Synthesis of Benzoazepine Derivatives via Azide Rearrangement and Evaluation of Their Antianxiety Activities

Article abstract of DOI:10.1021/acsmedchemlett.1c00275

A new synthetic method for the construction of benzoazepine analogues has been developed employing ortho-arylmethylbenzyl azide derivatives as precursors using an azide rearrangement reaction. In this work, 14 benzoazepine compounds were successfully synthesized in moderate to excellent yields. All synthetic benzoazepines were evaluated for their cytotoxicity against normal human kidney cell line (HEK cell). The results showed that compound 18c had the lowest cytotoxicity (IC50 = 65.68 μM) among tested compounds, which was comparable with the antianxiety drug diazepam (IC50 = 87.90 μM). Based on the cytotoxicity results, five benzoazepine analogues (compounds 18c, 18h, 18j, 18n, and 18p) were selected to determine the antianxiety effect on stressed rats using elevated plus maze (EPM) and open field test (OFT) methods. Interestingly, compound 18c showed better anxiolytic activity than diazepam without a sedative effect by showing superior hyperlocomotor activity. Therefore, this discovery could pave the way for drug development to treat patients with anxiety disorder.

Full text of DOI:10.1021/acsmedchemlett.1c00275

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Letter
Synthesis of Benzoazepine Derivatives via Azide Rearrangement
and Evaluation of Their Antianxiety Activities
Onrapak Reamtong, Sarawut Lapmanee, Jumreang Tummatorn,* Nitwaree Palavong,
Charnsak Thongsornkleeb, and Somsak Ruchirawat
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ABSTRACT: A new synthetic method for the construction of
benzoazepine analogues has been developed employing ortho-
arylmethylbenzyl azide derivatives as precursors using an azide
rearrangement reaction. In this work, 14 benzoazepine compounds
were successfully synthesized in moderate to excellent yields. All
synthetic benzoazepines were evaluated for their cytotoxicity
against normal human kidney cell line (HEK cell). The results
showed that compound 18c had the lowest cytotoxicity (IC50
=
65.68 μM) among tested compounds, which was comparable with
the antianxiety drug diazepam (IC50 = 87.90 μM). Based on the
cytotoxicity results, five benzoazepine analogues (compounds 18c,
18h, 18j, 18n, and 18p) were selected to determine the antianxiety
effect on stressed rats using elevated plus maze (EPM) and open
field test (OFT) methods. Interestingly, compound 18c showed better anxiolytic activity than diazepam without a sedative effect by
showing superior hyperlocomotor activity. Therefore, this discovery could pave the way for drug development to treat patients with
anxiety disorder.
KEYWORDS: Benzoazepine, Azide, Antianxiety, Diazepam
sant,16,17 anti-HIV-1,18,19 and antihypertension properties20
he impact of rapid growth of technology and social media
(Figure 1).
Thas changed human behavior in both positive and
negative manners.1,2 The negative effects can lead to mental
As a result of its prominent biological activities, the
benzoazepine core structure has a high potential to be used
in drug design to develop novel pharmaceutical agents.
According to our research interest in azide chemistry,21−27
we envision that benzoazepine could be prepared using azide
as the nitrogen source. In addition, azide was employed in a
broad range of reactions for the synthesis of N-containing
compounds, including N-methylarylamines, indoloquinolines,
quinolines, tetrahydroquinolines, and phenanthridines.21−27
Our research group has been interested in azide rearrangement
chemistry to develop new methods for the synthesis of
biologically active compounds. Benzyl azide derivatives were
employed as a common precursor for the generation of an
iminium ion intermediate, which could react with a variety of
nucleophiles either in an intramolecular or intermolecular
reaction to provide the corresponding N-containing com-
health problems such as major depressive disorder and
dysthymic disorder.3 In addition, genetics is another factor of
this symptom. Anxiety disorder is a type of psychiatric disorder
involving an excessive behavioral response to stress.4 This
symptom can affect job duties, career path, relationship among
friends, and family. Nowadays, the prevalence of this disorder
has increased every year and could contribute to depression
and suicide.5 Due to these negative effects, patients need
behavioral therapy and/or medical treatment. However,
patients have different responsiveness to the drug treatment.
