Even though cholinesterase (ChE) inhibitors and N‐methyl‐D‐aspartate (NMDA) receptor antagonist are clinically approved to treat Alzheimer's disease (AD) patients, new therapeutic compounds still ...need to be developed. Therefore, many new targets and novel anti‐AD drugs targeting them have been developed. As inhibition of ChE is still considered to be one of the most effective targets to treat AD patients, many new classes of ChE inhibitors have been synthesized. In an effort to identify new types of cholinergic drugs, S‐allyl cysteine (SAC), which is the major ingredient of aged‐garlic extract (AGE), was coupled with natural antioxidants. As SAC derivatives showed butyrylcholinesterase (BuChE) inhibitory activity, they constitute a new class of inhibitors for ChE and can be used as a novel natural‐compounds‐derived drug to treat AD patients.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
In the previous paper (Bull. Korean Chem. Soc., 2011, 32, 2997), the hybrid molecules between α-lipoic acid (ALA) and polyphenols (PPs) connected with neutral 2-(2-aminoethoxy)ethanol linker ...(linker-1) showed new biological activity such as butyrylcholinesterase (BuChE) inhibition. In order to increase the binding affinity of the hybrid compounds to cholinesterase (ChE), the neutral 2-(2-aminoethoxy)ethanol (linker 1) was switched to the cationic 2-(piperazin-1-yl)ethanol linker (linker 2). The IC50 values of the linker-2 hybrid molecules for BuChE inhibition were lower than those of linker-1 hybrid molecules (except 9-2) and they also had the same great selectivity for BuChE over AChE (> 800 fold) as linker-1 hybrid molecules. ALA-acetyl caffeic acid (10- 2, ALA-AcCA) was shown as an effective inhibitor of BuChE (IC50 = 0.44 ± 0.24 μM). A kinetic study using 7- 2 showed that it is the same mixed type inhibition as 7-1. Its inhibition constant (Ki) to BuChE is 4.3 ± 0.09 μM. KCI Citation Count: 10
The synthesis of two novel (+)-isocampholenic acid-derived amines has been realized starting from commercially available (1
S
)-(+)-10-camphorsulfonic acid. The novel amines as well as ...(+)-isocampholenic acid have been used as building blocks in the construction of a library of amides using various aliphatic, aromatic, and amino acid-derived coupling partners using BPC and CDI as activating agents. Amide derivatives have been assayed against several enzymes that hold potential for the development of new drugs to battle bacterial infections and Alzheimer’s disease. Compounds
20c
and
20e
showed promising selective sub-micromolar inhibition of human butyrylcholinesterase
(
h
BChE
)
(
IC
50
values
0.80
±
0.05
and
0.25
±
0.02
μ
M
, respectively).
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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
Isosorbide-2-carbamate-5-esters are highly potent and selective butyrylcholinesterase inhibitors with potential utility in the treatment of Alzheimer’s Disease (AD). They are stable in human plasma ...but in mouse plasma they undergo hydrolysis at the 5-ester group potentially attenuating in vivo potency. In this paper we explore the role of the 5-position in modulating potency. The focus of the study was to increase metabolic stability while preserving potency and selectivity. Dicarbamates and 5-keto derivatives were markedly less potent than the ester class. The 2-benzylcarbamate-5-benzyl ether was found to be potent (IC
50 52
nM) and stable in the presence of mouse plasma and liver homogenate. The compound produces sustained moderate inhibition of mouse butyrylcholinesterase at 1
mg/kg, IP.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
► A synthetic compound, HBU-39, potently inhibited butyrylcholinesterase. ► Scopolamine-induced amnesia showed significant reduction in neurogenesis. ► HBU-39 strongly ameliorated the reduction of ...neurogenesis induced by scopolamine.
In this study, we synthesized 1-(4-(benzod1,3dioxol-5-ylmethyl)piperazin-1-yl)-5-(1,2-dithiolan-3-yl)pentan-1-one, HBU-39, a (α)-lipoic acid derivative, and found this compound strongly inhibited butyrylcholinesterase (BuChE) in an in vitro experiment. We also examined the effects of HBU-39 on cell proliferation and neuroblast differentiation using the specific markers Ki67 and doublecortin (DCX), respectively, in the hippocampal dentate gyrus of a rat model of scopolamine-induced amnesia. For this, scopolamine was subcutaneously administered for 28days by an ALzet osmotic minipump (44mg/mL delivered at 2.5μL/h). HBU-39 (1mg/kg per day) and galantamine (an acetylcholinesterase inhibitor used as a control; 5mg/kg per day) were intraperitoneally administered for 28days. The administration of scopolamine significantly decreased the mean number of Ki67- and DCX-immunoreactive cells in the dentate gyrus. However, treatment with both HBU-39 and galantamine significantly ameliorated the reductions in cell proliferation and neuroblast differentiation. In particular, the mean number of Ki67- and DCX-immunoreactive cells was prominently abundant in the HBU-treated group compared to that in the galantamine-treated group. These results suggest that the BuChE inhibitor, HBU-39, can ameliorate the scopolamine-induced reductions of cell proliferation and neuroblast differentiation, and HBU-39 may be applicable to amnesia patients to promote memory functions.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
A series of novel 7‐alkoxyl substituted indolizinoquinoline‐5,12‐dione derivatives were synthesized. The cholinesterase inhibition assays indicated that most synthesized compounds exhibited good ...activity for acetylcholinesterase (AChE) and high selectivity index of AChE over butyrylcholinesterase (BuChE). Compound 12b exhibited the most potent AChE inhibitory activity with an IC50 value of 0.068 µM and the highest selectivity index of 144. Kinetic study of AChE indicated that a mixed type of inhibition pattern existed for these indolizinoquinoline‐5,12‐dione derivatives. Molecular docking study indicated that compound 12b could bind to both the catalytically active site and the peripheral anionic site of AChE.
