|
Compound was evaluated for the inhibition of acetylcholinesterase (AChE) in electric eel
|
Electrophorus electricus
|
46.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and activity studies of N-[omega-N'-(adamant-1'-yl)aminoalkyl]- 2-(4'-dimethylaminophenyl)acetamides: in the search of selective inhibitors for the different molecular forms of acetylcholinesterase.
Year : 1998
Volume : 8
Issue : 6
First Page : 575
Last Page : 580
Authors : Perola E, Cellai L, Brufani M.
Abstract : A series of N-[omega-N'-(adamant-1'-yl)aminoalkyl]-2-(4'- dimethylaminophenyl)acetamides were synthesized and tested as acetylcholinesterase inhibitors. A significant selectivity toward acetylcholinesterases from various natural sources, mainly differing in their quaternary structure and solubility, was pointed out. The interest of this kind of molecules as potential therapeutic agents for Alzheimer's disease is discussed.
|
Compound was evaluated for the inhibition of acetylcholinesterase (AChE) in Torpedo californica
|
Torpedo californica
|
46.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and activity studies of N-[omega-N'-(adamant-1'-yl)aminoalkyl]- 2-(4'-dimethylaminophenyl)acetamides: in the search of selective inhibitors for the different molecular forms of acetylcholinesterase.
Year : 1998
Volume : 8
Issue : 6
First Page : 575
Last Page : 580
Authors : Perola E, Cellai L, Brufani M.
Abstract : A series of N-[omega-N'-(adamant-1'-yl)aminoalkyl]-2-(4'- dimethylaminophenyl)acetamides were synthesized and tested as acetylcholinesterase inhibitors. A significant selectivity toward acetylcholinesterases from various natural sources, mainly differing in their quaternary structure and solubility, was pointed out. The interest of this kind of molecules as potential therapeutic agents for Alzheimer's disease is discussed.
|
Compound was evaluated for the inhibition of acetylcholinesterase (AChE) in bovine brain
|
None
|
146.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and activity studies of N-[omega-N'-(adamant-1'-yl)aminoalkyl]- 2-(4'-dimethylaminophenyl)acetamides: in the search of selective inhibitors for the different molecular forms of acetylcholinesterase.
Year : 1998
Volume : 8
Issue : 6
First Page : 575
Last Page : 580
Authors : Perola E, Cellai L, Brufani M.
Abstract : A series of N-[omega-N'-(adamant-1'-yl)aminoalkyl]-2-(4'- dimethylaminophenyl)acetamides were synthesized and tested as acetylcholinesterase inhibitors. A significant selectivity toward acetylcholinesterases from various natural sources, mainly differing in their quaternary structure and solubility, was pointed out. The interest of this kind of molecules as potential therapeutic agents for Alzheimer's disease is discussed.
|
Compound was evaluated for the inhibition of acetylcholinesterase (AChE) in bovine erythrocytes
|
None
|
123.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and activity studies of N-[omega-N'-(adamant-1'-yl)aminoalkyl]- 2-(4'-dimethylaminophenyl)acetamides: in the search of selective inhibitors for the different molecular forms of acetylcholinesterase.
Year : 1998
Volume : 8
Issue : 6
First Page : 575
Last Page : 580
Authors : Perola E, Cellai L, Brufani M.
Abstract : A series of N-[omega-N'-(adamant-1'-yl)aminoalkyl]-2-(4'- dimethylaminophenyl)acetamides were synthesized and tested as acetylcholinesterase inhibitors. A significant selectivity toward acetylcholinesterases from various natural sources, mainly differing in their quaternary structure and solubility, was pointed out. The interest of this kind of molecules as potential therapeutic agents for Alzheimer's disease is discussed.
|
Concentration required to inhibit hydrolytic activity of Acetylcholinesterase by 50%
|
None
|
30.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity studies on a potent antagonist to organophosphate-induced toxicity.
Year : 1991
Volume : 34
Issue : 5
First Page : 1582
Last Page : 1584
Authors : Cannon JG, Sahin MF, Bhatnagar RK, Flynn JR, Long JP.
Abstract : Molecular modifications have been made on a highly potent, active antagonist to organophosphate-induced toxicity, 4,4'-bis[1,3-dioxan-2-ylmethyl)methylamino]acetyl]biphenyl dimethobromide (1). Stepwise removal of the oxygen atoms from the dioxane rings, as well as changing the position of attachment of substituents on the 1,3-dioxane rings and decreasing the ring size from six-membered to five-membered caused drastic or complete loss of pharmacological effect. Partial structures of 1 were all inactive. Thus, the structure of 1 seems to be remarkably specific. Additional pharmacological data are reported for 1.
|
In vitro inhibitory activity against acetylcholinesterase from electric eel
|
eel
|
61.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and anticholinesterase activity of (-)-N1-norphysostigmine, (-)-eseramine, and other N(1)-substituted analogues of (-)-physostigmine.
Year : 1988
Volume : 31
Issue : 12
First Page : 2297
Last Page : 2300
Authors : Yu QS, Atack JR, Rapoport SI, Brossi A.
Abstract : (-)-N1-Benzylnorphysostigmine (4), prepared from synthetic (-)-O-methyl-N1-noreseroline (1) by N-benzylation, ether cleavage, and reaction of (-)-N1-benzylnoreseroline (3) with methyl isocyanate, was the intermediate used to prepare the title compounds. Catalytic debenzylation of 4 afforded (-)-N1-norphysostigmine (5), and (-)-eseramine (6) was obtained by reaction of 5 with methyl isocyanate. Reductive N-methylation of 5 gave (-)-physostigmine (9) while reaction of 5 with allyl bromide and phenethyl bromide afforded carbamates 7 and 8, respectively. Data on the in vitro potencies (IC50) and activities of certain of these compounds (4-8) as inhibitors of electric eel acetyl cholinesterase are reported. (-)-N1-Norphysostigmine (5) was found to be similarly potent against AChE as (-)-physostigmine (9).
|
Inhibition of acetylcholinesterase (AChE) in electric eel (type V-S) by modified radiometric assay
|
Electrophorus electricus
|
275.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The synthesis and in vitro acetylcholinesterase and butyrylcholinesterase inhibitory activity of tacrine (Cognex) derivaties
Year : 1992
Volume : 2
Issue : 8
First Page : 861
Last Page : 864
Authors : Gregor VE, Emmerling MR, Lee C, Moore CJ
|
Inhibitory activity against acetylcholinesterase as a prodrug was demonstarted
|
Electrophorus electricus
|
1.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of 1-(2-Indolyl)pyridinium salts: a prodrug approach to acetylcholinesterase inhibition
Year : 1992
Volume : 2
Issue : 2
First Page : 123
Last Page : 126
Authors : Ares JJ, Ronkin SM, Wallace LJ
|
Inhibitory activity against Acetylcholinesterase in electric eel
|
Electrophorus electricus
|
28.0
nM
|
|
Journal : J. Med. Chem.
Title : Alfred Burger award address. Bioactive alkaloids. 4. Results of recent investigations with colchicine and physostigmine.
Year : 1990
Volume : 33
Issue : 9
First Page : 2311
Last Page : 2319
Authors : Brossi A.
|
In vitro inhibition of Acetylcholinesterase from human erythrocytes
|
None
|
19.0
nM
|
|
Journal : J. Med. Chem.
Title : 5,7-dihydro-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-6H- pyrrolo[3,2-f]-1,2-benzisoxazol-6-one: a potent and centrally-selective inhibitor of acetylcholinesterase with an improved margin of safety.
Year : 1995
Volume : 38
Issue : 15
First Page : 2802
Last Page : 2808
Authors : Villalobos A, Butler TW, Chapin DS, Chen YL, DeMattos SB, Ives JL, Jones SB, Liston DR, Nagel AA, Nason DM.
Abstract : A series of N-benzylpiperidines (2a-d, 10) with novel isoxazole-containing tricycles has been prepared. This series has shown potent in vitro inhibition of the enzyme acetylcholinesterase (AChE), with IC50S = 0.33 - 3.6 nM. Compound 2a was the most potent inhibitor with an IC50 = 0.33 +/- 0.09 nM. Derivatives 2a-d and 10 displayed weak in vitro inhibition of butyrylcholinesterase (BuChE) with IC50S = 600 - 23,000 nM. The most selective compound was 2a with a BuChE/AChE ratio in excess of 4 orders of magnitude (> 10,000). Pyrrolobenzisoxazole 2a also displayed a favorable profile in vivo. In microdialysis experiments, 2a produced a 200% increase in extracellular levels of acetylcholine (ACh) at a dose of 0.4 mg/kg in freely moving, conscious rats. Peripheral side effects (salivation ED50 = 26 +/- 1.5 mg/kg) and acute lethality (LD50[1 h] = 42 mg/kg) were observed at > 60-fold higher doses. These data indicate that 2a is an AChE inhibitor with good central selectivity and a favorable margin of safety. Compound 2a, designated as CP-118,954, is currently in clinical development for the treatment of cognitive disorders.
|
Anticholinesterase activity against erythrocyte acetylcholinesterase (AChE) in humans.
|
None
|
27.9
nM
|
|
Journal : J. Med. Chem.
Title : Syntheses and anticholinesterase activities of (3aS)-N1, N8-bisnorphenserine, (3aS)-N1,N8-bisnorphysostigmine, their antipodal isomers, and other potential metabolites of phenserine.
Year : 1998
Volume : 41
Issue : 13
First Page : 2371
Last Page : 2379
Authors : Yu Q, Greig NH, Holloway HW, Brossi A.
Abstract : Hydrolysis of the carbamate side chains in phenserine [(-)1] and physostigmine [(-)2] yields the metabolite (-)-eseroline (3), and the red dye rubreserine (4) on air oxidation of the former compound. Both compounds lacked anticholinesterase activity in concentrations up to 30 mM, which would be unachievable in vivo. A second group of potential metabolites of 1 and 2 are the N1,N8-bisnorcarbamates (-)9 and (-)10, prepared from (3aS)-N8-benzylnoresermethole (-)12 by the carbinolamine route. These entirely novel compounds proved to be highly potent inhibitors of acetylcholinesterase [(-)9] and of acetyl- and butyrylcholinesterase (AChE and BChE) [(-)10], respectively. To elucidate further the structure/anticholinesterase activity relationship of the described compounds, the antipodal isomers (3aR)-N1,N8-bisnorcarbamates (+)9 and (+)10 were likewise synthesized from (3aR)-N8-benzylnoresermethole (+)12 and assessed. The compounds possessed moderate but less potent anticholinesterase activity, with the same selectivity as their 3aS enantiomers. Finally, the anticholinesterase activities of intermediates N1, N8-bisnorbenzylcarbamates (-)18, (-) 19, (+)18, and (+)19, also novel compounds, were additionally measured. The 3aS enantiomers proved to be potent and selective inhibitors of BChE, particularly (-)19, whereas the antipodal isomers lacked activity.
|
In vitro inhibition of human erythrocyte Acetylcholinesterase.
|
None
|
14.1
nM
|
|
Journal : J. Med. Chem.
Title : Acetylcholinesterase inhibitors: SAR and kinetic studies on omega-[N-methyl-N-(3-alkylcarbamoyloxyphenyl)methyl]aminoalkoxyaryl derivatives.
Year : 2001
Volume : 44
Issue : 23
First Page : 3810
Last Page : 3820
Authors : Rampa A, Piazzi L, Belluti F, Gobbi S, Bisi A, Bartolini M, Andrisano V, Cavrini V, Cavalli A, Recanatini M, Valenti P.
Abstract : In this work, we further investigated a class of carbamic cholinesterase inhibitors introduced in a previous paper (Rampa et al. J. Med. Chem. 1998, 41, 3976). Some new omega-[N-methyl-N-(3-alkylcarbamoyloxyphenyl)methyl]aminoalkoxyaryl analogues were designed, synthesized, and evaluated for their inhibitory activity against both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The structure of the lead compound (xanthostigmine) was systematically varied with the aim to optimize the different parts of the molecule. Moreover, such a structure-activity relationships (SAR) study was integrated with a kinetic analysis of the mechanism of AChE inhibition for two representative compounds. The structural modifications lead to a compound (12b) showing an IC(50) value for the AChE inhibition of 0.32 +/- 0.09 nM and to a group of BuChE inhibitors also active at the nanomolar level, the most potent of which (15d) was characterized by an IC(50) value of 3.3 +/- 0.4 nM. The kinetic analysis allowed for clarification of the role played by different molecular moieties with regard to the rate of AChE carbamoylation and the duration of inhibition. On the basis of the results presented here, it was concluded that the cholinesterase inhibitors of this class possess promising characteristics in view of a potential development as drugs for the treatment of Alzheimer's disease.
|
Evaluated for the in vitro inhibition of the Acetylcholinesterase (AChE) from human erythrocytes
|
None
|
19.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel benzisoxazole derivatives as potent and selective inhibitors of acetylcholinesterase.
Year : 1994
Volume : 37
Issue : 17
First Page : 2721
Last Page : 2734
Authors : Villalobos A, Blake JF, Biggers CK, Butler TW, Chapin DS, Chen YL, Ives JL, Jones SB, Liston DR, Nagel AA.
Abstract : A series of N-benzylpiperidine benzisoxazoles has been developed as potent and selective inhibitors of the enzyme acetylcholinesterase (AChE). The benzisoxazole heterocycle was found to be an appropriate bioisosteric replacement for the benzoyl functionality present in the N-benzylpiperidine class of inhibitors. The title compounds were synthesized by alkylating 3-methyl-1,2-benzisoxazoles with an iodo piperidine derivatives as the key step. Benzisoxazoles 1b-j,o displayed potent inhibition of AChE in vitro with IC50's = 0.8-14 nM. Particularly interesting were N-acetyl and morpholino derivatives 1g (IC50 = 3 nM) and 1j (IC50 = 0.8 nM), respectively, which displayed outstanding selectivity for acetyl-over butyrylcholinesterase, in excess of 3 orders of magnitude. N-Acetyl 1g also displayed a favorable profile in vivo. This analog showed a dose-dependent elevation of total acetylcholine in mouse forebrain after oral administration with an ED50 = 2.4 mg/kg. In addition, 1g was able to reverse amnesia in a mouse passive avoidance model at doses of 3.2 and 5.6 mg/kg with an average reversal of 89.7%. Molecular dynamics simulations were used to study the possible binding modes of N-benzylpiperidine benzisoxazoles to AChE from Torpedo californica. Key structural insights were obtained regarding the potency of this class of inhibitors. Specifically, Asp-72, Trp-84, Trp-279, Phe-288, and Phe-330 are implicated in the binding of these inhibitors. The N-benzylpiperidine benzisoxazoles may be suitable compounds for the palliative treatment of Alzheimer's Disease.
|
Compound was evaluated for the inhibition of acetylcholinesterase (AChE) in human erythrocytes
|
None
|
47.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and activity studies of N-[omega-N'-(adamant-1'-yl)aminoalkyl]- 2-(4'-dimethylaminophenyl)acetamides: in the search of selective inhibitors for the different molecular forms of acetylcholinesterase.
Year : 1998
Volume : 8
Issue : 6
First Page : 575
Last Page : 580
Authors : Perola E, Cellai L, Brufani M.
Abstract : A series of N-[omega-N'-(adamant-1'-yl)aminoalkyl]-2-(4'- dimethylaminophenyl)acetamides were synthesized and tested as acetylcholinesterase inhibitors. A significant selectivity toward acetylcholinesterases from various natural sources, mainly differing in their quaternary structure and solubility, was pointed out. The interest of this kind of molecules as potential therapeutic agents for Alzheimer's disease is discussed.
|
Concentration required to inhibit 50% of Acetylcholinesterase obtained from human erythrocytes was determined in vitro
|
None
|
18.9
nM
|
|
Journal : J. Med. Chem.
Title : Design and synthesis of 1-heteroaryl-3-(1-benzyl-4-piperidinyl)propan-1-one derivatives as potent, selective acetylcholinesterase inhibitors.
Year : 1995
Volume : 38
Issue : 7
First Page : 1084
Last Page : 1089
Authors : Nagel AA, Liston DR, Jung S, Mahar M, Vincent LA, Chapin D, Chen YL, Hubbard S, Ives JL, Jones SB.
Abstract : Herein is described the synthesis and structure--activity relationship of a novel series of aromatic and heteroaromatic 3-(1-benzyl-4-piperidinyl)propan-1-one derivatives that display potent and selective inhibition of the enzyme acetylcholinesterase (AChE). 1-(2-Methyl-6-benzothiazolyl)-3-(N-benzyl-4-piperidinyl)propan-1-one hydrochloride, 6d, is one of the most active compounds within this series exhibiting an IC50 for the inhibition of the AChE enzyme equal to 6.8 nM. Compound 6d has shown a dose-dependent elevation of total acetylcholine (ACh) levels in the mouse forebrain with an oral ED50 = 9.8 mg/kg. In addition, in vivo microdialysis experiments in the rat demonstrate that 6d increases extracellular ACh (100% over basal) 1-3 h postdose with an oral ED50 = 4.8 mg/kg.
|
Concentration required to inhibit acetylcholinesterase isolated from human erythrocytes
|
None
|
128.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Total synthesis of an optically active 8-carba-physostigmine analog: a potent acetylcholinesterase inhibitor
Year : 1991
Volume : 1
Issue : 1
First Page : 47
Last Page : 50
Authors : Chen YL, Hedberg K
|
In vitro inhibition of human acetylcholinesterase.
|
None
|
43.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and cholinergic properties of N-aryl-2-[[[5-[(dimethylamino)methyl]-2-furanyl]methyl]thio]ethylamino analogs of ranitidine.
Year : 1992
Volume : 35
Issue : 17
First Page : 3141
Last Page : 3147
Authors : Valli MJ, Tang Y, Kosh JW, Chapman JM, Sowell JW.
Abstract : A series of N-aryl-2-[[[5-[(dimethylamino)methyl]-2- furanyl]methyl]thio]ethylamino analogs of the H2-antagonist, ranitidine, was synthesized and the abilities of the compounds to alleviate the cholinergic deficit characteristic of Alzheimer's disease evaluated. The compounds were initially tested for their ability to inhibit human erythrocyte acetylcholinesterase activity in vitro. Selected compounds were further evaluated for butyrylcholinesterase inhibition, M1 and M2 cholinergic receptor binding, potentiation of ileal contractions, and the ability to elevate brain acetylcholine levels in mice. The analogs were compared to tetrahydroaminoacridine and to a recently reported series of bis-[[(dimethylamino)methyl]furans]. The N-aryl-2-[[[5-[(dimethylamino)methyl]-2- furanyl]methyl]thio]ethylamine derivatives were generally comparable to tetrahydroaminoacridine and the bis[[(dimethylamino)methyl]furans] in acetylcholinesterase inhibition, M1/M2 receptor binding, and the potentiation of ileal contractions, while being more potent inhibitors of acetylcholinesterase than butyrylcholinesterase. The 4-nitro-3-pyridazinyl analog, 26, was notable in demonstrating a potent and selective binding to the M2 receptor, with an M2 IC50/M1 IC50 of 0.060. Compounds in which the substituents on the dinitro-N-aryl moiety were relatively small were the best at inhibiting acetylcholinesterase in vitro. The N-aryl-2-[[[5-[(dimethylamino)methyl]-2- furanyl]methyl]thio]ethylamines in general, and those with small N-aryl substituents in particular, were superior to the bis[[(dimethylamino)methyl]furans] in elevating brain ACh levels in mice, probably due to enhanced distribution into the CNS. The 1,5-difluoro-2,4-dinitrophenyl analog, 8, resulted in the largest elevation in brain acetylcholine levels, affording a 53% increase at 88 mg/kg.
|
Inhibition of acetylcholinesterase (AChE) of human red blood cell (type XIII) by modified radiometric AChE assay
|
Homo sapiens
|
61.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The synthesis and in vitro acetylcholinesterase and butyrylcholinesterase inhibitory activity of tacrine (Cognex) derivaties
Year : 1992
Volume : 2
Issue : 8
First Page : 861
Last Page : 864
Authors : Gregor VE, Emmerling MR, Lee C, Moore CJ
|
Inhibition of Acetylcholinesterase (AChE) from human RBC
|
Homo sapiens
|
30.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and structure-activity relationships of new acetylcholinesterase inhibitors: Morpholinoalkylcarbamoyloxyeseroline derivatives
Year : 1995
Volume : 5
Issue : 18
First Page : 2077
Last Page : 2080
Authors : Alisi MA, Brufani M, Filocamo L, Gostoli G, Licandro E, Cesta M, Lappa S, Marchesini D, Pagella P
|
In vitro inhibitory activity against human acetylcholinesterase
|
Homo sapiens
|
128.0
nM
|
|
Journal : J. Med. Chem.
Title : Syntheses and anticholinesterase activity of tetrahydrobenzazepine carbamates.
Year : 1994
Volume : 37
Issue : 13
First Page : 1996
Last Page : 2000
Authors : Chen YL, Liston D, Nielsen J, Chapin D, Dunaiskis A, Hedberg K, Ives J, Johnson J, Jones S.
Abstract : The synthesis of a series of alkylcarbamates of 1,5-methano-2,3,4,5-tetrahydro-1H-2-benzazepin-7-ol is reported. Many of these compounds are potent acetylcholinesterase (AChE) inhibitors. The in vitro AChE inhibition, cholinergic effects, acute toxicity, and elevation of brain acetylcholine levels in vivo of this series of compounds are described. A representative compound, 1d (5.6 mg/kg, po), was able to reverse hemicolinium-3-induced amnesia in the mouse passive avoidance assay.
|
In vitro inhibitory activity against human AchE (Acetylcholinesterase)
|
None
|
128.0
nM
|
|
Journal : J. Med. Chem.
Title : Syntheses, resolution, and structure-activity relationships of potent acetylcholinesterase inhibitors: 8-carbaphysostigmine analogues.
Year : 1992
Volume : 35
Issue : 8
First Page : 1429
Last Page : 1434
Authors : Chen YL, Nielsen J, Hedberg K, Dunaiskis A, Jones S, Russo L, Johnson J, Ives J, Liston D.
Abstract : The synthesis of a series of 1,2,3,3a,8,8a-hexahydroindeno[2,1-b]pyrrole 5-alkylcarbamates and their resolution are reported. These compounds are structurally related to physostigmine with substitution of a methylene group in place of the NMe group at position 8 of physostigmine. Many of these 8-carbaphysostigmine analogues are more potent acetylcholinesterase inhibitors in vitro and less toxic in vivo than physostigmine. The (-)-enantiomer (e.g., 1d and 1g) possessing the same absolute configuration at C3a and C8a as that of physostigmine, is about 6 to 12-fold more potent at inhibiting acetylcholinesterase than the corresponding (+)-enantiomer (e.g., 1e and 1h).
|
Inhibitory activity against Acetylcholinesterase
|
None
|
57.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure-based alignment and comparative molecular field analysis of acetylcholinesterase inhibitors.
Year : 1996
Volume : 39
Issue : 26
First Page : 5064
Last Page : 5071
Authors : Cho SJ, Garsia ML, Bier J, Tropsha A.
Abstract : The method of comparative molecular field analysis (CoMFA) was used to develop quantitative structure-activity relationships for physostigmine, 9-amino-1,2,3,4-tetrahydroacridine (THA), edrophonium (EDR), and other structurally diverse inhibitors of acetylcholinesterase (AChE). The availability of the crystal structures of enzyme/inhibitor complexes (EDR/AChE, THA/AChE, and decamethonium (DCM)/AChE) (Harel, M.; et al. Quaternary ligand binding to aromatic residues in the active-site gorge of acetylcholinesterase. Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 9031-9035) provided information regarding not only the active conformation of the inhibitors but also the relative mutual orientation of the inhibitors in the active site of the enzyme. Crystallographic conformations of EDR and THA were used as templates onto which additional inhibitors were superimposed. The application of cross-validated R2 guided region selection method, recently developed in this laboratory (Cho, S.J.; Tropsha, A. Cross-Validated R2 Guided Region Selection for Comparative Molecular Field Analysis (CoMFA): A Simple Method to Achieve Consistent Results. J. Med. Chem. 1995, 38, 1060-1066), to 60 AChE inhibitors led to a highly predictive CoMFA model with the q2 of 0.734.
|
Inhibition of human acetylcholinesterase from erythrocytes (RBC)
|
Homo sapiens
|
27.9
nM
|
|
Journal : J. Med. Chem.
