Design, Synthesis, and Biological Evaluation of 6-Benzoxazole Benzimidazole Derivatives with Antihypertension Activities

Article abstract of DOI:10.1021/acsmedchemlett.8b00335

A series of new angiotensin II receptor 1 antagonists were prepared. They displayed nanomolar affinity to AT₁ receptor and could decrease blood pressure efficiently in spontaneously hypertensive rats. Among them, compounds 1b and 2b could reduce the blood pressure with more or equal potency compared to Losartan. So, compounds 1b and 2b could be considered as potential antihypertension drug candidates.

Full text of DOI:10.1021/acsmedchemlett.8b00335

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Letter
Design, synthesis and biological evaluation of 6-benzoxazole
ben-zimidazole derivatives with anti-hypertension activities
Zhuo Wu, Xiao-Lu Bao, Weibo Zhu, Yan-Hui Wang, Nguyen Thi
Phuong Anh, Xiao-Feng Wu, Yi-Jia Yan, and Zhi-Long Chen
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.8b00335 • Publication Date (Web): 31 Dec 2018
Downloaded from http://pubs.acs.org on January 1, 2019
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Design, synthesis and biological evaluation of 6-benzoxazole
benzimidazole derivatives with anti-hypertension activities
Zhuo Wu1, Xiao-Lu Bao1, Wei-Bo Zhu1, Yan-Hui Wang1, Nguyen Thi Phuong Anh1, Xiao-Feng Wu2,
Yi-Jia Yan2*, Zhi-Long Chen1*
1Department of Pharmaceutical Science and Technology, College of Chemistry and Biology, Donghua
University, Shanghai 201620, China
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2Shanghai Xianhui Pharmaceutical Co., Ltd., Shanghai 200433, China
Corresponding Author: Yi-Jia Yan, Email: y_yan11@sina.com; Zhi-Long Chen, Email:
zlchen1967@qq.com
Keywords: Hypertension; Antihypertension drug; Angiotensin II receptor 1 antagonist.
ABSTRACT: A series of new angiotensin II receptor 1 antagonists were prepared. They displayed
nanomolar affinity to AT1 receptor and could decrease blood pressure efficiently in spontaneously
hypertensive rats. Among them, compounds 1b and 2b could reduce the blood pressure with more or
equal potency compared to Losartan. So, compounds 1b and 2b could be considered as potential anti-
hypertension drug candidates.
1. Introduction
associated with hydrophobic pocket of the AT1
receptor, and an acidic group like COOH and
tetrazole at the ortho position of the biphenyl
group which will bind to a basic position of the
receptor, are required for potent anti-hypertension
activity. The biphenyl moiety, which acts as a
spacer connecting the acidic group with other
features, could be replaced by other similar
spacers such as N-phenyl indole [10]. The
imidazole ring could also be replaced by other
heterocyclic ring like benzimidazole to act as an
acceptor in a hydrogen-bonding interaction with
the receptor [13-16]. Further studies to the
benzimidazole derived AT1 antagonists showed
that periphery substitution to the benzimidazole
ring with basic heterocycles could result potent
AT1 antagonist like telmisartan [13]. A methyl
group in position 4 of the benzimidazole ring will
be helpful to reduce the metabolism rate in vivo.
Hypertension is one of the most shared
cardiovascular disease in the world, which has
significant morbidity and mortality [1, 3]. There are
about 200 million hypertension patients in the
world, and is increasing by 10% every year. The
renin angiotensin system (RAS) consists of a
cascade of enzymatic reactions which plays a
crucial role in the electrolyte/fluid homeostasis
and regulation of blood pressure [3-6]. Angiotensin
II receptor 1 antagonist (ARB) is a novel class of
antihypertensive drug with the characteristics of
high potency, long-term effect and low toxicity [7,
8]. Several ARBs have been discovered and
clinically used after modification of Losartan
(Fig.1) which is the first drug used in clinics [8-10]
.
