Blood–brain barrier permeable anticholinesterase aurones: Synthesis, structure–activity relationship, and drug-like properties

Liew, Kok-Fui; Chan, Kit‐Lam; Lee, Chong Yew

doi:10.1016/j.ejmech.2015.02.055

Cited by 44 publications

(24 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Embelin was evaluated for its inhibitory activity of AChE from electric eel ( Electrophorus electricus ). Donepezil was used as a positive control and to validate the assay by comparing IC 50 value obtained in this study with reported values (Liew et al, 2015). Embelin was tested at a series of concentration from 3.68 to 58.9 μg/mL in order to determine the IC 50 value using standard curve generated using Microsoft Excel.…”

Section: Resultsmentioning

confidence: 75%

“…This finding is consistent with AChE inhibitory activity of embelin. Higher binding interaction energy indicating embelin may bound to the AChE active site which likely to trigger the catalytic site for its inhibitory activity for AChE (Liew et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…AChE inhibition of embelin was evaluated using the Ellman's method (Ellman et al, 1961; Liew et al, 2015) with slight modifications. A serial dilution of embelin which highest concentration lesser than 200 μM was prepared using DMSO and 0.1 M sodium phosphate buffer (pH 7.8), with DMSO final concentration of <1% (v/v).…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Embelin, a Potent Molecule for Alzheimer's Disease: A Proof of Concept From Blood-Brain Barrier Permeability, Acetylcholinesterase Inhibition and Molecular Docking Studies

et al. 2019

View full text Add to dashboard Cite

Embelin is well-known in ethnomedicine and reported to have central nervous system activities. However, there is no report on blood-brain barrier (BBB) permeability of embelin. Here the BBB permeability of embelin was evaluated using in vitro primary porcine brain endothelial cell (PBEC) model of the BBB. Embelin was also evaluated for acetylcholinesterase (AChE) inhibitory activity and docking prediction for interaction with AChE and amyloid beta (Aβ) binding sites. Embelin was found to be non-toxic to the PBECs and did not disturb the PBEC barrier function. The PBECs showed restrictive tight junctions with average transendothelial electrical resistance of 365.37 ± 113.00 Ω.cm 2 , for monolayers used for permeability assays. Permeability assays were conducted from apical-to-basolateral direction (blood-to-brain side). Embelin showed apparent permeability ( P app ) value of 35.46 ± 20.33 × 10 −6 cm/s with 85.53% recovery. In vitro AChE inhibitory assay demonstrated that embelin could inhibit the enzyme. Molecular docking study showed that embelin binds well to active site of AChE with CDOCKER interaction energy of −65.75 kcal/mol which correlates with the in vitro results. Docking of embelin with Aβ peptides also revealed the promising binding with low CDOCKER interaction energy. Thus, findings from this study indicate that embelin could be a suitable molecule to be further developed as therapeutic molecule to treat neurological disorders particularly Alzheimer's disease.

show abstract

Section: Resultsmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Embelin, a Potent Molecule for Alzheimer's Disease: A Proof of Concept From Blood-Brain Barrier Permeability, Acetylcholinesterase Inhibition and Molecular Docking Studies

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Moreover it possessed radical scavenging capacity (IC 50 = 1.64 µM) against 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid (ABTS) which was significantly better than the reference quercetin (IC 50 = 15.49 µM). Among the various aurone derivatives [206,207] the 3′-chloro substituted aurone derivative 136 ( Figure 25) was very good AChE inhibitor (eeAChE IC 50 =160 nM) [208] in Torpedo californica. It showed high passive BBB permeability and moderate CYP450 metabolic stability which indicated that this promising drug-like lead should be considering for further development.…”

Section: Novel Heterocyclic Moleculesmentioning

confidence: 99%

The Structural Hybrids of Acetylcholinesterase Inhibitors in the Treatment of Alzheimer’s Disease: A Review

