
(
E)-3-(3H-benzo[f]chromen-2-yl)-1-(2,4-dichlorophenyl)
140.0, 142.6, 153.9, 188.1. IR (KBr) cm : 1654 (C=O),
1547 (C–O). HRMS m/z: calcd for C H BrO 390.03,
found 390.01 (M + H ).
propyl-2-en-1-one (2g)
2
2
15
2
+
1
Yield: 44.4%, m.p. 191.8–193.9 °C. H-NMR (300 MHz,
CDCl ): δ 5.12 (s, 2H, –CH ), 6.50 (d, J = 16.00 Hz, 1H, =
(E)-3-(3H-benzo[f]chromen-2-yl)-1-(4-(trifluoromethyl)
phenyl)-propyl-2-en-1-one (2k)
3
2
CH), 7.11 (s, 1H, = CH), 7.31–7.46 (m, 2H, Ar–H), 7.50 (d,
J = 16.00 Hz, 1H, = CH), 7.59 (m, 1H, Ar–H), 7.67 (m, 1H,
Ar–H), 7.73–7.77 (m, 3H, Ar–H), 7.91–8.02 (m, 3H, Ar–H).
1
Yield: 39.6%, m.p. 187.5–189.1 °C. H-NMR (300 MHz,
1
3
C-NMR (75 MHz, CDCl ): 64.9, 115.0, 117.4, 121.2,
CDCl ): δ 5.21 (s, 2H, –CH ), 6.88 (d, J = 15.63 Hz, 1H, =
3
3
2
1
1
24.2, 124.4, 127.0, 127.4,127.6, 128.8, 129.4, 129.6, 130.1,
30.2, 130.4, 132.0, 132.1, 136.6, 137.4, 143.8, 153.9, 192.0.
CH), 7.16 (s, 1H, = CH), 7.42–7.48 (m, 1H, Ar–H), 7.56(d,
J = 15.63 Hz, 1H, = CH), 7.57–7.65 (m, 2H, Ar–H), 7.73
−1
IR (KBr) cm : 1655 (C=O), 1547 (C–O). HRMS m/z:
calcd for C H Cl O 380.04, found 380.13 (M + H ).
(m, 1H, Ar–H), 7.75–7.85 (m, 4H, Ar–H), 7.97–8.11 (d,
+
13
J = 8.07 Hz, 2H, Ar–H). C-NMR (75 MHz, CDCl ): 65.1,
2
2
14
2
2
3
115.7, 116.4, 117.8, 119.3, 121.0, 122.2, 123.7, 124.8,
(
2
E)-3-(3H-benzo[f]chromen-2-yl)-1-(2-bromophenyl) propyl-
-en-1-one (2h)
126.1, 127.1, 127.6, 128.0, 128.7, 129.1, 129.5, 129.6,
−
1
129.8, 132.2, 142.2, 143.1, 153.9, 188.8. IR (KBr) cm :
656 (C=O), 1548 (C–O). HRMS m/z: calcd for
1
1
+
Yield: 40.3%, m.p. 157.6–160.6 °C. H-NMR (300 MHz,
CDCl ): δ 5.12 (s, 2H, –CH ), 6.50 (d, J = 16.00 Hz, 1H, =
C H F O 380.10, found 380.19 (M + H ).
23 15 3 2
3
2
CH), 7.11 (s, 1H, = CH), 7.33 (m, J = 8.55 Hz, 2H, Ar–H),
.45 (d, 1H, = CH), 7.57 (s, 1H, Ar–H), 7.61–7.77 (m, 4H,
Ar–H), 7.79–7.95 (m, 3H, Ar–H). C-NMR (75 MHz,
(E)-3-(3H-benzo[f]chromen-2-yl)-1-(4-nitrophenyl) propyl-2-
en-1-one (2l)
7
13
1
CDCl ): 65.0, 115.0, 117.4, 119.5, 121.1, 124.3, 124.5,
Yield: 37.6%, m.p. 223.7–225.8 °C. H-NMR (300 MHz,
3
1
27.1, 127.4,127.5, 128.8, 129.2, 129.3, 129.5, 130.2,
CDCl ): δ 5.25 (s, 2H, –CH ), 7.13 (s, 1H, = CH),
3
2

Medicinal Chemistry Research
7
1
1
7
.26 (d, J = 3.51, 15.35 Hz, 1H, = CH), 7.34–7.43 (m,
H, Ar–H), 7.54 (t, J = 7.67 Hz, 1H, Ar–H), 7.72(d, J =
5.57 Hz, 1H, = CH), 7.81 (m, J = 6.58 Hz,3H, Ar–H),
(C–O). HRMS m/z: calcd for C H NO 355.16, found
355.22 (M + H ).