These ARBs can block the effects of angiotensin
II by selectively antagonizing the AT1 receptor [10-
11]. The angiotensin II receptor blockers, regarded
as antihypertensive drugs, have developed rapidly
and occupied the main position of the market over
the past 30 years.
H
H
Cl
L1
H
N
HO
N
N
N
N
N
N
N
N
O
H
H
L1
L1
N
N
N
O
H
O
H
N
Structure-activity relationships of Losartan
have been reported [12]. A lipophilic liner alkyl
group at the 2-position of imidazole which will
N
N
O
O
H
Lorsartan
1b / 2b
1
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OH
4
Fig.1 Binding profile of Losartan, 1 and 1b\2b
OHC
5
4
5
1
2
3
4
5
6
7
8
where L1 is lipophilic pockets and H is H-bond
donor site.
4
N
N
OHC
5
b
c
a
CN
CN
N
H
5a
5b
4a
4b
4-CH2OH
5-CH2OH
3a
3b
4-CHO
5-CHO
4-CHO
5-CHO
In a previous paper [17], we reported an
effective and long-lasting anti-hypertension
compound (1) with dibenzimidazole, indole and
benzoic acid moieties. Here a series of 6-
OH
4
OH
4
Br
4
5
5
5
d
e
N
N
N
COOCH3
COOH
COOCH3
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6a
6b
4-CH2OH
5-CH2OH
7a
7b
4-CH2OH
5-CH2OH
8a
8b
4-CH2Br
5-CH2Br
benzoxazole
substituted
benzimidazole
derivatives with 1, 4- or 1, 5- disubstituted indoles
moieties (1a - f, 2a - f) (Fig.1) were prepared and
evaluated.
Scheme 1. Reagents and reaction conditions: (a)
2- Fluor benzonitrile, K2CO3, DMF, reflux; (b)
NaBH4, EtOH, THF, ice bath; (c) NaOH, DMF,
reflux; (d) CH3I, dichloromethane; (e) HBr/ AcOH
(35%), dichloromethane, ice bath.
2. Results and discussion
The benzimidazoles10a-c were prepared
from the commercially available methyl 4-amino-
3-methylbenzoate (9) through four-step procedure
reported by our laboratory as shown in Scheme 2
[17-18]. Phenylamine 9 was reacted with acyl
chlorides in dichloromethane, then nitrated with
Fuming HNO3. The resulted nitrobenzene was
hydrogenated with Raney Ni, and then cyclized in
acetic acid to produce benzimidazoles 10a-c. 10a-
c were hydrolyzed by 2M sodium hydroxide
solution in methanol, the resulted acids were
condensed and cyclized with 2-amino-3-
methylphenol/2-amino-6-methylphenol in the
presence of polyphosphoric acid to give
benzimidazole derivatives 11a-f in yield 38.5% -
55.2%. 11a-f were alkylated with indole methyl
bromides 8a or 8b in DMF to generate 12a-f, 13a-
f in yields over 40%, then hydrolyzed with 2M
sodium hydroxide solution in methanol to afford
the 1a-f or 2a-f with yield 40.3% to 49.0% .
2.1 Chemistry
Compounds 1a - f and 2a - f were
synthesized by multi-step procedure outlined in
Schemes 1 to 3.
As shown in Schemes 1, indole-4-
formaldehyde 3a or indole - 5 - formaldehyde 3b
was reacted with 2- Fluor benzonitrile to afford
compound 4a or 4b in yield about 89% according
to our previously reported methods [17]. 4a or 4b
was hydrogenated with sodium borohydride in the
mixed solution of ethanol and tetrahydrofuran at 0
oC to provide alcohol 5a or 5b in yield about 93%
or 85%. After hydrolyzation of 5a or 5b by
sodium hydroxide in boiling DMF in yield of 87%
or 94%, the resulting acid 6a or 6b was reacted
with iodomethane in dichloromethane to give
methyl benzoate compounds 7a or 7b in yield 96%
or 93%. Compound 8a or 8b, which was obtained
after the bromination of compounds 7a or 7b with
HBr saturated AcOH in yield 90% or 87%, was
used in subsequent reactions.
