In recent years, butyrylcholinesterase (BChE) has gradually gained worldwide interests as a novel target for treating Alzheimer's disease (AD). Here, two pharmacophore models were generated using ...Schrödinger suite and used to virtually screen ChemDiv database, from which three hits were obtained. Among them, 2513–4169 displayed the highest inhibitory activity and selectivity against BChE (eeAChE IC50 > 10 μM, eqBChE IC50 = 3.73 ± 1.90 μM). Molecular dynamic (MD) simulation validated the binding pattern of 2513–4169 in BChE, and it could form a various of receptor-ligand interactions with adjacent residues. In vitro cytotoxicity assay proved the safety of 2513–4169 on diverse neural cell lines. Moreover, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay performed on SH-SY5Y cells proved the neuroprotective effect of 2513–4169 against toxic Aβ1–42. In vivo behavioral study further confirmed the great efficacy of 2513–4169 on reversing Aβ1–42-induced cognitive impairment of mice and clearing the toxic Aβ1–42 in brains. Moreover, 2513–4169 was proved to be able to cross blood-brain barrier (BBB) through a parallel artificial membrane permeation assay of BBB (PAMPA-BBB). Taken together, 2513–4169 is a promising lead compound for future optimization to discover anti-AD treating agents.
Display omitted
•Great capacity of clearing Aβ1–42in vivo•First discovery of a selective butyrylcholinesterase inhibitor with totally new scaffold•Good inhibitory activity against butyrylcholinesterase•Low cytotoxicity against various neural cell lines and neuroprotective effects•Excellent in vivo effect on cognitive improvement
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
A series of substituted benzimidazole derivatives were synthesized and evaluated AChE/BuChE enzyme inhibitor activities.
A series of N-{2-4-(1H-benzimidazole-2-yl)phenoxyethyl}substituted amine ...derivatives were designed to assess cholinesterase inhibitor activities. Acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitor activities were evaluated in vitro by using Ellman’s method. It was discovered that most of the compounds displayed AChE and/or BuChE inhibitor activity and few compounds were selective against AChE/BuChE. Compound 3c and 3e were the most active compounds in the series against eeAChE and hAChE, respectively. Molecular docking studies and molecular dynamics simulations were also carried out.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Alzheimer's disease (AD) is a progressive mental disorder that brings a huge economic burden to the healthcare systems. During this illness, acetylcholine levels in the cholinergic systems gradually ...diminish, which results in severe memory loss and cognitive impairments. Moreover, Butyrylcholinesterase (BuChE) enzyme participates in cholinergic neurotransmission regulation by playing a prominent role in the latter phase of AD. In this study, based on donepezil, which is an effective acetylcholinesterase (AChE) inhibitor, a series of 1,2,4-oxadiazole compounds were designed, synthesized and their inhibitory activities towards AChE and BuChE enzymes were evaluated. Some structures exhibited a higher selectivity rate towards BuChE in comparison to donepezil. Notably, compound
6n
with an IC
50
value of 5.07 µM and an SI ratio greater than 19.72 showed the highest potency and selectivity towards BuChE enzyme. The docking result revealed that compound
6n
properly fitted the active site pocket of BuChE enzyme, and formed desirable lipophilic interactions and hydrogen bonds. Moreover, according to
in silico
ADME studies, these compounds have proper potential for being developed as new oral anti-Alzheimer's agents (Figure 1
(Fig. 1)
).
A series of new coumarin/1,2,4-oxadiazole hybrids were synthesized and evaluated for cholinesterase inhibitory and neuroprotective activities. Among them, enantiomers 5u and 5v showed potent hBChE ...inhibitory activity with IC
50
values of 8.17 and 9.56 μM, respectively, and also exhibited good selectivity for hBChE over hAChE by 9.49- and 7.58-fold, respectively. In addition, both compounds could protect SH-SY5Y cells against Aβ
25-35
-induced neurotoxicity. The preliminary bioassay results provided a new chemotype for multifunctional anti-Alzheimer's disease agents and continuing investigation into compounds 5u and 5v is warranted.
Full text
Available for:
BFBNIB, DOBA, GIS, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
An increase activity of butyrylcholinesterase is believed to contribute to Alzheimer's disease. Bambuterol is a known potent inhibitor of butyrylcholinesterase, but it has undesired cardiac effects ...and less lipophilicity. Thirteen bambuterol analogues were synthesized using 1-(3, 5-dihydroxyphenyl) ethanone as a starting material. In-vitro cholinesterase assay established that the majority of the compounds are specific butyrylcholinesterase inhibitors. Out of the 13 compounds, two bambuterol derivatives, BD-6 and BD-11 exhibited similar efficacies in inhibiting butyrylcholinesterase with fewer effects on heart and enhanced possibilities of permeating through the blood-brain barrier as compared to bambuterol. These bambuterol analogues may provide better alternatives for treatments of Alzheimer's disease.