Therefore, a variety of drugs is needed for the treatment of
these symptoms.6 The benzoazepine core structure is a well-
known pharmacophore that is present in several mood disorder
drugs,7,8 especially in the class of mood-stabilizing drugs such
as imipramine, diazepam, and lorazepam.9,10 In addition, this
core structure shows various biological activities associated
with several commercial drugs. For example, this core structure
is present in commercial anticancer drugs such as olanzapine,
rucaparib, clozapine, anthramycin, and tomaymycin.11−14
Furthermore, the benzoazepine motif plays key roles in other
biological activities including antibacterial,15 anticonvul-
Received: May 13, 2021
Accepted: July 13, 2021
https://doi.org/10.1021/acsmedchemlett.1c00275
© XXXX American Chemical Society
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Scheme 1. Our Proposed Synthetic Method
PBr3 in DCM. Upon completion, DCM was removed to give
crude product, which was then taken up in DMSO before
NaN3 was added. The reactions could provide the desired
products 17 in moderate to good yields in three steps.
However, ortho-arylmethylbenzyl aldehydes 21d and 21m
could not be purified, and they were therefore subjected to the
reduction conditions to provide alcohol products 28d and 28m
in good yields. Furthermore, alcohol products from the
reduction of compounds 21g, 21j−21l, 21p, and 21s could
not be purified. Therefore, they were directly used in the
bromination and azidation steps to give the corresponding
azides 17 in moderate to good yields. In the case of substrate
17f, it was prepared using the same protocol as shown in
Scheme 2. However, both aldehyde and alcohol products could
not be obtained in pure forms; thus, the bromination and
azidation reactions were carried out in successive order to give
azide 17f in 27% overall yield (Scheme 3). In addition, a
different method was used for the preparation of compound
17e. Compound 22e, prepared from a Friedel−Crafts reaction
between phthalic anhydride and 1,2,4-trimethoxybenzene
followed by esterification, was employed as the starting
material. Compound 22e was subjected to reduction
conditions to give compound 23e, which was converted to
the corresponding product 17e by reduction, bromination, and
azidation as shown in Scheme 3.
Figure 1. Representatives of commercial benzoazepine drugs.
pounds as shown in Scheme 1. In this work, we aimed to utilize
our research background in azide rearrangement chemistry in
the design and synthesis of benzoazepine derivatives for the
development of an antianxiety agent (Scheme 1).
In this study, ortho-arylmethylbenzyl azide derivatives (17)
were prepared as substrates for the synthesis of benzoazepines.
The results are reported in Scheme 2. 2-Formylphenyl boronic
acid 19a was used as the starting material, which was coupled
with 3-methoxybenzyl bromide 20c-Br (X = Br) via Suzuki
cross-coupling28,29 to obtain biarylmethane aldehyde product
21c in 36% yield along with the formation of a benzylethyl
ether side product. Therefore, toluene was used instead of
EtOH to avoid the formation of this side product and provide
only compound 21c in 48% yield due to the low solubility of
the boronic acid in toluene. Later on, we found that the best
partner to couple with 2-formylboronic acid 19a via a Suzuki
cross-coupling reaction was 3-methoxybenzyl chloride 20c-Cl
(X = Cl), which could give the corresponding biarylmethane
derivatives 21c in 76% yield. Therefore, commercially available
benzyl chloride derivatives were employed as the partner for a
Suzuki cross-coupling reaction. However, in some cases, benzyl
bromide derivatives were used for the synthesis of compounds
21, because they were commercially available. The results are
demonstrated in Scheme 2.
Substrate 17t, which would cyclize to give an eight-
membered ring product, was prepared by the coupling reaction
between 2-bromobenzaldehyde (24) and 3-methoxystyrene
(25) via a Heck reaction to give product 26 in 84% yield.