R2
NH2
N
e,f
N
O
a,b,c,d
R1
N
N
H
H3COOC
H3COOC
R1
N
H
R3
10a-c
11a-f
9
11a
11b
11c
11d
11e
: R1=Et, R2=Me, R3=H,
: R1=n-pr, R2=Me, R3=H,
: R1=n-Bu, R2=Me, R3=H,
: R1=Et, R2=H, R3=Me,
: R1=n-pr, R2=H, R3=Me,
: R1=n-Bu, R2=H, R3=Me,
10a
10b
10c
: R1=Et
: R1=n-pr
: R1=n-Bu
11f
Scheme 2. Reagents and reaction conditions: (a)
RCOCl, Et3N, DCM; (b) Fuming HNO3, -15oC; (c) Raney
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Ni, N2H4 H2O; (d) CH3COOH, reflux; (e) NaOH, H2O，
MeOH, reflux; (f) 2-amino-3-methylphenol/2-
amino-6-methylphenol, PPA, 150 oC.
2a- f, Losartan (*P<0.05, **P<0.01 VS Losartan).
1
2
3
Compou R1
nd
R2 R3
IC50±SE
M (nM)
Ki (nM)
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
Et
Me
H
H
H
10.3 ± 1.6
4.0 ± 0.5**
9.9 ± 0.9
7.5 ± 0.8
2.9 ± 0.2
7.2 ± 0.6
8.8 ± 1.2
3.8 ± 0.9
7.6 ± 1.2
8.7 ± 1.6
3.2 ± 0.2
7.7 ± 1.7
9.8 ± 0.2
4.0 ± 0.6
7.0 ± 0.5
R2
R2
N
N
N
N
N
O
N
O
R1
R1
b
a
11a-f + 8a
n-Pr Me
n-Bu Me
R3
R3
N
N
COOCH3
COOH
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1a
1b
1c
1d
1e
: R1=Et, R2=Me, R3=H,
: R1=n-pr, R2=Me, R3=H,
: R1=n-Bu, R2=Me, R3=H,
: R1=Et, R2=H, R3=Me,
: R1=n-pr, R2=H, R3=Me,
: R1=n-Bu, R2=H, R3=Me,
12a-f
1a-f
Et
n-Pr
H
H
Me 12.1 ± 0.3
Me 5.3 ± 1.1**
Me 10.5 ± 1.8
1f
R2
R2
N
N
N
N
O
N
O
R1
R1
N
b
R3
COOCH3
a
R3
11a-f + 8b
N
N
n-Bu
Et
H
COOH
2a
2b
2c
2d
2e
: R1=Et, R2=Me, R3=H,
: R1=n-pr, R2=Me, R3=H,
: R1=n-Bu, R2=Me, R3=H,
: R1=Et, R2=H, R3=Me,
: R1=n-pr, R2=H, R3=Me,
: R1=n-Bu, R2=H, R3=Me,
2a
2b
2c
2d
2e
2f
Me
H
H
H
12.0 ± 1.7
4.4 ± 0.2**
10.7 ± 2.3
2a-f
13a-f
2f
n-Pr Me
n-Bu Me
Scheme 3. Reagents and reaction conditions: (a)
NaH, DMF, 50 oC; (b) NaOH, H2O, CH3OH, reflux.