Title : Total syntheses and anticholinesterase activities of (3aS)-N(8)-norphysostigmine, (3aS)-N(8)-norphenserine, their antipodal isomers, and other N(8)-substituted analogues.
Year : 1997
Volume : 40
Issue : 18
First Page : 2895
Last Page : 2901
Authors : Yu QS, Pei XF, Holloway HW, Greig NH, Brossi A.
Abstract : N(8)-Benzylesermethole (6) was prepared from 5-methoxytryptamine (1) in five steps. Resolution of compound 6 by dibenzoyl- and ditoluyltartaric acid provided enantiomers (-)- and (+)-7. After demethylation, reaction with isocyanates and catalytic debenzylation over hydrogen, the total syntheses of (-)- and (+)-N(8)-norphysostigmine [(-)- and (+)-11] and (-)- and (+)-N(8)-norphenserine [(-)- and (+)-12] were accomplished, (-)-N(8)-Norphysostigmine [(-)-11] and (-)-N(8)-norphenserine [(-)-12] were also obtained by transformations of natural physostigmine [(-)-13] and phenserine [(-)-14] prepared from (-)-13. The absolute configurations and optical purity of compounds (-)-11, (-)-12, (+)-11, and (+)-12 were confirmed by a comparison of their optical rotations with those of the compounds synthesized from physostigmine [(-)-13]. The anticholinesterase activities of N(8)-nor- and N(8)-substituted analogues, (-)- and (+)-9, -10, -11, -12, 15, and 16, were compared with those of physostigmine [(-)- and (+)-13] and phenserine [(-)- and (+)-14] and are reported.
|
In vitro inhibition of human erythrocyte acetylcholinesterase.
|
None
|
28.0
nM
|
|
Journal : J. Med. Chem.
Title : Methyl analogues of the experimental Alzheimer drug phenserine: synthesis and structure/activity relationships for acetyl- and butyrylcholinesterase inhibitory action.
Year : 2001
Volume : 44
Issue : 24
First Page : 4062
Last Page : 4071
Authors : Yu Q, Holloway HW, Flippen-Anderson JL, Hoffman B, Brossi A, Greig NH.
Abstract : With the goal of developing potential Alzheimer's pharmacotherapeutics, we have synthesized a series of novel analogues of the potent anticholinesterases phenserine (2) and physostigmine (1). These derivatives contain methyl (3, 4, 6), dimethyl (5, 7, 8, 10, 11) and trimethyl (14) substituents in each position of the phenyl group of the phenylcarbamoyl moieties, and with N-methyl and 6-methyl substituents (12, 13, 31, 33). We also quantified the inhibitory action of these compounds against human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). An analysis of the structure/anticholinesterase activity relationship of the described compounds, together with molecular modeling, confirmed the catalytic triad mechanism of the binding of this class of carabamate analogues within AChE and BChE and defined structural requirements for their differential inhibition.
|
Inhibitory activity against Acetylcholinesterase in cortex
|
Homo sapiens
|
31.0
nM
|
|
Journal : J. Med. Chem.
Title : Alfred Burger award address. Bioactive alkaloids. 4. Results of recent investigations with colchicine and physostigmine.
Year : 1990
Volume : 33
Issue : 9
First Page : 2311
Last Page : 2319
Authors : Brossi A.
|
Inhibitory activity against Acetylcholinesterase in erythrocyte
|
Homo sapiens
|
35.0
nM
|
|
Journal : J. Med. Chem.
Title : Alfred Burger award address. Bioactive alkaloids. 4. Results of recent investigations with colchicine and physostigmine.
Year : 1990
Volume : 33
Issue : 9
First Page : 2311
Last Page : 2319
Authors : Brossi A.
|
The compound was evaluated for the inhibition of human Acetylcholinesterase
|
None
|
43.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and cholinergic properties of bis[[(dimethylamino)methyl]furanyl] analogues of ranitidine.
Year : 1992
Volume : 35
Issue : 6
First Page : 1102
Last Page : 1108
Authors : Sowell JW, Tang Y, Valli MJ, Chapman JM, Usher LA, Vaughan CM, Kosh JW.
Abstract : The histaminergic H2 antagonist, ranitidine, has also been found to significantly inhibit acetylcholinesterase (AChE) in vitro. In an effort to develop novel, nonquaternary AChE inhibitors capable of penetrating into the CNS and alleviating the cholinergic deficit characteristic of Alzheimer's disease, a series of bis[[(dimethylamino)methyl]furanyl] analogues of ranitidine has been synthesized. All compounds were evaluated for human erythrocyte AChE inhibitory activity and compared to ranitidine, physostigmine, and tetrahydro-9-aminoacridine (THA). The most active AChE inhibitors were N,N'-disubstituted derivatives of 2-nitro-1,1-ethenediamine and 4,6-dinitro-1,3-benzenediamine, with compound 8 demonstrating activity greater than physostigmine. Deletion of the diaminonitroethene group in a series of alkyl and aryl bis-thioethers, yielded a number of slightly less active compounds, comparable in potency to THA. The 13 most active AChE inhibitors all demonstrated a more selective inhibition of AChE, as opposed to butyrylcholinesterase inhibition, than did THA. Compounds 3 and 22 were equally active to THA in potentiating rat ileal contractions. Binding studies demonstrated M1 and M2 cholinergic receptor affinities slightly greater than or equal to THA. Differential receptor binding studies showed compound 12 resembled THA in agonist/antagonist activity. Compounds 11-13 significantly elevated mouse brain acetylcholine levels, when administered at 80% of their approximate lethal doses, but were less active than THA or physostigmine.
|
Inhibition against Acetylcholinesterase (AChE)
|
None
|
18.97
nM
|
|
Journal : J. Med. Chem.
Title : A comparative molecular field analysis study of N-benzylpiperidines as acetylcholinesterase inhibitors.
Year : 1996
Volume : 39
Issue : 2
First Page : 380
Last Page : 387
Authors : Tong W, Collantes ER, Chen Y, Welsh WJ.
Abstract : A series of 1-benzyl-4-[2-(N-benzoylamino)ethyl]piperidine derivatives and of N-benzylpiperidine benzisoxazoles has been investigated using the comparative molecular field analysis (CoMFA) approach. These compounds have been found to inhibit the metabolic breakdown of the neurotransmitter acetylcholine (ACh) by the enzyme acetylcholinesterase (AChE) and hence alleviate memory deficits in patients with Alzheimer's Disease by potentiating cholinergic transmission. Development of the CoMFA model considered two separate alignments: (i) alignment I which emphasized the electrostatic fitting of the subject compounds and (ii) alignment II which emphasized their steric fitting. In addition, the inhibitor compounds were considered both as neutral species and as N-piperidine-protonated species. The resulting 3D-QSAR indicates a strong correlation between the inhibitory activity of these N-benzylpiperidines and the steric and electronic factors which modulate their biochemical activity. A CoMFA model with considerable predictive ability was obtained.
|
Inhibitory activity against acetylcholinesterase in human erythrocytes
|
None
|
17.78
nM
|
|
Journal : J. Med. Chem.
Title : Hexahydrochromeno[4,3-b]pyrrole derivatives as acetylcholinesterase inhibitors.
Year : 2001
Volume : 44
Issue : 1
First Page : 105
Last Page : 109
Authors : Bolognesi ML, Andrisano V, Bartolini M, Minarini A, Rosini M, Tumiatti V, Melchiorre C.
Abstract : In a search for less flexible analogues of caproctamine (1), a diamine diamide endowed with an interesting AChE affinity profile, we discovered compound 2, in which the terminal 2-methoxybenzyl groups of 1 have been incorporated into a tricyclic system. Since this compound retains good AChE inhibitory activity and its hexahydrochromeno[4,3-b]pyrrole moiety is reminiscent of the hexahydropyrrolo[2,3-b]indole of physostigmine (3), we have designed and synthesized carbamates 4-6, and their biological evaluation has been assessed in vitro against human AChE and BChE. The 6-carbamate 4 was almost as potent as physostigmine and was 60- and 550-fold more potent than the 7-carbamate 5 and the 8-carbamate 6, respectively. The two enantiomers of 4, (-)-4 and (+)-4, did not show a marked enantioselectivity. Finally, a similar time-dependent pattern of inhibition of AChE was observed for 3 and 4.
|
Inhibitory concentration against acetylcholinesterase from human erythrocytes
|
None
|
17.78
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationships of acetylcholinesterase noncovalent inhibitors based on a polyamine backbone. 2. Role of the substituents on the phenyl ring and nitrogen atoms of caproctamine.
Year : 2003
Volume : 46
Issue : 6
First Page : 954
Last Page : 966
Authors : Tumiatti V, Rosini M, Bartolini M, Cavalli A, Marucci G, Andrisano V, Angeli P, Banzi R, Minarini A, Recanatini M, Melchiorre C.
Abstract : Continuing our studies on polyamine-based compounds of potential interest in the field of Alzheimer's disease therapeutics, we investigated the structure-activity relationships (SAR) of a lead compound (caproctamine, 3) identified in a previous work. In particular, we varied the substituents on the phenyl ring and on the nitrogen functions (both the amine and the amide), and studied the effects of such modifications on the inhibitory potency against isolated acetyl- and butyryl-cholinesterase (AChE and BChE). Moreover, the ability of selected compounds to reverse the d-tubocurarine-induced neuromuscular blockade and their antagonism toward muscarinic M(2) receptors in guinea pig left atrium were assayed. The most interesting SAR result was the identification of a relationship between the electronic characteristics of 2-substituents (measured by pK(a)) and the AChE inhibitory potency (pIC(50)) of tertiary amine compounds 6-12, which was confirmed by the invariance of the pIC(50) values of the corresponding methiodide derivatives 14-20. With regard to the biological profile, the most interesting compound was the N-ethyl-analogue of caproctamine (9), that showed pIC(50) values of 7.73 (+/-0.02) and 5.65 (+/-0.03) against AChE and BChE, respectively. The ability to increase the acetylcholine level was maintained in the functional assay (pAI(50) for reversing the neuromuscular blockade was 6.45 (+/-0.07)), as well as the ability to antagonize the M(2) receptors (pK(b) = 5.65 (+/-0.06)). Moreover, 9 showed a long duration of action as AChE inhibitor, an useful property in view of a possible development of this compound as a therapeutic agent.
|
Inhibition of acetylcholinesterase (AChE) of human erythrocytes
|
Homo sapiens
|
14.13
nM
|
|
Journal : J. Med. Chem.
Title : Acetylcholinesterase noncovalent inhibitors based on a polyamine backbone for potential use against Alzheimer's disease.
Year : 1998
Volume : 41
Issue : 22
First Page : 4186
Last Page : 4189
Authors : Melchiorre C, Andrisano V, Bolognesi ML, Budriesi R, Cavalli A, Cavrini V, Rosini M, Tumiatti V, Recanatini M.
|
Inhibitory activity against acetylcholinesterase
|
None
|
0.68
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of acetylcholinesterase inhibitors: 1-benzyl-4-[(5,6-dimethoxy-1-oxoindan-2-yl)methyl]piperidine hydrochloride and related compounds.
Year : 1995
Volume : 38
Issue : 24
First Page : 4821
Last Page : 4829
Authors : Sugimoto H, Iimura Y, Yamanishi Y, Yamatsu K.
Abstract : Following the discovery of a new series of anti-acetylcholinesterase (anti-AChE) inhibitors such as 1-benzyl-4-[2-(N-benzoylamino)ethyl]piperidine (1), we reported that its rigid analogue, 1-benzyl-4-(2-isoindolin-2-ylethyl)piperidine (5), had more potent activity. We have extended the structure-activity relationship (SAR) study for the rigid analogue and found that the 2-isoindoline moiety in compound 5 can be replaced with a indanone moiety (8) without a major loss in potency. Among the indanone derivatives, 1-benzyl-4-[(5,6-dimethoxy-1-oxoindan-2-yl)methyl]piperidine (13e) (E2020) (IC50 = 5.7 nM) was found to be one of the most potent anti-AChE inhibitors. Compound 13e showed a selective affinity 1250 times greater for AChE than for butyrylcholinesterase. In vivo studies demonstrated that 13e has a longer duration of action than physostigmine at a dose of 5 mg/kg (po) and produced a marked and significant increase in acetylcholine content in rat cerebral cortex. We report the synthesis, SAR, and a proposed hypothetical binding site of 13e (E2020).
|
In vitro inhibitory concentration against acetylcholinesterase (AChE) obtained from mouse brain homogenate.
|
None
|
0.69
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of acetylcholinesterase inhibitors: 1-benzyl-4-(2-phthalimidoethyl)piperidine and related derivatives.
Year : 1992
Volume : 35
Issue : 24
First Page : 4542
Last Page : 4548
Authors : Sugimoto H, Tsuchiya Y, Sugumi H, Higurashi K, Karibe N, Iimura Y, Sasaki A, Araki S, Yamanishi Y, Yamatsu K.
Abstract : Following the discovery of a new series of 1-benzyl-4-[2-(N-benzoyl-N-methylamino)ethyl]piperidine (2) derivatives with a potent anti-acetylcholinesterase (anti-AChE) activity, we extended the structure-activity relationships (SAR) to rigid analogues (4) and 1-benzyl-4-[2-(N-benzoyl-N-phenylamino)ethyl]piperidine derivatives (3). Introduction of a phenyl group on the nitrogen atom of the amide moieties resulted in enhanced activity. The rigid analogue containing isoindolone (9) was found to exhibit potent anti-AChE activity comparable to that of 2. Furthermore, replacement of the isoindolone with other heterobicyclic ring systems was examined. Among the compounds prepared in these series, 1-benzyl-4-[2-[4-(benzoylamino)phthalimido]ethyl]piperidine hydrochloride (19) (IC50 = 1.2 nM) is one of the most potent inhibitors of AChE. Compound 19 showed a definite selectivity to AChE over the BuChE (about 34700-fold) and, at dosages of 10-50 mg/kg, exerted a dose-dependent inhibitory effect on AChE in rat brain.
|
In vitro inhibitory effect on rat Acetylcholinesterase
|
None
|
80.0
nM
|
|
Journal : J. Med. Chem.
Title : Flexible 1-[(2-aminoethoxy)alkyl]-3-ar(o)yl(thio)ureas as novel acetylcholinesterase inhibitors. Synthesis and biochemical evaluation.
Year : 1995
Volume : 38
Issue : 15
First Page : 2969
Last Page : 2973
Authors : Vidaluc JL, Calmel F, Bigg DC, Carilla E, Briley M.
Abstract : A series of flexible 1-(2-aminoethoxy)-3-ar(o)yl(thio)ureas was synthesized and assessed for antiacetylcholinesterase activity. This series was designed in order to optimize the spacer length linking the two pharmacophoric moieties, i.e., the basic nitrogen and the ar(o)yl(thio)-urea unit, and to test compounds with greater conformational flexibility. Thus, the replacement of the previously described spacer, 4-piperidinylethyl, by a linear ethoxyethyl chain gave compounds of slightly comparable potency, providing that they were correctly substituted. The results show that this new flexible spacer is compatible with high inhibitory activities. The optimal chain length corresponds to five methylene groups, allowing an efficient interaction between the two pharmacophoric units and the two reported hypothetical enzyme hydrophobic binding sites. Moreover, the initially optimized benzyl group, attached to the basic nitrogen, was found to be advantageously replaced by a cyclohexyl group, showing that an aromatic residue does not represent a prerequisite for activity.
|
Inhibitory activity against acetylcholine esterase (AChE)
|
None
|
190.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel [2-(4-piperidinyl)ethyl](thio)ureas: synthesis and antiacetylcholinesterase activity.
Year : 1994
Volume : 37
Issue : 5
First Page : 689
Last Page : 695
Authors : Vidaluc JL, Calmel F, Bigg D, Carilla E, Stenger A, Chopin P, Briley M.
Abstract : A series of 1-ar(o)yl-3-[2-(1-benzyl-4-piperidinyl)ethyl](thio)urea derivatives was synthesized and evaluated for antiacetylcholinesterase activity. Most aroyl(thio)urea derivatives showed potent inhibitory activity in the sub-micromolar range. A comparable potency was obtained with the aryl(thio)urea analogues by replacing the phenyl with a 2-pyridyl group. The substituted guanidine variations proved to be almost inactive whereas the nitroethylene analogues appeared to be quite efficient. These results were interpreted in terms of the preferential cis-trans conformation of the aroyl(thio)urea and 2-pyridyl(thio)urea moieties involving the existence of hydrogen bonding. In vivo experiments showed that compound 7m had maximal antiamnestic activity at 0.03 mg/kg with a therapeutic ratio greater than 1000, while cholinergic side effects were only seen at doses 100-fold the maximally effective antiamnestic dose. Compound 7m represents a potentially interesting antidementia agent.
|
Inhibitory concentration in vitro and ex vivo for anti-AChE activity in rat brain
|
None
|
0.68
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and anti-acetylcholinesterase activity of 1-benzyl-4-[(5,6-dimethoxy-1-indanon-2-yl)methyl]piperidine hydrochloride (E2020) and related compounds
Year : 1992
Volume : 2
Issue : 8
First Page : 871
Last Page : 876
Authors : Sugimoto H, Iimura Y, Yamanishi Y, Yamatsu K
|
Inhibition of rat acetylcholinesterase (AChE)
|
None
|
14.0
nM
|
|
Journal : J. Med. Chem.
Title : Acetylcholinesterase inhibitors: synthesis and structure-activity relationships of omega-[N-methyl-N-(3-alkylcarbamoyloxyphenyl)- methyl]aminoalkoxyheteroaryl derivatives.
Year : 1998
Volume : 41
Issue : 21
First Page : 3976
Last Page : 3986
Authors : Rampa A, Bisi A, Valenti P, Recanatini M, Cavalli A, Andrisano V, Cavrini V, Fin L, Buriani A, Giusti P.
Abstract : Acetylcholinesterase (AChE) inhibitors are one of the most actively investigated classes of compounds in the search for an effective treatment of Alzheimer's disease. This work describes the synthesis, AChE inhibitory activity, and structure-activity relationships of some compounds related to a recently discovered series of AChE inhibitors: the omega-[N-methyl-N-(3-alkylcarbamoyloxyphenyl)methyl]aminoalkoxy xanthen-9-ones. The influence of structural variations on the inhibitory potency was carefully investigated by modifying different parts of the parent molecule, and a theoretical model of the binding of one representative compound to the enzyme was developed. The biological properties of the series were investigated in some detail by considering not only the activity on isolated enzyme but the selectivity with respect to butyrylcholinesterase (BuChE) and the in vitro inhibitory activity on rat cerebral cortex as well. Some of the newly synthesized derivatives, when tested on isolated and/or AChE-enriched rat brain cortex fraction, displayed a selective inhibitory activity and were more active than physostigmine. In particular, compound 13, an azaxanthone derivative, displayed the best rat cortex AChE inhibition (190-fold higher than physostigmine), as well as a high degree of enzyme selectivity (over 60-fold more selective for AChE than for BuChE). When tested in the isolated enzyme, compound 13 was less active, suggesting some differences either in drug availability/biotransformation or in the inhibitor-sensitive residues of the enzyme when biologically positioned in rat brain membranes.
|
Inhibitory concentration against rat brain acetylcholinesterase AChE
|
Rattus norvegicus
|
2.0
nM
|
|
Journal : J. Med. Chem.
Title : Acetylcholinesterase inhibitors: synthesis and structure-activity relationships of omega-[N-methyl-N-(3-alkylcarbamoyloxyphenyl)- methyl]aminoalkoxyheteroaryl derivatives.
Year : 1998
Volume : 41
Issue : 21
First Page : 3976
Last Page : 3986
Authors : Rampa A, Bisi A, Valenti P, Recanatini M, Cavalli A, Andrisano V, Cavrini V, Fin L, Buriani A, Giusti P.
Abstract : Acetylcholinesterase (AChE) inhibitors are one of the most actively investigated classes of compounds in the search for an effective treatment of Alzheimer's disease. This work describes the synthesis, AChE inhibitory activity, and structure-activity relationships of some compounds related to a recently discovered series of AChE inhibitors: the omega-[N-methyl-N-(3-alkylcarbamoyloxyphenyl)methyl]aminoalkoxy xanthen-9-ones. The influence of structural variations on the inhibitory potency was carefully investigated by modifying different parts of the parent molecule, and a theoretical model of the binding of one representative compound to the enzyme was developed. The biological properties of the series were investigated in some detail by considering not only the activity on isolated enzyme but the selectivity with respect to butyrylcholinesterase (BuChE) and the in vitro inhibitory activity on rat cerebral cortex as well. Some of the newly synthesized derivatives, when tested on isolated and/or AChE-enriched rat brain cortex fraction, displayed a selective inhibitory activity and were more active than physostigmine. In particular, compound 13, an azaxanthone derivative, displayed the best rat cortex AChE inhibition (190-fold higher than physostigmine), as well as a high degree of enzyme selectivity (over 60-fold more selective for AChE than for BuChE). When tested in the isolated enzyme, compound 13 was less active, suggesting some differences either in drug availability/biotransformation or in the inhibitor-sensitive residues of the enzyme when biologically positioned in rat brain membranes.
|
In vitro inhibitory activity against acetylcholinesterase
|
None
|
0.43
nM
|
|
Journal : J. Med. Chem.
Title : QSAR analyses of the substituted indanone and benzylpiperidine rings of a series of indanone-benzylpiperidine inhibitors of acetylcholinesterase.
Year : 1992
Volume : 35
Issue : 3
First Page : 584
Last Page : 589
Authors : Cardozo MG, Iimura Y, Sugimoto H, Yamanishi Y, Hopfinger AJ.
Abstract : QSAR analyses have been performed on the substituted indanone and benzylpiperidine ring substructures of a set of acetylcholinesterase, AChE, inhibitors of which 1-benzyl-4-[(5,6-dimethoxy-1-oxoindan-2-yl)methyl]piperidine hydrochloride is a potent in vitro and ex vivo inhibitor. The method of molecular decomposition-recomposition was used to define the sets of molecular substructures and corresponding in vitro inhibition databases. A QSAR involving the magnitude of the dipole moment, the highest occupied molecular orbital (HOMO) energy, and a specific pi-orbital wave function coefficient of the substituted indanone ring substructure was constructed and found to be significant. The absence of any molecular-shape or bulk term in the QSAR, coupled with some of the relatively large substituents used to construct the QSAR, suggests considerable space is available around the indanone ring during the inhibition process. A set of QSARs were constructed and evaluated for substituents on the aromatic ring of the benzylpiperidine substructure. The most significant QSAR involves a representation of molecular shape, the largest principal moment of inertia, and the HOMO of the substituted aromatic ring. It appears that upon binding the receptor "wall" is closely fit around the benzyl ring, especially near the para position. Overall, the QSAR analysis suggests inhibition potency can be better enhanced by substitution on the indanone ring, as compared to the aromatic sites of the benzylpiperidine ring. Moreover, inhibition potency can be rapidly diminished, presumably through steric interactions with the receptor surface of AChE, by substitution of moderate to large groups on the benzyl ring, particularly at the para position.
|
Inhibition acetylcholinesterase (AChE) enzyme.
|
None
|
57.02
nM
|
|
Journal : J. Med. Chem.
