Novel coumarin derivatives as multifunctional anti-AD agents: Design, synthesis, X-ray crystal structure and biological evaluation

Yang, Ai-Hong; Zhang, Hongwei; Hu, Chengting; Wang, Xi; Shen, Rui; Kou, Xiaodi; Wang, Huiyan

doi:10.1016/j.molstruc.2022.133747

Cited by 7 publications

(5 citation statements)

References 41 publications

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“…As shown in Table 1, 1-3 exhibited potent * OH scavenging activities (IC 50 = 1.33 -1.54 μM), which were stronger than corresponding compounds without 7-OH (IC 50 = 2.61 -2.94 μM). [14] These results were consistent with those of the DFT calculations which once again proved the promoting antioxidant activity of 7-OH.…”

Section: The Ability To Scavenge Hydroxyl Radicalssupporting

confidence: 90%

“…When compared with the activity of 2 and 3, as nitrogen had weaker electron withdrawing ability than oxygen, the nitrogen atom on the piperazine group was more easily protonated than that of morpholine group. Furthermore, the inhibition activity of 1 was slightly weaker than 1', [14] which could also be explained with the DFT calculation showing the electron density concentrated around the Schiff base moiety of 1' (Figure 3). The concentrated electron density was beneficial to the protonation of the tertiary amine group on the Schiff base moiety.…”

Section: Inhibitory Activities Of Ache and Buche Inhibition Experimentsmentioning

confidence: 53%

“…Coumarin was a class of compounds which was used widely in antioxidant drug design and also played an important role in the study of AD therapeutics [13–18] . However, the research on the development of coumarins with multi‐target anti‐AD activities based on ROS scavenging activity is still limited.…”

Section: Introductionmentioning

confidence: 99%

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Design, Synthesis, Calculation and Biological Activity Studies Based on Privileged Coumarin Derivatives as Multifunctional Anti‐AD Lead Compound

Wang

Su²,

Shi

et al. 2022

Chemistry & Biodiversity

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Coumarins and their derivatives possessed a variety of biological activities and some of coumarin-based drugs have been approved by the US Food and Drug Administration. Alzheimer's disease (AD) has caused great losses to human society. However, due to its complex pathogenesis, the ideal therapeutic approach has not been found yet. Free radical scavenging activity which is one of the main activities of coumarin core structure is closely related to other anti-AD activities. Therefore, in this work coumarins were chosen as privileged lead compounds for the development of anti-AD drugs based on strategy of multi-target directed ligands (MTDLs). Derivatives 1 -3 which could modulate multiple targets simultaneously, including ROS, cholinesterase, βamyloid (Aβ) aggregation, and metal dyshomeostasis were designed and for the first time synthesized. Their anti-AD activities were studied both in vitro and in silico. Results showed that 1-3 possessed potent antioxidant activities and 7-OH group did change the electron distribution of the molecule and enhance the antioxidant activities. They also have good inhibition activities on acetylcholinesterase (AChE) and Aβ aggregation and compound 1 had the strongest AChE inhibitory effect among the three compounds (AChE IC 50 = 11.15 μM). Compound 1-3 could also selectively chelate with Cu 2 + and Al 3 + to regulate the metal homeostasis. In silico simulations, including molecular docking and prediction of ADMET performance, indicated that 1-3 could interact with target proteins and cross the blood brain barrier. In conclusion, 1-3 could be promising MTDLs applied as anti-AD candidate drugs.