2
4
21
2
+
13
.94 (m, 1H, Ar–H), 8.11–8.23 (m,4H, Ar–H). C-NMR
(E)-3-(3H-benzo[f]chromen-2-yl)-1-(4-aminophenyl) propyl-
(
75 MHz, CDCl ):65.1, 115.3, 116.2, 117.7, 119.2, 120.7,
2-en-1-one (2p)
3
1
1
22.0, 123.6, 124.1, 124.6, 126.1, 127.8, 128.0, 128.4,
28.8, 129.1, 129.5, 130.1, 132.2, 143.4, 153.7, 188.2. IR
1
Yield: 29.8%, m.p. 222.5–224.6 °C. H-NMR (300 MHz,
−
1
(
KBr) cm : 1655(C=O), 1548 (C–O). HRMS m/z: calcd
CDCl ): δ 5.25 (s, 2H, –CH ), 6.35 (s, 2H, –NH ), 7.12 (s,
3
2
2
+
for C H NO 357.10, found 357.06 (M + H ).
1H, = CH), 7.21 (d, J = 15.57 Hz, 1H, = CH), 7.32–7.55
m, 2H, Ar–H), 7.68(d, J = 15.57 Hz, 1H, = CH), 7.78 (m,
J = 6.58 Hz, 3H, Ar–H), 7.89–7.99 (m, 2H, Ar–H),
8.04–8.13 (m,3H, Ar–H). C-NMR (75 MHz, CDCl3):
5.3, 113.2, 115.8, 117.8, 120.1, 121.9, 122.1, 124.3,
125.8, 127.4, 128.2, 128.6, 129.0, 129.5, 130.3, 131.5,
2
2
15
4
(
(
2
E)-3-(3H-benzo[f]chromen-2-yl)-1-(4-methylphenyl) propyl-
-en-1-one (2m)
1
3
6
1
Yield: 44.4%, m.p. 174.5–176.4 °C. H-NMR (300 MHz,
CDCl ): δ 3.90–3.97 (m, 3H, –CH ),5.21 (s, 2H, –CH ), 6.96
−
1
136.2, 139.5, 141.4, 154.0, 163.5, 186.1. IR (KBr) cm :
3
3
2
(
d, J = 15.63 Hz, 1H, = CH), 7.03 (d, J = 8.74 Hz, 2H,
1656 (C=O), 1548 (C–O). HRMS m/z: calcd for
+
Ar–H), 7.15(s, 1H, = CH), 7.40–7.47 (m, 1H, Ar–H),
C H NO 327.13, found 327.19 (M + H ).
2
2
17
2
7
7
.55–7.62(m, 1H, Ar–H), 7.65 (d,J = 15.63 Hz,1H, = CH),
.68–7.84 (m, 3H, Ar–H), 8.01–8.09 (m,3H, Ar–H). C-
1
3
(E)-3-(3H-benzo[f]chromen-2-yl)-1-(4-ethylphenyl) propyl-2-
NMR (75 MHz, CDCl ):21.7, 65.2, 115.2, 117.4, 120.3,
en-1-one (2q)
3
1
1
21.2, 124.3, 125.0, 127.4, 127.5, 128.3, 128.6, 128.8, 129.4,
29.5, 130.2, 131.6, 132.3, 135.7, 141.7, 143.6, 153.7, 189.6.
1
Yield: 38.3%, m.p. 158.7–161.1 °C. H-NMR (300 MHz,
−1
IR (KBr) cm : 1653 (C=O), 1546 (C–O). HRMS m/z:
calcd for C H O 326.13, found 326.70 (M + H ).
CDCl ): δ 1.27 (m, 3H, –CH ), 3.32 (m, 2H, –CH ),5.20 (s,
2H, –CH ), 7.05 (d, J = 15.63 Hz, 1H, = CH), 7.11 (s, 1H,
3
3
2
+
2
3
18
2
2
=
CH), 7.33–7.38 (m, 2H, Ar–H), 7.52–7.65 (m, 2H,
(
E)-3-(3H-benzo[f]chromen-2-yl)-1-(4-methoxyphenyl)
Ar–H), 7.75 (d, J = 15.63 Hz,1H, = CH), 7.76–7.95 (m,
3H, Ar–H), 7.97–8.06 (m, 3H, Ar–H). C-NMR (75 MHz,
1
3
propyl-2-en-1-one (2n)
CDCl ):15.3, 29.0, 65.2, 115.2, 117.4, 120.3, 121.2, 124.3,
3
1
Yield: 37.7%, m.p. 159.1–160.6 °C. H-NMR (300 MHz,
CDCl ): δ 3.94 (m, 3H, –CH ),5.21 (s, 2H, –CH ), 6.96 (d,
126.2, 127.5, 128.2, 128.7, 128.8, 129.4, 130.2, 131.6,
132.3, 135.9, 137.4, 141.7, 143.6, 149.8, 153.7, 189.6. IR
3
3
2
−
1
J = 15.63 Hz, 1H, = CH), 7.03 (d, J = 8.74 Hz, 2H, Ar–H),
(KBr) cm : 1655 (C=O), 1548 (C–O). HRMS m/z: calcd
+
7
2
3
.15 (s, 1H, = CH), 7.40–7.47 (m, 1H, Ar–H), 7.56–7.60(m,
H, Ar–H), 7.68 (d, J = 15.63 Hz, 1H, = CH), 7.73–7.84 (m,
H, Ar–H), 8.01–8.09 (m, 2H, Ar–H). 1 C-NMR (75 MHz,
for C H O 340.15, found 340.08 (M + H ).