Title : Three-dimensional quantitative structure-activity relationships from molecular similarity matrices and genetic neural networks. 2. Applications.
Year : 1997
Volume : 40
Issue : 26
First Page : 4360
Last Page : 4371
Authors : So SS, Karplus M.
Abstract : Validation of a method that uses a genetic neural network with electrostatic and steric similarity matrices (SM/GNN) to obtain quantitative structure-activity relationships (QSARs) is performed with eight data sets. Biological and physicochemical properties from a broad range of chemical classes are correlated and predicted using this technique. Quantitatively the results compare favorably with the benchmarks obtained by a number of well-established QSAR methods; qualitatively the models are consistent with the published descriptions on the relative contribution of steric and electrostatic factors. The results demonstrate the general utility of this method in deriving QSARs. The implication of the importance of molecular alignment and possible methodological improvements are discussed.
|
Compound was evaluated for its inhibitory concentration against Horse serum Butyrylcholinesterase
|
Equus caballus
|
16.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Conformationally restricted carbamate inhibitors of horse serum butyrylcholinesterase.
Year : 1998
Volume : 8
Issue : 19
First Page : 2747
Last Page : 2750
Authors : Lin G, Chen GH, Ho HC.
Abstract : Conformationally restricted carbamate inhibitors, exo-2-norbornyl-N-butylcarbamate (1), endo-2-norbornyl-N-butylcarbamate (2), l-adamantyl-N-butylcarbamate (3), and 2-adamantyl-N-butylcarbamate (4) as active site-directed irreversible inhibitors of horse serum butyrylcholinesterase are investigated for values of the dissociation constant (KI), the carbamylation constant (k2), and the bimolecular rate constant (ki). Compound 1 is the most potent inhibitor of the enzyme and the values of KI and ki are 20 nM and 1.1 x 10(5) M-1sec-1, respectively.
|
In vitro inhibition of Butyrylcholinesterase from human serum
|
None
|
73.0
nM
|
|
Journal : J. Med. Chem.
Title : 5,7-dihydro-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-6H- pyrrolo[3,2-f]-1,2-benzisoxazol-6-one: a potent and centrally-selective inhibitor of acetylcholinesterase with an improved margin of safety.
Year : 1995
Volume : 38
Issue : 15
First Page : 2802
Last Page : 2808
Authors : Villalobos A, Butler TW, Chapin DS, Chen YL, DeMattos SB, Ives JL, Jones SB, Liston DR, Nagel AA, Nason DM.
Abstract : A series of N-benzylpiperidines (2a-d, 10) with novel isoxazole-containing tricycles has been prepared. This series has shown potent in vitro inhibition of the enzyme acetylcholinesterase (AChE), with IC50S = 0.33 - 3.6 nM. Compound 2a was the most potent inhibitor with an IC50 = 0.33 +/- 0.09 nM. Derivatives 2a-d and 10 displayed weak in vitro inhibition of butyrylcholinesterase (BuChE) with IC50S = 600 - 23,000 nM. The most selective compound was 2a with a BuChE/AChE ratio in excess of 4 orders of magnitude (> 10,000). Pyrrolobenzisoxazole 2a also displayed a favorable profile in vivo. In microdialysis experiments, 2a produced a 200% increase in extracellular levels of acetylcholine (ACh) at a dose of 0.4 mg/kg in freely moving, conscious rats. Peripheral side effects (salivation ED50 = 26 +/- 1.5 mg/kg) and acute lethality (LD50[1 h] = 42 mg/kg) were observed at > 60-fold higher doses. These data indicate that 2a is an AChE inhibitor with good central selectivity and a favorable margin of safety. Compound 2a, designated as CP-118,954, is currently in clinical development for the treatment of cognitive disorders.
|
Anticholinesterase activity against plasma Butyrylcholinesterase (BChE) in humans.
|
None
|
16.0
nM
|
|
Journal : J. Med. Chem.
Title : Syntheses and anticholinesterase activities of (3aS)-N1, N8-bisnorphenserine, (3aS)-N1,N8-bisnorphysostigmine, their antipodal isomers, and other potential metabolites of phenserine.
Year : 1998
Volume : 41
Issue : 13
First Page : 2371
Last Page : 2379
Authors : Yu Q, Greig NH, Holloway HW, Brossi A.
Abstract : Hydrolysis of the carbamate side chains in phenserine [(-)1] and physostigmine [(-)2] yields the metabolite (-)-eseroline (3), and the red dye rubreserine (4) on air oxidation of the former compound. Both compounds lacked anticholinesterase activity in concentrations up to 30 mM, which would be unachievable in vivo. A second group of potential metabolites of 1 and 2 are the N1,N8-bisnorcarbamates (-)9 and (-)10, prepared from (3aS)-N8-benzylnoresermethole (-)12 by the carbinolamine route. These entirely novel compounds proved to be highly potent inhibitors of acetylcholinesterase [(-)9] and of acetyl- and butyrylcholinesterase (AChE and BChE) [(-)10], respectively. To elucidate further the structure/anticholinesterase activity relationship of the described compounds, the antipodal isomers (3aR)-N1,N8-bisnorcarbamates (+)9 and (+)10 were likewise synthesized from (3aR)-N8-benzylnoresermethole (+)12 and assessed. The compounds possessed moderate but less potent anticholinesterase activity, with the same selectivity as their 3aS enantiomers. Finally, the anticholinesterase activities of intermediates N1, N8-bisnorbenzylcarbamates (-)18, (-) 19, (+)18, and (+)19, also novel compounds, were additionally measured. The 3aS enantiomers proved to be potent and selective inhibitors of BChE, particularly (-)19, whereas the antipodal isomers lacked activity.
|
In vitro inhibition of human serum Butyrylcholinesterase.
|
None
|
23.1
nM
|
|
Journal : J. Med. Chem.
Title : Acetylcholinesterase inhibitors: SAR and kinetic studies on omega-[N-methyl-N-(3-alkylcarbamoyloxyphenyl)methyl]aminoalkoxyaryl derivatives.
Year : 2001
Volume : 44
Issue : 23
First Page : 3810
Last Page : 3820
Authors : Rampa A, Piazzi L, Belluti F, Gobbi S, Bisi A, Bartolini M, Andrisano V, Cavrini V, Cavalli A, Recanatini M, Valenti P.
Abstract : In this work, we further investigated a class of carbamic cholinesterase inhibitors introduced in a previous paper (Rampa et al. J. Med. Chem. 1998, 41, 3976). Some new omega-[N-methyl-N-(3-alkylcarbamoyloxyphenyl)methyl]aminoalkoxyaryl analogues were designed, synthesized, and evaluated for their inhibitory activity against both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The structure of the lead compound (xanthostigmine) was systematically varied with the aim to optimize the different parts of the molecule. Moreover, such a structure-activity relationships (SAR) study was integrated with a kinetic analysis of the mechanism of AChE inhibition for two representative compounds. The structural modifications lead to a compound (12b) showing an IC(50) value for the AChE inhibition of 0.32 +/- 0.09 nM and to a group of BuChE inhibitors also active at the nanomolar level, the most potent of which (15d) was characterized by an IC(50) value of 3.3 +/- 0.4 nM. The kinetic analysis allowed for clarification of the role played by different molecular moieties with regard to the rate of AChE carbamoylation and the duration of inhibition. On the basis of the results presented here, it was concluded that the cholinesterase inhibitors of this class possess promising characteristics in view of a potential development as drugs for the treatment of Alzheimer's disease.
|
Concentration required to inhibit 50% of Butyrylcholinesterase obtained from human serum was determined in vitro
|
None
|
73.0
nM
|
|
Journal : J. Med. Chem.
Title : Design and synthesis of 1-heteroaryl-3-(1-benzyl-4-piperidinyl)propan-1-one derivatives as potent, selective acetylcholinesterase inhibitors.
Year : 1995
Volume : 38
Issue : 7
First Page : 1084
Last Page : 1089
Authors : Nagel AA, Liston DR, Jung S, Mahar M, Vincent LA, Chapin D, Chen YL, Hubbard S, Ives JL, Jones SB.
Abstract : Herein is described the synthesis and structure--activity relationship of a novel series of aromatic and heteroaromatic 3-(1-benzyl-4-piperidinyl)propan-1-one derivatives that display potent and selective inhibition of the enzyme acetylcholinesterase (AChE). 1-(2-Methyl-6-benzothiazolyl)-3-(N-benzyl-4-piperidinyl)propan-1-one hydrochloride, 6d, is one of the most active compounds within this series exhibiting an IC50 for the inhibition of the AChE enzyme equal to 6.8 nM. Compound 6d has shown a dose-dependent elevation of total acetylcholine (ACh) levels in the mouse forebrain with an oral ED50 = 9.8 mg/kg. In addition, in vivo microdialysis experiments in the rat demonstrate that 6d increases extracellular ACh (100% over basal) 1-3 h postdose with an oral ED50 = 4.8 mg/kg.
|
Inhibition of human Butyrylcholinesterase
|
Homo sapiens
|
16.0
nM
|
|
Journal : J. Med. Chem.
Title : Total syntheses and anticholinesterase activities of (3aS)-N(8)-norphysostigmine, (3aS)-N(8)-norphenserine, their antipodal isomers, and other N(8)-substituted analogues.
Year : 1997
Volume : 40
Issue : 18
First Page : 2895
Last Page : 2901
Authors : Yu QS, Pei XF, Holloway HW, Greig NH, Brossi A.
Abstract : N(8)-Benzylesermethole (6) was prepared from 5-methoxytryptamine (1) in five steps. Resolution of compound 6 by dibenzoyl- and ditoluyltartaric acid provided enantiomers (-)- and (+)-7. After demethylation, reaction with isocyanates and catalytic debenzylation over hydrogen, the total syntheses of (-)- and (+)-N(8)-norphysostigmine [(-)- and (+)-11] and (-)- and (+)-N(8)-norphenserine [(-)- and (+)-12] were accomplished, (-)-N(8)-Norphysostigmine [(-)-11] and (-)-N(8)-norphenserine [(-)-12] were also obtained by transformations of natural physostigmine [(-)-13] and phenserine [(-)-14] prepared from (-)-13. The absolute configurations and optical purity of compounds (-)-11, (-)-12, (+)-11, and (+)-12 were confirmed by a comparison of their optical rotations with those of the compounds synthesized from physostigmine [(-)-13]. The anticholinesterase activities of N(8)-nor- and N(8)-substituted analogues, (-)- and (+)-9, -10, -11, -12, 15, and 16, were compared with those of physostigmine [(-)- and (+)-13] and phenserine [(-)- and (+)-14] and are reported.
|
In vitro inhibition of human plasma butyrylcholinesterase.
|
None
|
16.0
nM
|
|
Journal : J. Med. Chem.
Title : Methyl analogues of the experimental Alzheimer drug phenserine: synthesis and structure/activity relationships for acetyl- and butyrylcholinesterase inhibitory action.
Year : 2001
Volume : 44
Issue : 24
First Page : 4062
Last Page : 4071
Authors : Yu Q, Holloway HW, Flippen-Anderson JL, Hoffman B, Brossi A, Greig NH.
Abstract : With the goal of developing potential Alzheimer's pharmacotherapeutics, we have synthesized a series of novel analogues of the potent anticholinesterases phenserine (2) and physostigmine (1). These derivatives contain methyl (3, 4, 6), dimethyl (5, 7, 8, 10, 11) and trimethyl (14) substituents in each position of the phenyl group of the phenylcarbamoyl moieties, and with N-methyl and 6-methyl substituents (12, 13, 31, 33). We also quantified the inhibitory action of these compounds against human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). An analysis of the structure/anticholinesterase activity relationship of the described compounds, together with molecular modeling, confirmed the catalytic triad mechanism of the binding of this class of carabamate analogues within AChE and BChE and defined structural requirements for their differential inhibition.
|
Inhibitory concentration against butyrylcholinesterase from human serum
|
None
|
22.91
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationships of acetylcholinesterase noncovalent inhibitors based on a polyamine backbone. 2. Role of the substituents on the phenyl ring and nitrogen atoms of caproctamine.
Year : 2003
Volume : 46
Issue : 6
First Page : 954
Last Page : 966
Authors : Tumiatti V, Rosini M, Bartolini M, Cavalli A, Marucci G, Andrisano V, Angeli P, Banzi R, Minarini A, Recanatini M, Melchiorre C.
Abstract : Continuing our studies on polyamine-based compounds of potential interest in the field of Alzheimer's disease therapeutics, we investigated the structure-activity relationships (SAR) of a lead compound (caproctamine, 3) identified in a previous work. In particular, we varied the substituents on the phenyl ring and on the nitrogen functions (both the amine and the amide), and studied the effects of such modifications on the inhibitory potency against isolated acetyl- and butyryl-cholinesterase (AChE and BChE). Moreover, the ability of selected compounds to reverse the d-tubocurarine-induced neuromuscular blockade and their antagonism toward muscarinic M(2) receptors in guinea pig left atrium were assayed. The most interesting SAR result was the identification of a relationship between the electronic characteristics of 2-substituents (measured by pK(a)) and the AChE inhibitory potency (pIC(50)) of tertiary amine compounds 6-12, which was confirmed by the invariance of the pIC(50) values of the corresponding methiodide derivatives 14-20. With regard to the biological profile, the most interesting compound was the N-ethyl-analogue of caproctamine (9), that showed pIC(50) values of 7.73 (+/-0.02) and 5.65 (+/-0.03) against AChE and BChE, respectively. The ability to increase the acetylcholine level was maintained in the functional assay (pAI(50) for reversing the neuromuscular blockade was 6.45 (+/-0.07)), as well as the ability to antagonize the M(2) receptors (pK(b) = 5.65 (+/-0.06)). Moreover, 9 showed a long duration of action as AChE inhibitor, an useful property in view of a possible development of this compound as a therapeutic agent.
|
Inhibition of Butyrylcholinesterase (BChE) of human erythrocytes [-log IC50 (uM)]
|
Homo sapiens
|
22.91
nM
|
|
Journal : J. Med. Chem.
Title : Acetylcholinesterase noncovalent inhibitors based on a polyamine backbone for potential use against Alzheimer's disease.
Year : 1998
Volume : 41
Issue : 22
First Page : 4186
Last Page : 4189
Authors : Melchiorre C, Andrisano V, Bolognesi ML, Budriesi R, Cavalli A, Cavrini V, Rosini M, Tumiatti V, Recanatini M.
|
Butyrylcholinesterase
|
None
|
8.1
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of acetylcholinesterase inhibitors: 1-benzyl-4-[(5,6-dimethoxy-1-oxoindan-2-yl)methyl]piperidine hydrochloride and related compounds.
Year : 1995
Volume : 38
Issue : 24
First Page : 4821
Last Page : 4829
Authors : Sugimoto H, Iimura Y, Yamanishi Y, Yamatsu K.
Abstract : Following the discovery of a new series of anti-acetylcholinesterase (anti-AChE) inhibitors such as 1-benzyl-4-[2-(N-benzoylamino)ethyl]piperidine (1), we reported that its rigid analogue, 1-benzyl-4-(2-isoindolin-2-ylethyl)piperidine (5), had more potent activity. We have extended the structure-activity relationship (SAR) study for the rigid analogue and found that the 2-isoindoline moiety in compound 5 can be replaced with a indanone moiety (8) without a major loss in potency. Among the indanone derivatives, 1-benzyl-4-[(5,6-dimethoxy-1-oxoindan-2-yl)methyl]piperidine (13e) (E2020) (IC50 = 5.7 nM) was found to be one of the most potent anti-AChE inhibitors. Compound 13e showed a selective affinity 1250 times greater for AChE than for butyrylcholinesterase. In vivo studies demonstrated that 13e has a longer duration of action than physostigmine at a dose of 5 mg/kg (po) and produced a marked and significant increase in acetylcholine content in rat cerebral cortex. We report the synthesis, SAR, and a proposed hypothetical binding site of 13e (E2020).
|
Inhibitory concentration was determined in in vitro for Butyrylcholinesterase in rat plasma
|
None
|
8.1
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and anti-acetylcholinesterase activity of 1-benzyl-4-[(5,6-dimethoxy-1-indanon-2-yl)methyl]piperidine hydrochloride (E2020) and related compounds
Year : 1992
Volume : 2
Issue : 8
First Page : 871
Last Page : 876
Authors : Sugimoto H, Iimura Y, Yamanishi Y, Yamatsu K
|
Inhibition of isolated Butyrylcholinesterase (BuChE )
|
Rattus norvegicus
|
23.0
nM
|
|
Journal : J. Med. Chem.
Title : Acetylcholinesterase inhibitors: synthesis and structure-activity relationships of omega-[N-methyl-N-(3-alkylcarbamoyloxyphenyl)- methyl]aminoalkoxyheteroaryl derivatives.
Year : 1998
Volume : 41
Issue : 21
First Page : 3976
Last Page : 3986
Authors : Rampa A, Bisi A, Valenti P, Recanatini M, Cavalli A, Andrisano V, Cavrini V, Fin L, Buriani A, Giusti P.
Abstract : Acetylcholinesterase (AChE) inhibitors are one of the most actively investigated classes of compounds in the search for an effective treatment of Alzheimer's disease. This work describes the synthesis, AChE inhibitory activity, and structure-activity relationships of some compounds related to a recently discovered series of AChE inhibitors: the omega-[N-methyl-N-(3-alkylcarbamoyloxyphenyl)methyl]aminoalkoxy xanthen-9-ones. The influence of structural variations on the inhibitory potency was carefully investigated by modifying different parts of the parent molecule, and a theoretical model of the binding of one representative compound to the enzyme was developed. The biological properties of the series were investigated in some detail by considering not only the activity on isolated enzyme but the selectivity with respect to butyrylcholinesterase (BuChE) and the in vitro inhibitory activity on rat cerebral cortex as well. Some of the newly synthesized derivatives, when tested on isolated and/or AChE-enriched rat brain cortex fraction, displayed a selective inhibitory activity and were more active than physostigmine. In particular, compound 13, an azaxanthone derivative, displayed the best rat cortex AChE inhibition (190-fold higher than physostigmine), as well as a high degree of enzyme selectivity (over 60-fold more selective for AChE than for BuChE). When tested in the isolated enzyme, compound 13 was less active, suggesting some differences either in drug availability/biotransformation or in the inhibitor-sensitive residues of the enzyme when biologically positioned in rat brain membranes.
|
In vitro inhibition of human butryl cholinesterase.
|
None
|
35.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and cholinergic properties of N-aryl-2-[[[5-[(dimethylamino)methyl]-2-furanyl]methyl]thio]ethylamino analogs of ranitidine.
Year : 1992
Volume : 35
Issue : 17
First Page : 3141
Last Page : 3147
Authors : Valli MJ, Tang Y, Kosh JW, Chapman JM, Sowell JW.
Abstract : A series of N-aryl-2-[[[5-[(dimethylamino)methyl]-2- furanyl]methyl]thio]ethylamino analogs of the H2-antagonist, ranitidine, was synthesized and the abilities of the compounds to alleviate the cholinergic deficit characteristic of Alzheimer's disease evaluated. The compounds were initially tested for their ability to inhibit human erythrocyte acetylcholinesterase activity in vitro. Selected compounds were further evaluated for butyrylcholinesterase inhibition, M1 and M2 cholinergic receptor binding, potentiation of ileal contractions, and the ability to elevate brain acetylcholine levels in mice. The analogs were compared to tetrahydroaminoacridine and to a recently reported series of bis-[[(dimethylamino)methyl]furans]. The N-aryl-2-[[[5-[(dimethylamino)methyl]-2- furanyl]methyl]thio]ethylamine derivatives were generally comparable to tetrahydroaminoacridine and the bis[[(dimethylamino)methyl]furans] in acetylcholinesterase inhibition, M1/M2 receptor binding, and the potentiation of ileal contractions, while being more potent inhibitors of acetylcholinesterase than butyrylcholinesterase. The 4-nitro-3-pyridazinyl analog, 26, was notable in demonstrating a potent and selective binding to the M2 receptor, with an M2 IC50/M1 IC50 of 0.060. Compounds in which the substituents on the dinitro-N-aryl moiety were relatively small were the best at inhibiting acetylcholinesterase in vitro. The N-aryl-2-[[[5-[(dimethylamino)methyl]-2- furanyl]methyl]thio]ethylamines in general, and those with small N-aryl substituents in particular, were superior to the bis[[(dimethylamino)methyl]furans] in elevating brain ACh levels in mice, probably due to enhanced distribution into the CNS. The 1,5-difluoro-2,4-dinitrophenyl analog, 8, resulted in the largest elevation in brain acetylcholine levels, affording a 53% increase at 88 mg/kg.
|
Compound was evaluated for the in vitro inhibition of the Butyrylcholinesterase from horse serum
|
Equus caballus
|
73.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel benzisoxazole derivatives as potent and selective inhibitors of acetylcholinesterase.
Year : 1994
Volume : 37
Issue : 17
First Page : 2721
Last Page : 2734
Authors : Villalobos A, Blake JF, Biggers CK, Butler TW, Chapin DS, Chen YL, Ives JL, Jones SB, Liston DR, Nagel AA.
Abstract : A series of N-benzylpiperidine benzisoxazoles has been developed as potent and selective inhibitors of the enzyme acetylcholinesterase (AChE). The benzisoxazole heterocycle was found to be an appropriate bioisosteric replacement for the benzoyl functionality present in the N-benzylpiperidine class of inhibitors. The title compounds were synthesized by alkylating 3-methyl-1,2-benzisoxazoles with an iodo piperidine derivatives as the key step. Benzisoxazoles 1b-j,o displayed potent inhibition of AChE in vitro with IC50's = 0.8-14 nM. Particularly interesting were N-acetyl and morpholino derivatives 1g (IC50 = 3 nM) and 1j (IC50 = 0.8 nM), respectively, which displayed outstanding selectivity for acetyl-over butyrylcholinesterase, in excess of 3 orders of magnitude. N-Acetyl 1g also displayed a favorable profile in vivo. This analog showed a dose-dependent elevation of total acetylcholine in mouse forebrain after oral administration with an ED50 = 2.4 mg/kg. In addition, 1g was able to reverse amnesia in a mouse passive avoidance model at doses of 3.2 and 5.6 mg/kg with an average reversal of 89.7%. Molecular dynamics simulations were used to study the possible binding modes of N-benzylpiperidine benzisoxazoles to AChE from Torpedo californica. Key structural insights were obtained regarding the potency of this class of inhibitors. Specifically, Asp-72, Trp-84, Trp-279, Phe-288, and Phe-330 are implicated in the binding of these inhibitors. The N-benzylpiperidine benzisoxazoles may be suitable compounds for the palliative treatment of Alzheimer's Disease.
|
Inhibitory activity against Butyrylcholinesterase in cortex
|
Homo sapiens
|
129.0
nM
|
|
Journal : J. Med. Chem.
Title : Alfred Burger award address. Bioactive alkaloids. 4. Results of recent investigations with colchicine and physostigmine.
Year : 1990
Volume : 33
Issue : 9
First Page : 2311
Last Page : 2319
Authors : Brossi A.
|
Inhibitory activity against Butyrylcholinesterase in plasma
|
Homo sapiens
|
15.0
nM
|
|
Journal : J. Med. Chem.
Title : Alfred Burger award address. Bioactive alkaloids. 4. Results of recent investigations with colchicine and physostigmine.
Year : 1990
Volume : 33
Issue : 9
First Page : 2311
Last Page : 2319
Authors : Brossi A.
|
The compound was evaluated for the inhibition human of Butyrylcholinesterase
|
None
|
35.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and cholinergic properties of bis[[(dimethylamino)methyl]furanyl] analogues of ranitidine.