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Section: The Ability To Scavenge Hydroxyl Radicalssupporting

confidence: 90%

Section: Inhibitory Activities Of Ache and Buche Inhibition Experimentsmentioning

confidence: 53%

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Design, Synthesis, Calculation and Biological Activity Studies Based on Privileged Coumarin Derivatives as Multifunctional Anti‐AD Lead Compound

Wang

Su²,

Shi

et al. 2022

Chemistry & Biodiversity

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“…A series of novel 4-hydroxycoumarin derivatives ( Figure 5 ) were synthesized and tested for antioxidant activity as part of an effort to synthesize compounds with anti-Alzheimer’s activity [ 27 ]. The authors aimed to improve metal chelation by adding Schiff base functionality in addition to the phenolic hydroxyl group.…”

Section: Antioxidant Properties Of Molecular Coumarinsmentioning

confidence: 99%

Antioxidant Activity of Coumarins and Their Metal Complexes

Todorov

Saso²,

Kostova

2023

Pharmaceuticals

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Ubiquitously present in plant life, coumarins, as a class of phenolic compounds, have multiple applications—in everyday life, in organic synthesis, in medicine and many others. Coumarins are well known for their broad spectrum of physiological effects. The specific structure of the coumarin scaffold involves a conjugated system with excellent charge and electron transport properties. The antioxidant activity of natural coumarins has been a subject of intense study for at least two decades. Significant research into the antioxidant behavior of natural/semi-synthetic coumarins and their complexes has been carried out and published in scientific literature. The authors of this review have noted that, during the past five years, research efforts seem to have been focused on the synthesis and examination of synthetic coumarin derivatives with the aim to produce potential drugs with enhanced, modified or entirely novel effects. As many pathologies are associated with oxidative stress, coumarin-based compounds could be excellent candidates for novel medicinal molecules. The present review aims to inform the reader on some prominent results from investigations into the antioxidant properties of novel coumarin compounds over the past five years.

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“…[12,13] A lot of coumarin derivatives are reported to possess acetylcholinesterase (AChE) inhibitory activities. [7,[14][15][16][17] Novel AChE inhibitors for the treatment of AD are regularly created using the structure of coumarin hybrids as a template. The coumarin cores of those hybrids can occupy the peripheral anionic site (PAS) of AChE.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis and Anticholinesterase Activity of Coumarin‐1,3,5‐triazine Derivatives

Zhang,

Wang,

Zou

et al. 2024

ChemistrySelect

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A series of coumarin‐1,3,5‐triazine derivatives were designed, synthesized and evaluated as acetylcholinesterase inhibitors. The structures of those compounds were characterized by IR, NMR, HRMS, HPLC, and X‐ray. The structures of those coumarin‐1,3,5‐triazine derivatives are the mixtures of two geometric isomers. The 1H‐NMR of compound 3 g without coumarin structure and its hydrochloride and single crystal structure of compound 3 g were studied to prove the coumarin‐1,3,5‐triazine derivatives are the mixtures of two geometric isomers. The acetylcholinesterase and butyrylcholinesterase inhibitory activities of the synthesized compounds were determinated by Ellman's method. The results showed that all the compounds could inhibit acetylcholinesterase selectively. Among them, compound 3 b was found to have the strongest inhibitory effect on acetylcholinesterase with an IC50 value of 0.018 μM, which was closest to the IC50 of the positive control donepezil (IC50=0.016 μM). Enzyme kinetic studies indicate that this compound inhibited acetylcholinesterase with a mixed mode. Molecular docking, molecular dynamics simulation study and binding free energy calculation experiments demonstrated that compound 3 b could stably interact with key amino acids in the catalytically active site and the peripheral anion site of acetylcholinesterase. According to the results, compound 3 b demonstrates promising potential as acetylcholinesterase inhibitors for the treatment of Alzheimer's disease.

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Novel coumarin derivatives as multifunctional anti-AD agents: Design, synthesis, X-ray crystal structure and biological evaluation

Cited by 7 publications

References 41 publications

Design, Synthesis, Calculation and Biological Activity Studies Based on Privileged Coumarin Derivatives as Multifunctional Anti‐AD Lead Compound

Design, Synthesis, Calculation and Biological Activity Studies Based on Privileged Coumarin Derivatives as Multifunctional Anti‐AD Lead Compound

Antioxidant Activity of Coumarins and Their Metal Complexes

Design, Synthesis and Anticholinesterase Activity of Coumarin‐1,3,5‐triazine Derivatives

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