Research paper
Design, synthesis and biological evaluation of AT1 receptor blockers derived from 6-substituted aminocarbonyl benzimidazoles

https://doi.org/10.1016/j.ejmech.2019.07.056Get rights and content

Highlights

  • •

    A series of new 6-substituted aminocarbonyl benzimidazoles derivatives with 1, 4-disubsituted or 1, 5-disubsituted indole moiety and benzoic acid moiety were designed and synthesized.

  • •

    Remarkably compounds 1h and 2e displayed the highest specific affinity to the AT1 receptor with the IC50 value of 2.3 ± 0.9 nM and the Ki value of 1.9 ± 0.8 nM.

  • •

    Notably, 2e and 1h were much more potent compounds with maximal reducing response 57.9 ± 2.3 mmHg and 57.6 ± 1.9 mmHg of MBP separately at 10 mg/kg after oral administration.

Abstract

A series of new 6-substituted aminocarbonyl benzimidazole derivatives with 1, 4-disubsituted or 1, 5-disubsituted indole moiety and benzoic acid moiety were designed, synthesized and pharmacologically evaluated. Most of the synthesized compounds could bind to the AT1 receptor and decrease blood pressure significantly. Notably, 2e and 1h could obviously decrease MBP in a dose dependent manner. The maximal response lowered 57.9 ± 2.3 mmHg (2e) and 57.6 ± 1.9 mmHg (1h) of MBP at 10 mg/kg after oral administration, and the antihypertensive effect lasted beyond 24 h, which performed better than Losartan (Fig. 1). These results indicate that 2e and 1h are effective and long-lasting anti-hypertension drug candidates and deserve further investigation for therapeutic application.

Graphical abstract

Compounds 1h and 2e have a high affinity to AT1 receptor and efficient anti-hypertensive effect.

Image 1
  1. Download : Download high-res image (94KB)
  2. Download : Download full-size image

Introduction

With significant morbidity and mortality, hypertension is one of the leading risk factors for heart attacks and strokes [1,2]. Nowadays, more than one billion people suffer from high blood pressure which causes more than 9.4 million deaths every year [3,4]. The renin-angiotensin system (RAS) consists of a cascade of enzymatic reactions which play a crucial role in the pathophysiology of hypertension [5]. AT1 receptor blockers (ARBs or sartans) are a novel class of antihypertensive drugs which share a common mechanism by blocking the harmful reaction of octapeptide hormone angiotensin II to motivate AT1 receptors. Until now, several ARBs have been discovered such as Losartan, Irbersartan, Candesartan, Telmisartan. They have the characteristics of high potency, long-term effect and low toxicity [6]. Most of these drugs share common structural features represented by a biphenyl fragment bearing an acidic moiety (COOH, tetrazole ring, SO2NHCO, etc), and a heterocycle moiety connecting with biphenyl fragment through a methylene group [7]. The modification of the heterocycle moiety, especially imidazole moiety is a primary strategy to design new nonpeptide Ang II antagonists. Among the wide varieties of heterocycles, the ortho-fused bicyclic moiety benzimidazole seems to be the most potent which is exemplified by the commercially available Telmisartan (Fig. 1) [8,9] (see Fig. 2).

As a noncompetitive antagonist used extensively in the treatment of hypertension, Telmisartan can prevent the potential development of cardiovascular diseases through inhibiting atherosclerosis, improving sugar metabolism and so on [[10], [11], [12]]. Though replacement of biphenyl moiety by N-phenyl indole group in Telmisartan structure, some antihypertensive compounds with high efficiency and low toxicity were discovered in our previous work [13,14]. It was reported that the 6-position of benzimidazole occupied by a carbamoyl group could contribute additional hydrogen-binding [14], which encouraged us to introduce an alkyl-chain with phenyl group to 6-position.

Here, a series of new 6-substituted aminocarbonyl benzimidazoles derivatives with 1, 4- or 1, 5-disubsituted indole moiety and benzoic acid moiety were designed, synthesized and pharmacologically evaluated (compounds 1a - l, 2a – i).

Section snippets

Chemistry

The synthesis of target compounds was shown in Scheme 1, Scheme 2. The indole-4-methylbromide 3a or indole-5-methylbromide 3b were synthesized according to our previous work from indole-4-formaldehyde or indole-5-formaldehyde [15] which were used in subsequent synthetic transformations. The substituted benzimidazoles (6a - c) were prepared from methyl 4-amino-3-methylbenzoate (4a) following the previously reported method [16]. Phenylamine 4a was reacted with acyl chlorides with the existence of

Conclusion

A series of new 6-substituted aminocarbonyl benzimidazoles derivatives with 1, 4-disubsituted or 1, 5-disubsituted indole acid moiety and benzoic acid moiety were designed and synthesized. They could bind to the AT1 receptor and decrease blood pressure obviously. Among them, compounds 1h and 2e exhibited effective antagonistic activities against angiotensin II receptor 1, and could reduce the blood pressure more significantly than Losartan. So compounds 1h and 2e could be considered as

Chemistry

All chemical reagents were purchased from commercial suppliers and applied without further purification. The progress of reactions was monitored through thin layer chromatography (TLC). The column chromatography was used for the purification of compounds with 300–400 meshes silica gel. Melting points (m. p.) were measured on an electro thermal melting point apparatus and were uncorrected. 1HNMR (400 MHz) and 13CNMR (101 MHz) spectra were measured on a Bruker NMR spectrometer with CDCl3 or DMSO‑d

Radioligand binding assay

The AT1 receptor binding assay was carried out with the vascular smooth muscle cells (VSMCs) (106 cells/well, 500 μL) which were gained from thoracic aorta of SD rats (Second Military Medical University, China) and performed at 37 °C, 5% CO2 in 24-well plates as described previously [19,20]. The test compounds and standards (Losartan) were dissolved in DMSO respectively and diluted to different concentrations (10−10 - 10−3 M) with PBS before experiments. 125I-Ang II (Zhongshan Hospital, Fudan

Acknowledgments

This work was supported by Foundation of the Shanghai Science and Technology Committee (No. 17431902600, 17430741800, 17430711900, 18430713000, 18411968000, 18410721700, 18430731600); the Fundamental Research Funds for the Central Universities (No.17D110513); The seed fund program of Shanghai University of Medicine & Health Sciences (SFP-18-21-13-001); The special program for collaborative innovation in Shanghai University of Medicine & Health Sciences (No.SPCI-18-13-001).

References (21)

There are more references available in the full text version of this article.

Cited by (5)

View full text
© 2019 Elsevier Masson SAS. All rights reserved.