Year : 1992
Volume : 35
Issue : 6
First Page : 1102
Last Page : 1108
Authors : Sowell JW, Tang Y, Valli MJ, Chapman JM, Usher LA, Vaughan CM, Kosh JW.
Abstract : The histaminergic H2 antagonist, ranitidine, has also been found to significantly inhibit acetylcholinesterase (AChE) in vitro. In an effort to develop novel, nonquaternary AChE inhibitors capable of penetrating into the CNS and alleviating the cholinergic deficit characteristic of Alzheimer's disease, a series of bis[[(dimethylamino)methyl]furanyl] analogues of ranitidine has been synthesized. All compounds were evaluated for human erythrocyte AChE inhibitory activity and compared to ranitidine, physostigmine, and tetrahydro-9-aminoacridine (THA). The most active AChE inhibitors were N,N'-disubstituted derivatives of 2-nitro-1,1-ethenediamine and 4,6-dinitro-1,3-benzenediamine, with compound 8 demonstrating activity greater than physostigmine. Deletion of the diaminonitroethene group in a series of alkyl and aryl bis-thioethers, yielded a number of slightly less active compounds, comparable in potency to THA. The 13 most active AChE inhibitors all demonstrated a more selective inhibition of AChE, as opposed to butyrylcholinesterase inhibition, than did THA. Compounds 3 and 22 were equally active to THA in potentiating rat ileal contractions. Binding studies demonstrated M1 and M2 cholinergic receptor affinities slightly greater than or equal to THA. Differential receptor binding studies showed compound 12 resembled THA in agonist/antagonist activity. Compounds 11-13 significantly elevated mouse brain acetylcholine levels, when administered at 80% of their approximate lethal doses, but were less active than THA or physostigmine.
|
In vitro inhibitory concentration against butyrylcholinesterase (BuChE) obtained from rat plasma
|
None
|
8.1
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of acetylcholinesterase inhibitors: 1-benzyl-4-(2-phthalimidoethyl)piperidine and related derivatives.
Year : 1992
Volume : 35
Issue : 24
First Page : 4542
Last Page : 4548
Authors : Sugimoto H, Tsuchiya Y, Sugumi H, Higurashi K, Karibe N, Iimura Y, Sasaki A, Araki S, Yamanishi Y, Yamatsu K.
Abstract : Following the discovery of a new series of 1-benzyl-4-[2-(N-benzoyl-N-methylamino)ethyl]piperidine (2) derivatives with a potent anti-acetylcholinesterase (anti-AChE) activity, we extended the structure-activity relationships (SAR) to rigid analogues (4) and 1-benzyl-4-[2-(N-benzoyl-N-phenylamino)ethyl]piperidine derivatives (3). Introduction of a phenyl group on the nitrogen atom of the amide moieties resulted in enhanced activity. The rigid analogue containing isoindolone (9) was found to exhibit potent anti-AChE activity comparable to that of 2. Furthermore, replacement of the isoindolone with other heterobicyclic ring systems was examined. Among the compounds prepared in these series, 1-benzyl-4-[2-[4-(benzoylamino)phthalimido]ethyl]piperidine hydrochloride (19) (IC50 = 1.2 nM) is one of the most potent inhibitors of AChE. Compound 19 showed a definite selectivity to AChE over the BuChE (about 34700-fold) and, at dosages of 10-50 mg/kg, exerted a dose-dependent inhibitory effect on AChE in rat brain.
|
Inhibitory activity towards acetylcholine esterase (AChE)
|
Torpedo californica
|
360.0
nM
|
|
Journal : J. Med. Chem.
Title : Efficient method for high-throughput virtual screening based on flexible docking: discovery of novel acetylcholinesterase inhibitors.
Year : 2004
Volume : 47
Issue : 20
First Page : 4818
Last Page : 4828
Authors : Mizutani MY, Itai A.
Abstract : A method of easily finding ligands, with a variety of core structures, for a given target macromolecule would greatly contribute to the rapid identification of novel lead compounds for drug development. We have developed an efficient method for discovering ligand candidates from a number of flexible compounds included in databases, when the three-dimensional (3D) structure of the drug target is available. The method, named ADAM&EVE, makes use of our automated docking method ADAM, which has already been reported. Like ADAM, ADAM&EVE takes account of the flexibility of each molecule in databases, by exploring the conformational space fully and continuously. Database screening has been made much faster than with ADAM through the tuning of parameters, so that computational screening of several hundred thousand compounds is possible in a practical time. Promising ligand candidates can be selected according to various criteria based on the docking results and characteristics of compounds. Furthermore, we have developed a new tool, EVE-MAKE, for automatically preparing the additional compound data necessary for flexible docking calculation, prior to 3D database screening. Among several successful cases of lead discovery by ADAM&EVE, the finding of novel acetylcholinesterase (AChE) inhibitors is presented here. We performed a virtual screening of about 160 000 commercially available compounds against the X-ray crystallographic structure of AChE. Among 114 compounds that could be purchased and assayed, 35 molecules with various core structures showed inhibitory activities with IC(50) values less than 100 microM. Thirteen compounds had IC(50) values between 0.5 and 10 microM, and almost all their core structures are very different from those of known inhibitors. The results demonstrate the effectiveness and validity of the ADAM&EVE approach and provide a starting point for development of novel drugs to treat Alzheimer's disease.
|
Inhibitory concentration against acetylcholinesterase
|
None
|
30.0
nM
|
|
Inhibitory concentration against acetylcholinesterase
|
None
|
0.008
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of tricyclic analogs of stephaoxocanidine and their evaluation as acetylcholinesterase inhibitors.
Year : 2005
Volume : 15
Issue : 11
First Page : 2711
Last Page : 2715
Authors : Bianchi DA, Hirschmann GS, Theoduloz C, Bracca AB, Kaufman TS.
Abstract : The synthesis of simplified analogs of the novel isoquinoline alkaloid stephaoxocanidine, carrying the oxazaphenalene ABC-ring system of the natural product, and their activity as inhibitors of the enzyme acetylcholinesterase, are reported. 5,6-Dimethoxy-7H -8-oxa-1-aza-phenalen-9-one (5) was as active as a Narcissus extract enriched in galantamine.
|
Inhibitory concentration against human plasma Butyrylcholinesterase
|
Homo sapiens
|
16.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel anticholinesterases based on the molecular skeletons of furobenzofuran and methanobenzodioxepine.
Year : 2005
Volume : 48
Issue : 4
First Page : 986
Last Page : 994
Authors : Luo W, Yu QS, Zhan M, Parrish D, Deschamps JR, Kulkarni SS, Holloway HW, Alley GM, Lahiri DK, Brossi A, Greig NH.
Abstract : Reductive cyclization of 5-hydroxy-3-methyl-3-methoxycarbonylmethylenebenzofuran-2(3H)-one (4) gave 5-hydroxy-3a-methyl-2,3,3a,8a-tatrahydrofuro[2,3-b]benzofuran (5) and the rearrangement product 7-hydroxy-4,5-dihydro-2,5-methano-1,3-benzodioxepine (6). Reaction of compounds 5 and 6 with different isocyanates provided two series novel carbamates (7-12) whose structures were confirmed by X-ray crystallography. These were assessed for anticholinesterase action against freshly prepared human enzyme and proved to be potent inhibitors of either acetyl- (AChE) or butyrylcholinesterase (BChE) with specific compounds exhibiting remarkable selectivity. Because the two series of carbamates (7-12) differ in their phenolic moieties, their respective potency and selectivity for AChE versus BChE was governed by their N-substituted groups. This same characteristic was also present in a series of physovenine analogues (1, 13, 15, 17) and physostigmine analogues (2, 14, 16, 18). These structure-activity relations proved valuable in elucidating the mechanisms underpinning the interaction between carbamate-based cholinesterase inhibitors and their enzyme target. In addition, because physostigmine analogues have demonstrated activity in lowering the Alzheimer's disease protein, amyloid precursor protein (APP), examples of the two new series of carbamates were characterized in culture assays of quantifying cell viability and synthesis of APP.
|
Inhibitory concentration against human erythrocyte Acetylcholinesterase
|
Homo sapiens
|
28.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel anticholinesterases based on the molecular skeletons of furobenzofuran and methanobenzodioxepine.
Year : 2005
Volume : 48
Issue : 4
First Page : 986
Last Page : 994
Authors : Luo W, Yu QS, Zhan M, Parrish D, Deschamps JR, Kulkarni SS, Holloway HW, Alley GM, Lahiri DK, Brossi A, Greig NH.
Abstract : Reductive cyclization of 5-hydroxy-3-methyl-3-methoxycarbonylmethylenebenzofuran-2(3H)-one (4) gave 5-hydroxy-3a-methyl-2,3,3a,8a-tatrahydrofuro[2,3-b]benzofuran (5) and the rearrangement product 7-hydroxy-4,5-dihydro-2,5-methano-1,3-benzodioxepine (6). Reaction of compounds 5 and 6 with different isocyanates provided two series novel carbamates (7-12) whose structures were confirmed by X-ray crystallography. These were assessed for anticholinesterase action against freshly prepared human enzyme and proved to be potent inhibitors of either acetyl- (AChE) or butyrylcholinesterase (BChE) with specific compounds exhibiting remarkable selectivity. Because the two series of carbamates (7-12) differ in their phenolic moieties, their respective potency and selectivity for AChE versus BChE was governed by their N-substituted groups. This same characteristic was also present in a series of physovenine analogues (1, 13, 15, 17) and physostigmine analogues (2, 14, 16, 18). These structure-activity relations proved valuable in elucidating the mechanisms underpinning the interaction between carbamate-based cholinesterase inhibitors and their enzyme target. In addition, because physostigmine analogues have demonstrated activity in lowering the Alzheimer's disease protein, amyloid precursor protein (APP), examples of the two new series of carbamates were characterized in culture assays of quantifying cell viability and synthesis of APP.
|
Inhibition of human AChE induced beta-amyloid aggregation in thioflavin T-based fluorometric assay
|
Homo sapiens
|
30.0
%
|
|
Journal : J. Med. Chem.
Title : Cholinesterase inhibitors: xanthostigmine derivatives blocking the acetylcholinesterase-induced beta-amyloid aggregation.
Year : 2005
Volume : 48
Issue : 13
First Page : 4444
Last Page : 4456
Authors : Belluti F, Rampa A, Piazzi L, Bisi A, Gobbi S, Bartolini M, Andrisano V, Cavalli A, Recanatini M, Valenti P.
Abstract : In continuing research that led us to identify a new class of carbamate derivatives acting as potent (Rampa et al. J. Med. Chem. 1998, 41, 3976) and long-lasting (Rampa et al. J. Med. Chem. 2001, 44, 3810) acetylcholinesterase (AChE) inhibitors, we obtained some analogues able to simultaneously block both the catalytic and the beta-amyloid (Abeta) proaggregatory activities of AChE. The key feature of these derivatives is a 2-arylidenebenzocycloalkanone moiety that provides the ability to bind at the AChE peripheral site responsible for promoting the Abeta aggregation. The new carbamates were tested in vitro for the inhibition of both cholinesterases and also for the ability to prevent the AChE-induced Abeta aggregation. All of the compounds had AChE IC(50) values in the nanomolar range and showed the ability to block the AChE-induced Abeta aggregation, thus supporting the feasibility of this new strategy in the search of compounds for the treatment of Alzheimer's disease.
|
Anticholinesterase activity against human erythrocyte AChE
|
Homo sapiens
|
28.0
nM
|
|
Journal : J. Med. Chem.
Title : Inhibition of human acetyl- and butyrylcholinesterase by novel carbamates of (-)- and (+)-tetrahydrofurobenzofuran and methanobenzodioxepine.
Year : 2006
Volume : 49
Issue : 7
First Page : 2174
Last Page : 2185
Authors : Luo W, Yu QS, Kulkarni SS, Parrish DA, Holloway HW, Tweedie D, Shafferman A, Lahiri DK, Brossi A, Greig NH.
Abstract : A new enantiomeric synthesis utilizing classical resolution provided two novel series of optically active inhibitors of cholinesterase: (-)- and (+)-O-carbamoyl phenols of tetrahydrofurobenzofuran and methanobenzodioxepine. An additional two series of (-)- and (+)-O-carbamoyl phenols of pyrroloindole and furoindole were obtained by known procedures, and their anticholinesterase actions were similarly quantified against freshly prepared human acetyl- (AChE) and butyrylcholinesterase (BChE). Both enantiomeric forms of each series demonstrated potent cholinesterase inhibitory activity (with IC(50) values as low as 10 nM for AChE and 3 nM for BChE), with the exception of the (+)-O-carbamoyl phenols of pyrroloindole, which lacked activity (IC(50) values >1 microM). Based on the biological data of these four series, a structure-activity relationship (SAR) analysis was provided by molecular volume calculations. In addition, a probable transition-state model was established according to the known X-ray structure of a transition-state complex of Torpedo californica AChE-m-(N,N,N-trimethylammonio)-2,2,2-trifluoroacetophenone (TcAChE-TMTFA). This model proved valuable in explaining the enantioselectivity and enzyme subtype selectivity of each series. These carbamates are more potent than, or similarly potent to, anticholinesterases in current clinical use, providing not only inhibitors of potential clinical relevance but also pharmacological tools to define drug-enzyme binding interactions within an enzyme crucial in the maintenance of cognition and numerous systemic physiological functions in health, aging, and disease.
|
Anticholinesterase activity against human plasma BChE
|
Homo sapiens
|
16.0
nM
|
|
Journal : J. Med. Chem.
Title : Inhibition of human acetyl- and butyrylcholinesterase by novel carbamates of (-)- and (+)-tetrahydrofurobenzofuran and methanobenzodioxepine.
Year : 2006
Volume : 49
Issue : 7
First Page : 2174
Last Page : 2185
Authors : Luo W, Yu QS, Kulkarni SS, Parrish DA, Holloway HW, Tweedie D, Shafferman A, Lahiri DK, Brossi A, Greig NH.
Abstract : A new enantiomeric synthesis utilizing classical resolution provided two novel series of optically active inhibitors of cholinesterase: (-)- and (+)-O-carbamoyl phenols of tetrahydrofurobenzofuran and methanobenzodioxepine. An additional two series of (-)- and (+)-O-carbamoyl phenols of pyrroloindole and furoindole were obtained by known procedures, and their anticholinesterase actions were similarly quantified against freshly prepared human acetyl- (AChE) and butyrylcholinesterase (BChE). Both enantiomeric forms of each series demonstrated potent cholinesterase inhibitory activity (with IC(50) values as low as 10 nM for AChE and 3 nM for BChE), with the exception of the (+)-O-carbamoyl phenols of pyrroloindole, which lacked activity (IC(50) values >1 microM). Based on the biological data of these four series, a structure-activity relationship (SAR) analysis was provided by molecular volume calculations. In addition, a probable transition-state model was established according to the known X-ray structure of a transition-state complex of Torpedo californica AChE-m-(N,N,N-trimethylammonio)-2,2,2-trifluoroacetophenone (TcAChE-TMTFA). This model proved valuable in explaining the enantioselectivity and enzyme subtype selectivity of each series. These carbamates are more potent than, or similarly potent to, anticholinesterases in current clinical use, providing not only inhibitors of potential clinical relevance but also pharmacological tools to define drug-enzyme binding interactions within an enzyme crucial in the maintenance of cognition and numerous systemic physiological functions in health, aging, and disease.
|
Inhibition of AChE
|
Homo sapiens
|
500.0
nM
|
|
Inhibition of AChE
|
Homo sapiens
|
493.17
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 6-Hydroxy- and 6-methoxy-beta-carbolines as acetyl- and butyrylcholinesterase inhibitors.
Year : 2006
Volume : 16
Issue : 22
First Page : 5840
Last Page : 5843
Authors : Schott Y, Decker M, Rommelspacher H, Lehmann J.
Abstract : In the course of studies directed toward the discovery of novel acetyl- and butyrylcholinesterase (AChE and BChE) inhibitors for the treatment of Alzheimer's disease, we focused on beta-carbolines (BCs). 6-Oxygenated beta-carboline and beta-carbolinium derivatives based on the serotonin template were synthesized and tested in vitro for their ability to inhibit AChE and BChE, respectively. Particularly the carbolinium salts, which can be formed by intracerebral methylation out of the tertiary-BC prodrugs, show inhibitory activity levels reaching those of galantamine, physostigmine, and rivastigmine.
|
Inhibition of human recombinant AChE
|
Homo sapiens
|
13.49
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationships of acetylcholinesterase noncovalent inhibitors based on a polyamine backbone. 3. Effect of replacing the inner polymethylene chain with cyclic moieties.
Year : 2004
Volume : 47
Issue : 26
First Page : 6490
Last Page : 6498
Authors : Tumiatti V, Andrisano V, Banzi R, Bartolini M, Minarini A, Rosini M, Melchiorre C.
Abstract : In the present paper we expanded SAR studies of 3, the ethyl analogue of the AChE inhibitor caproctamine (2), by investigating the role of its octamethylene spacer separating the two amide functions through the replacement with dipiperidine and dianiline moieties. Compounds 4 and 8 were the most interesting of the two series of compounds. Compound 4 was the most potent AChE inhibitor with a pIC50 value of 8.48 +/- 0.02, while displaying also significant muscarinic M2 antagonistic activity (pKb value of 6.18 +/- 0.20). The availability of a suitable assay allowed us to verify whether 2, 3, 4, and 8 inhibit AChE-induced Abeta aggregation. Although all four derivatives caused a mixed type of AChE inhibition (active site and PAS), only 4 and 8, which bear an inner constrained spacer, were able to inhibit AChE-induced Abeta aggregation to a greater extent than donepezil. Clearly, the ability of an AChE inhibitor, based on a linear polyamine backbone, to bind both AChE sites may not be a sufficient condition to inhibit also AChE-induced Abeta aggregation. Dipiperidine derivative 4 emerged as a valuable pharmacological tool and a promising lead compound for new ligands to investigate and, hopefully, treat Alzheimer's disease.
|
Inhibition of human recombinant BChE
|
Homo sapiens
|
26.3
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationships of acetylcholinesterase noncovalent inhibitors based on a polyamine backbone. 3. Effect of replacing the inner polymethylene chain with cyclic moieties.
Year : 2004
Volume : 47
Issue : 26
First Page : 6490
Last Page : 6498
Authors : Tumiatti V, Andrisano V, Banzi R, Bartolini M, Minarini A, Rosini M, Melchiorre C.
Abstract : In the present paper we expanded SAR studies of 3, the ethyl analogue of the AChE inhibitor caproctamine (2), by investigating the role of its octamethylene spacer separating the two amide functions through the replacement with dipiperidine and dianiline moieties. Compounds 4 and 8 were the most interesting of the two series of compounds. Compound 4 was the most potent AChE inhibitor with a pIC50 value of 8.48 +/- 0.02, while displaying also significant muscarinic M2 antagonistic activity (pKb value of 6.18 +/- 0.20). The availability of a suitable assay allowed us to verify whether 2, 3, 4, and 8 inhibit AChE-induced Abeta aggregation. Although all four derivatives caused a mixed type of AChE inhibition (active site and PAS), only 4 and 8, which bear an inner constrained spacer, were able to inhibit AChE-induced Abeta aggregation to a greater extent than donepezil. Clearly, the ability of an AChE inhibitor, based on a linear polyamine backbone, to bind both AChE sites may not be a sufficient condition to inhibit also AChE-induced Abeta aggregation. Dipiperidine derivative 4 emerged as a valuable pharmacological tool and a promising lead compound for new ligands to investigate and, hopefully, treat Alzheimer's disease.
|
Inhibition of electric eel AChE by modified Ellman method
|
Electrophorus electricus
|
41.0
nM
|
|
Journal : J. Nat. Prod.
Title : New triterpenoid alkaloid cholinesterase inhibitors from Buxus hyrcana.
Year : 2003
Volume : 66
Issue : 6
First Page : 739
Last Page : 742
Authors : Choudhary MI, Shahnaz S, Parveen S, Khalid A, Majeed Ayatollahi SA, Atta-Ur-Rahman, Parvez M.
Abstract : Three new triterpenoid alkaloids, (+)-N-benzoylbuxahyrcanine [(20S)-3beta-benzoylamino-20-dimethylaminobux-9(11)-ene-10alpha-ol] (1), (+)-N-tigloylbuxahyrcanine [(20S)-20-(dimethylamino)-3beta-(2'-methyl-2'-butenoylamino)bux-9(11)-en-10alpha-ol] (2), and (+)-N-isobutyroylbuxahyrcanine [(20S)-20-(dimethylamino)-3beta-(2'-methylpropanoyl)bux-9(11)-en-10alpha-ol] (3), have been isolated from the leaf extracts of Buxus hyrcana collected in Iran. Their structures were determined using spectroscopic methods. The structures of compounds 1 and 2 were unambiguously confirmed by single-crystal X-ray diffraction techniques. Compounds 1-3 were evaluated for their acetylcholinesterase and butyrylcholinesterase inhibitory activities, and compound 2 was found to be active against both enzymes.
|
Inhibition of BChE
|
None
|
857.0
nM
|
|
Journal : J. Nat. Prod.
Title : New triterpenoid alkaloid cholinesterase inhibitors from Buxus hyrcana.
Year : 2003
Volume : 66
Issue : 6
First Page : 739
Last Page : 742
Authors : Choudhary MI, Shahnaz S, Parveen S, Khalid A, Majeed Ayatollahi SA, Atta-Ur-Rahman, Parvez M.
Abstract : Three new triterpenoid alkaloids, (+)-N-benzoylbuxahyrcanine [(20S)-3beta-benzoylamino-20-dimethylaminobux-9(11)-ene-10alpha-ol] (1), (+)-N-tigloylbuxahyrcanine [(20S)-20-(dimethylamino)-3beta-(2'-methyl-2'-butenoylamino)bux-9(11)-en-10alpha-ol] (2), and (+)-N-isobutyroylbuxahyrcanine [(20S)-20-(dimethylamino)-3beta-(2'-methylpropanoyl)bux-9(11)-en-10alpha-ol] (3), have been isolated from the leaf extracts of Buxus hyrcana collected in Iran. Their structures were determined using spectroscopic methods. The structures of compounds 1 and 2 were unambiguously confirmed by single-crystal X-ray diffraction techniques. Compounds 1-3 were evaluated for their acetylcholinesterase and butyrylcholinesterase inhibitory activities, and compound 2 was found to be active against both enzymes.
|
Inhibition of electric eel AChE by Ellman's method
|
Electrophorus electricus
|
41.0
nM
|
|
Journal : J. Nat. Prod.
Title : Steroidal alkaloids from the leaves of Sarcococca coriacea of Nepalese origin.
Year : 2001
Volume : 64
Issue : 6
First Page : 842
Last Page : 844
Authors : Kalauni SK, Choudhary MI, Shaheen F, Manandhar MD, Atta-ur-Rahman, Gewali MB, Khalid A.
Abstract : Two new steroidal alkaloids, (-)-vaganine D (1) [(20S)-20-(N,N-dimethylamino)-3 beta-(senecioylamino)-5 alpha-pregn-16-en-4 beta-yl acetate], and (+)-nepapakistamine A (2) [(20S)-20-(N-methylamino)-3 beta-(tigloylamino)-5 alpha-pregn-16-en-2 beta,4 beta-diacetate], were isolated from the leaves of Sarcococca coriacea. Their structures were elucidated on the basis of their spectral properties. Compounds 1 and 2 were found to be cholinesterase inhibitors.
|
Inhibition of horse BChE
|
Equus caballus
|
857.0
nM
|
|
Journal : J. Nat. Prod.
Title : Steroidal alkaloids from the leaves of Sarcococca coriacea of Nepalese origin.
Year : 2001
Volume : 64
Issue : 6
First Page : 842
Last Page : 844
Authors : Kalauni SK, Choudhary MI, Shaheen F, Manandhar MD, Atta-ur-Rahman, Gewali MB, Khalid A.
