A quinoxaline scaffold exhibits various bioactivities in pharmacotherapeutic interests. In this research, twelve quinoxaline derivatives were synthesized and evaluated as new acetylcholinesterase ...inhibitors. We found all compounds showed potent inhibitory activity against acetylcholinesterase (AChE) with IC50 values of 0.077 to 50.080 µM, along with promising predicted drug-likeness and blood–brain barrier (BBB) permeation. In addition, potent butyrylcholinesterase (BChE) inhibitory activity with IC50 values of 14.91 to 60.95 µM was observed in some compounds. Enzyme kinetic study revealed the most potent compound (6c) as a mixed-type AChE inhibitor. No cytotoxicity from the quinoxaline derivatives was noticed in the human neuroblastoma cell line (SHSY5Y). In silico study suggested the compounds preferred the peripheral anionic site (PAS) to the catalytic anionic site (CAS), which was different from AChE inhibitors (tacrine and galanthamine). We had proposed the molecular design guided for quinoxaline derivatives targeting the PAS site. Therefore, the quinoxaline derivatives could offer the lead for the newly developed candidate as potential acetylcholinesterase inhibitors.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
In order to obtain multi-functional molecules for Alzheimer’s disease, a series of deferiprone derivatives has been synthesized and evaluated in vitro with the hypothesis that they can restore the ...cholinergic tone and attenuate the dyshomeostasis of the metals mainly involved in the pathology. These compounds were designed as dual binding site AChE inhibitors: they possess an arylalkylamine moiety connected via an alkyl chain to a 3-hydroxy-4-pyridone fragment, to allow the simultaneous interaction with catalytic active site (CAS) and peripheral anionic site (PAS) of the enzyme. Deferiprone moiety and 2-aminopyridine, 2-aminopyrimidine or 2,4-diaminopyrimidine groups have been incorporated into these compounds, in order to obtain molecules potentially able to chelate bio-metals colocalized in Aβ plaques and involved in the generation of radical species. Synthesized compounds were tested by enzymatic inhibition studies towards EeAChE and eqBChE using Ellman’s method. The most potent EeAChE inhibitor is compound 5a, with a Ki of 788 ± 51 nM, while the most potent eqBChE inhibitors are compounds 12 and 19, with Ki values of 182 ± 18 nM and 258 ± 25 nM respectively. Selected compounds, among the most potent cholinesterases inhibitors, were able to form complex with iron and in some cases with copper and zinc. Moreover, these compounds were characterized by low toxicity on U-87 MG Cell Line from human brain (glioblastoma astrocytoma).
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•Designed deferiprone derivatives act as dual binding site AChE inhibitors.•Best inhibitors are uncompetitive or mixed type, with submicromolar Ki values.•Docking studies show π-π interactions with enzyme CAS and PAS.•The most potent inhibitors are able to chelate metallic cations (Fe+3, Cu+2, Zn+2).•These compounds display low toxicity and good predicted ADME parameters.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Complex pathomechanism of Alzheimer’s disease (AD) prompts researchers to develop multifunctional molecules in order to find effective therapy against AD. We designed and synthesized novel ...multifunctional ligands for which we assessed their activities towards butyrylcholinesterase, beta secretase, amyloid beta (Aβ) and tau protein aggregation as well as antioxidant and metal-chelating properties. All compounds showed dual anti-aggregating properties towards Aβ and tau protein in the in cellulo assay in Escherichia coli. Of particular interest are compounds 24b and 25b, which efficiently inhibit aggregation of Aβ and tau protein at 10 μM (24b: 45% for Aβ, 53% for tau; 25b: 49% for Aβ, 54% for tau). They display free radical scavenging capacity and antioxidant activity in ABTS and FRAP assays, respectively, and selectively chelate copper ions. Compounds 24b and 25b are also the most potent inhibitors of BuChE with IC50 of 2.39 μM and 1.94 μM, respectively. Promising in vitro activities of the presented multifunctional ligands as well as their original scaffold are a very interesting starting point for further research towards effective anti-AD treatment.
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•Novel multifunctional ligands were designed and synthesized.•Inhibition of BuChE, BACE1, amyloid beta and tau aggregation plus antioxidant and metal-chelating properties were tested.•Derivatives 24b and 25b efficiently inhibit aggregation Aβ and tau protein in the in cellulo assay in Escherichia coli.•Additionally, they display free radical scavenging capacity, antioxidant activity and selectively chelate Cu2+
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The multitarget approach is a promising paradigm in drug discovery, potentially leading to new treatment options for complex disorders, such as Alzheimer’s disease. Herein, we present the discovery ...of a unique series of 1-benzylamino-2-hydroxyalkyl derivatives combining inhibitory activity against butyrylcholinesterase, β-secretase, β-amyloid, and tau protein aggregation, all related to mechanisms which underpin Alzheimer’s disease. Notably, diphenylpropylamine derivative 10 showed balanced activity against both disease-modifying targets, inhibition of β-secretase (IC50 hBACE‑1 = 41.60 μM), inhibition of amyloid β aggregation (IC50 Aβ = 3.09 μM), inhibition of tau aggregation (55% at 10 μM); as well as against symptomatic targets, butyrylcholinesterase inhibition (IC50 hBuChE = 7.22 μM). It might represent an encouraging starting point for development of multifunctional disease-modifying anti-Alzheimer’s agents.
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IJS, KILJ, NUK, PNG, UL, UM, UPUK
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•Novel series of multifunctional ligands targeting symptoms and causes of Alzheimer’s disease was designed and synthesized.•The inhibitory potency of the compounds against BuChE and ...β-amyloid was evaluated in vitro.•Compounds display drug-like properties and advantageous CNS MPO scores.•Chiral separation of the most potent compound was performed and the potency of the enantiomers was evaluated.•Molecular modelling studies have illustrated the binding mode of compounds and explained the differences in their potencies.