A series of novel 7‐alkoxyl substituted indolizinoquinoline‐5,12‐dione derivatives were synthesized. The cholinesterase inhibition assays indicated that compound 12b exhibited the most potent AChE inhibitory activity and the highest selectivity index.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Three new oxygenated xanthones, fuscaxanthones L-N (1–3), and 14 known xanthones 4–17, together with the other known metabolites 18–20 were isolated from the stem barks of Garcinia fusca Pierre. ...Their chemical structures were determined based on NMR and MS spectroscopic data analysis, as well as single X-ray crystallography. The geranylated compounds, cowanin (13), cowagarcinone E (15), norcowanin (16) and cowanol (17) exhibited potent inhibitions against acetylcholinesterase (AChE) (IC50 0.33–1.09 μM) and butyrylcholinesterase (BChE) (IC50 0.048–1.84 μM), which were more active than the reference drug, galanthamine. Compound 15 was highly potent BChE inhibitor (IC50 0.048 μM) and was 76-fold more potent than the drug. Structure-activity relationship studies indicated that the C-2 prenyl and C-8 geranyl substituents in the tetraoxygenated scaffold are important for high activity. Molecular docking studies revealed that the leads 13 and 15–17 showed similar binding orientations on both enzymes and very well-fitted at the double binding active sites of PAS and CAS with strong hydrophobic interactions from both isoprenyl side chains.
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•Three new oxygenated xanthones and 17 known metabolites were isolated from the stem barks of Garcinia fusca.•Geranylated xanthones 13 and 15–17 were potent AChE (IC50 0.33–1.09 μM) and BChE (IC50 0.048–1.84 μM) inhibitors which were more active than the reference drug, galanthamine.•Compound 15 was highly potent BChE inhibitor (IC50 0.048 μM) and was 76-fold more active than the drug.•Molecular docking studies revealed that the leads showed similar binding orientations on both enzymes and very well-fitted at the double binding active sites of PAS and CAS.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Acetylcholine is the most common neurotransmitter of the parasympathetic nervous system. Several cholinergic drugs are widely used in Alzheimer's disease, urinary retention, glaucoma, and myasthenia ...gravis. Acetylcholinesterase is the enzyme which destroys naturally occurring acetylcholine, and acetylcholinesterase inhibitors (AChEIs) which block the enzyme are currently used in the treatment of several diseases, most importantly Alzheimer's disease. Previous studies from our laboratory have shown a few isoquinoline analogs to be potential acetylcholinesterase inhibitors. In the present study we have extended analysis of the structure-activity relationship (SAR) of the isoquinoline ring system as an AChEI. The corresponding reduced form of 1-(3,4-dimethoxybenzyl)-6,7-dimethoxyisoquinoline, ring-opened analog, and related analogs were evaluated for AChE inhibitory activity. Our results showed that the dihydroisoquinoline ring analog compound 6 (IC₅₀ = 7.0 ± 1.4 μM) and compound 4 (IC₅₀ = 5.5 ± 1.0 μM) displayed potent AChE inhibition. These compounds are currently the lead compounds for further studies in our laboratory.
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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
109.
Two new coumarins from Murraya paniculata Saied, Sumayya; Nizami, Shaikh Sirajuddin; Anis, Itrat
Journal of asian natural products research,
06/2008, Volume:
10, Issue:
6
Journal Article
Peer reviewed
Two new coumarins, murrmeranzin (1) and murralonginal (2), together with four known compounds minumicrolin (3), murrangatin (4), meranzin hydrate (5) and hainanmurpanin (6) have been isolated from ...the aerial parts of Murraya paniculata. The structures of these compounds were determined through spectral analysis. Minumicrolin (3) showed mild butyrylcholinesterase inhibition activity.
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BFBNIB, DOBA, GIS, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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