Then, this compound was hydrogenated using Pd/C and
hydrogen gas to obtain compound 27 in 95% yield. Finally, the
aldehyde moiety was converted to azide using the same
Then, substrate 21 was reduced using NaBH4 in MeOH to
provide the corresponding alcohol product. After purification,
this alcohol was converted to a benzyl bromide derivative using
B
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Scheme 2. Preparation of Compound 21
Scheme 4. Preparation of Compound 17t
investigated as shown in Table 1. The results showed that
dry DCM provided the desired product in lower yield (89%)
Table 1. Reaction Conditions
a
entry
TfOH (equiv)
solvent
yield (%) 18c
1
2
3
1.0
1.0
1.0
DCM (0.10 M)
PhMe (0.10 M)
PhMe (0.05 M)
89
93
84
a
Isolated yield.
than dry toluene (93%), while the reaction at higher
concentration (0.10 M) (entry 2) provided the desired
product in a better yield than the lower concentration (0.05
M). The results were demonstrated in Table 1.
After we have the optimal conditions in hand, several
substrates were subjected to this rearrangement. Substrate 17a
containing a benzyl substituent could not provide the desired
product possibly due to the poor nucleophilicity of the phenyl
ring. A similar result was obtained with the substrate
containing 3-chlorobenzyl group 17b; the reaction could not
give the corresponding product as well. Therefore, we
attempted the reaction with a substrate bearing the 3-
methoxybenzyl group 17c. The transformation smoothly
took place to give benzoazepine product 18c in 93% yield,
while substrate 17d could also provide the desired product 18d
in excellent yield (93%). These results showed that an
intramolecular reaction and the resonance effect of halogen
atom of the phenyl and 3-chlorophenyl groups were not
sufficient to drive electrophilic aromatic substitution reactions
to occur under these optimal conditions. The substrate
containing a 3-methoxyphenyl group, however, efficiently
proceeded under these conditions. These results implied that
the minimum requirement for this electrophilic aromatic
substitution to proceed, the substrates need to contain one
methoxy group, which served as an electron-donating group of
aromatic nucleophiles. It is important to note that the
resonance effect of the methoxy group at the 3-position
(entry 3) also gave the desired product in a comparable yield
(93%). Unfortunately, the substrate containing a 2,4,5-
trimethoxybenzyl group (17e) failed to give the desired
product; only compound 27e was obtained in 40% yield. This
result showed that the inductive effect of the 2,4-dimethoxy
group imposed a stronger effect than the resonance effect of
the 5-methoxy group (entry 5). These results demonstrated
that the resonance effect of the 3-substituent group was very
Scheme 3. Preparation of Compounds 17e and 17f
reaction sequence as discussed above to give compound 17t in
83% yield (Scheme 4).30
According to the previous works,23 TfOH was the best acid
to induce the generation of an iminium ion via azide
rearrangement. The reaction conditions were easily optimiz-
able using this acid. As we know, only TfOH in DCM or
toluene could be used for an azide rearrangement; therefore,
only the solvent and concentration of reactions were
C
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a
Table 2. Substrate Scope
a
Isolated yield.
crucial in this conversion. Next, the reaction of a substrate
containing 3-phenoxybenzyl yielded the desired product 18g in
a slightly lower yield (73%), possibly due to the lower
nucleophilicity of the 3-phenoxybenzyl group. To evaluate the
electronic effect of R1, several substrates were prepared and
subjected to the optimal conditions. Substrate 17h containing
a fluorine atom at position 7 on aryl ring A was converted to
the desired product 18h in 98% yield, while substrate 17i
D
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a
Table 3. In Vitro Cytotoxic Activity of Benzoazepine Analogues 18 against Normal Human Kidney Cell Line (HEK)
a
Benzoazepine analogues were tested as free bases.
containing a methoxy group at position 8 on aryl ring A
underwent the reaction to provide the benzoazepine product
18i in a much lower yield (54%). This was to be expected as
electron-rich benzyl azide derivatives provided unstable
iminium ion intermediates leading to decomposition and
giving products in low yields. On the contrary, the substrate
containing a chlorine atom at the same position could furnish
the desired product 18j in excellent yield (97%).