Display omitted
•Butyrylcholinesterase inhibition is a new strategy for Alzheimer's disease therapy.•Cardiac effects and poor brain distribution limit the use of bambuterol.•Bambuterol analogues were synthesized as novel butyrylcholinesterase inhibitors.•The analogues displayed reduced cardiac effects and improved lipophilicity.•Two analogues are promising drugs for treatment of Alzheimer's disease.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
A series of 4-phthalimidobenzenesulfonamide derivatives were designed, synthesized and evaluated for the inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). ...Structures of the title compounds were confirmed by spectral and elemental analyses. The cholinesterase (ChE) inhibitory activity studies were carried out using Ellman's colorimetric method. The biological activity results revealed that all of the title compounds (except for compound 8) displayed high selectivity against AChE. Among the tested compounds, compound 7 was found to be the most potent against AChE (IC
50
= 1.35 ± 0.08 μM), while compound 3 exhibited the highest inhibition against BuChE (IC
50
= 13.41 ± 0.62 μM). Molecular docking studies of the most active compound 7 in AChE showed that this compound can interact with both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
We have firstly established a method of high-performance liquid chromatography−ultraviolet analysis coupled with electrospray ionization−ion trap−time-of-flight mass spectrometry and ...butyrylcholinesterase biochemical detection (HPLC-UV-ESI-IT-TOF-MS-BChEBCD). Applying this on-line method to the identification of BChE inhibitors in a Plumula nelumbinis sample, three alkaloids, namely liensinine, isoliensinine, and neferine, have been detected as having a strong BChE inhibition activity for the first time; in addition, norisoliensinine and 6-hydroxynorisoliensinine were proposed as two new compounds identified by their UV and MS data. The HPLC fingerprint, the MS fragments of the components, and the BChE activity profile could be simultaneously recorded during real-time analysis of complex samples using this on-line approach. Tacrine, a BChE inhibitor, was used as a positive reference compound, and its detection limit in the biochemical detection system was 1nmol. The BChE activity of 1g of P. nelumbinis sample was equal to that of 127.88μmol tacrine. The proposed on-line method has been validated as having good precision and reproducibility, and could be used to rapidly identify BChE inhibitors and to screen potential drugs for the treatment of Alzheimer's disease in complicated samples.
Scheme for BChE inhibitor detection. BChE, butyrylcholinesterase; BTCI, S-butyrylthiocholine iodide; DTNB, 5,5′-dithiobis2-nitrobenzoic acid; UV, ultraviolet detector; FS, flow splitter; MS, mass spectrometer. Display omitted
► On-line HPLC-ESI-MS-BChEBCD method was firstly established. ► Enable simultaneously separating, identifying, evaluating activity of BChE inhibitor. ► Liensinine, isoliensinine, and neferine are new-found BChE inhibitors. ► BChE activity of 1g Plumula nelumbinis is equal to that of 127.88μmol tacrine. ► Norisoliensinine and 6-hydroxynorisoliensinine were proposed as two new compounds.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Galanthamine as an Amaryllidaceae alkaloid has an important role in the treatment of Alzheimer's disease. Some efforts were made to elaborate the total synthesis, and hundreds of its derivatives were ...prepared to find a more effective molecule with advantageous properties. Moreover, almost every part of the tetracycle was changed; in members of the rings, in the nature and position of the heteroatoms, and ring-opened analogues were also synthesized. In this review the basic synthetic works and the most important derivatives and analogues are overviewed.
A series of pyridinium salts bearing alkylphenyl groups at 1 position and hydrazone structure at 4 position of the pyridinium ring were synthesized and evaluated for the inhibition of both ...acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes. The cholinesterase (ChE) inhibitory activity studies were carried out by using the Ellman’s colorimetric method. All compounds displayed considerable AChE and BuChE inhibitory activity and some of the compounds manifested remarkable anti-AChE activity compared to the reference compound, galantamine. Among the title compounds, the series including benzofuran aromatic ring exhibited the best inhibitory activity both on AChE and BuChE enzymes. Compound 3b, 4-2-(1-(benzofuran-2-yl)ethylidene)hydrazinyl-1-(3-phenylpropyl)pyridinium bromide, was the most active compound with IC50 value of 0.23 (0.24) µM against enantiomeric excess (ee)AChE (human (h)AChE) while compound 3a, 4-2-(1-(benzofuran-2-yl)ethylidene)hydrazinyl-1-phenethylpyridinium bromide, was the most active compound with IC50 value of 0.95 µM against BuChE. Moreover, 3a and b exhibited higher activity than the reference compound galantamine (eeAChE (hAChE) IC50 0.43 (0.52) µM; BuChE IC50 14.92 µM). Molecular docking studies were carried out on 3b having highest inhibitory activity against AChE.
A series of
N
-{2-2-(1
H
-benzimidazole-2-yl)phenoxyethyl} substituted amine derivatives were synthesized and tested for their cholinesterase inhibitor activity. Acetylcholinesterase and ...butyrylcholinesterase inhibitor activities were evaluated in vitro by using Ellman’s method. According to the activity results, all of the compounds displayed moderate acetylcholinesterase inhibitory activity and most of the compounds displayed remarkable butyrylcholinesterase inhibitory activity. Compound
3d
was the most active compound in the series and also a selective butyrylcholinesterase inhibitor. Molecular docking studies and molecular dynamic simulations were also carried out.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
PDF
