|
In vitro inhibitory concentration against purified Acetylcholinesterase of human erythrocytes; value ranges from 0.74-1.2
|
None
|
920.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel dual inhibitors of AChE and MAO derived from hydroxy aminoindan and phenethylamine as potential treatment for Alzheimer's disease.
Year : 2002
Volume : 45
Issue : 24
First Page : 5260
Last Page : 5279
Authors : Sterling J, Herzig Y, Goren T, Finkelstein N, Lerner D, Goldenberg W, Miskolczi I, Molnar S, Rantal F, Tamas T, Toth G, Zagyva A, Zekany A, Finberg J, Lavian G, Gross A, Friedman R, Razin M, Huang W, Krais B, Chorev M, Youdim MB, Weinstock M.
Abstract : Carbamate derivatives of N-propargylaminoindans (Series I) and N-propargylphenethylamines (Series II) were synthesized via multistep procedures from the corresponding hydroxy precursors. The respective rasagiline- and selegiline-related series were designed to combine inhibitory activities of both acetylcholine esterase (AChE) and monoamine oxidase (MAO) by virtue of their carbamoyl and propargylamine pharmacophores. Each compound was tested for these activities in vitro in order to find molecules with similar potencies against each enzyme. Compounds with such dual AChE and MAO inhibitory activities are expected to have potential for the treatment of Alzheimer's disease. The observed SAR also offers insight into the requirements of the active sites on these enzymes. A carbamate moiety was found to be essential for AChE inhibition, which was absent in the corresponding hydroxy precursors. The propargyl group caused 2-70-fold decrease in AChE inhibitory activity (depending on the position of the carbamoyl group) of Series I, but had little or no effect in Series II. Thus, the 6- and 7-carbamyloxyphenyls in Series I were either equipotent to, or slightly (2- to 5-fold) less active as AChE inhibitors than, the corresponding compounds in Series II, while the 4-carbamyloxyphenyls were more potent. The presence of the carbamate moiety in 6- and 7-carbamyloxyphenyls of Series I, considerably decreased MAO-A and -B inhibitory activity, compared to that of the parent hydroxy analogues, while the opposite was true for Series II. Thus, the 6- and 7-carbamyloxyphenyls in Series I were 2-3 orders of magnitude weaker MAO inhibitors while the 4- carbamyloxyphenyls were equipotent with the corresponding compounds in Series II. In both series, N-methylation of the propargylamine enhanced the MAO (A and B equally) inhibitory activities and decreased the AChE inhibitory activity. Two candidates belonging to the indan and tetralin ring systems (24c, 27b) and one phenethylamine (53d) were identified as possible leads for further development based on the following criteria: (a) comparable AChE and MAO-B inhibitory activities, (b) good to moderate AChE inhibitory activity, and (c) lack of strong MAO-A selectivity. However, it is likely that these compounds will be metabolized to the corresponding phenols, with inhibitory activities against AChE and/or MAO-A or -B, different from those of the parent carbamates. Thus, the apparent enzyme inhibition will be a result of the combined inhibition of all of these individual metabolites. The results of our ongoing in vivo screening programs will be published elsewhere.
|
In vitro inhibitory concentration against Butyrylcholinesterase of horse serum; value ranges from 0.81-0.86
|
Equus caballus
|
830.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel dual inhibitors of AChE and MAO derived from hydroxy aminoindan and phenethylamine as potential treatment for Alzheimer's disease.
Year : 2002
Volume : 45
Issue : 24
First Page : 5260
Last Page : 5279
Authors : Sterling J, Herzig Y, Goren T, Finkelstein N, Lerner D, Goldenberg W, Miskolczi I, Molnar S, Rantal F, Tamas T, Toth G, Zagyva A, Zekany A, Finberg J, Lavian G, Gross A, Friedman R, Razin M, Huang W, Krais B, Chorev M, Youdim MB, Weinstock M.