2
4
20
2
3
(E)-3-(3H-benzo[f]chromen-2-yl)-1-(2,4-dimethylphenyl)
CDCl ):55.6, 65.3, 113.9, 115.3, 117.4, 120.1, 121.3, 124.3,
propyl-2-en-1-one (2r)
3
1
1
1
3
25.2, 127.5, 127.6, 128.1, 128.6, 128.8, 129.4, 129.5, 130.2,
31.2, 131.6, 141.4, 153.7, 163.5, 188.3. IR (KBr) cm :
−1
1
Yield: 37.8%, m.p. 117.8–119.7 °C. H-NMR (300 MHz,
655 (C=O), 1547 (C–O). HRMS m/z: calcd for C H O
42.13, found 342.20 (M + H ).
CDCl ): δ 2.41 (s, 3H, -CH ), 3.47 (s, 3H, –CH ),5.13 (s,
2H, –CH ), 6.56 (d, J = 16.00 Hz, 1H, = CH), 7.11 (s, 1H,
2
3
18
3
3
3
3
+
2
=
CH), 7.35–7.47 (m, 4H, Ar–H), 7.54 (d, J = 16.00 Hz,
(
E)-3-(3H-benzo[f]chromen-2-yl)-1-(4-(dimethylamino)
1H, = CH), 7.57–7.76 (m, 2H, Ar–H), 7.76–7.98 (m, 3H,
1
3
phenyl)prop-2-en-1-one (2o)
Ar–H). C-NMR (75 MHz, CDCl ):20.4, 21.4, 65.1, 115.1,
3
1
17.4, 121.2, 124.3, 125.0, 126.2, 127.3, 127.4, 128.2,
1
Yield: 30.8%, m.p. 214.5–216.3 °C. H-NMR (300 MHz,
CDCl ): δ 3.06–3.30 (s, 6H, –CH ),5.24 (s, 2H, –CH ), 6.74
(
128.5, 128.8, 129.5, 130.2, 131.7, 132.3, 136.2, 137.4,
141.0, 142.5, 153.7, 195.5. IR (KBr) cm : 1656 (C=O),
1549(C–O). HRMS m/z: calcd for C H O 340.15, found
−
1
3
3
2
d, J = 15.63 Hz, 1H, = CH), 7.14 (s, 1H, = CH), 7.29–7.47
m, 2H, Ar–H), 7.50–7.59 (m, 2H, Ar–H), 7.61 (d, J =
2
4
20
2
+
(
340.23 (M + H ).
1
5.63 Hz, 1H, = CH), 7.77–7.86 (m, 4H, Ar–H), 8.00 (d,
J = 8.99 Hz, 1H, Ar–H), 8.18 (d, J = 8.55 Hz, 1H, Ar–H).
(E)-3-(3H-benzo[f]chromen-2-yl)-1-(2,4-dimethoxyphenyl)
propyl-2-en-1-one (2s)
1
3
C-NMR (75 MHz, CDCl ):55.6, 65.3, 78.9, 79.3, 79.6,
3
7
1
1
9.8, 111.19, 115.3, 117.4, 120.1, 122.1, 124.3, 125.77,
27.6, 128.6, 128.8, 129.5, 130.2, 131.2, 131.6, 141.4,
53.7, 163.5, 188.3. IR (KBr) cm : 1654 (C=O), 1547
1
Yield: 33.5%, m.p. 139.8–141.9 °C. H-NMR (300 MHz,
−
1
CDCl ): δ 3.86 (d, 3H, –OCH ), 3.89 (d, 3H, –OCH ),5.11
3
3
3

Medicinal Chemistry Research
(
1
s, 2H, –CH ), 6.55–6.58 (m, 2H, Ar–H), 6.96 (d, J =
5.78 Hz, 1H, = CH), 7.11 (s, 1H, = CH), 7.36–7.45 (m, 2H,
Mice were considered to be immobile only when they hung
passively and were completely motionless [47].
