更新于：2024-11-01

MAO-A x Cholinesterase x AChE

更新于：2024-11-01

基本信息

关联

项与 MAO-A x Cholinesterase x AChE 相关的药物

MT-031

靶点

AChE x Cholinesterase x MAO-A

作用机制

AChE抑制剂 [+2]

在研机构

Youdim Pharmaceuticals Ltd. [+1]

原研机构

Technion-Israel Institute of Technology

在研适应症

阿尔茨海默症

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 MAO-A x Cholinesterase x AChE 相关的临床结果

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100 项与 MAO-A x Cholinesterase x AChE 相关的转化医学

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0 项与 MAO-A x Cholinesterase x AChE 相关的专利（医药）

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项与 MAO-A x Cholinesterase x AChE 相关的文献（医药）

2024-06-01·International Journal of Biological Macromolecules

Design and discovery of anthranilamide derivatives as a potential treatment for neurodegenerative disorders via targeting cholinesterases and monoamine oxidases

Article

作者: Al-Odayni, Abdel-Basit ; Younas, Muhammad Tayyab ; Al-Kahtani, Abdullah A ; Ibrar, Aliya ; Khan, Imtiaz ; Zaib, Sumera ; Ali, Hafiz Saqib

Neurodegenerative diseases with progressive cellular loss of the central nervous system and elusive disease etiology provide a continuous impetus to explore drug discovery programmes aiming at identifying robust and effective inhibitors of cholinesterase and monoamine oxidase enzymes. We herein present a concise library of anthranilamide derivatives involving a palladium-catalyzed Suzuki-Miyaura cross-coupling reaction to install the diverse structural diversity required for the desired biological action. Using Ellman's method, cholinesterase inhibitory activity was performed against AChE and BuChE enzymes. In vitro assay results demonstrated that anthranilamides are potent inhibitors with remarkable potency. Compound 6k emerged as the lead candidate and dual inhibitor of both enzymes with IC₅₀ values of 0.12 ± 0.01 and 0.49 ± 0.02 μM against AChE and BuChE, respectively. Several other compounds were found as highly potent and selective inhibitors. Anthranilamide derivatives were also tested against monoamine oxidase (A and B) enzymes using fluorometric method. In vitro data revealed compound 6h as the most potent inhibitor against MAO-A, showing an IC₅₀ value of 0.44 ± 0.02 μM, whereas, compound 6k emerged as the top inhibitor of MAO-B with an IC₅₀ value of 0.06 ± 0.01 μM. All the lead inhibitors were analyzed for the identification of their mechanism of action using Michaelis-Menten kinetics experiments. Compound 6k and 6h depicted a competitive mode of action against AChE and MAO-A, whereas, a non-competitive and mixed-type of inhibition was observed against BuChE and MAO-B by compounds 6k. Molecular docking analysis revealed remarkable binding affinities of the potent inhibitors with specific residues inside the active site of receptors. Furthermore, molecular dynamics simulations were performed to explore the ability of potent compounds to form energetically stable complexes with the target protein. Finally, in silico ADME calculations also demonstrated that the potent compounds exhibit promising pharmacokinetic profile, satisfying the essential criteria for drug-likeness. Altogether, the findings reported in the current work clearly suggest that the identified anthranilamide derivatives have the potential to serve as effective drug candidates for future investigations.

2023-05-10·Mini-Reviews in Medicinal Chemistry

A Recent Appraisal of Small-Organic Molecules as Anti-Alzheimer’s Agents

Article

作者: Nain, Sumitra ; Khan, Shabana Kausar ; Ojha, Madhwi ; Gupta, Mohan ; Kumar, Avinash

Background:Alzheimer’s disease (AD) is an irreversible, progressive and very complex brain disorder. There is still uncertainty about the etiology of AD; however, a few hallmarks like an aggregation of tau proteins, amyloid-β plaques, oxidative stress, low level of choline in the brain etc., play significant roles.Objective:In the present work, we aim to evaluate the recent progress in the development of small organic molecules containing heterocycles like thiazole, pyridines, dihydropyridines, piperidines, pyrrolidines, pyrazoles, quinolines etc. as anti-Alzheimer’s agents.Method:Several databases, including SciFinder, ScienceDirect, Bentham Science, and PubMed, were searched for relevant articles and reviewed for the present work.Results:Several research groups are actively working on these heterocycle-based compounds as potent single-target inhibitors. Most of the analogues have been evaluated for their cholinesterase (acetylcholinesterase and butyrylcholinesterase) inhibition potential. Several studies have also reported the inhibitory potential of the analogues against MAO-A, MAO-B, and BACE-1 enzymes. However, instead of targeting one enzyme or protein, more than one heterocycle ring is being joined to develop MTDLs (multi-target-directed ligands). Donepezil has become the focal point of anti-AD drug discovery projects. Several research groups have reported various donepezil-based analogues by replacing/ modifying its various ring systems like indanone, piperidine or the methylene linker.Conclusion:Small molecules with nitrogen-containing heterocycles have become the core of drug discovery efforts for AD. With the increasing prominence of the MTDL approach, several new ligands are being discovered as potent anti-AD agents.

2023-04-23·International journal of molecular sciences

Chemical and Biological Evaluation of Novel 1H-Chromeno[3,2-c]pyridine Derivatives as MAO Inhibitors Endowed with Potential Anticancer Activity.

Article

作者: Voskressensky, Leonid G. ; Boccarelli, Angelina ; Reza, Raesi Gh. ; de Candia, Modesto ; Altomare, Cosimo D. ; Sblano, Sabina ; Tafeenko, Viktor A. ; Catto, Marco ; Kulikova, Larisa N. ; Beloglazkin, Andrey A. ; Levickaya, Daria D. ; Purgatorio, Rosa

About twenty mols. sharing 1H-chromeno[3,2-c]pyridine as the scaffold and differing in the degree of saturation of the pyridine ring, oxidation at C10, 1-phenylethynyl at C1 and 1H-indol-3-yl fragments at C10, as well as a few small substituents at C6 and C8, were synthesized starting from 1,2,3,4-tetrahydro-2-methylchromeno[3,2-c]pyridin-10-ones (1,2,3,4-THCP-10-ones, 1) or 2,3-dihydro-2-methyl-1H-chromeno[3,2-c]pyridines (2,3-DHPCs, 2).The newly synthesized compounds were tested as inhibitors of the human isoforms of monoamine oxidase (MAO A and B) and cholinesterase (AChE and BChE), and the following main SARs were inferred: (i) The 2,3-DHCP derivatives 2 inhibit MAO A (IC50 about 1 μM) preferentially; (ii) the 1,2,3,4-THCP-10-one 3a, bearing the phenylethynyl fragment at C1, returned as a potent MAO B inhibitor (IC50 0.51 μM) and moderate inhibitor of both ChEs (IC50s 7-8 μM); (iii) the 1H-indol-3-yl fragment at C10 slightly increases the MAO B inhibition potency, with the analog 6c achieving MAO B IC50 of 3.51 μM.The MAO B inhibitor 3a deserves further pharmacol. studies as a remedy in the symptomatic treatment of Parkinson′s disease and neuroprotectant for Alzheimer′s disease.Besides the established neuroprotective effects of MAO inhibitors, the role of MAOs in tumor insurgence and progression has been recently reported.Herein, antiproliferative assays with breast (MCF-7), colon (HCT116) and cisplatin-resistant ovarian (SK-OV-3) tumor cells revealed that the 10-indolyl-bearing 2,3,4,10-THCP analog 6c exerts anti-tumor activity with IC50s in the range 4.83-11.3 μM.