Butyrylcholinesterase (BuChE) and amyloid β (Aβ) aggregation remain important biological target and mechanism in the search for effective treatment of Alzheimer’s disease. Simultaneous inhibition thereof by the application of multifunctional agents may lead to improvement in terms of symptoms and causes of the disease. Here, we present the rational design, synthesis, biological evaluation and molecular modelling studies of novel series of fluorene-based BuChE and Aβ inhibitors with drug-like characteristics and advantageous Central Nervous System Multiparameter Optimization scores. Among 17 synthesized and tested compounds, we identified 22 as the most potent eqBuChE inhibitor with IC50 of 38 nM and 37.4% of Aβ aggregation inhibition at 10 μM. Based on molecular modelling studies, including molecular dynamics, we determined the binding mode of the compounds within BuChE and explained the differences in the activity of the two enantiomers of compound 22. A novel series of fluorenyl compounds meeting the drug-likeness criteria seems to be a promising starting point for further development as anti-Alzheimer agents.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
A new series of pyrimidine and pyridine diamines was designed as dual binding site inhibitors of cholinesterases (ChEs), characterized by two small aromatic moieties separated by a diaminoalkyl ...flexible linker. Many compounds are mixed or uncompetitive acetylcholinesterase (AChE) and/or butyrylcholinesterase (BChE) nanomolar inhibitors, with compound 9 being the most active on Electrophorus electricus AChE (EeAChE) (K i = 0.312 μM) and compound 22 on equine BChE (eqBChE) (K i = 0.099 μM). Molecular docking and molecular dynamic studies confirmed the interaction mode of our compounds with the enzymatic active site. UV–vis spectroscopic studies showed that these compounds can form complexes with Cu2+ and Fe3+ and that compounds 18, 20, and 30 have antioxidant properties. Interestingly, some compounds were also able to reduce Aβ42 and tau aggregation, with compound 28 being the most potent (22.3 and 17.0% inhibition at 100 μM on Aβ42 and tau, respectively). Moreover, the most active compounds showed low cytotoxicity on a human brain cell line and they were predicted as BBB-permeable.
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IJS, KILJ, NUK, PNG, UL, UM, UPUK
Butyrylcholinesterase (BuChE) and neuroinflammation have recently emerged as promising therapeutic directions for Alzheimer's disease (AD). Herein, we synthesised 19 novel pyranone-carbamate ...derivatives and evaluated their activities against cholinesterases and neuroinflammation. The optimal compound
exhibited balanced BuChE inhibitory activity (eqBuChE IC
= 4.68 nM; huBuChE IC
= 9.12 nM) and anti-neuroinflammatory activity (NO inhibition = 28.82% at 10 μM, comparable to hydrocortisone). Enzyme kinetic and docking studies confirmed compound
was a mix-type BuChE inhibitor. Additionally, compound
displayed favourable drug-likeness properties in silico prediction, and exhibited high BBB permeability in the PAMPA-BBB assay. Compound
had good safety in vivo as verified by an acute toxicity assay (LD
> 1000 mg/kg). Most importantly, compound
effectively mitigated cognitive and memory impairments in the scopolamine-induced mouse model, showing comparable effects to Rivastigmine. Therefore, we envisioned that compound
could serve as a promising lead compound for treating AD.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
In Alzheimer's disease, butyrylcholinesterase (BuChE) activity gradually increases, while acetylcholinesterase (AChE) activity decreases or remains unchanged. Dual inhibitors have important roles in ...regulation of synaptic acetylcholine levels and progression of Alzheimer's disease.
1-(Thiomorpholin-4-ylmethyl)/benzyl-5-trifluoromethoxy-2-indolinones (
) were synthesized. AChE and BuChE inhibitory effects were investigated with Ellman's method. Molecular docking studies were performed for analyzing the possible binding interactions at active sites.
Compound
was the strongest inhibitor against both AChE (
= 0.35 μM) and BuChE (
= 0.53 μM). It showed higher inhibitory effects than both donepezil and galantamine. Moreover, compound
had a higher inhibitory effect than galantamine and the effect was comparable to that of donepezil against both AChE (
= 0.69 μM) and BuChE (
= 0.95 μM).
The benzyl substitution compared with 1-(thiomorpholin-4-ylmethyl) group significantly increased both AChE and BuChE inhibitory effects.
A series of novel tetrahydropyrimidin-4-yl)pyridine derivatives 6(a-h) have been designed and synthesized as inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The chemical ...structures of all newly synthesized compounds were characterized by spectroscopic methods (IR,
1
H NMR,
13
C NMR) and elemental analyzes. The in vitro studies showed that all the synthesized derivatives showed significant BChE inhibitory activity more potent than donepezil as the standard (IC
50
values less than 0.1 µM). All the target compounds demonstrated good AChE inhibitory effects comparable with donepezil as the reference drug with IC
50
values ranging from 0.08 to 0.1 µM. The best results were obtained by 4-methyl substituted derivative 6d with IC
50
value of 0.082 µM which was comparable with AChE inhibitory effects of donepezil (IC
50
= 0.079 µM).
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BFBNIB, DOBA, GIS, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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Structural optimization of butyrylcholinesterase inhibitors, 5-bromomethyl- and 5-iodomethyl-N,N-disubstituted 2-aminothiazolines, led to a series of their annulated bicyclic ...analogues, obtained by intramolecular cyclization of cycloalkenylthioureas. The most active compound in this series, cycloheptadthiazol-2-amine, is a mixed-type butyryl-cholinesterase inhibitor with IC50 = 130 nm, highly selective compared to acetylcholinesterase and non-toxic at 100 μm concentrations.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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