Saxena¹

2019

AND

View full text Add to dashboard Cite

Alzheimer's Disease (AD) is characterized by the loss of memory and learning ability in elderly patients affecting large population worldwide. The enzyme Acetylcholinesterase (AChE), (E.C.3.1.1.7) plays a major role in the hydrolysis of the released neurotransmitter acetylcholine. Most of the clinically used drugs to treat AD are Acetylcholinesterase Inhibitors (AChEIs). These drugs can provide symptomatic benefits only and suffer with loss of therapeutic potential with time. Therefore, there is an urgent need of novel cholinesterase inhibitors with wider therapeutic window for the treatment of AD. The strategies targeting the AChE enzyme along with other target(s) like Butyrylcholinesterase (BChE), amyloid-β (Aβ), β-secretase-1 (BACE), metals (Cu 2+ , Zn 2+ , or Fe 2+), antioxidant properties and free radical scavenging capacity have been mainly focused in the last five years. A number of hybrid molecules incorporating sub-structures with the desired well-established pharmacological profile into a single scaffold have been investigated. The main sub structures used in developing these molecules are derived from diverse chemical classes such as acridine, quinoline, carbamates, huperzine and other heterocyclic analogs. It has been followed by optimization of activity through structural modifications of the prototype molecules for developing the Structure Activity Relationship (SAR). This has led to the development of novel molecules with desired AChE inhibitory activity along with other desirable pharmacological properties. This review summarizes the current therapeutic strategies for the development of these AChEI in the last seven years.

show abstract

“…Many of the potential or approved commercially available pharmaceutical substances acting as AChE inhibitors contain carbamate functional group among others 16,32 ; for instance, human drug Rivastigmin 33,34 , which is used in the therapy of patients in the early or middle stage of AD. Besides this, many of differently substituted carbamate derivatives are described in literature [35][36][37][38][39][40][41][42][43][44][45][46] , which embody significant inhibition activity against AChE and/or BChE. Unfortunately, the clinical applicability of these compounds is limited with regard to many side effects or demerits, e.g.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, characterization andin vitroevaluation of substitutedN-(2-phenylcyclopropyl)carbamates as acetyl- and butyrylcholinesterase inhibitors

Horáková

Drabina

Brož

et al. 2016

Journal of Enzyme Inhibition and Medicinal Chemistry

View full text Add to dashboard Cite

A serie of O-substituted N-2-phenylcyclopropylcarbamates was prepared and characterized. These carbamates were tested as inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). It was found, that these compounds exhibit moderate inhibition activity with values of IC 50 in the range of 54.8-94.4 mM (for AChE) and up to 5.8 mM (for BChE). The AChE/ BChE selectivity for each carbamate was calculated. These values varied from 0.50 to 9.46, two carbamate derivatives inhibited only AChE selectively. The most promising derivative was prepared in all optically pure forms (four isomers). It was found that individual stereoisomers differed only slightly in the inhibition ability. The cytotoxicity of all carbamates was evaluated using the standard in vitro test with Jurkat cells. With regard to their inhibition activity and cytotoxicity as well as easy preparation, O-substituted N-2-phenylcyclopropylcarbamates can be considered as promising compounds for potential medicinal applications.

show abstract

Blood–brain barrier permeable anticholinesterase aurones: Synthesis, structure–activity relationship, and drug-like properties

Cited by 44 publications

References 45 publications

Embelin, a Potent Molecule for Alzheimer's Disease: A Proof of Concept From Blood-Brain Barrier Permeability, Acetylcholinesterase Inhibition and Molecular Docking Studies

Embelin, a Potent Molecule for Alzheimer's Disease: A Proof of Concept From Blood-Brain Barrier Permeability, Acetylcholinesterase Inhibition and Molecular Docking Studies

The Structural Hybrids of Acetylcholinesterase Inhibitors in the Treatment of Alzheimer’s Disease: A Review

Synthesis, characterization andin vitroevaluation of substitutedN-(2-phenylcyclopropyl)carbamates as acetyl- and butyrylcholinesterase inhibitors

Contact Info

Product

Resources

About