Next, substrates bearing a more highly nucleophilic group
than the benzyl group, such as α- and β-naphthylmethyl groups
(17k and 17l), were examined. However, the reactions were
unsuccessful in both cases. Substrates containing a variety of R1
on a 1-(azidomethyl)-2-(3-methoxybenzyl)benzene core struc-
ture were next studied (entries 13−19). Compound 17m (R1
= 7-F) smoothly converted to the desired product in 95%
yield. Moreover, compounds containing a fluorine atom at
other positions, compounds 17n (R1 = 9-F) and 17o (R1 = 10-
F), were also examined. The reactions of these substrates
provided the corresponding products in 99 and 94% yields,
respectively. Furthermore, substrates with chlorine substituents
were prepared and subjected to the optimal conditions. Thus,
the reactions of compounds 17p (R1 = 8-Cl) and 17q (R1 = 9-
Cl) gave the corresponding products 18p and 18q in 75 and
92% yields, respectively. These results showed that substrates
containing a halogen atom at various positions were well-
tolerated under these conditions; their presence did not
significantly affect the yields of products. In the case of
substrate 17r, bearing 5-methoxybenzyl azide, the reaction
provided the desired product in 75% yield, which was better
than the result of compound 17i possibly due to the OMe
group being more electron-donating than the OPh group,
making the aryl ring become more nucleophilic in adding to an
iminium ion intermediate. However, these conditions were not
compatible with the dioxymethylene protecting group in
substrate 17s, leading to decomposition of the substrate to
give the corresponding product 18s in 12% yield. Moreover,
this method was also applied to synthesize eight-membered
product 18t (entry 20), which produced a 53% yield of the
eight-membered product.
In vitro cytotoxicity evaluation: Upon obtaining these
synthetic benzoazepine derivatives, all of them were subjected
to evaluation of their cytotoxicity. The results are shown in
Table 3. A total of 14 benzoazepine analogues in their free base
forms were subjected to in vitro cytotoxicity evaluation. The
cytotoxic assay was performed against a normal human kidney
cell line (HEK) using the MTT method.31 The cytotoxicity of
diazepam was employed to compare with our tested
compounds. It is important to note that several tested
compounds have low toxicity, especially compound 18c,
which had the lowest toxicity (IC50 = 65.68 μM) among the
series and had slightly higher cytotoxicity than diazepam (IC50
= 87.90 μM), which is currently used as an antianxiety drug.
E
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Figure 2. Effect of benzoazepine analogues on anxiety- and locomotion-related behaviors in rats as determined by EPM (three rats per group). (A)
The anxiety index reflected the exploratory behaviors (the greater anxiety index indicated higher anxiety). (B) The total open arm entry in normal
rats with acute 0.4, 2, or 10 mg/kg diazepam (DZP) or benzoazepine analogues (18c, 18h, 18j, 18n, and 18p). *p < 0.05, **p < 0.01, and ***p <
0.001 compared with the control nonstress vehicle (control)-treated group. †p < 0.05, ††p < 0.01, and †††p < 0.001 compared with the stress
DZP-treated group.
However, the toxicity increased when dimethoxy groups were
placed in aryl ring B of compound 18d having an IC50 value of
6.44 μM. Then, a substrate containing an OPh group at
position 3 was examined (entry 3, compound 18g) with the
toxicity enhanced to give an IC50 value of 4.43 μM. The results
from entries 1−3 suggested that compounds with an anisole
moiety exhibited less toxicity than dimethylresorcinol and
diaryl ether moieties. Interestingly, the addition of a fluorine
substituent at position 7 of aryl ring A in compound 18h could
decrease the toxicity of the compound with an IC50 value of
13.73 μM when compared with compound 18g. However, the
toxicity of compound 18i was increased when a methoxy
substituent was installed at carbon position 8 on aryl ring A,
giving an IC50 value of 2.12 μM. Therefore, we decided to
prepare the benzoazepine derivatives containing an anisole
moiety on aryl ring B while also varying the substituent groups
on aromatic ring A. Unexpected results were obtained when
the substrate contained a fluorine atom at position 7:
compound 18m (IC50 = 6.19 μM) exhibited significantly
higher toxicity than compound 18h with an IC50 value of 13.73
μM. In addition, we found that when a fluorine atom was
located at positions 9 (compound 18n) and 10 (compound
18o), it provided even higher toxicity with IC50 values of 0.16
and 0.77 μM, respectively. Changing from a fluorine
substituent to a chlorine atom, compound 18p, containing a
chlorine atom at position 8, showed lower toxicity with an IC50
value of 12.64 μM, while compound 18q, bearing a chlorine
atom at position 9, showed higher toxicity with an IC50 value of
2.29 μM.