Abstract : Two new steroidal alkaloids, (-)-vaganine D (1) [(20S)-20-(N,N-dimethylamino)-3 beta-(senecioylamino)-5 alpha-pregn-16-en-4 beta-yl acetate], and (+)-nepapakistamine A (2) [(20S)-20-(N-methylamino)-3 beta-(tigloylamino)-5 alpha-pregn-16-en-2 beta,4 beta-diacetate], were isolated from the leaves of Sarcococca coriacea. Their structures were elucidated on the basis of their spectral properties. Compounds 1 and 2 were found to be cholinesterase inhibitors.
|
Inhibition of human plasma BuchE by Ellman's method
|
Homo sapiens
|
28.0
nM
|
|
Journal : J. Med. Chem.
Title : Isosorbide-2-carbamate esters: potent and selective butyrylcholinesterase inhibitors.
Year : 2008
Volume : 51
Issue : 20
First Page : 6400
Last Page : 6409
Authors : Carolan CG, Dillon GP, Gaynor JM, Reidy S, Ryder SA, Khan D, Marquez JF, Gilmer JF.
Abstract : In this study, we report the SAR and characterization of two groups of isosorbide-based cholinesterase inhibitors. The first was based directly on the clinically used nitrate isosorbide mononitrate (ISMN) retention of the 5-nitrate group and introduction of a series of 2-carbamate functionalities. The compounds proved to be potent and selective inhibitors of human plasma butyrylcholinesterase ( huBuChE). In the second group, the nitrate ester was removed and replaced with a variety of alkyl and aryl esters. These generally exhibited nanomolar potency with high selectivity for BuChE over acetylcholinesterase (AChE). The most potent and selective compound was isosorbide-2-benzyl carbamate-5-benzoate with an IC 50 of 4.3 nM for BuChE and >50000 fold selectivity over human erythrocyte AChE. Inhibition with these compounds is time-dependent, competitive, and slowly reversible, indicating active site carbamylation.
|
Inhibition of electric eel AchE by Ellman's method
|
Electrophorus electricus
|
103.0
nM
|
|
Journal : J. Med. Chem.
Title : Isosorbide-2-carbamate esters: potent and selective butyrylcholinesterase inhibitors.
Year : 2008
Volume : 51
Issue : 20
First Page : 6400
Last Page : 6409
Authors : Carolan CG, Dillon GP, Gaynor JM, Reidy S, Ryder SA, Khan D, Marquez JF, Gilmer JF.
Abstract : In this study, we report the SAR and characterization of two groups of isosorbide-based cholinesterase inhibitors. The first was based directly on the clinically used nitrate isosorbide mononitrate (ISMN) retention of the 5-nitrate group and introduction of a series of 2-carbamate functionalities. The compounds proved to be potent and selective inhibitors of human plasma butyrylcholinesterase ( huBuChE). In the second group, the nitrate ester was removed and replaced with a variety of alkyl and aryl esters. These generally exhibited nanomolar potency with high selectivity for BuChE over acetylcholinesterase (AChE). The most potent and selective compound was isosorbide-2-benzyl carbamate-5-benzoate with an IC 50 of 4.3 nM for BuChE and >50000 fold selectivity over human erythrocyte AChE. Inhibition with these compounds is time-dependent, competitive, and slowly reversible, indicating active site carbamylation.
|
Inhibition of BuChE in human liver microsomes
|
Homo sapiens
|
19.0
nM
|
|
Journal : J. Med. Chem.
Title : Isosorbide-2-benzyl carbamate-5-salicylate, a peripheral anionic site binding subnanomolar selective butyrylcholinesterase inhibitor.
Year : 2010
Volume : 53
Issue : 3
First Page : 1190
Last Page : 1199
Authors : Carolan CG, Dillon GP, Khan D, Ryder SA, Gaynor JM, Reidy S, Marquez JF, Jones M, Holland V, Gilmer JF.
Abstract : Isosorbide-2-benzyl carbamate-5-benzoate is a highly potent and selective BuChE inhibitor. Meanwhile, isosorbide-2-aspirinate-5-salicylate is a highly effective aspirin prodrug that relies on the salicylate portion to interact productively with human BuChE. By integrating the salicylate group into the carbamate design, we have produced isosorbide-2-benzyl carbamate-5-salicylate, an inhibitor of high potency (150 pM) and selectivity for human BuChE over AChE (666000) and CES2 (23000). Modeling and mutant studies indicate that it achieves its exceptional potency because of an interaction with the polar D70/Y332 cluster in the PAS of BuChE in addition to pseudosubstrate interactions with the active site.
|
Inhibition of electric eel AChE type 6S
|
Electrophorus electricus
|
53.0
nM
|
|
Journal : J. Med. Chem.
Title : Isosorbide-2-benzyl carbamate-5-salicylate, a peripheral anionic site binding subnanomolar selective butyrylcholinesterase inhibitor.
Year : 2010
Volume : 53
Issue : 3
First Page : 1190
Last Page : 1199
Authors : Carolan CG, Dillon GP, Khan D, Ryder SA, Gaynor JM, Reidy S, Marquez JF, Jones M, Holland V, Gilmer JF.
Abstract : Isosorbide-2-benzyl carbamate-5-benzoate is a highly potent and selective BuChE inhibitor. Meanwhile, isosorbide-2-aspirinate-5-salicylate is a highly effective aspirin prodrug that relies on the salicylate portion to interact productively with human BuChE. By integrating the salicylate group into the carbamate design, we have produced isosorbide-2-benzyl carbamate-5-salicylate, an inhibitor of high potency (150 pM) and selectivity for human BuChE over AChE (666000) and CES2 (23000). Modeling and mutant studies indicate that it achieves its exceptional potency because of an interaction with the polar D70/Y332 cluster in the PAS of BuChE in addition to pseudosubstrate interactions with the active site.
|
Inhibition of mouse brain AChE after 1 hr by modified Ellman's colorimetric method
|
Mus musculus
|
40.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis, evaluation and QSAR analysis of N(1)-substituted norcymserine derivatives as selective butyrylcholinesterase inhibitors.
Year : 2010
Volume : 20
Issue : 5
First Page : 1718
Last Page : 1720
Authors : Takahashi J, Hijikuro I, Kihara T, Murugesh MG, Fuse S, Kunimoto R, Tsumura Y, Akaike A, Niidome T, Okuno Y, Takahashi T, Sugimoto H.
Abstract : We synthesized a series of N(1)-substituted norcymserine derivatives 7a-p and evaluated their anti-cholinesterase activities. In vitro evaluation showed that the pyridinylethyl derivatives 7m-o and the piperidinylethyl derivative 7p improved the anti-butyrylcholinesterase activity by approximately threefold compared to N(1)-phenethylnorcymserine (PEC, 2). A quantitative structure-activity relationship (QSAR) study indicated that logS might be a key feature of the improved compounds.
|
Inhibition of mouse serum BChE after 1 hr by modified Ellman's colorimetric method
|
Mus musculus
|
280.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis, evaluation and QSAR analysis of N(1)-substituted norcymserine derivatives as selective butyrylcholinesterase inhibitors.
Year : 2010
Volume : 20
Issue : 5
First Page : 1718
Last Page : 1720
Authors : Takahashi J, Hijikuro I, Kihara T, Murugesh MG, Fuse S, Kunimoto R, Tsumura Y, Akaike A, Niidome T, Okuno Y, Takahashi T, Sugimoto H.
Abstract : We synthesized a series of N(1)-substituted norcymserine derivatives 7a-p and evaluated their anti-cholinesterase activities. In vitro evaluation showed that the pyridinylethyl derivatives 7m-o and the piperidinylethyl derivative 7p improved the anti-butyrylcholinesterase activity by approximately threefold compared to N(1)-phenethylnorcymserine (PEC, 2). A quantitative structure-activity relationship (QSAR) study indicated that logS might be a key feature of the improved compounds.
|
Inhibition of mouse brain AChE after 1 hr by modified Ellman's colorimetric method
|
Mus musculus
|
40.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis and evaluation of carbamate-modified (-)-N(1)-phenethylnorphysostigmine derivatives as selective butyrylcholinesterase inhibitors.
Year : 2010
Volume : 20
Issue : 5
First Page : 1721
Last Page : 1723
Authors : Takahashi J, Hijikuro I, Kihara T, Murugesh MG, Fuse S, Tsumura Y, Akaike A, Niidome T, Takahashi T, Sugimoto H.
Abstract : We synthesized carbamate-modified (-)-N(1)-phenethylnorphysostigmine derivatives 3a-u and evaluated their anti-cholinesterase activities. In vitro evaluation showed that cyclohexylmethylcarbamate derivative 3u potently and selectively inhibits butyrylcholinesterase.
|
Inhibition of mouse serum BChE after 1 hr by modified Ellman's colorimetric method
|
Mus musculus
|
280.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis and evaluation of carbamate-modified (-)-N(1)-phenethylnorphysostigmine derivatives as selective butyrylcholinesterase inhibitors.
Year : 2010
Volume : 20
Issue : 5
First Page : 1721
Last Page : 1723
Authors : Takahashi J, Hijikuro I, Kihara T, Murugesh MG, Fuse S, Tsumura Y, Akaike A, Niidome T, Takahashi T, Sugimoto H.
Abstract : We synthesized carbamate-modified (-)-N(1)-phenethylnorphysostigmine derivatives 3a-u and evaluated their anti-cholinesterase activities. In vitro evaluation showed that cyclohexylmethylcarbamate derivative 3u potently and selectively inhibits butyrylcholinesterase.
|
Inhibition of rat brain AChE by Ellman's method
|
Rattus norvegicus
|
1.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of physostigmine analogues and evaluation of their anticholinesterase activities.
Year : 2010
Volume : 20
Issue : 5
First Page : 1532
Last Page : 1534
Authors : Zhan ZJ, Bian HL, Wang JW, Shan WG.
Abstract : A series of physostigmine analogues were prepared and evaluated for cholinesterase inhibition activities, including acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Most of them showed potent inhibition activities against AChE, in which compound 17 especially exhibited significantly higher selectivity over BChE than phenserine, a compound currently on clinical trial. Discussion about the relationships between structure and activity of these derivatives was also presented.
|
Inhibition of rat plasma BChE by Ellman's method
|
Rattus norvegicus
|
7.6
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of physostigmine analogues and evaluation of their anticholinesterase activities.
Year : 2010
Volume : 20
Issue : 5
First Page : 1532
Last Page : 1534
Authors : Zhan ZJ, Bian HL, Wang JW, Shan WG.
Abstract : A series of physostigmine analogues were prepared and evaluated for cholinesterase inhibition activities, including acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Most of them showed potent inhibition activities against AChE, in which compound 17 especially exhibited significantly higher selectivity over BChE than phenserine, a compound currently on clinical trial. Discussion about the relationships between structure and activity of these derivatives was also presented.
|
Inhibition of electric eel AChE at 350 mM by microplate assay
|
Electrophorus electricus
|
87.0
%
|
|
Journal : J. Nat. Prod.
Title : Acetylcholinesterase inhibitory pyridine alkaloids of the leaves of Senna multijuga.
Year : 2010
Volume : 73
Issue : 3
First Page : 482
Last Page : 484
Authors : Serrano MA, Pivatto M, Francisco W, Danuello A, Regasini LO, Lopes EM, Lopes MN, Young MC, Bolzani VS.
Abstract : Two unusual pyridine alkaloids, 7'-multijuguinone (1) and 12'-hydroxy-7'-multijuguinone (2), were isolated from the leaves of Senna multijuga, together with the known flavonoid rutin. The structures of the new alkaloids were established on the basis of spectroscopic data interpretation. Compounds 1 and 2 exhibited moderate in vitro acetylcholinesterase (AChE) inhibitory activity, in comparison with the standard compound physostigmine.
|
Inhibition of human FAAH at 1 uM
|
Homo sapiens
|
18.85
%
|
|
Inhibition of human FAAH at 1 uM
|
Homo sapiens
|
12.37
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Mining biologically-active molecules for inhibitors of fatty acid amide hydrolase (FAAH): identification of phenmedipham and amperozide as FAAH inhibitors.
Year : 2009
Volume : 19
Issue : 23
First Page : 6793
Last Page : 6796
Authors : Vincent F, Nguyen MT, Emerling DE, Kelly MG, Duncton MA.
Abstract : The screening of known medicinal agents against new biological targets has been shown to be a valuable approach for revealing new pharmacology of marketed compounds. Recently, carbamate, urea and ketone inhibitors of fatty acid amide hydrolase (FAAH) have been described as promising treatments for pain, anxiety, depression and other CNS-related conditions. In order to find novel FAAH inhibitors, a focused screen of molecules containing potentially reactive moieties or having in vivo effects that are possibly relevant to the biology of FAAH was conducted. These studies revealed phenmedipham 13 and amperozide 14 to be inhibitors of human FAAH, with an IC(50) of 377 nM and 1.34 microM, respectively.
|
Inhibition of human whole RBC AChE pretreated for 30 mins by Ellman technique
|
Homo sapiens
|
27.9
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Long-acting anticholinesterases for myasthenia gravis: synthesis and activities of quaternary phenylcarbamates of neostigmine, pyridostigmine and physostigmine.
Year : 2010
Volume : 18
Issue : 13
First Page : 4687
Last Page : 4693
Authors : Yu QS, Holloway HW, Luo W, Lahiri DK, Brossi A, Greig NH.
Abstract : The N-monophenylcarbamate analogues of neostigmine methyl sulfate (6) and pyridostigmine bromide (8) together with their precursors (5), (7), and the N(1)-methylammonium analogues of (-)-phenserine (12), (-)-tolserine (14), (-)-cymserine (16) and (-)-phenethylcymserine (18) were synthesized to produce long-acting peripheral inhibitors of acetylcholinesterase or butyrylcholinesterase. Evaluation of their cholinesterase inhibition against human enzyme ex vivo demonstrated that, whereas compounds 5-8 possessed only marginal activity, 12, 14, 16 and 18 proved to be potent anticholinesterases. An extended duration of cholinesterase inhibition was determined in rodent, making them of potential interest as long-acting agents for myasthenia gravis.
|
Inhibition of human plasma BChE pretreated for 30 mins by Ellman technique
|
Homo sapiens
|
16.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Long-acting anticholinesterases for myasthenia gravis: synthesis and activities of quaternary phenylcarbamates of neostigmine, pyridostigmine and physostigmine.
Year : 2010
Volume : 18
Issue : 13
First Page : 4687
Last Page : 4693
Authors : Yu QS, Holloway HW, Luo W, Lahiri DK, Brossi A, Greig NH.
Abstract : The N-monophenylcarbamate analogues of neostigmine methyl sulfate (6) and pyridostigmine bromide (8) together with their precursors (5), (7), and the N(1)-methylammonium analogues of (-)-phenserine (12), (-)-tolserine (14), (-)-cymserine (16) and (-)-phenethylcymserine (18) were synthesized to produce long-acting peripheral inhibitors of acetylcholinesterase or butyrylcholinesterase. Evaluation of their cholinesterase inhibition against human enzyme ex vivo demonstrated that, whereas compounds 5-8 possessed only marginal activity, 12, 14, 16 and 18 proved to be potent anticholinesterases. An extended duration of cholinesterase inhibition was determined in rodent, making them of potential interest as long-acting agents for myasthenia gravis.
|
Inhibition of human AChE by Ellmans test
|
Homo sapiens
|
56.7
nM
|
|
Journal : J. Med. Chem.
Title : Novel carbamates as orally active acetylcholinesterase inhibitors found to improve scopolamine-induced cognition impairment: pharmacophore-based virtual screening, synthesis, and pharmacology.
Year : 2010
Volume : 53
Issue : 17
First Page : 6490
Last Page : 6505
Authors : Chaudhaery SS, Roy KK, Shakya N, Saxena G, Sammi SR, Nazir A, Nath C, Saxena AK.
Abstract : A systematic virtual screening (VS) experiment, consisting of the development of 3D-pharmacophore, screening of virtual library, synthesis, and pharmacology, is reported. The predictive pharmacophore model (correlation = 0.955) with one H-bond donor and three hydrophobic features was developed using HypoGen on a training set of 24 carbamates as AChE inhibitors. The model was validated on a test set of 40 carbamates (correlation = 0.844). The pharmacophore-based VS of virtual library led to the identification of novel carbamates as potent AChE inhibitors. The synthesis and pharmacological evaluation of nine carbamates against three diverse assay systems, namely (i) in vitro Ellman method, (ii) in vivo passive avoidance test, and (iii) aldicarb-sensitivity assay, led to the discovery of orally active novel AChE inhibitors which improved scopolamine-induce cognition impairment in Swiss male mice. Finally, two novel lead compounds 85 and 86 are selected as candidate molecules for further optimization.
|
DRUGMATRIX: Acetylcholinesterase enzyme inhibition (substrate: acetylthiocholine)
|
None
|
175.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: CYP450, 2D6 enzyme inhibition (substrate: 3-Cyano-7-ethoxycoumarin)
|
None
|
200.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
Inhibition of human erythrocyte AChE assessed as acetylthiocholine iodide hydrolysis after 10 mins preincubation by spectrophotometry
|
Homo sapiens
|
150.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Cholinestrase inhibitory effects of geranylated flavonoids from Paulownia tomentosa fruits.
Year : 2012
Volume : 20
Issue : 8
First Page : 2595
Last Page : 2602
Authors : Cho JK, Ryu YB, Curtis-Long MJ, Ryu HW, Yuk HJ, Kim DW, Kim HJ, Lee WS, Park KH.
Abstract : Alzheimer's disease is rapidly becoming one of the most prevalent human diseases. Inhibition of human acetylcholinestrase (hAChE) and butyrylcholinestrase (BChE) has been linked to amelioration of Alzheimer's symptoms and research into inhibitors is of critical importance. Purification of the methanol extract of Paulownia tomentosa fruits yielded potent hAChE and BChE inhibitory flavonoids (1-9). A comparative activity screen indicated that a geranyl group at C6 is crucial for both hAChE and BChE. For example, diplacone (8) showed 250-fold higher efficacy than its parent eriodictyol (12). IC(50)s of diplacone (8) were 7.2 μM for hAChE and 1.4 μM for BChE. Similar trends were also observed for 4'-O-methyldiplacone (4) (vs its parent, hesperetin 10) and mimulone (7) (vs its parent, naringenin 11). Representative inhibitors (1-8) showed mixed inhibition kinetics as well as time-dependent, reversible inhibition toward hAChE. The binding affinities of these compounds to hAChE were investigated by monitoring quenching of inherent enzyme fluorescence. The affinity constants (K(SA)) increased in proportion to inhibitory potencies.
|
Inhibition of electric eel AChE using acetylthiocholine as substrate at 350 uM by Ellman's method
|
Electrophorus electricus
|
94.0
%
|
|
Journal : J. Nat. Prod.
Title : Pyridine alkaloids from Senna multijuga as acetylcholinesterase inhibitors.
Year : 2012
Volume : 75
Issue : 3
First Page : 408
Last Page : 413
Authors : Francisco W, Pivatto M, Danuello A, Regasini LO, Baccini LR, Young MC, Lopes NP, Lopes JL, Bolzani VS.
Abstract : As part of an ongoing research project on Senna and Cassia species, five new pyridine alkaloids, namely, 12'-hydroxy-7'-multijuguinol (1), 12'-hydroxy-8'-multijuguinol (2), methyl multijuguinate (3), 7'-multijuguinol (4), and 8'-multijuguinol (5), were isolated from the leaves of Senna multijuga (syn. Cassiamultijuga). Their structures were elucidated on the basis of spectroscopic data analysis. Mass spectrometry was used for confirmation of the positions of the hydroxy groups in the side-chains of 1, 2, 4, and 5. All compounds exhibited weak in vitro acetylcholinesterase inhibitory activity as compared with the standard compound physostigmine.
|
Inhibition of AChE in Wistar rat brain homogenate using acetylthiocholine iodide as substrate after 0.5 hrs by Ellman's method
|
Rattus norvegicus
|
11.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis of phenserine analogues and evaluation of their cholinesterase inhibitory activities.
Year : 2012
Volume : 20
Issue : 16
First Page : 4901
Last Page : 4914
Authors : Shinada M, Narumi F, Osada Y, Matsumoto K, Yoshida T, Higuchi K, Kawasaki T, Tanaka H, Satoh M.
Abstract : Phenserine is a potentially attractive drug for Alzheimer's disease. In order to further expand SAR study for inhibitions of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), the methyl group at the 3a-position of phenserine was replaced with an alkyl or alkenyl group, and its phenylcarbamoyl moiety was substituted at the o- or p-position. The synthetic methodology for these phenserine analogues includes the efficient cascade reactions for introduction of the 3a-substituent and assembly of the quaternary carbon center followed by reductive cyclization to the key pyrroloindoline structure. The bulkiness of the substituent at 3a-position of phenserine derivatives tends to reduce the inhibitory effect on AChE activity in the following order: methyl > ethyl > vinyl > propyl ≈ allyl > reverse-prenyl groups. Among the series synthesized, the 3a-ethyl derivative demonstrated the highest AChE selectivity. In construct, the 3a-reverse-prenyl derivative indicated modest BuChE selectivity.
|
Inhibition of BuChE in Wistar rat plasma using acetylthiocholine iodide as substrate after 0.5 hrs by Ellman's method
|
Rattus norvegicus
|
58.4
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis of phenserine analogues and evaluation of their cholinesterase inhibitory activities.
Year : 2012
Volume : 20
Issue : 16
First Page : 4901
Last Page : 4914
Authors : Shinada M, Narumi F, Osada Y, Matsumoto K, Yoshida T, Higuchi K, Kawasaki T, Tanaka H, Satoh M.
Abstract : Phenserine is a potentially attractive drug for Alzheimer's disease. In order to further expand SAR study for inhibitions of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), the methyl group at the 3a-position of phenserine was replaced with an alkyl or alkenyl group, and its phenylcarbamoyl moiety was substituted at the o- or p-position. The synthetic methodology for these phenserine analogues includes the efficient cascade reactions for introduction of the 3a-substituent and assembly of the quaternary carbon center followed by reductive cyclization to the key pyrroloindoline structure. The bulkiness of the substituent at 3a-position of phenserine derivatives tends to reduce the inhibitory effect on AChE activity in the following order: methyl > ethyl > vinyl > propyl ≈ allyl > reverse-prenyl groups. Among the series synthesized, the 3a-ethyl derivative demonstrated the highest AChE selectivity. In construct, the 3a-reverse-prenyl derivative indicated modest BuChE selectivity.
|
Inhibition of Electric eel AChE using acetylthiocholine as substrate after 2 mins
|
Electrophorus electricus
|
90.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Neuroprotective Tri- and Tetracyclic BChE Inhibitors Releasing Reversible Inhibitors upon Carbamate Transfer.
Year : 2012
Volume : 3
Issue : 11
First Page : 914
Last Page : 919
Authors : Darras FH, Kling B, Heilmann J, Decker M.
Abstract : Tri- and tetracyclic nitrogen-bridgehead compounds were designed and synthesized to yield micromolar cholinesterase (ChE) inhibitors. Structure-activity relationships identified potent compounds with butyrylcholinesterase selectivity. These compounds were selected as starting points for the design and synthesis of carbamate-based (pseudo)irreversible inhibitors. Compounds with superior inhibitory activity and selectivity were obtained and kinetically characterized also with regard to the velocity of enzyme carbamoylation. Structural elements were identified and introduced that additionally showed neuroprotective properties on a hippocampal neuronal cell line (HT-22) after glutamate-induced intracellular reactive oxygen species generation. We have identified potent and selective pseudoirreversible butyrylcholinesterase inhibitors that release reversible inhibitors with neuroprotective properties after carbamate transfer to the active site of cholinesterases.
|
Inhibition of equine serum BChE using acetylthiocholine as substrate after 2 mins
|
Equus caballus
|
42.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Neuroprotective Tri- and Tetracyclic BChE Inhibitors Releasing Reversible Inhibitors upon Carbamate Transfer.
