Design, synthesis and biological evaluation of edaravone derivatives bearing the <i>N</i>-benzyl pyridinium moiety as multifunctional anti-Alzheimer’s agents

Zondagh, Luke S.; Malan, Sarel F.; Joubert, Jacques

doi:10.1080/14756366.2020.1801673

Cited by 11 publications

(6 citation statements)

References 72 publications

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“…1-[(2-Fluorophenyl)methyl]-4-({[4–(3-methyl-5-oxo-4 H pyrazol-1-yl)phenyl]foramido}methyl)pyridin-1-ium bromide ( A14 ) displayed the most promising activity inhibiting AChE and an IC 50 value of 1.2 μM. The selectivity index (selectivity against AChE over BuChE) for the compound A14 was found to be >833 . A molecular docking study was conducted against the most potent compound ( A14 ) in the series against VX-phosphonylated hAChE (PDB ID: 6U37) to assess the binding affinity.…”

Section: Pyrazolines As Ach Aβ and Tau Inhibitorsmentioning

confidence: 99%

“…The selectivity index (selectivity against AChE over BuChE) for the compound A14 was found to be >833. 81 A molecular docking study was conducted against the most potent compound ( A14 ) in the series against VX-phosphonylated hAChE (PDB ID: 6U37 ) to assess the binding affinity. With a docking score of −7.626 kcal/mol and interactions with the residues Asp74 (H-bond), and Tyr124, Tyr341, and Trp286 (π–π-stacking), compound A14 was found to display an efficient binding within the active site of hAChE.…”

Section: Pyrazolines As Ach a β And Tau Inhibitorsmentioning

confidence: 99%

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Pyrazoline Containing Compounds as Therapeutic Targets for Neurodegenerative Disorders

Ahsan¹,

Ali

et al. 2022

ACS Omega

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Pyrazolines are a significant class of heterocyclic compounds with essential biological activities. They are quite stable, which has inspired medicinal chemists to experiment with the ring's structure in many different ways to create a variety of pharmacological activities. The structures of numerous commercially available therapeutic agents contain a pyrazoline ring. Pyrazolines are well-known for their ability to treat neurodegenerative diseases. The neurodegenerative diseases that affect huge populations globally include Alzheimer's disease (AD), Parkinson's disease (PD), and psychiatric disorders. The neuroprotective properties of pyrazolines published since 2003 are covered in the current review. Structure−activity relationships (SARs), molecular docking simulation, anticholinesterase (anti-AChE), and monoamine oxidase (MAO A/B) inhibitory actions are all covered in this article. Pyrazolines were discovered to have beneficial effects in the management of AD and were revealed to be inhibitors of acetylcholine esterase (AChE) and beta-amyloid (A β ) plaques. They were discovered to be efficient against PD and also targeted MAO B and COMT. It was discovered that the pyrazolines block MAO A to treat psychiatric diseases. Pyrazolines are significant heteroaromatic scaffolds with a variety of biological functions. They were discovered to be remarkably stable and serve as an indispensable anchor for the development of new drugs. By blocking AChE and MAOs, they may be used to treat neurodegenerative diseases. The discussion outlined here is an essential and helpful resource for medicinal chemists who are investigating and applying pyrazolines in neurodegenerative research initiatives as well as to expedite future research programs on neurodegenerative disorders.

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Section: Pyrazolines As Ach Aβ and Tau Inhibitorsmentioning

confidence: 99%

Section: Pyrazolines As Ach a β And Tau Inhibitorsmentioning

confidence: 99%

Pyrazoline Containing Compounds as Therapeutic Targets for Neurodegenerative Disorders

Ahsan¹,

Ali

et al. 2022

ACS Omega

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“…This interaction study demonstrated that compound 1 was strongly bound to both the binding sites CAS and PAS of AChE, which showed a consistent inhibitory pattern on AChE to what revealed by its kinetic study and propidium displacement test. As the PAS of AChE is involved in an increased Aβ aggregation rate, dual interaction with two binding sites (CAS and PAS) would be especially advantageous for slowing the progression of AD [24,25].…”

Section: Molecular Docking Studiesmentioning

confidence: 99%

Discovery of Guanidine Derivatives from Buthus martensii Karsch with Metal-Binding and Cholinesterase Inhibition Properties

2021

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Two rare guanidine-type alkaloids, Buthutin A (1) and Buthutin B (2), along with two other compounds (3, 4), were isolated from Buthus martensii Karsch, and determined using extensive spectroscopic data analysis and high resolution-mass spectrometry. Compound 1 showed the most potent inhibition on AChE and BChE with IC50 values of 7.83 ± 0.06 and 47.44 ± 0.95 μM, respectively. Kinetic characterization of compound 1 confirmed a mixed-type of AChE inhibition mechanism in accordance with the docking results, which shows its interaction with both catalytic active (CAS) and peripheral anionic (PAS) sites. The specific binding of compound 1 to PAS domain of AChE was also confirmed experimentally. Moreover, compounds 1 and 3 exhibited satisfactory biometal binding abilities toward Cu2+, Fe2+, Zn2+ and Al3+ ions. These results provide a new evidence for further development and utilization of B. martensii in health and pharmaceutical products.

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“…These concepts significantly impacted the treatment of neurodegenerative diseases such as PD. Interestingly, recently, the screening approach has been widely used in the development of multi-target ligands useful in the treatment of neurodegenerative disorders [ 60 , 61 , 62 , 63 , 64 , 65 , 66 ]. Jaiteh et al performed molecular docking screens against the binding sites of A 2A adenosine receptor and monoamine oxidase B (MAO-B) to identify dual inhibitors of these targets.…”

Section: Computational Approaches Used In the Development Of Novel Drugs Against Parkinson’s Diseasementioning

confidence: 99%

Current Approaches and Tools Used in Drug Development against Parkinson’s Disease

et al. 2021

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Parkinson’s disease is a progressive neurodegenerative disorder characterized by the death of nerve cells in the substantia nigra of the brain. The treatment options for this disease are very limited as currently the treatment is mainly symptomatic, and the available drugs are not able to completely stop the progression of the disease but only to slow it down. There is still a need to search for new compounds with the most optimal pharmacological profile that would stop the rapidly progressing disease. An increasing understanding of Parkinson’s pathogenesis and the discovery of new molecular targets pave the way to develop new therapeutic agents. The use and selection of appropriate cell and animal models that better reflect pathogenic changes in the brain is a key aspect of the research. In addition, computer-assisted drug design methods are a promising approach to developing effective compounds with potential therapeutic effects. In light of the above, in this review, we present current approaches for developing new drugs for Parkinson’s disease.

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Design, synthesis and biological evaluation of edaravone derivatives bearing the N-benzyl pyridinium moiety as multifunctional anti-Alzheimer’s agents

Cited by 11 publications

References 72 publications

Pyrazoline Containing Compounds as Therapeutic Targets for Neurodegenerative Disorders

Pyrazoline Containing Compounds as Therapeutic Targets for Neurodegenerative Disorders

Discovery of Guanidine Derivatives from Buthus martensii Karsch with Metal-Binding and Cholinesterase Inhibition Properties

Current Approaches and Tools Used in Drug Development against Parkinson’s Disease

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