value of 1.09 μM, whereas compound 18s containing a
methylenedioxy moiety could decrease the toxicity of the
benzoazepine analogue with an IC50 value of 14.46 μM.
However, the synthesis of this compound gave the desired
product in low yield. In further evaluation, the substrate with a
larger cyclic amine, tetrahydrodibenzoazocine 18t, was
prepared, which also provided the product in a moderate
yield. This compound showed an IC50 value of 14.11 μM. For
the biological activity evaluation, the four lowest toxicity
benzoazepine derivatives were selected. However, compounds
18s and 18t were excluded from the list, because the synthesis
of these compounds provided only low to moderate yields of
products that were not suitable for further study in drug
development. Therefore, compounds 18c, 18h, 18j, and 18p
were selected to test for their antianxiety property. In addition,
we also selected compound 18n having the highest toxicity in
this study to compare the results with the lowest toxicity
compounds.
Effect of benzoazepine analogues on anxiety- and
locomotion-related behaviors in rats: In this study, benzoaze-
pines 18c, 18h, 18j, 18n, and 18p were examined for their
anxiolytic property in rats. The stress was induced by restraint
stress induction. This method was accomplished to induce the
anxiety-like behaviors in rats in numerous studies. Initially,
stress was induced in rats by being immobilized in a plastic
restrainer for 2 h/day for 14 days. The stress was evaluated
using two methods including elevated plus maze (EPM) and
open field test (OFT).32,33 As compared to the control group,
the 2-week stress induction showed anxiety-like behavior as
demonstrated by both EPM and OFT. To establish a suitable
dose of substances for antianxiety evaluation in rats, diazepam
In the case of compound 18r containing a methoxy group at
position 8, it also provided an unimpressive result with an IC50
F
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Figure 3. Effect of benzoazepine analogues on anxiety-like behaviors in stressed rats as determined by EPM (six rats per group). (A) The percent
open arm entry, (B) the percent open arm time, and (C) the anxiety index in stressed rats with acute 2 mg/kg diazepam (DZP) or benzoazepine
analogues (18c, 18h, 18j, 18n, and 18p). **p < 0.01 and ***p < 0.001 compared with the control nonstress vehicle (Con)-treated group. †p <
0.05 and †††p < 0.001 compared with the stress vehicle (Veh)-treated group.
(DZP) and benzoazepine analogues (18c, 18h, 18j, 18n, and
18p) were employed for the screening for the optimal dosage
using EPM. The results were illustrated in Figure 2. For the
EPM test, 2 mg/kg DZP-treated rats showed a significant
decrease in anxiety index (Figure 2A), while 0.4 and 10 mg/kg
DZP-treated rats did not change in the total open arm entry.
Similarly, the treatment of 2 mg/kg of benzoazepine analogues
(18c, 18h, 18j, 18n, and 18p) had not affected locomotor
activity as compared to the vehicle control group (Figure 2B).
Therefore, diazepam (2 mg/kg) and benzoazepine analogues
(2 mg/kg) were proposed to be a suitable anxiolytic dose for
the study of anxiolytic-like effects of benzoazepine analogues in
the animal model.