Year : 2012
Volume : 3
Issue : 11
First Page : 914
Last Page : 919
Authors : Darras FH, Kling B, Heilmann J, Decker M.
Abstract : Tri- and tetracyclic nitrogen-bridgehead compounds were designed and synthesized to yield micromolar cholinesterase (ChE) inhibitors. Structure-activity relationships identified potent compounds with butyrylcholinesterase selectivity. These compounds were selected as starting points for the design and synthesis of carbamate-based (pseudo)irreversible inhibitors. Compounds with superior inhibitory activity and selectivity were obtained and kinetically characterized also with regard to the velocity of enzyme carbamoylation. Structural elements were identified and introduced that additionally showed neuroprotective properties on a hippocampal neuronal cell line (HT-22) after glutamate-induced intracellular reactive oxygen species generation. We have identified potent and selective pseudoirreversible butyrylcholinesterase inhibitors that release reversible inhibitors with neuroprotective properties after carbamate transfer to the active site of cholinesterases.
|
Time dependent inhibition of Electric eel AChE assessed as stability constants of inhibitor-enzyme complex using acetylthiocholine as substrate after 60 mins
|
Electrophorus electricus
|
34.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Neuroprotective Tri- and Tetracyclic BChE Inhibitors Releasing Reversible Inhibitors upon Carbamate Transfer.
Year : 2012
Volume : 3
Issue : 11
First Page : 914
Last Page : 919
Authors : Darras FH, Kling B, Heilmann J, Decker M.
Abstract : Tri- and tetracyclic nitrogen-bridgehead compounds were designed and synthesized to yield micromolar cholinesterase (ChE) inhibitors. Structure-activity relationships identified potent compounds with butyrylcholinesterase selectivity. These compounds were selected as starting points for the design and synthesis of carbamate-based (pseudo)irreversible inhibitors. Compounds with superior inhibitory activity and selectivity were obtained and kinetically characterized also with regard to the velocity of enzyme carbamoylation. Structural elements were identified and introduced that additionally showed neuroprotective properties on a hippocampal neuronal cell line (HT-22) after glutamate-induced intracellular reactive oxygen species generation. We have identified potent and selective pseudoirreversible butyrylcholinesterase inhibitors that release reversible inhibitors with neuroprotective properties after carbamate transfer to the active site of cholinesterases.
|
Time dependent inhibition of equine serum BChE assessed as stability constants of inhibitor-enzyme complex using acetylthiocholine as substrate after 60 mins
|
Equus caballus
|
41.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Neuroprotective Tri- and Tetracyclic BChE Inhibitors Releasing Reversible Inhibitors upon Carbamate Transfer.
Year : 2012
Volume : 3
Issue : 11
First Page : 914
Last Page : 919
Authors : Darras FH, Kling B, Heilmann J, Decker M.
Abstract : Tri- and tetracyclic nitrogen-bridgehead compounds were designed and synthesized to yield micromolar cholinesterase (ChE) inhibitors. Structure-activity relationships identified potent compounds with butyrylcholinesterase selectivity. These compounds were selected as starting points for the design and synthesis of carbamate-based (pseudo)irreversible inhibitors. Compounds with superior inhibitory activity and selectivity were obtained and kinetically characterized also with regard to the velocity of enzyme carbamoylation. Structural elements were identified and introduced that additionally showed neuroprotective properties on a hippocampal neuronal cell line (HT-22) after glutamate-induced intracellular reactive oxygen species generation. We have identified potent and selective pseudoirreversible butyrylcholinesterase inhibitors that release reversible inhibitors with neuroprotective properties after carbamate transfer to the active site of cholinesterases.
|
Inhibition of electric eel AChE at 2 mg/ml by Ellman's method
|
Electrophorus electricus
|
89.33
%
|
|
Journal : Bioorg. Med. Chem.
Title : Exploration of natural compounds as sources of new bifunctional scaffolds targeting cholinesterases and beta amyloid aggregation: the case of chelerythrine.
Year : 2012
Volume : 20
Issue : 22
First Page : 6669
Last Page : 6679
Authors : Brunhofer G, Fallarero A, Karlsson D, Batista-Gonzalez A, Shinde P, Gopi Mohan C, Vuorela P.
Abstract : The presented project started by screening a library consisting of natural and natural based compounds for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity. Active compounds were chemically clustered into groups and further tested on the human cholinesterases isoforms. The aim of the presented study was to identify compounds that could be used as leads to target two key mechanisms associated with the AD's pathogenesis simultaneously: cholinergic depletion and beta amyloid (Aβ) aggregation. Berberin, palmatine and chelerythrine, chemically clustered in the so-called isoquinoline group, showed promising cholinesterase inhibitory activity and were therefore further investigated. Moreover, the compounds demonstrated moderate to good inhibition of Aβ aggregation as well as the ability to disaggregate already preformed Aβ aggregates in an experimental set-up using HFIP as promotor of Aβ aggregates. Analysis of the kinetic mechanism of the AChE inhibition revealed chelerythrine as a mixed inhibitor. Using molecular docking studies, it was further proven that chelerythrine binds on both the catalytic site and the peripheral anionic site (PAS) of the AChE. In view of this, we went on to investigate its effect on inhibiting Aβ aggregation stimulated by AChE. Chelerythrine showed inhibition of fibril formation in the same range as propidium iodide. This approach enabled for the first time to identify a cholinesterase inhibitor of natural origin-chelerythrine-acting on AChE and BChE with a dual ability to inhibit Aβ aggregation as well as to disaggregate preformed Aβ aggregates. This compound could be an excellent starting point paving the way to develop more successful anti-AD drugs.
|
Inhibition of horse BChE at 2 mg/ml by Ellman's method
|
Equus caballus
|
87.96
%
|
|
Journal : Bioorg. Med. Chem.
Title : Exploration of natural compounds as sources of new bifunctional scaffolds targeting cholinesterases and beta amyloid aggregation: the case of chelerythrine.
Year : 2012
Volume : 20
Issue : 22
First Page : 6669
Last Page : 6679
Authors : Brunhofer G, Fallarero A, Karlsson D, Batista-Gonzalez A, Shinde P, Gopi Mohan C, Vuorela P.
Abstract : The presented project started by screening a library consisting of natural and natural based compounds for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity. Active compounds were chemically clustered into groups and further tested on the human cholinesterases isoforms. The aim of the presented study was to identify compounds that could be used as leads to target two key mechanisms associated with the AD's pathogenesis simultaneously: cholinergic depletion and beta amyloid (Aβ) aggregation. Berberin, palmatine and chelerythrine, chemically clustered in the so-called isoquinoline group, showed promising cholinesterase inhibitory activity and were therefore further investigated. Moreover, the compounds demonstrated moderate to good inhibition of Aβ aggregation as well as the ability to disaggregate already preformed Aβ aggregates in an experimental set-up using HFIP as promotor of Aβ aggregates. Analysis of the kinetic mechanism of the AChE inhibition revealed chelerythrine as a mixed inhibitor. Using molecular docking studies, it was further proven that chelerythrine binds on both the catalytic site and the peripheral anionic site (PAS) of the AChE. In view of this, we went on to investigate its effect on inhibiting Aβ aggregation stimulated by AChE. Chelerythrine showed inhibition of fibril formation in the same range as propidium iodide. This approach enabled for the first time to identify a cholinesterase inhibitor of natural origin-chelerythrine-acting on AChE and BChE with a dual ability to inhibit Aβ aggregation as well as to disaggregate preformed Aβ aggregates. This compound could be an excellent starting point paving the way to develop more successful anti-AD drugs.
|
Inhibition of AChE (unknown origin) using acetylthiocholine iodide as substrate incubated for 20 min prior to substrate addition measured after 20 min by Ellman's method
|
Homo sapiens
|
0.013
ug.mL-1
|
|
Journal : Med Chem Res
Title : Skimmianine, a furoquinoline alkaloid from Zanthoxylum nitidum as a potential acetylcholinesterase inhibitor
Year : 2012
Volume : 21
Issue : 6
First Page : 722
Last Page : 725
Authors : Yang Z, Zhang D, Ren J, Yang M
|
Inhibition of Electrophorus electricus (electric eel) AChE using acetylthiocholine iodide as substrate incubated for 15 min prior to substrate addition measured after 30 min by Ellman's spectrophotometric method
|
Electrophorus electricus
|
0.034
ug.mL-1
|
|
Journal : Med Chem Res
Title : Apoptotic effects of some carbazole derivatives on lung carcinoma and glioma cell lines
Year : 2013
Volume : 22
Issue : 8
First Page : 3751
Last Page : 3759
Authors : Ciftci GA, Temel HE, Yldrm SU, Kaplanckl ZA, Altntop MD, Genc L
|
Inhibition of acetylcholinesterase (unknown origin) using acetylcholine iodide as substrate preincubated for 15 mins prior to substrate addition by spectrophotometric analysis
|
Homo sapiens
|
2.9
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : New bioactive dihydrofuranocoumarins from the roots of the Tunisian Ferula lutea (Poir.) Maire.
Year : 2013
Volume : 23
Issue : 14
First Page : 4248
Last Page : 4252
Authors : Ben Salem S, Jabrane A, Harzallah-Skhiri F, Ben Jannet H.
Abstract : A phytochemical investigation of the roots of Ferula lutea (Poir.) Maire led to the isolation of new dihydrofuranocoumarins as two inseparable isomers, (-)-5-hydroxyprantschimgin 1 and (-)-5-hydroxydeltoin 2, together with eight known compounds, (-)-prantschimgin 3, (-)-deltoin 4, psoralen 5, xanthotoxin 6, umbelliferone 7, caffeic acid 8, β-sitosterol 9 and stigmasterol 10. Their structures were elucidated on the basis of extensive spectroscopic methods, including 1D and 2D NMR experiments and mass spectroscopy analysis, as well as by comparison with literature data. The anti-acetylcholinesterase and cytotoxic effects of the isolates and antioxidant activities of the mixture (1+2) were also evaluated in this work. Results showed that the mixture (1+2) has the most cytotoxic activity with IC50 values 0.29±0.05 and 1.61±0.57μM against the cell lines HT-29 and HCT 116, respectively. The greatest acetylcholinesterase inhibitory activity (IC50=0.76±0.03) was exhibited by the xanthotoxin 6. In addition, the mixture (1+2) was investigated for its antioxidant activity and showed IC50 values 18.56, 13.06, 7.59, and 4.81μM towards DPPH free radical scavenging, ABTS radical monocation, singlet oxygen and hydrogen peroxide, respectively.
|
Inhibition of BChE (unknown origin) using butyryl thiocholine iodide as substrate after 30 mins by Ellman's method
|
Homo sapiens
|
850.0
nM
|
|
Journal : Med Chem Res
Title : Synthesis, molecular docking studies, and in vitro screening of barbiturates/thiobarbiturates as antibacterial and cholinesterase inhibitors
Year : 2013
First Page : 1
Last Page : 12
Authors : Mumtaz S, Hussain R, Rauf A, Fatmi MQ, Bokhari H, Oelgemoller M, Qureshi AM
|
Inhibition of AChE (unknown origin) using acetyl thiocholine iodide as substrate after 30 mins by Ellman's method
|
Homo sapiens
|
40.0
nM
|
|
Journal : Med Chem Res
Title : Synthesis, molecular docking studies, and in vitro screening of barbiturates/thiobarbiturates as antibacterial and cholinesterase inhibitors
Year : 2013
First Page : 1
Last Page : 12
Authors : Mumtaz S, Hussain R, Rauf A, Fatmi MQ, Bokhari H, Oelgemoller M, Qureshi AM
|
Inhibition of BChE (unknown origin) using butyryl thiocholine iodide as substrate at 0.25 mM after 30 mins by Ellman's method
|
Homo sapiens
|
92.54
%
|
|
Journal : Med Chem Res
Title : Synthesis, molecular docking studies, and in vitro screening of barbiturates/thiobarbiturates as antibacterial and cholinesterase inhibitors
Year : 2013
First Page : 1
Last Page : 12
Authors : Mumtaz S, Hussain R, Rauf A, Fatmi MQ, Bokhari H, Oelgemoller M, Qureshi AM
|
Inhibition of AChE (unknown origin) using acetyl thiocholine iodide as substrate at 0.25 mM after 30 mins by Ellman's method
|
Homo sapiens
|
92.54
%
|
|
Journal : Med Chem Res
Title : Synthesis, molecular docking studies, and in vitro screening of barbiturates/thiobarbiturates as antibacterial and cholinesterase inhibitors
Year : 2013
First Page : 1
Last Page : 12
Authors : Mumtaz S, Hussain R, Rauf A, Fatmi MQ, Bokhari H, Oelgemoller M, Qureshi AM
|
Inhibition of sodium fluorescein uptake in OATP1B1-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
78.13
%
|
|
Journal : Mol. Pharmacol.
Title : Structure-based identification of OATP1B1/3 inhibitors.
Year : 2013
Volume : 83
Issue : 6
First Page : 1257
Last Page : 1267
Authors : De Bruyn T, van Westen GJ, Ijzerman AP, Stieger B, de Witte P, Augustijns PF, Annaert PP.
Abstract : Several recent studies show that inhibition of the hepatic transport proteins organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) can result in clinically relevant drug-drug interactions (DDI). To avoid late-stage development drug failures due to OATP1B-mediated DDI, predictive in vitro and in silico methods should be implemented at an early stage of the drug candidate evaluation process. In the present study, we first developed a high-throughput in vitro transporter inhibition assay for the OATP1B subfamily. A total of 2000 compounds were tested as potential modulators of the uptake of the OATP1B substrate sodium fluorescein, in OATP1B1- or 1B3-transfected Chinese hamster ovary cells. At an equimolar substrate-inhibitor concentration of 10 µM, 212 and 139 molecules were identified as OATP1B1 and OATP1B3 inhibitors, respectively (minimum 50% inhibition). For 69 compounds, previously not identified as OATP1B inhibitors, concentration-dependent inhibition was also determined, yielding Ki values ranging from 0.06 to 6.5 µM. Based on these in vitro data, we subsequently developed a proteochemometrics-based in silico model, which predicted OATP1B inhibitors in the test group (20% of the dataset) with high specificity (86%) and sensitivity (78%). Moreover, several physicochemical compound properties and substructures related to OATP1B1/1B3 inhibition or inactivity were identified. Finally, model performance was prospectively verified with a set of 54 compounds not included in the original dataset. This validation indicated that 80 and 74% of the compounds were correctly classified for OATP1B1 and OATP1B3 inhibition, respectively.
|
Inhibition of sodium fluorescein uptake in OATP1B3-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
80.76
%
|
|
Journal : Mol. Pharmacol.
Title : Structure-based identification of OATP1B1/3 inhibitors.
Year : 2013
Volume : 83
Issue : 6
First Page : 1257
Last Page : 1267
Authors : De Bruyn T, van Westen GJ, Ijzerman AP, Stieger B, de Witte P, Augustijns PF, Annaert PP.
Abstract : Several recent studies show that inhibition of the hepatic transport proteins organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) can result in clinically relevant drug-drug interactions (DDI). To avoid late-stage development drug failures due to OATP1B-mediated DDI, predictive in vitro and in silico methods should be implemented at an early stage of the drug candidate evaluation process. In the present study, we first developed a high-throughput in vitro transporter inhibition assay for the OATP1B subfamily. A total of 2000 compounds were tested as potential modulators of the uptake of the OATP1B substrate sodium fluorescein, in OATP1B1- or 1B3-transfected Chinese hamster ovary cells. At an equimolar substrate-inhibitor concentration of 10 µM, 212 and 139 molecules were identified as OATP1B1 and OATP1B3 inhibitors, respectively (minimum 50% inhibition). For 69 compounds, previously not identified as OATP1B inhibitors, concentration-dependent inhibition was also determined, yielding Ki values ranging from 0.06 to 6.5 µM. Based on these in vitro data, we subsequently developed a proteochemometrics-based in silico model, which predicted OATP1B inhibitors in the test group (20% of the dataset) with high specificity (86%) and sensitivity (78%). Moreover, several physicochemical compound properties and substructures related to OATP1B1/1B3 inhibition or inactivity were identified. Finally, model performance was prospectively verified with a set of 54 compounds not included in the original dataset. This validation indicated that 80 and 74% of the compounds were correctly classified for OATP1B1 and OATP1B3 inhibition, respectively.
|
Inhibition of recombinant human AChE expressed in HEK293 cells using acetylthiocholine iodide as substrate preincubated for 5 mins before substrate addition measured after 10 mins by Ellman's method
|
Homo sapiens
|
160.0
nM
|
|
Journal : MedChemComm
Title : 3-Substituted coumarins as dual inhibitors of AChE and MAO for the treatment of Alzheimer's disease
Year : 2012
Volume : 3
Issue : 2
First Page : 213
Last Page : 218
Authors : Vina D, Matos MJ, Yanez M, Santana L, Uriarte E
|
Inhibition of acetylcholine esterase in chicken biventer cervicis muscle assessed as rate of acetylcholine hydrolysis by Ellman's method
|
Gallus gallus
|
20.0
nM
|
|
Journal : J. Med. Chem.
Title : Actions of two dopamine derivatives at adreno- and cholinoceptors.
Year : 1979
Volume : 22
Issue : 1
First Page : 117
Last Page : 119
Authors : Rodger IW, Hersom AS, Waigh RD.
Abstract : Salsolinol (1)and 6,7-dihydroxy-1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline hydrobromide (2) were synthesized and their effects at adreno- and cholinoceptors investigated both in vivo and in vitro. Both 1 and 2 produced agonist effects at cholinoceptors and alpha- and beta-adrenoceptors. Neuromuscular blocking actions were evident in vitro. Compound 2 exhibited anticholinesterase properties both in vivo and in vitro. These results indicate that dopamine derivatives of this type exhibit not only sympathomimetic activity but also complex actions at cholinoceptors.
|
Inhibition of equine serum BChE by Ellman's method
|
Equus caballus
|
60.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Identification of a neuroprotective and selective butyrylcholinesterase inhibitor derived from the natural alkaloid evodiamine.
Year : 2014
Volume : 81
First Page : 15
Last Page : 21
Authors : Huang G, Kling B, Darras FH, Heilmann J, Decker M.
Abstract : Two sets of carbamates based on the natural alkaloid evodiamine were designed, synthesized and evaluated as potential butyrylcholinesterase inhibitors. Although a set of carbamates of 3-hydroxyevodiamine (10a-f) is inactive both at AChE and BChE, carbamates of 5-deoxo-3-hydroxyevodiamine (11a-f) exhibit much better potency with selectivity toward BChE. The heptyl carbamate of 5-deoxo-3-hydroxyevodiamine (11c) shows the best potency with an IC50 value of 77 nM and very good selectivity over AChE. ORAC and cell-based assays indicate 11c owns pronounced antioxidant properties with 1.75 Trolox equivalents and strong neuroprotection even from 1 μM onwards. These combined activities might enable compound 11c to be a potential candidate for treatment of Alzheimer's disease.
|
Inhibition of electric eel AChE by Ellman's method
|
Electrophorus electricus
|
7.7
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Identification of a neuroprotective and selective butyrylcholinesterase inhibitor derived from the natural alkaloid evodiamine.
Year : 2014
Volume : 81
First Page : 15
Last Page : 21
Authors : Huang G, Kling B, Darras FH, Heilmann J, Decker M.
Abstract : Two sets of carbamates based on the natural alkaloid evodiamine were designed, synthesized and evaluated as potential butyrylcholinesterase inhibitors. Although a set of carbamates of 3-hydroxyevodiamine (10a-f) is inactive both at AChE and BChE, carbamates of 5-deoxo-3-hydroxyevodiamine (11a-f) exhibit much better potency with selectivity toward BChE. The heptyl carbamate of 5-deoxo-3-hydroxyevodiamine (11c) shows the best potency with an IC50 value of 77 nM and very good selectivity over AChE. ORAC and cell-based assays indicate 11c owns pronounced antioxidant properties with 1.75 Trolox equivalents and strong neuroprotection even from 1 μM onwards. These combined activities might enable compound 11c to be a potential candidate for treatment of Alzheimer's disease.
|
Inhibition of equine serum BChE at 10 uM by Ellman's method
|
Equus caballus
|
7.22
%
|
|
Journal : Eur. J. Med. Chem.
Title : Identification of a neuroprotective and selective butyrylcholinesterase inhibitor derived from the natural alkaloid evodiamine.
Year : 2014
Volume : 81
First Page : 15
Last Page : 21
Authors : Huang G, Kling B, Darras FH, Heilmann J, Decker M.
Abstract : Two sets of carbamates based on the natural alkaloid evodiamine were designed, synthesized and evaluated as potential butyrylcholinesterase inhibitors. Although a set of carbamates of 3-hydroxyevodiamine (10a-f) is inactive both at AChE and BChE, carbamates of 5-deoxo-3-hydroxyevodiamine (11a-f) exhibit much better potency with selectivity toward BChE. The heptyl carbamate of 5-deoxo-3-hydroxyevodiamine (11c) shows the best potency with an IC50 value of 77 nM and very good selectivity over AChE. ORAC and cell-based assays indicate 11c owns pronounced antioxidant properties with 1.75 Trolox equivalents and strong neuroprotection even from 1 μM onwards. These combined activities might enable compound 11c to be a potential candidate for treatment of Alzheimer's disease.
|
Inhibition of electric eel AChE at 10 uM by Ellman's method
|
Electrophorus electricus
|
8.11
%
|
|
Journal : Eur. J. Med. Chem.
Title : Identification of a neuroprotective and selective butyrylcholinesterase inhibitor derived from the natural alkaloid evodiamine.
Year : 2014
Volume : 81
First Page : 15
Last Page : 21
Authors : Huang G, Kling B, Darras FH, Heilmann J, Decker M.
Abstract : Two sets of carbamates based on the natural alkaloid evodiamine were designed, synthesized and evaluated as potential butyrylcholinesterase inhibitors. Although a set of carbamates of 3-hydroxyevodiamine (10a-f) is inactive both at AChE and BChE, carbamates of 5-deoxo-3-hydroxyevodiamine (11a-f) exhibit much better potency with selectivity toward BChE. The heptyl carbamate of 5-deoxo-3-hydroxyevodiamine (11c) shows the best potency with an IC50 value of 77 nM and very good selectivity over AChE. ORAC and cell-based assays indicate 11c owns pronounced antioxidant properties with 1.75 Trolox equivalents and strong neuroprotection even from 1 μM onwards. These combined activities might enable compound 11c to be a potential candidate for treatment of Alzheimer's disease.
|
Inhibition of BChE (unknown origin) using BCh iodide as substrate preincubated for 15 mins prior to substrate addition measured after 10 mins by Ellman's method
|
Homo sapiens
|
930.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Dual inhibition of the α-glucosidase and butyrylcholinesterase studied by molecular field topology analysis.
Year : 2014
Volume : 80
First Page : 228
Last Page : 242
Authors : Jabeen F, Oliferenko PV, Oliferenko AA, Pillai GG, Ansari FL, Hall CD, Katritzky AR.
Abstract : A striking dual inhibition of enzymes α-glucosidase and butyrylcholinesterase by small drug-like molecules, including 1,4-disubstituted-1,2,3-triazoles, chalcones, and benzothiazepines, was rationalized with the help of Molecular Field Topology Analysis, a 3D QSAR technique similar to CoMFA. A common pharmacophore supported the concept of a link existing between type-2 diabetes mellitus and Alzheimer's disease. These findings will be instrumental for rational design of drug candidates for both of these conditions.
|
Inhibition of Pacific electric ray AChE using acetylthiocholine iodide as substrate after 60 mins by Ellman's method
|
Torpedo californica
|
11.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Preparation, anticholinesterase activity and molecular docking of new lupane derivatives.
