Subscriber access provided by University of Birmingham
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
Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.
Page 1 of 8 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
ACS Medicinal Chemistry Letters
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 2Shanghai Xianhui Pharmaceutical Co., Ltd., Shanghai 200433, China Corresponding Author: Yi-Jia Yan, Email:
[email protected]; Zhi-Long Chen, Email:
[email protected] 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 antihypertension drug candidates. associated with hydrophobic pocket of the AT1 1. Introduction receptor, and an acidic group like COOH and Hypertension is one of the most shared tetrazole at the ortho position of the biphenyl cardiovascular disease in the world, which has [1, 3] group which will bind to a basic position of the significant morbidity and mortality . There are receptor, are required for potent anti-hypertension about 200 million hypertension patients in the activity. The biphenyl moiety, which acts as a world, and is increasing by 10% every year. The spacer connecting the acidic group with other renin angiotensin system (RAS) consists of a features, could be replaced by other similar cascade of enzymatic reactions which plays a spacers such as N-phenyl indole [10]. The crucial role in the electrolyte/fluid homeostasis imidazole ring could also be replaced by other and regulation of blood pressure [3-6]. Angiotensin heterocyclic ring like benzimidazole to act as an II receptor 1 antagonist (ARB) is a novel class of acceptor in a hydrogen-bonding interaction with antihypertensive drug with the characteristics of [7, the receptor [13-16]. Further studies to the high potency, long-term effect and low toxicity 8]. Several ARBs have been discovered and benzimidazole derived AT1 antagonists showed that periphery substitution to the benzimidazole clinically used after modification of Losartan ring with basic heterocycles could result potent (Fig.1) which is the first drug used in clinics [8-10]. AT1 antagonist like telmisartan [13]. A methyl These ARBs can block the effects of angiotensin group in position 4 of the benzimidazole ring will II by selectively antagonizing the AT1 receptor [1011]. The angiotensin II receptor blockers, regarded be helpful to reduce the metabolism rate in vivo. as antihypertensive drugs, have developed rapidly and occupied the main position of the market over the past 30 years. Structure-activity relationships of Losartan have been reported [12]. A lipophilic liner alkyl group at the 2-position of imidazole which will
H
H L1
Cl
H
N
HO
N
N L1
N N N N
ACS Paragon Plus Environment
H
N N
O
H
L1
N
N
1
H
O N
O
H O
O
H Lorsartan
N
N
N
1b / 2b
ACS Medicinal Chemistry Letters 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Fig.1 Binding profile of Losartan, 1 and 1b\2b where L1 is lipophilic pockets and H is H-bond donor site. 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 6benzoxazole substituted benzimidazole derivatives with 1, 4- or 1, 5- disubstituted indoles moieties (1a - f, 2a - f) (Fig.1) were prepared and evaluated.
2. Results and discussion 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-4formaldehyde 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.
Page 2 of 8 OHC 4 5
OHC 4 5
5 N
a
OH 4
N
b CN
c CN
N H
5
5a 4-CH2OH 5b 5-CH2OH
4a 4-CHO 4b 5-CHO
3a 4-CHO 3b 5-CHO OH 4
5
OH 4 5
d
N
Br 4
e
N
N
COOCH3
COOH
6a 4-CH2OH 6b 5-CH2OH
COOCH3
7a 4-CH2OH 7b 5-CH2OH
8a 4-CH2Br 8b 5-CH2Br
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. The benzimidazoles10a-c were prepared from the commercially available methyl 4-amino3-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. 10ac were hydrolyzed by 2M sodium hydroxide solution in methanol, the resulted acids were condensed and cyclized with 2-amino-3methylphenol/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, 13af 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% . NH2 H3COOC
R2 N
a,b,c,d
N H
H3COOC
R1
e,f
N
N
O
N H
R3 9
10a-c 10a: R1=Et 10b: R1=n-pr 10c: R1=n-Bu
11a-f 11a: R1=Et, R2=Me, R3=H, 11b: R1=n-pr, R2=Me, R3=H, 11c: R1=n-Bu, R2=Me, R3=H, 11d: R1=Et, R2=H, R3=Me, 11e: R1=n-pr, R2=H, R3=Me, 11f: R1=n-Bu, R2=H, R3=Me,
Scheme 2. Reagents and reaction conditions: (a) RCOCl, Et3N, DCM; (b) Fuming HNO3, -15oC; (c) Raney
ACS Paragon Plus Environment
R1
Page 3 of 8 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
ACS Medicinal Chemistry Letters
Ni, N2H4.H2O; (d) CH3COOH, reflux; (e) NaOH, H2O，
2-amino-3-methylphenol/2amino-6-methylphenol, PPA, 150 oC. MeOH,
reflux;
(f)
R2
N R1 11a-f + 8a
N
R1
O
a
R2
N
N b
N
O R3 COOH
1a: R1=Et, R2=Me, R3=H, 1b: R1=n-pr, R2=Me, R3=H, 1c: R1=n-Bu, R2=Me, R3=H, 1d: R1=Et, R2=H, R3=Me, 1e: R1=n-pr, R2=H, R3=Me, 1f: R1=n-Bu, R2=H, R3=Me,
12a-f
R2
N
11a-f + 8b
R2
R3
IC50±SE M (nM)
Ki (nM)
1a
Et
Me
H
10.3 ± 1.6
7.5 ± 0.8
1b
n-Pr
Me
H
4.0 ± 0.5**
2.9 ± 0.2
1c
n-Bu
Me
H
9.9 ± 0.9
7.2 ± 0.6
1d
Et
H
Me
12.1 ± 0.3
8.8 ± 1.2
R1
O
1e
n-Pr
H
Me
5.3 ± 1.1**
3.8 ± 0.9
R3
a
1f
n-Bu
H
Me
10.5 ± 1.8
7.6 ± 1.2
2a
Et
Me
H
12.0 ± 1.7
8.7 ± 1.6
2b
n-Pr
Me
H
4.4 ± 0.2**
3.2 ± 0.2
2c
n-Bu
Me
H
10.7 ± 2.3
7.7 ± 1.7
2d
Et
H
Me
13.6 ± 1.5
9.8 ± 0.2
2e
n-Pr
H
Me
5.6 ± 0.8**
4.0 ± 0.6
2f
n-Bu
H
Me
9.7 ± 0.9*
7.0 ± 0.5
Losarta n
/
14.6 ± 1.6
10.5 ± 1.2
1a-f
R2
N
N
N
N
N
O
b
R3
N
N COOCH3
13a-f
R1
N COOCH3
R1
Compou nd
N
R3 N
2a- f, Losartan (*P