2
Ar–H), 7.53 (d, J = 15.78 Hz, 1H, = CH), 7.57–7.84 (m, 4H,
13
Ar–H), 7.99 (m, J = 8.33 Hz, 1H, Ar–H).
C-NMR
Maximum electroconvulsive seizure (MES) test
(
75 MHz, CDCl ):55.6, 55.7, 65.3, 98.7, 105.3, 115.3,
3
1
1
17.3, 121.2, 124.2, 125.8, 126.2, 127.1, 127.3, 128.0, 128.7,
29.5, 130.2, 131.2, 132.9, 139.4, 153.4, 160.4, 164.3, 189.9.
The power supply parameters of the maximum electro-
convulsive instrument were set to 50 mA, 60 Hz alternating
current, single electrode stimulation voltage of 110 V, time
0.3 s. The experiment was started 30 min after intraper-
itoneal administration in each group. Normal saline was
evenly applied to the edges of the mouse’s ears, then the
edges of the mouse’s ears were clamped with the alligator
clip provided with the instrument. Mice were given a single
0.3 s electrical stimulation. After the mouse was electrically
stimulated, if the hind limbs were rigid, the mouse was used
in the next step. If the hind limbs are not rigid, it indicates
that the compound has antimaximal electroconvulsive
activity [48].
−1
IR (KBr) cm : 1654 (C=O), 1546 (C–O). HRMS m/z: calcd
for C H O 372.14, found 372.17 (M + H ).
+
2
4 20 4
Animals
The processing programs of all the animals were carried out
according to the supervision standards established by the
Government of China. The Animal Research Laboratory,
School of Pharmacy, Zhejiang Academy of Medical Sci-
ences (Zhejiang, China) provided the ICR mice (20 ± 2 g).
All animals were allowed to adapt to the environment for a
week before the experiment. Mice were placed in a tem-
perature controlled (23 ± 2 °C) environment and maintained
on standard tap water and food pellets (unless stated
otherwise) and a light-dark cycle of 12 h before and during
the experiment.
Neurotoy screening
The compound’s neurovirulence was evaluated by the
rotating rod test. Before the experiment, the mice were
trained to stay on a speed rotary bar (diameter, 3.2 cm) which
is rotated at 10 revolutions per min. Whether the mice in
each experiment maintained balance on the rod for at least
1 min was used as the evaluation criterion for neurotoxicity
[49]. Trained mice were administered 3H-benzo[f]chromen
chalcone derivative 2a–2s intraperitoneally 30 min before the
test, and were then placed on the accelerating rotating rod. If
the mice maintained their balance for 1 min without falling in
three consecutive experiments, the compound was con-
sidered not to show neurotoxicity at that dose.
Forced swimming test (FST)
Male ICR mice (20 ± 2 g) were allowed to drink and eat
normally before the experiment, and eight mice were raised
in each group. The 19 3H-benzo[f]chromen chalcone deri-
vatives and the positive drug, fluoxetine hydrochloride, were
dissolved in DMSO. The negative control was the carrier
solvent and the positive control was fluoxetine. On the day of
the experiment, 30 min after intraperitoneal administration of
the drugs, mice were placed into a Plexiglass™ cylinder
containing 10 cm of water (height, 25 cm; diameter, 10 cm;
temperature, 22 ± 3 °C) one at a time for ~6 min. The mice
struggled slightly in the first 2 min and then entered the
observation range of immobile time. The immobility dura-
tion was recorded in the last 4 min of the test. The time for
rest was considered as the time spent by mice floating in the
water without struggling and stroking its limbs only to
maintain its head floating above the water [24, 43].
Statistical analyses
Prism version 2.0 (GraphPad, San Diego, CA, USA) was
used for statistical analysis of categorical data. Data were
represented as the average ± SEM. Differences between the
two groups were compared with Student’s t-test, and p <
0.05 was considered statistically significant.
Acknowledgements This work was supported by Zhejiang Province
Public Technology Application Project of China (No. 2017C33131).
We thank Arshad Makhdum, PhD, from LiwenBianji, Edanz Group
China (www.liwenbianji.cn/ac), for editing the English text of a draft
of this manuscript.
Tail suspension test (TST)
Mice were hung by their tails (clipped 2 cm from the end)
5
cm above the base of a box (25 × 25 × 30 cm). The test
was conducted in a dark room with little-to-no background
noise. All mice were suspended for 6 min to observe the
immobility duration and immobility was measured in the
last 4 min of the test. Video cameras were fixed directly
above the box to record all the test phenomena. Two pro-
fessional observers watched the videos and scored them.
Compliance with ethical standards
Conflict of interest The authors declare no competing interests.
Publisher’s note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.

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