2.2 Biological evaluation
Et
n-Pr
H
H
H
Me 13.6 ± 1.5
Me 5.6 ± 0.8**
Me 9.7 ± 0.9*
2.2.1. Radioligand binding assays
The binding affinity of synthesized
compounds for Ang II receptor 1 in vitro were
detected using vascular smooth muscle cells in a
competition radioligand binding assay with [125I]
Ang II and as described previously [13, 19]. As
expected, they all displayed nanomolar affinity to
the AT1 receptor (Table 1, Fig. 2). Of these
compounds, 1b, 2b, 1e, 2e and 2f exhibited higher
affinity to AT1 receptor than Losartan (1b: IC50 =
4.0 ± 0.5 nM, Ki = 2.9 ± 0.2 nM; 2b: IC50 = 4.4 ±
0.2 nM, Ki = 3.2 ± 0.2 nM and losartan IC50 = 14.6
± 1.6 nM, Ki = 10.5 ± 1.2 nM). It was also found
that compounds with 1, 4-disubstituted indole
moiety have relative higher binding ability than
with 1, 5-disubstituted indole moiety. The receptor
affinity was not significantly influenced by methyl
substituents, regardless of their position of R2 or
R3. In these compounds the n-propyl residue in
position 2 of the benzimidazole gave higher
affinity than other alkyl groups.
n-Bu
/
Losarta
n
14.6 ± 1.6 10.5 ± 1.2
Fig. 2. Inhibitory effects of compounds 1b, 2b and
Losartan on the specific binding of 125I-Ang II to
AT1 receptors in VSMCs.
2.2.2. In vivo anti-hypertension effects
All compounds (5 mg/kg, 10 mg/kg) were
Table 1: IC50 and Ki value of compounds 1a - f,
tested for anti-hypertension effects in vivo to the
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mean blood pressure (MBP) in spontaneously
to the AT1 receptor and decrease blood pressure
significantly. Among them, compounds 1b and 2b
exhibited effective antagonistic activities against
angiotensin II receptor 1, and could reduce the
blood pressure with equal or more potency
compared to Losartan. So compounds 1b and 2b
could be considered as potential anti-hypertension
drug candidates and deserved further investigation.
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4
5
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hypertensive rats (SHRs) model after oral
administration. These compounds could decrease
blood pressure significantly at 5 mg/kg and 10
mg/kg (Fig. 3 and Fig. 4 in supporting
information). The maximal MBP reduction of 1b
was 54.57 ± 0.05 mmHg which was more potent
than Losartan, and 2b was 41.91 ± 6.34 mmHg
which was almost equal to Losartan (42.50 ± 4.64
mmHg) at the dose of 10 mg/kg respectively. The
significant (p < 0.01) antihypertensive effect of 1b
and 2b sustained for at least 24 h. No influence
was observed for these compounds on the heart
rates of rats.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available for free
on the ACS Publications website.
Experimental procedures for the biological
experiments and synthetic procedures and
characterization data for the compounds (PDF).
AUTHOR INFORMATION
Corresponding Author
* Email: zlchen1967@qq.com;
Email: y_yan11@sina.com
Present Addresses
† Department of Pharmaceutical Science and
Technology, College of Chemistry and Biology,
Donghua University, Shanghai 201620, China
Author Contributions
The manuscript was written through contributions
of all authors. / All authors have given approval to
the final version of the manuscript.
Acknowledgments
This work was supported by Foundation of the
Shanghai Science and Technology Committee
(No. 16ZR1400600, 17PJ1432800, 17431902600,
17430741800, 17430711900, 18430713000,
Fig. 3 Effects of 1b, 2b and Losartan on MBP of
SHRs (n = 6) (*P<0.05, **P<0.01 VS Control).
3. Conclusion
A series of new 6-substituted benzimidazoles
indole derivatives with 1, 4-disubsituted or 1, 5-
disubsituted indole moiety and benzoic moiety
were designed and synthesized. They could bound
18411968000, 18410721700，18430731600), the
Fundamental Research Funds for the Central
Universities (No.17D110513) ， Foundation of
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Songjiang
Science
District(No.16SJGG20),
and Technology
Ningbo
Bureau
antagonists as anti-hypertension drugs. Bioorg.
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Med. Chem. 2016, 24, 2023 - 2031.
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ACS Medicinal Chemistry Letters
Page 8 of 8
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Graphical abstract
Compounds 1b and 2b have a high affinity to AT1 receptor and efficient
anti-hypertensive effect.
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