Year : 2014
Volume : 22
Issue : 13
First Page : 3341
Last Page : 3350
Authors : Castro MJ, Richmond V, Romero C, Maier MS, Estévez-Braun A, Ravelo AG, Faraoni MB, Murray AP.
Abstract : A set of twenty one lupane derivatives (2-22) was prepared from the natural triterpenoid calenduladiol (1) by transformations on the hydroxyl groups at C-3 and C-16, and also on the isopropenyl moiety. The derivatives were tested for their inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) and some structure-activity relationships were outlined with the aid of enzyme kinetic studies and docking modelization. The most active compound resulted to be 3,16,30-trioxolup-20(29)-ene (22), with an IC50 value of 21.5μM for butyrylcholinesterase, which revealed a selective inhibitor profile towards this enzyme.
|
Inhibition of BChE in horse serum using butyrylthiocholine iodide as substrate after 120 mins by Ellman's method
|
Equus caballus
|
14.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Preparation, anticholinesterase activity and molecular docking of new lupane derivatives.
Year : 2014
Volume : 22
Issue : 13
First Page : 3341
Last Page : 3350
Authors : Castro MJ, Richmond V, Romero C, Maier MS, Estévez-Braun A, Ravelo AG, Faraoni MB, Murray AP.
Abstract : A set of twenty one lupane derivatives (2-22) was prepared from the natural triterpenoid calenduladiol (1) by transformations on the hydroxyl groups at C-3 and C-16, and also on the isopropenyl moiety. The derivatives were tested for their inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) and some structure-activity relationships were outlined with the aid of enzyme kinetic studies and docking modelization. The most active compound resulted to be 3,16,30-trioxolup-20(29)-ene (22), with an IC50 value of 21.5μM for butyrylcholinesterase, which revealed a selective inhibitor profile towards this enzyme.
|
Inhibition of electric eel AChE using ATC iodide substrate by DTNB based assay
|
Electrophorus electricus
|
90.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Cyclic acyl guanidines bearing carbamate moieties allow potent and dirigible cholinesterase inhibition of either acetyl- or butyrylcholinesterase.
Year : 2014
Volume : 22
Issue : 17
First Page : 5020
Last Page : 5034
Authors : Darras FH, Kling B, Sawatzky E, Heilmann J, Decker M.
Abstract : A series of cyclic acyl guanidine with carbamate moieties have been synthesized and evaluated in vitro for their AChE and BChE inhibitory activities. Structure-activity relationships identified compound 23 as a nanomolar and selective BChE inhibitor, while compound 32 exhibited nanomolar and selective AChE inhibition, selectivity depending on both the structure of the carbamate substituent as well as the position of guanidines-N substitution. The velocity of enzyme carbamoylation was analyzed and showed similar behavior to physostigmine. Phenolic compounds formed after carbamate transfer to the active site of cholinesterases showed additional neuroprotective properties on a hippocampal neuronal cell line (HT-22) after glutamate-induced intracellular reactive oxygen species generation.
|
Inhibition of equine serum BChE using ATC iodide substrate by DTNB based assay
|
Equus caballus
|
40.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Cyclic acyl guanidines bearing carbamate moieties allow potent and dirigible cholinesterase inhibition of either acetyl- or butyrylcholinesterase.
Year : 2014
Volume : 22
Issue : 17
First Page : 5020
Last Page : 5034
Authors : Darras FH, Kling B, Sawatzky E, Heilmann J, Decker M.
Abstract : A series of cyclic acyl guanidine with carbamate moieties have been synthesized and evaluated in vitro for their AChE and BChE inhibitory activities. Structure-activity relationships identified compound 23 as a nanomolar and selective BChE inhibitor, while compound 32 exhibited nanomolar and selective AChE inhibition, selectivity depending on both the structure of the carbamate substituent as well as the position of guanidines-N substitution. The velocity of enzyme carbamoylation was analyzed and showed similar behavior to physostigmine. Phenolic compounds formed after carbamate transfer to the active site of cholinesterases showed additional neuroprotective properties on a hippocampal neuronal cell line (HT-22) after glutamate-induced intracellular reactive oxygen species generation.
|
Inhibition of AChE (unknown origin) using acetylthiocholine iodide as substrate at 0.5 mM preincubated for 30 mins before substrate addition measured after 30 mins by Ellman method relative to control
|
Homo sapiens
|
91.27
%
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis of novel triazoles and a tetrazole of escitalopram as cholinesterase inhibitors.
Year : 2015
Volume : 23
Issue : 17
First Page : 6014
Last Page : 6024
Authors : Mehr-un-Nisa, Munawar MA, Chattha FA, Kousar S, Munir J, Ismail T, Ashraf M, Khan MA.
Abstract : A novel serie of escitalopram triazoles (60-88) and a tetrazole (89) have been synthesized and subjected to a study to establish the inhibitory potential of these compounds toward acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Some selectivity in inhibition has been observed. The 4-chlorophenyl- (75, IC50, 6.71 ± 0.25 μM) and 2-methylphenyl- (70, IC50, 9.52 ± 0.23 μM) escitalopram triazole derivatives depicted high AChE inhibition, while 2-fluorophenyl- (76, IC50 = 4.52 ± 0.17 μM) and 4-fluorophenyl- (78, IC50 = 5.31 ± 0.43 μM) have found to be excellent BChE inhibitors. It has also been observed that ortho, meta and para substituted electron donating groups increase the inhibition, while electron withdrawing groups reduce the inhibition. Docking analyses of inhibitors with AChE have depicted the binding energies for 70 and 75 as ΔG(bind) -6.42 and -6.93 kcal/mol, respectively, while ligands 76 and 78 have shown the binding affinity ΔG(bind) -9.04 and -8.51 kcal/mol, respectively, for BChE.
|
Inhibition of AChE (unknown origin) using acetylthiocholine iodide as substrate preincubated for 30 mins before substrate addition measured after 30 mins by Ellman method
|
Homo sapiens
|
40.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis of novel triazoles and a tetrazole of escitalopram as cholinesterase inhibitors.
Year : 2015
Volume : 23
Issue : 17
First Page : 6014
Last Page : 6024
Authors : Mehr-un-Nisa, Munawar MA, Chattha FA, Kousar S, Munir J, Ismail T, Ashraf M, Khan MA.
Abstract : A novel serie of escitalopram triazoles (60-88) and a tetrazole (89) have been synthesized and subjected to a study to establish the inhibitory potential of these compounds toward acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Some selectivity in inhibition has been observed. The 4-chlorophenyl- (75, IC50, 6.71 ± 0.25 μM) and 2-methylphenyl- (70, IC50, 9.52 ± 0.23 μM) escitalopram triazole derivatives depicted high AChE inhibition, while 2-fluorophenyl- (76, IC50 = 4.52 ± 0.17 μM) and 4-fluorophenyl- (78, IC50 = 5.31 ± 0.43 μM) have found to be excellent BChE inhibitors. It has also been observed that ortho, meta and para substituted electron donating groups increase the inhibition, while electron withdrawing groups reduce the inhibition. Docking analyses of inhibitors with AChE have depicted the binding energies for 70 and 75 as ΔG(bind) -6.42 and -6.93 kcal/mol, respectively, while ligands 76 and 78 have shown the binding affinity ΔG(bind) -9.04 and -8.51 kcal/mol, respectively, for BChE.
|
Inhibition of BChE (unknown origin) using butyrylthiocholine chloride as substrate at 0.5 mM preincubated for 30 mins before substrate addition measured after 30 mins by Ellman method relative to control
|
Homo sapiens
|
82.82
%
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis of novel triazoles and a tetrazole of escitalopram as cholinesterase inhibitors.
Year : 2015
Volume : 23
Issue : 17
First Page : 6014
Last Page : 6024
Authors : Mehr-un-Nisa, Munawar MA, Chattha FA, Kousar S, Munir J, Ismail T, Ashraf M, Khan MA.
Abstract : A novel serie of escitalopram triazoles (60-88) and a tetrazole (89) have been synthesized and subjected to a study to establish the inhibitory potential of these compounds toward acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Some selectivity in inhibition has been observed. The 4-chlorophenyl- (75, IC50, 6.71 ± 0.25 μM) and 2-methylphenyl- (70, IC50, 9.52 ± 0.23 μM) escitalopram triazole derivatives depicted high AChE inhibition, while 2-fluorophenyl- (76, IC50 = 4.52 ± 0.17 μM) and 4-fluorophenyl- (78, IC50 = 5.31 ± 0.43 μM) have found to be excellent BChE inhibitors. It has also been observed that ortho, meta and para substituted electron donating groups increase the inhibition, while electron withdrawing groups reduce the inhibition. Docking analyses of inhibitors with AChE have depicted the binding energies for 70 and 75 as ΔG(bind) -6.42 and -6.93 kcal/mol, respectively, while ligands 76 and 78 have shown the binding affinity ΔG(bind) -9.04 and -8.51 kcal/mol, respectively, for BChE.
|
Inhibition of BChE (unknown origin) using butyrylthiocholine chloride as substrate preincubated for 30 mins before substrate addition measured after 30 mins by Ellman method
|
Homo sapiens
|
850.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis of novel triazoles and a tetrazole of escitalopram as cholinesterase inhibitors.
Year : 2015
Volume : 23
Issue : 17
First Page : 6014
Last Page : 6024
Authors : Mehr-un-Nisa, Munawar MA, Chattha FA, Kousar S, Munir J, Ismail T, Ashraf M, Khan MA.
Abstract : A novel serie of escitalopram triazoles (60-88) and a tetrazole (89) have been synthesized and subjected to a study to establish the inhibitory potential of these compounds toward acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Some selectivity in inhibition has been observed. The 4-chlorophenyl- (75, IC50, 6.71 ± 0.25 μM) and 2-methylphenyl- (70, IC50, 9.52 ± 0.23 μM) escitalopram triazole derivatives depicted high AChE inhibition, while 2-fluorophenyl- (76, IC50 = 4.52 ± 0.17 μM) and 4-fluorophenyl- (78, IC50 = 5.31 ± 0.43 μM) have found to be excellent BChE inhibitors. It has also been observed that ortho, meta and para substituted electron donating groups increase the inhibition, while electron withdrawing groups reduce the inhibition. Docking analyses of inhibitors with AChE have depicted the binding energies for 70 and 75 as ΔG(bind) -6.42 and -6.93 kcal/mol, respectively, while ligands 76 and 78 have shown the binding affinity ΔG(bind) -9.04 and -8.51 kcal/mol, respectively, for BChE.
|
Inhibition of equine serum butyrylcholinesterase using butyrylcholine iodide as substrate preincubated for 30 mins followed by substrate addition measured after 2.5 mins by Ellman's spectrophotometric method
|
Equus caballus
|
78.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of Highly Selective and Nanomolar Carbamate-Based Butyrylcholinesterase Inhibitors by Rational Investigation into Their Inhibition Mode.
Year : 2016
Volume : 59
Issue : 5
First Page : 2067
Last Page : 2082
Authors : Sawatzky E, Wehle S, Kling B, Wendrich J, Bringmann G, Sotriffer CA, Heilmann J, Decker M.
Abstract : Butyrylcholinesterase (BChE) is a promising target for the treatment of later stage cognitive decline in Alzheimer's disease. A set of pseudo-irreversible BChE inhibitors with high selectivity over hAChE was synthesized based on carbamates attached to tetrahydroquinazoline scaffolds with the 2-thiophenyl compound 2p as the most potent inhibitor of eqBChE (KC = 14.3 nM) and also of hBChE (KC = 19.7 nM). The inhibitors transfer the carbamate moiety onto the active site under release of the phenolic tetrahydroquinazoline scaffolds that themselves act as neuroprotectants. By combination of kinetic data with molecular docking studies, a plausible binding model was probed describing how the tetrahydroquinazoline scaffold guides the carbamate into a close position to the active site. The model explains the influence of the carrier scaffold onto the affinity of an inhibitor just before carbamate transfer. This strategy can be used to utilize the binding mode of other carbamate-based inhibitors.
|
Inhibition of human acetylcholinesterase using acetylcholine iodide as substrate preincubated for 30 mins followed by substrate addition measured after 2.5 mins by Ellman's spectrophotometric method
|
Homo sapiens
|
32.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of Highly Selective and Nanomolar Carbamate-Based Butyrylcholinesterase Inhibitors by Rational Investigation into Their Inhibition Mode.
Year : 2016
Volume : 59
Issue : 5
First Page : 2067
Last Page : 2082
Authors : Sawatzky E, Wehle S, Kling B, Wendrich J, Bringmann G, Sotriffer CA, Heilmann J, Decker M.
Abstract : Butyrylcholinesterase (BChE) is a promising target for the treatment of later stage cognitive decline in Alzheimer's disease. A set of pseudo-irreversible BChE inhibitors with high selectivity over hAChE was synthesized based on carbamates attached to tetrahydroquinazoline scaffolds with the 2-thiophenyl compound 2p as the most potent inhibitor of eqBChE (KC = 14.3 nM) and also of hBChE (KC = 19.7 nM). The inhibitors transfer the carbamate moiety onto the active site under release of the phenolic tetrahydroquinazoline scaffolds that themselves act as neuroprotectants. By combination of kinetic data with molecular docking studies, a plausible binding model was probed describing how the tetrahydroquinazoline scaffold guides the carbamate into a close position to the active site. The model explains the influence of the carrier scaffold onto the affinity of an inhibitor just before carbamate transfer. This strategy can be used to utilize the binding mode of other carbamate-based inhibitors.
|
Inhibition of equine serum BChE using S-butyrylthiocholine chloride as substrate incubated for 30 mins by Ellman's microplate assay
|
Equus caballus
|
220.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Natural cholinesterase inhibitors from Myristica cinnamomea King.
Year : 2016
Volume : 26
Issue : 15
First Page : 3785
Last Page : 3792
Authors : Abdul Wahab SM, Sivasothy Y, Liew SY, Litaudon M, Mohamad J, Awang K.
Abstract : A new acylphenol, malabaricone E (1) together with the known malabaricones A-C (2-4), maingayones A and B (5 and 6) and maingayic acid B (7) were isolated from the ethyl acetate extract of the fruits of Myristica cinnamomea King. Their structures were determined by 1D and 2D NMR techniques and LCMS-IT-TOF analysis. Compounds 3 (1.84±0.19 and 1.76±0.21μM, respectively) and 4 (1.94±0.27 and 2.80±0.49μM, respectively) were identified as dual inhibitors, with almost equal acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes inhibiting potentials. The Lineweaver-Burk plots of compounds 3 and 4 indicated that they were mixed-mode inhibitors. Based on the molecular docking studies, compounds 3 and 4 interacted with the peripheral anionic site (PAS), the catalytic triad and the oxyanion hole of the AChE. As for the BChE, while compound 3 interacted with the PAS, the catalytic triad and the oxyanion hole, compound 4 only interacted with the catalytic triad and the oxyanion hole.
|
Inhibition of AChE (unknown origin) using acetylthiocholine iodide as substrate incubated for 30 mins by Ellman's microplate assay
|
Homo sapiens
|
80.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Natural cholinesterase inhibitors from Myristica cinnamomea King.
Year : 2016
Volume : 26
Issue : 15
First Page : 3785
Last Page : 3792
Authors : Abdul Wahab SM, Sivasothy Y, Liew SY, Litaudon M, Mohamad J, Awang K.
Abstract : A new acylphenol, malabaricone E (1) together with the known malabaricones A-C (2-4), maingayones A and B (5 and 6) and maingayic acid B (7) were isolated from the ethyl acetate extract of the fruits of Myristica cinnamomea King. Their structures were determined by 1D and 2D NMR techniques and LCMS-IT-TOF analysis. Compounds 3 (1.84±0.19 and 1.76±0.21μM, respectively) and 4 (1.94±0.27 and 2.80±0.49μM, respectively) were identified as dual inhibitors, with almost equal acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes inhibiting potentials. The Lineweaver-Burk plots of compounds 3 and 4 indicated that they were mixed-mode inhibitors. Based on the molecular docking studies, compounds 3 and 4 interacted with the peripheral anionic site (PAS), the catalytic triad and the oxyanion hole of the AChE. As for the BChE, while compound 3 interacted with the PAS, the catalytic triad and the oxyanion hole, compound 4 only interacted with the catalytic triad and the oxyanion hole.
|
Inhibition of electric eel AChE preincubated for 15 mins followed by addition of acetylthiocholine iodide as substrate measured after 30 mins by Ellman's microplate assay
|
Electrophorus electricus
|
160.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Cholinesterase inhibitory activity of isoquinoline alkaloids from three Cryptocarya species (Lauraceae).
Year : 2016
Volume : 24
Issue : 18
First Page : 4464
Last Page : 4469
Authors : Wan Othman WN, Liew SY, Khaw KY, Murugaiyah V, Litaudon M, Awang K.
Abstract : Alzheimer's disease is the most common form of dementia among older adults. Acetylcholinesterase and butyrylcholinesterase are two enzymes involved in the breaking down of the neurotransmitter acetylcholine. Inhibitors for these enzymes have potential to prolong the availability of acetylcholine. Hence, the search for such inhibitors especially from natural products is needed in developing potential drugs for Alzheimer's disease. The present study investigates the cholinesterase inhibitory activity of compounds isolated from three Cryptocarya species towards acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Nine alkaloids were isolated; (+)-nornantenine 1, (-)-desmethylsecoantofine 2, (+)-oridine 3, (+)-laurotetanine 4 from the leaves of Cryptocarya densiflora BI., atherosperminine 5, (+)-N-methylisococlaurine 6, (+)-N-methyllaurotetanine 7 from the bark of Cryptocarya infectoria Miq., 2-methoxyatherosperminine 8 and (+)-reticuline 9 from the bark of Cryptocarya griffithiana Wight. In general, most of the alkaloids showed higher inhibition towards BChE as compared to AChE. The phenanthrene type alkaloid; 2-methoxyatherosperminine 8, exhibited the most potent inhibition against BChE with IC50 value of 3.95μM. Analysis of the Lineweaver-Burk (LB) plot of BChE activity over a range of substrate concentration suggested that 2-methoxyatherosperminine 8 exhibited mixed-mode inhibition with an inhibition constant (Ki) of 6.72μM. Molecular docking studies revealed that 2-methoxyatherosperminine 8 docked well at the choline binding site and catalytic triad of hBChE (butyrylcholinesterase from Homo sapiens); hydrogen bonding with Tyr 128 and His 438 residues respectively.
|
Inhibition of equine serum BChE preincubated for 15 mins followed by addition of S-butyrylthiocholine chloride as substrate measured after 30 mins by Ellman's microplate assay
|
Equus caballus
|
580.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Cholinesterase inhibitory activity of isoquinoline alkaloids from three Cryptocarya species (Lauraceae).
Year : 2016
Volume : 24
Issue : 18
First Page : 4464
Last Page : 4469
Authors : Wan Othman WN, Liew SY, Khaw KY, Murugaiyah V, Litaudon M, Awang K.
Abstract : Alzheimer's disease is the most common form of dementia among older adults. Acetylcholinesterase and butyrylcholinesterase are two enzymes involved in the breaking down of the neurotransmitter acetylcholine. Inhibitors for these enzymes have potential to prolong the availability of acetylcholine. Hence, the search for such inhibitors especially from natural products is needed in developing potential drugs for Alzheimer's disease. The present study investigates the cholinesterase inhibitory activity of compounds isolated from three Cryptocarya species towards acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Nine alkaloids were isolated; (+)-nornantenine 1, (-)-desmethylsecoantofine 2, (+)-oridine 3, (+)-laurotetanine 4 from the leaves of Cryptocarya densiflora BI., atherosperminine 5, (+)-N-methylisococlaurine 6, (+)-N-methyllaurotetanine 7 from the bark of Cryptocarya infectoria Miq., 2-methoxyatherosperminine 8 and (+)-reticuline 9 from the bark of Cryptocarya griffithiana Wight. In general, most of the alkaloids showed higher inhibition towards BChE as compared to AChE. The phenanthrene type alkaloid; 2-methoxyatherosperminine 8, exhibited the most potent inhibition against BChE with IC50 value of 3.95μM. Analysis of the Lineweaver-Burk (LB) plot of BChE activity over a range of substrate concentration suggested that 2-methoxyatherosperminine 8 exhibited mixed-mode inhibition with an inhibition constant (Ki) of 6.72μM. Molecular docking studies revealed that 2-methoxyatherosperminine 8 docked well at the choline binding site and catalytic triad of hBChE (butyrylcholinesterase from Homo sapiens); hydrogen bonding with Tyr 128 and His 438 residues respectively.
|
Inhibition of electric eel AChE using acetylthiocholine iodide as substrate preincubated for 10 mins followed by substrate addition measured after 30 mins by Ellman's method
|
Electrophorus electricus
|
40.0
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis of novel 5-(aroylhydrazinocarbonyl)escitalopram as cholinesterase inhibitors.
Year : 2017
Volume : 138
First Page : 396
Last Page : 406
Authors : Nisa MU, Munawar MA, Iqbal A, Ahmed A, Ashraf M, Gardener QA, Khan MA.
Abstract : A novel series of 5-(aroylhydrazinocarbonyl)escitalopram (58-84) have been designed, synthesized and tested for their inhibitory potential against cholinesterases. 3-Chlorobenzoyl- (71) was found to be the most potent compound of this series having IC50 1.80 ± 0.11 μM for acetylcholinesterase (AChE) inhibition. For the butyrylcholinesterase (BChE) inhibition, 2-bromobenzoyl- (76) was the most active compound of the series with IC50 2.11 ± 0.31 μM. Structure-activity relationship illustrated that mild electron donating groups enhanced enzyme inhibition while electron withdrawing groups reduced the inhibition except o-NO2. However, size and position of the substituents affected enzyme inhibitions. . In docking study of AChE, the ligands 71, 72 and 76 showed the scores of 5874, 5756 and 5666 and ACE of -64.92,-203.25 and -140.29 kcal/mol, respectively. In case of BChE, ligands 71, 76 and 81 depicted high scores 6016, 6150 and 5994 with ACE values -170.91, -256.84 and -235.97 kcal/mol, respectively.
|
Inhibition of equine serum BCHE using butyrylthiocholine iodide as substrate preincubated for 10 mins followed by substrate addition measured after 30 mins by Ellman's method
|
Equus caballus
|
850.0
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis of novel 5-(aroylhydrazinocarbonyl)escitalopram as cholinesterase inhibitors.
Year : 2017
Volume : 138
First Page : 396
Last Page : 406
Authors : Nisa MU, Munawar MA, Iqbal A, Ahmed A, Ashraf M, Gardener QA, Khan MA.
Abstract : A novel series of 5-(aroylhydrazinocarbonyl)escitalopram (58-84) have been designed, synthesized and tested for their inhibitory potential against cholinesterases. 3-Chlorobenzoyl- (71) was found to be the most potent compound of this series having IC50 1.80 ± 0.11 μM for acetylcholinesterase (AChE) inhibition. For the butyrylcholinesterase (BChE) inhibition, 2-bromobenzoyl- (76) was the most active compound of the series with IC50 2.11 ± 0.31 μM. Structure-activity relationship illustrated that mild electron donating groups enhanced enzyme inhibition while electron withdrawing groups reduced the inhibition except o-NO2. However, size and position of the substituents affected enzyme inhibitions. . In docking study of AChE, the ligands 71, 72 and 76 showed the scores of 5874, 5756 and 5666 and ACE of -64.92,-203.25 and -140.29 kcal/mol, respectively. In case of BChE, ligands 71, 76 and 81 depicted high scores 6016, 6150 and 5994 with ACE values -170.91, -256.84 and -235.97 kcal/mol, respectively.
|
Inhibition of electric eel AChE at 0.5 mM using acetylthiocholine iodide as substrate preincubated for 10 mins followed by substrate addition measured after 30 mins by Ellman's method relative to control
|
Electrophorus electricus
|
91.27
%
|
|
Journal : Eur J Med Chem
Title : Synthesis of novel 5-(aroylhydrazinocarbonyl)escitalopram as cholinesterase inhibitors.