The elevated plus maze (EPM) test: The effect of
benzoazepine analogues (18c, 18h, 18j, 18n, and 18p) on
anxiety-like behaviors in nonstressed control rats and stressed
rats was determined using EPM. This protocol correlated the
fear of novelty and open spaces with stress. The behavior of
rats with a high percentage of the frequency of open-space
entries and high percentage of time spent in the open arms was
used to indicate a decrease of stress level in rats. To determine
the therapeutic effects of benzoazepine analogues on the
anxiety-like behaviors, stressed rats were administered with 2
mg/kg of test compounds for 30 min prior to the behavioral
tests. In this study, all experiments were conducted employing
six rats per group. The results in Figure 3A showed that the
percentage of the open arm entry of nonstressed rats (Con)
was significantly higher than the stressed rats (Veh). These
results showed that the restraint stress induction was successful
to induce anxiety-like behaviors in rats (Veh). Next, the
stressed rats were treated with diazepam (DZP), an antianxiety
drug, which resulted in a slightly lower percent open arm entry
compared with Con. These results showed the effectiveness of
diazepam, which corresponded with the results from other
reported works. Acute amphetamine withdrawal rats were
found to show increased anxiety-like behavior in the EPM.34
Diazepam administration demonstrated anxiolytic efficacy in
hemiparkinsonian rats.35 In this study, five synthetic
benzoazepine analogues (18c, 18h, 18j, 18n, and 18p) were
evaluated for an antianxiety property. Interestingly, compound
18c containing a methoxy group at position 3 of aromatic ring
B provided a higher percent open arm entry than the DZP
standard. In addition, this compound showed very low
cytotoxicity against normal human kidney cell line (HEK
cells) with a comparable IC50 to diazepam. Then, compound
18h containing a fluorine atom at position 7 of aromatic ring A
and a phenoxy group at position 3 of aromatic ring B was
employed and showed the best activity among the tested
compounds and the DZP standard. Compound 18j containing
a phenoxy group at the same position with 18h and chlorine
atom at position 8 of aromatic ring A showed slightly lower
activity than compound 18h but provided a comparable
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Figure 4. Effect of benzoazepine analogue treatments on anxiety-like behaviors and locomotor activity in stressed rats as determined by OFT (six
rats per group). (A) The inner zone time, (B) the outer zone time, (C) the number of total lines crossed in stressed rats with acute 2 mg/kg
diazepam (DZP) or benzoazepine analogues (18c, 18h, 18j, 18n, and 18p). *p < 0.05 and ***p < 0.001 compared with the control nonstress
vehicle (Veh)-treated group. ††p < 0.01 and †††p < 0.001 compared with the stress vehicle (Veh)-treated group. #p < 0.05, ##p < 0.01, and ###p
< 0.001 compared with the stress DZP-treated group.
activity to DZP. In the case of compound 18n containing a
fluorine atom and methoxy group at positions 9 of ring A and 3
of ring B, respectively, displayed the lowest percent open arm
entry among tested compounds. Meanwhile, compound 18p
containing a chlorine atom and methoxy group at positions 8
of ring A and 3 of ring B, respectively, provided a comparable
activity with the diazepam standard. This study showed that all
tested benzoazepines had a significant effect in reducing the
anxiety level of stressed rats, especially compounds 18c and
18h, which showed higher efficacy than the diazepine drug. In
addition, time spent in open arms was also examined as shown
in Figure 3B. The results showed that only compound 18c
showed the highest amount of time spent in the open arms by
the stressed rats when compared with DZP and other synthetic
benzoazepines (18h, 18j, 18n, and 18p). In addition,
compounds 18h, 18j, and 18p showed a comparable amount
of time spent in open arms with DZP, whereas compound 18n
had the lowest ability to reduce anxiety in the stressed rats.
