Design, synthesis and biological evaluation of 6-substituted aminocarbonyl benzimidazole derivatives as nonpeptidic angiotensin II AT1 receptor antagonists

Wang, Jinliang; Zhang, Jun; Zhou, Zhiming; Li, Zhi-Huai; Xue, Wei-Zhe; Xu, Di; Hao, Liping; Han, Xiao-Feng; Fan, Fei; Liu, Ting; Liang, Aihua

doi:10.1016/j.ejmech.2012.01.009

Cited by 35 publications

(16 citation statements)

References 27 publications

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“…Gyrophoric acid from virtual screening was further assessed to antagonize AT1 in recombinant cells (HEK293/Ga15/AT1 cells) using the intracellular calcium influx assay. Telmisartan was used as positive control for AT1 assays with IC 50 of 1.83 nM, which were very close to literature 36,37 . Gyrophoric acid was confirmed to be a validated AT1 antagonist with IC 50 of 29.76 μM (Fig.…”

Section: Resultssupporting

confidence: 69%

Discovery of Novel Multi-target Inhibitor of angiotensin type 1 receptor and neprilysin inhibitors from Traditional Chinese Medicine

Huo¹,

Qiao²,

Chen³

et al. 2019

Sci Rep

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Angiotensin II type-1 receptor–neprilysin inhibitor (ARNi) is consisted of Angiotensin II type-1 receptor (AT1) antagonist and neprilysin (NEP) inhibitor, which could simultaneously increase the vasodilators of the natriuretic peptides and antagonize vasoconstrictors of Ang II. ARNi has been proved a superior effect and lower risks of death on chronic heart failure (CHF) and hypertension. In this paper, ARNi from Traditional Chinese Medicines (TCM) was discovered based on target combination of AT1 and NEP by virtual screening, biological assay and molecular dynamics (MD) simulations. Two customized strategies of combinatorial virtual screening were implemented to discover AT1 antagonist and NEP inhibitor based on pharmacophore modeling and docking computation respectively. Gyrophoric acid (PubChem CID: 135728) from Parmelia saxatilis was selected as AT1 antagonist and assayed with IC50 of 29.76 μM by calcium influx assay. And 3,5,3′-triiodothyronine (PubChem CID: 861) from Bos taurus domesticus was screened as NEP inhibitor and has a dose dependent inhibitory activity by biochemistry fluorescence assay. Combined with MD simulations, these compounds can generate interaction with the target, key interactive residues of ARG167, TRP84, and VAL108 in AT1, and HIS711 in NEP were also identified respectively. This study designs the combinatorial strategy to discover novel frames of ARNi from TCM, and gyrophoric acid and 3,5,3′-triiodothyronine could provide the clues and revelations of drug design and therapeutic method of CHF and hypertension for TCM clinical applications.

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Section: Resultssupporting

confidence: 69%

Discovery of Novel Multi-target Inhibitor of angiotensin type 1 receptor and neprilysin inhibitors from Traditional Chinese Medicine

Huo¹,

Qiao²,

Chen³

et al. 2019

Sci Rep

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“…The determination of the absolute conformation of the drugs targeting AT1R through 2D NOESY experiments has been also applied to 6-substituted aminocarbonylbenzimidazole derivatives [31] aiming to inhibit AT1R's action.…”

Section: Conformational Properties Drug Action and Stability Of At1r Antagonists In Solventsmentioning

confidence: 99%

On the Rational Drug Design for Hypertension through NMR Spectroscopy

2020

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Antagonists of the AT1receptor (AT1R) are beneficial molecules that can prevent the peptide hormone angiotensin II from binding and activating the specific receptor causing hypertension in pathological states. This review article summarizes the multifaced applications of solid and liquid state high resolution nuclear magnetic resonance (NMR) spectroscopy in antihypertensive commercial drugs that act as AT1R antagonists. The 3D architecture of these compounds is explored through 2D NOESY spectroscopy and their interactions with micelles and lipid bilayers are described using solid state 13CP/MAS, 31P and 2H static solid state NMR spectroscopy. Due to their hydrophobic character, AT1R antagonists do not exert their optimum profile on the AT1R. Therefore, various vehicles are explored so as to effectively deliver these molecules to the site of action and to enhance their pharmaceutical efficacy. Cyclodextrins and polymers comprise successful examples of effective drug delivery vehicles, widely used for the delivery of hydrophobic drugs to the active site of the receptor. High resolution NMR spectroscopy provides valuable information on the physical-chemical forces that govern these drug:vehicle interactions, knowledge required to get a deeper understanding on the stability of the formed complexes and therefore the appropriateness and usefulness of the drug delivery system. In addition, it provides valuable information on the rational design towards the synthesis of more stable and efficient drug formulations.

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“…Wang JL et al [15], reported that a series of 6-substituted aminocarbonyl benzimidazole derivatives (Figure 15, Table 3) were designed and synthesized as nonpeptidic angiotensin II AT1 receptor antagonists. The preliminary pharmacological evaluation revealed nanomolar AT1 receptor binding affinity and good AT1 receptor selectivity over AT2 receptor for all compounds of the series.…”

Section: Figure 14: 6-substituted Aminocarbonyl Benzimidazole Derivativementioning

confidence: 99%

A Review On Substituted Benzimidazoles: Biologically Active Compounds

Madawali¹,

N²,

Kalyane³

et al. 2019

AJPTR

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Benzimidazole is the heterocyclic compound which contains a phenyl ring fused to an imidazole ring, Benzimidazole analogs are of crucial importance because of their different clinical applications and biological activity. Benzimidazoles are known as an optimistic class of bioactive heterocyclic compounds possessing a wide variety of biological activities. Benzimidazole derivatives play an important role in medical field with so many pharmacological activities such as antimicrobial, antiviral, anticancer activity, antioxidant, antiparasitic, antiproliferative, antitumor, anti-HIV, anticonvulsant, antiprotozoal, analgesic and anti-inflammatory, antihypertensive, anticancer, androgen receptor antagonist, vasorelaxant etc. This review is summarized to understand the chemistry of various derivatives of substituted benzimidazoles with their pharmacological activities.

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Design, synthesis and biological evaluation of 6-substituted aminocarbonyl benzimidazole derivatives as nonpeptidic angiotensin II AT1 receptor antagonists

Cited by 35 publications

References 27 publications

Discovery of Novel Multi-target Inhibitor of angiotensin type 1 receptor and neprilysin inhibitors from Traditional Chinese Medicine

Discovery of Novel Multi-target Inhibitor of angiotensin type 1 receptor and neprilysin inhibitors from Traditional Chinese Medicine

On the Rational Drug Design for Hypertension through NMR Spectroscopy

A Review On Substituted Benzimidazoles: Biologically Active Compounds

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