Year : 2017
Volume : 138
First Page : 396
Last Page : 406
Authors : Nisa MU, Munawar MA, Iqbal A, Ahmed A, Ashraf M, Gardener QA, Khan MA.
Abstract : A novel series of 5-(aroylhydrazinocarbonyl)escitalopram (58-84) have been designed, synthesized and tested for their inhibitory potential against cholinesterases. 3-Chlorobenzoyl- (71) was found to be the most potent compound of this series having IC50 1.80 ± 0.11 μM for acetylcholinesterase (AChE) inhibition. For the butyrylcholinesterase (BChE) inhibition, 2-bromobenzoyl- (76) was the most active compound of the series with IC50 2.11 ± 0.31 μM. Structure-activity relationship illustrated that mild electron donating groups enhanced enzyme inhibition while electron withdrawing groups reduced the inhibition except o-NO2. However, size and position of the substituents affected enzyme inhibitions. . In docking study of AChE, the ligands 71, 72 and 76 showed the scores of 5874, 5756 and 5666 and ACE of -64.92,-203.25 and -140.29 kcal/mol, respectively. In case of BChE, ligands 71, 76 and 81 depicted high scores 6016, 6150 and 5994 with ACE values -170.91, -256.84 and -235.97 kcal/mol, respectively.
|
Inhibition of equine serum BCHE at 0.5 mM using butyrylthiocholine iodide as substrate preincubated for 10 mins followed by substrate addition measured after 30 mins by Ellman's method relative to control
|
Equus caballus
|
82.82
%
|
|
Journal : Eur J Med Chem
Title : Synthesis of novel 5-(aroylhydrazinocarbonyl)escitalopram as cholinesterase inhibitors.
Year : 2017
Volume : 138
First Page : 396
Last Page : 406
Authors : Nisa MU, Munawar MA, Iqbal A, Ahmed A, Ashraf M, Gardener QA, Khan MA.
Abstract : A novel series of 5-(aroylhydrazinocarbonyl)escitalopram (58-84) have been designed, synthesized and tested for their inhibitory potential against cholinesterases. 3-Chlorobenzoyl- (71) was found to be the most potent compound of this series having IC50 1.80 ± 0.11 μM for acetylcholinesterase (AChE) inhibition. For the butyrylcholinesterase (BChE) inhibition, 2-bromobenzoyl- (76) was the most active compound of the series with IC50 2.11 ± 0.31 μM. Structure-activity relationship illustrated that mild electron donating groups enhanced enzyme inhibition while electron withdrawing groups reduced the inhibition except o-NO2. However, size and position of the substituents affected enzyme inhibitions. . In docking study of AChE, the ligands 71, 72 and 76 showed the scores of 5874, 5756 and 5666 and ACE of -64.92,-203.25 and -140.29 kcal/mol, respectively. In case of BChE, ligands 71, 76 and 81 depicted high scores 6016, 6150 and 5994 with ACE values -170.91, -256.84 and -235.97 kcal/mol, respectively.
|
Inhibition of AChE (unknown origin)
|
Homo sapiens
|
220.0
nM
|
|
Journal : Bioorg Med Chem
Title : In silico studies, synthesis and pharmacological evaluation to explore multi-targeted approach for imidazole analogues as potential cholinesterase inhibitors with neuroprotective role for Alzheimer's disease.
Year : 2018
Volume : 26
Issue : 8
First Page : 1511
Last Page : 1522
Authors : Gurjar AS, Darekar MN, Yeong KY, Ooi L.
Abstract : Alzheimer's disease (AD) is a progressive neurodegenerative disorder with multiple factors associated with its pathogenesis. Our strategy against AD involves design of multi-targeted 2-substituted-4,5-diphenyl-1H-imidazole analogues which can interact and inhibit AChE, thereby, increasing the synaptic availability of ACh, inhibit BuChE, relieve induced oxidative stress and confer a neuroprotective role. Molecular docking was employed to study interactions within the AChE active site. In silico ADME study was performed to estimate pharmacokinetic parameters. Based on computational studies, some analogues were synthesized and subjected to pharmacological evaluation involving antioxidant activity, toxicity and memory model studies in animals followed by detailed mechanistic in vitro cholinesterase inhibition study. Amongst the series, analogue 13 and 20 are the most promising multi-targeted candidates which can potentially increase memory, decrease free radical levels and protect neurons against cognitive deficit.
|
Inhibition of BuChE (unknown origin) using butyrylthiocholine chloride as substrate preincubated for 15 mins followed by substrate addition measured after 30 mins by Ellman's method
|
Homo sapiens
|
850.0
nM
|
|
Journal : Eur J Med Chem
Title : Triazole derivatives as inhibitors of Alzheimer's disease: Current developments and structure-activity relationships.
Year : 2019
Volume : 180
First Page : 656
Last Page : 672
Authors : Xu M, Peng Y, Zhu L, Wang S, Ji J, Rakesh KP.
Abstract : Alzheimer's disease (AD) is a well known neurodegenerative disorder alarming millions of people worldwide and the subsequent epidemiological statistics highlights the implication of the disease. AD is a multi-factorial disease, a variety of single-target directed drugs that have reached clinical trials have unsuccessful. Hence, various factors associated without set of AD have been considered in targeted drug discovery and development. Triazoles are five-membered heterocyclic scaffold due to their broad range of biological activities. The present review focuses on the recent developments in the area of medicinal chemistry to explore the diverse chemical structures of potential inhibitors of Alzheimer's disease and also look at its structure-activity relationships (SAR) studies of bioactive compounds for future discovery of suitable drug candidates. The prominence has been given on the major advancements in the medicinal brochure of this pharmacophore for the period during 2012-2019.
|
Inhibition of Electrophorus electricus AChE using acetylthiocholine iodide as substrate preincubated for 30 mins followed by substrate addition and measured after 5 mins by Ellman's method
|
Electrophorus electricus
|
3.0
nM
|
|
Journal : J Nat Prod
Title : Labdanes, Withanolides, and Other Constituents from <i>Physalis nicandroides</i>.
Year : 2019
Volume : 82
Issue : 9
First Page : 2489
Last Page : 2500
Authors : Torres FR, Pérez-Castorena AL, Arredondo L, Toscano RA, Nieto-Camacho A, Martínez M, Maldonado E.
Abstract : Chemical investigation of the aerial parts (except fruits and calixes) of <i>Physalis nicandroides</i> var. <i>attenuata</i> led to the isolation of a series of new labdane-type diterpenoids, including the closely related compounds <b>1</b>-<b>3</b>, the labdane glucosides <b>4</b> and <b>5</b>, a mixture of the epimeric alcohols <b>6</b> and <b>7</b>, and one labdanetriol, isolated as its tri-<i>O</i>-acetyl derivative <b>9</b>. In addition, three new withanolides (<b>14</b>-<b>16</b>) and six known compounds were isolated. The structures of these compounds were elucidated by analysis of their spectroscopic data and chemical transformations, and those of compounds <b>1</b>, <b>4</b>, and <b>16</b> were confirmed by X-ray diffraction analysis of the natural product (<b>1</b>) and of the corresponding acetyl derivatives <b>4a</b> and <b>16a</b>. Fourteen of these compounds were assayed for their in vitro inhibitory activity against yeast α-glucosidase and acetylcholinesterase enzymes. The results were negative in both cases, except for compound <b>3a</b> that marginally inhibited the activity of acetylcholinesterase with an IC<sub>50</sub> value of 64.4 μM.
|
Inhibition of electric eel AChE at 50 uM incubated for 15 mins by Ellman's method relative to control
|
Electrophorus electricus
|
99.8
%
|
|
Journal : J Nat Prod
Title : Cholinesterase Inhibitory Arisugacins L-Q from a <i>Penicillium</i> sp. Isolate Obtained through a Citizen Science Initiative and Their Activities in a Phenotype-Based Zebrafish Assay.
Year : 2019
Volume : 82
Issue : 9
First Page : 2627
Last Page : 2637
Authors : Dai W, Sandoval IT, Cai S, Smith KA, Delacruz RGC, Boyd KA, Mills JJ, Jones DA, Cichewicz RH.
Abstract : Phenotype-based screening of a fungal extract library yielded an active sample from a <i>Penicillium</i> sp. isolate that impaired zebrafish motility. Bioassay-guided purification led to the identification of 14 meroterpenoids including six new metabolites, arisugacins L-Q (<b>4</b>, <b>5</b>, <b>8</b>, and <b>12</b>-<b>14</b>), seven known arisugacins (<b>1</b>-<b>3</b>, <b>6</b>, <b>7</b>, <b>9</b>, and <b>10</b>), and one known terreulactone (<b>11</b>). Their structures were determined using a combination of NMR and HRESIMS data, evidence secured from theoretical and experimental ECD spectra, and the modified Mosher's method. The purified compounds were tested in zebrafish embryos, as well as in vitro for cholinesterase inhibition activities. Compound <b>12</b> produced defects in myotome structure (metameric muscle, which is critical for locomotion) in vivo and showed the most potent and selective acetylcholinesterase inhibitory activity with an IC<sub>50</sub> of 191 nM in vitro. The phenotype assay was also used to reveal bioactivities for several previously reported arisugacins, which had failed to show activity in prior cell-based and in vitro testing. This study demonstrates that utilization of the zebrafish phenotype assay is an effective approach for the identification of bioactive extracts, is compatible with the bioassay-guided compound purification strategies, and offers a valuable tool for probing complex natural product sources to detect bioactive small molecules with potential therapeutic or other commercial applications.
|
Inhibition of equine serum BChE at 50 uM using S-butyrylthiocholine iodide as substrate incubated for 15 mins by Ellman's method relative to control
|
Equus caballus
|
93.2
%
|
|
Journal : J Nat Prod
Title : Cholinesterase Inhibitory Arisugacins L-Q from a <i>Penicillium</i> sp. Isolate Obtained through a Citizen Science Initiative and Their Activities in a Phenotype-Based Zebrafish Assay.
Year : 2019
Volume : 82
Issue : 9
First Page : 2627
Last Page : 2637
Authors : Dai W, Sandoval IT, Cai S, Smith KA, Delacruz RGC, Boyd KA, Mills JJ, Jones DA, Cichewicz RH.
Abstract : Phenotype-based screening of a fungal extract library yielded an active sample from a <i>Penicillium</i> sp. isolate that impaired zebrafish motility. Bioassay-guided purification led to the identification of 14 meroterpenoids including six new metabolites, arisugacins L-Q (<b>4</b>, <b>5</b>, <b>8</b>, and <b>12</b>-<b>14</b>), seven known arisugacins (<b>1</b>-<b>3</b>, <b>6</b>, <b>7</b>, <b>9</b>, and <b>10</b>), and one known terreulactone (<b>11</b>). Their structures were determined using a combination of NMR and HRESIMS data, evidence secured from theoretical and experimental ECD spectra, and the modified Mosher's method. The purified compounds were tested in zebrafish embryos, as well as in vitro for cholinesterase inhibition activities. Compound <b>12</b> produced defects in myotome structure (metameric muscle, which is critical for locomotion) in vivo and showed the most potent and selective acetylcholinesterase inhibitory activity with an IC<sub>50</sub> of 191 nM in vitro. The phenotype assay was also used to reveal bioactivities for several previously reported arisugacins, which had failed to show activity in prior cell-based and in vitro testing. This study demonstrates that utilization of the zebrafish phenotype assay is an effective approach for the identification of bioactive extracts, is compatible with the bioassay-guided compound purification strategies, and offers a valuable tool for probing complex natural product sources to detect bioactive small molecules with potential therapeutic or other commercial applications.
|
Inhibition of electric eel AChE incubated for 15 mins by Ellman's method
|
Electrophorus electricus
|
7.8
nM
|
|
Journal : J Nat Prod
Title : Cholinesterase Inhibitory Arisugacins L-Q from a <i>Penicillium</i> sp. Isolate Obtained through a Citizen Science Initiative and Their Activities in a Phenotype-Based Zebrafish Assay.
Year : 2019
Volume : 82
Issue : 9
First Page : 2627
Last Page : 2637
Authors : Dai W, Sandoval IT, Cai S, Smith KA, Delacruz RGC, Boyd KA, Mills JJ, Jones DA, Cichewicz RH.
Abstract : Phenotype-based screening of a fungal extract library yielded an active sample from a <i>Penicillium</i> sp. isolate that impaired zebrafish motility. Bioassay-guided purification led to the identification of 14 meroterpenoids including six new metabolites, arisugacins L-Q (<b>4</b>, <b>5</b>, <b>8</b>, and <b>12</b>-<b>14</b>), seven known arisugacins (<b>1</b>-<b>3</b>, <b>6</b>, <b>7</b>, <b>9</b>, and <b>10</b>), and one known terreulactone (<b>11</b>). Their structures were determined using a combination of NMR and HRESIMS data, evidence secured from theoretical and experimental ECD spectra, and the modified Mosher's method. The purified compounds were tested in zebrafish embryos, as well as in vitro for cholinesterase inhibition activities. Compound <b>12</b> produced defects in myotome structure (metameric muscle, which is critical for locomotion) in vivo and showed the most potent and selective acetylcholinesterase inhibitory activity with an IC<sub>50</sub> of 191 nM in vitro. The phenotype assay was also used to reveal bioactivities for several previously reported arisugacins, which had failed to show activity in prior cell-based and in vitro testing. This study demonstrates that utilization of the zebrafish phenotype assay is an effective approach for the identification of bioactive extracts, is compatible with the bioassay-guided compound purification strategies, and offers a valuable tool for probing complex natural product sources to detect bioactive small molecules with potential therapeutic or other commercial applications.
|
Inhibition of acetylcholinesterase (unknown origin) using acetylthiocholine as substrate preincubated for 30 mins followed by substrate addition and measured after 2 mins by Ellman's method
|
Homo sapiens
|
538.0
nM
|
|
Journal : J Nat Prod
Title : Furofuranone Lignans from <i>Leucophyllum ambiguum</i>.
Year : 2020
Volume : 83
Issue : 5
First Page : 1424
Last Page : 1431
Authors : Rios MY, Ocampo-Acuña YD, Ramírez-Cisneros MÁ, Salazar-Rios ME.
Abstract : Eight furofuranone lignans with an <i>endo</i>,<i>endo</i> relationship between the oxygen atoms, an <i>exo</i>,<i>exo</i> relationship between the aryl groups, and a chair,chair conformation (<b>1</b>-<b>4</b> and <b>6</b>-<b>9</b>), in addition to the α-amino acid (3<i>S</i>)-hydroxy-3',4'-dimethoxy-L-phenylalanine (<b>5</b>), veratric acid (<b>10</b>), and β-sitosterol (<b>11</b>), were isolated from the powdered and defatted air-dried aerial parts of <i>Leucophyllum ambiguum</i>. Four of these lignans, ciquitins A-D, <b>1</b>-<b>4</b>, were isolated for the first time as natural products. The structures of these compounds were established based on their spectrometric/spectroscopic data. Additionally, single-crystal X-ray crystallography confirmed the structure of ciquitin A (<b>1</b>), and derivatization with (9<i>S</i>)-naproxen and X-ray diffraction crystallography data established its absolute configuration. Ciquitins A (<b>1</b>) and B (<b>2</b>) possess a 9-hydroxy group; this chemical characteristic grants these species conformational isomerism not seen in the other six lignans. The conformers of <b>1</b> and <b>2</b> are distinguishable via their <sup>1</sup>H and <sup>13</sup>C NMR spectroscopic data. This is the first report of this phenomenon, and hence, a complete assignment of the signals in both spectra of each conformer for each compound is presented. Compounds <b>1</b>-<b>9</b> were found to exhibit potent inhibitory activity in the 1.0 × 10<sup>-3</sup> to 2.2 μM range against acetylcholinesterase, an enzyme directly involved in the etiology of Alzheimer's disease and senile dementia. Thus, these natural products are promising agents that are potentially useful for the treatment of neurological degeneration.
|
Inhibition of human AChE using acetylthiocholine iodide as substrate measured for 1 min by spectrophotometric based Ellman's method
|
Homo sapiens
|
63.0
nM
|
|
Journal : J Nat Prod
Title : Aromatic Esters of the Crinane Amaryllidaceae Alkaloid Ambelline as Selective Inhibitors of Butyrylcholinesterase.
Year : 2020
Volume : 83
Issue : 5
First Page : 1359
Last Page : 1367
Authors : Maříková J, Ritomská A, Korábečný J, Peřinová R, Al Mamun A, Kučera T, Kohelová E, Hulcová D, Kobrlová T, Kuneš J, Nováková L, Cahlíková L.
Abstract : A total of 20 derivatives (<b>1</b>-<b>20</b>) of the crinane-type alkaloid ambelline were synthesized. These semisynthetic derivatives were assessed for their potency to inhibit both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). To predict central nervous system (CNS) availability, logBB was calculated, and the data correlated well with those obtained from the parallel artificial membrane permeability assay (PAMPA). All compounds should be able to permeate the blood-brain barrier (BBB) according to the obtained results. A total of 7 aromatic derivatives (<b>5</b>, <b>6</b>, <b>7</b>, <b>9</b>, <b>10, 12</b>, and <b>16</b>) with different substitution patterns showed inhibitory potency against human serum BuChE (IC<sub>50</sub> < 5 μM), highlighting the three top-ranked compounds as follows: 11-<i>O</i>-(1-naphthoyl)ambelline (<b>16</b>), 11-<i>O</i>-(2-methylbenzoyl)ambelline (<b>6</b>), and 11-<i>O</i>-(2-methoxybenzoyl)ambelline (<b>9</b>) with IC<sub>50</sub> values of 0.10 ± 0.01, 0.28 ± 0.02, and 0.43 ± 0.04 μM, respectively. Notably, derivatives <b>6</b>, <b>7</b>, <b>9</b>, and <b>16</b> displayed selective human BuChE (<i>h</i>BuChE) inhibition profiles with a selectivity index > 100. The in vitro results were supported by computational studies predicting plausible binding modes of the compounds in the active sites of <i>h</i>BuChE.
|
Inhibition of human BuChE using butyrylthiocholine iodide as substrate measured for 1 min by spectrophotometric based Ellman's method
|
Homo sapiens
|
130.0
nM
|
|
Journal : J Nat Prod
Title : Aromatic Esters of the Crinane Amaryllidaceae Alkaloid Ambelline as Selective Inhibitors of Butyrylcholinesterase.
Year : 2020
Volume : 83
Issue : 5
First Page : 1359
Last Page : 1367
Authors : Maříková J, Ritomská A, Korábečný J, Peřinová R, Al Mamun A, Kučera T, Kohelová E, Hulcová D, Kobrlová T, Kuneš J, Nováková L, Cahlíková L.
Abstract : A total of 20 derivatives (<b>1</b>-<b>20</b>) of the crinane-type alkaloid ambelline were synthesized. These semisynthetic derivatives were assessed for their potency to inhibit both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). To predict central nervous system (CNS) availability, logBB was calculated, and the data correlated well with those obtained from the parallel artificial membrane permeability assay (PAMPA). All compounds should be able to permeate the blood-brain barrier (BBB) according to the obtained results. A total of 7 aromatic derivatives (<b>5</b>, <b>6</b>, <b>7</b>, <b>9</b>, <b>10, 12</b>, and <b>16</b>) with different substitution patterns showed inhibitory potency against human serum BuChE (IC<sub>50</sub> < 5 μM), highlighting the three top-ranked compounds as follows: 11-<i>O</i>-(1-naphthoyl)ambelline (<b>16</b>), 11-<i>O</i>-(2-methylbenzoyl)ambelline (<b>6</b>), and 11-<i>O</i>-(2-methoxybenzoyl)ambelline (<b>9</b>) with IC<sub>50</sub> values of 0.10 ± 0.01, 0.28 ± 0.02, and 0.43 ± 0.04 μM, respectively. Notably, derivatives <b>6</b>, <b>7</b>, <b>9</b>, and <b>16</b> displayed selective human BuChE (<i>h</i>BuChE) inhibition profiles with a selectivity index > 100. The in vitro results were supported by computational studies predicting plausible binding modes of the compounds in the active sites of <i>h</i>BuChE.
|
Inhibition of electric eel acetylcholinesterase using acetylthiocholine iodide as substrate at 10 mg/ml by Ellman's method relative to control
|
Electrophorus electricus
|
98.0
%
|
|
Journal : Bioorg Med Chem
Title : Pyridine alkaloids with activity in the central nervous system.
Year : 2020
Volume : 28
Issue : 24
First Page : 115820
Last Page : 115820
Authors : Lin SX,Curtis MA,Sperry J
Abstract : This review discusses all pyridine alkaloids with CNS activity, their therapeutic potential, and the interesting array of sources whence they originate.
|
Inhibition of human erythrocytes AChE using acetylthiocholine iodide as substrate measured after 30 mins by Ellman's method
|
Homo sapiens
|
80.0
nM
|
|
Journal : Eur J Med Chem
Title : Neuroprotective effects of prenylated flavanones isolated from Dalea species, in vitro and in silico studies.
Year : 2020
Volume : 206
First Page : 112718
Last Page : 112718
Authors : Santi MD,Arredondo F,Carvalho D,Echeverry C,Prunell G,Peralta MA,Cabrera JL,Ortega MG,Savio E,Abin-Carriquiry JA
Abstract : Neurodegenerative diseases (NDs) represent a global problem on public health, with a growing incidence as human longevity increases. Currently, although there are palliative strategies available for most of these diseases, there is a lack of effective therapies for their cure. Flavonoids are extensively studied for their multi-target behavior. Among numerous biological activities, it has been reported that they act at the CNS level, presenting neuroprotective activity through different mechanisms of action. Dalea L. (Fabaceae) is an American genus, with about 172 species. Dalea elegans Gillies ex. Hook. & Arn and Dalea pazensis Rusby, both South American species, are the important source of natural compounds of the prenylated flavanones type. In the present study, five prenylated flavanones isolated from Dalea species were assayed for their neuroprotective activity in two in vitro models of neurodegeneration. Flavanones 1 and 2 exhibited neuroprotective effects against oxidative stress-induced death in both models, granular cerebellar neurons and (NGF)-differentiated PC12 cells. Structure-activity relationships were also reported. Our results indicated that an 8-prenyl group at the A-ring accompanied by an unsubstituted B-ring, or a 2',4'-dihydroxy-5'-dimethylallyl substitution, lead to the most potent flavanones. Furthermore, in silico studies were performed, and several putative targets in NDs were identified for compounds 1 and 2. Between them, the enzyme acetylcholinesterase was selected for its validation in vitro. The present in vitro and in silico results imply that prenylated flavanones 1 and 2 may be useful in the development and design of future strategies for the treatment of NDs diseases.
|
Inhibition of human AChE using acetylthiocholine as substrate by Ellman's method
|
Homo sapiens
|
200.0
nM
|
|
|
Inhibition of human BuChE at 100 uM using butyrylthiocholine chloride as substrate by Ellman's method
|
Homo sapiens
|
99.9
%
|
|
|
Inhibition of human BuChE using butyrylthiocholine chloride as substrate by Ellman's method
|
Homo sapiens
|
300.0
nM
|
|
|
Inhibition of AChE (unknown origin)
|
Homo sapiens
|
16.0
nM
|
|
|
Inhibition of BuChE (unknown origin)
|
Homo sapiens
|
16.0
nM
|
|