Figure 3C indicated the increased anxiety level of rats. These
results clearly showed an anxiolytic property of benzoazepine
analogues in stressed rats. It is important to note that
compound 18c gave the best antianxiety property compared
with diazepam and other benzoazepine analogues.
activity in stressed rats was determined by an OFT test (six rats
per group). According to the OFT results, restraint stress
induction was successful to induce anxiety-like behaviors in
rats as shown in Figure 4. For the OFT test, a decrease in the
inner zone time indicated a high anxiety level of rats while
changing the number of total lines crossed and rearing
correlated to locomotor activity and a tendency to want to
explore the spaces of rats, respectively. In our study, the results
showed that the stressed rats had a lower amount of time spent
in the inner zone (Figure 4A) and spent more time in the outer
zone (Figure 4B) without any alteration in the number of total
lines crossed (Figure 4C). Next, the stressed rats were treated
with the DZP standard when measuring a stress response; we
found that rats spent more time both in the inner and outer
zones (Figure 4A,B) and also showed a lower number of
rearing than vehicle-treated stressed rats (Veh) (Figure 4C). In
addition, the treatment of stressed rats with DZP could alter
the number of line crossings in the OFT test (Figure 4C).
Compared to vehicle-treated stressed rats (Veh, Figure 4A),
rats treated with benzoazepine analogues, 18c, 18h, 18j, 18n,
and 18p, displayed a significant increase in the time spent in
the inner zone of OFT (Figure 4A). It should be noted that
compound 18n demonstrated a higher increase in the amount
of time spent in the inner zone by the stressed rats compared
to the DZP-treated ones. Moreover, all tested compounds,
The open field test (OFT) test: The effect of benzoazepine
analogue treatments on anxiety-like behaviors and locomotor
H
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including DZP, showed hyperlocomotor activity in stressed
rats as illustrated in Figure 4C. Therefore, these results
suggested that benzoazepine analogues possessed anxiolytic
effects and could enhance the behavior response in stressed
rats without the sedative effect.
Education, Bangkok 10210, Thailand; Chulabhorn Research
Institute, Bangkok 10210, Thailand
Complete contact information is available at:
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In conclusion, we have developed a new method for the
synthesis of benzoazepine analogues using azide rearrangement
chemistry. In this work, 14 derivatives were successfully
prepared in moderate to excellent yields. All benzoazepine
analogues were evaluated for their cytotoxicity against normal
human kidney cell line (HEK cell). The results showed that
several compounds had low cytotoxicity. A total of five
derivatives were employed to evaluate the antianxiety property
including compounds 18c, 18h, 18j, 18n, and 18p. In this
work, we discovered that compound 18c had higher potency to
reduce the anxiety of the stressed rats and also had very low
cytotoxicity comparable with diazepam. Therefore, compound
18c could be used as a lead compound for further drug
development to treat patients with anxiety disorder.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research project is supported by Thailand Science
Research and Innovation (FFB640035 Project code 50170)
and Project code 69864, Chulabhorn Graduate Institute,
Chulabhorn Royal Academy, Chulabhorn Research Institute,
and the Center of Excellence on Environmental Health and
Toxicology, Science & Technology Postgraduate Education
and Research Development Office (PERDO), Ministry of
Education. In addition, we would like to thank Ms. Warabhorn
Rodphon for drawing the table of content graphic in this
manuscript.
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REFERENCES
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1
Copies of H and 13C NMR spectra for compounds
21a−21c, 21g−21l, 21n−21s, 23e, and 26. Copies of
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1
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AUTHOR INFORMATION
Corresponding Author
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Jumreang Tummatorn − Program on Chemical Sciences,
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Authors
Onrapak Reamtong − Department of Molecular Tropical
Medicine and Genetics, Faculty of Tropical Medicine,
Mahidol University, Bangkok 10400, Thailand
Sarawut Lapmanee − Preclinical Department, Faculty of
Medicine, Siam University, Bangkok 10160, Thailand
Nitwaree Palavong − Program on Chemical Sciences,
Chulabhorn Graduate Institute, Center of Excellence on
Environmental Health and Toxicology, CHE, Ministry of
Education, Bangkok 10210, Thailand
Charnsak Thongsornkleeb − Program on Chemical Sciences,
Chulabhorn Graduate Institute, Center of Excellence on
Environmental Health and Toxicology, CHE, Ministry of
Education, Bangkok 10210, Thailand; Chulabhorn Research
Institute, Bangkok 10210, Thailand; orcid.org/0000-
0003-2653-5137
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