Abstract : Carbamate derivatives of N-propargylaminoindans (Series I) and N-propargylphenethylamines (Series II) were synthesized via multistep procedures from the corresponding hydroxy precursors. The respective rasagiline- and selegiline-related series were designed to combine inhibitory activities of both acetylcholine esterase (AChE) and monoamine oxidase (MAO) by virtue of their carbamoyl and propargylamine pharmacophores. Each compound was tested for these activities in vitro in order to find molecules with similar potencies against each enzyme. Compounds with such dual AChE and MAO inhibitory activities are expected to have potential for the treatment of Alzheimer's disease. The observed SAR also offers insight into the requirements of the active sites on these enzymes. A carbamate moiety was found to be essential for AChE inhibition, which was absent in the corresponding hydroxy precursors. The propargyl group caused 2-70-fold decrease in AChE inhibitory activity (depending on the position of the carbamoyl group) of Series I, but had little or no effect in Series II. Thus, the 6- and 7-carbamyloxyphenyls in Series I were either equipotent to, or slightly (2- to 5-fold) less active as AChE inhibitors than, the corresponding compounds in Series II, while the 4-carbamyloxyphenyls were more potent. The presence of the carbamate moiety in 6- and 7-carbamyloxyphenyls of Series I, considerably decreased MAO-A and -B inhibitory activity, compared to that of the parent hydroxy analogues, while the opposite was true for Series II. Thus, the 6- and 7-carbamyloxyphenyls in Series I were 2-3 orders of magnitude weaker MAO inhibitors while the 4- carbamyloxyphenyls were equipotent with the corresponding compounds in Series II. In both series, N-methylation of the propargylamine enhanced the MAO (A and B equally) inhibitory activities and decreased the AChE inhibitory activity. Two candidates belonging to the indan and tetralin ring systems (24c, 27b) and one phenethylamine (53d) were identified as possible leads for further development based on the following criteria: (a) comparable AChE and MAO-B inhibitory activities, (b) good to moderate AChE inhibitory activity, and (c) lack of strong MAO-A selectivity. However, it is likely that these compounds will be metabolized to the corresponding phenols, with inhibitory activities against AChE and/or MAO-A or -B, different from those of the parent carbamates. Thus, the apparent enzyme inhibition will be a result of the combined inhibition of all of these individual metabolites. The results of our ongoing in vivo screening programs will be published elsewhere.
|
Ex vivo inhibition of human plasma Butyrylcholinesterase.
|
None
|
37.0
nM
|
|
Journal : J. Med. Chem.
Title : Anticholinesterase activity of compounds related to geneserine tautomers. N-Oxides and 1,2-oxazines.
Year : 2002
Volume : 45
Issue : 17
First Page : 3684
Last Page : 3691
Authors : Yu QS, Zhu X, Holloway HW, Whittaker NF, Brossi A, Greig NH.
Abstract : A series of phenylcarbamate analogues of geneserine (8, 10, 12, 14) were synthesized from their counterparts, the phenylcarbamate analogues of physostigmine (2-5), by oxidation. The geneserine analogues can undergo tautomerism between N-oxide and 1,2-oxazine structures in a pH- and time-dependent manner. Assessment by (1)H NMR indicated that the N-oxide structure is adopted at neutral pH and that the compound exists in an equilibrium between several epimers. Evaluation of their biological action to inhibit human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), ex vivo, demonstrated that the N-oxide (7, 9, 11, 13, 15) and 1,2-oxazine (6, 8, 10, 12, 14) structures possessed similar potencies against AChE, but the latter structures were more potent against BChE. With the exception of the BChE selective inhibitor, 12, none of the geneserine analogues were as potent or enzyme subtype selective as their physostigmine analogue counterparts.
|
Inhibitory concentration against human serum butyrylcholinesterase activity
|
Homo sapiens
|
301.0
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and biological evaluation of conformationally restricted rivastigmine analogues.
Year : 2004
Volume : 47
Issue : 24
First Page : 5945
Last Page : 5952
Authors : Bolognesi ML, Bartolini M, Cavalli A, Andrisano V, Rosini M, Minarini A, Melchiorre C.
Abstract : Rivastigmine (1), an acetylcholinesterase (AChE) inhibitor approved in 2000 for the treatment of Alzheimer disease, bears a carbamate moiety in its structure, which is able to react covalently with the active site of the enzyme. Kinetic and structural studies on the interaction of 1 with different cholinesterases have been published, giving deeper, but not definitive, insights on the catalysis mechanism. On the basis of these findings and in connection with our previous studies on a series of benzopyrano[4,3-b]pyrrole carbamates as AChE inhibitors, we designed a series of conformationally restricted analogues of 1 by including the dimethylamino-alpha-methylbenzyl moiety in different tricyclic systems. A superimposition between the conformation of 1 and the carbon derivative 4, as obtained from Monte Carlo simulations, supported the idea that the tricyclic derivatives might act as rigid analogues of 1. The biological profile of 4-9, assessed in vitro against human AChE and BChE, validated our rational design. Compound 5, bearing a sulfur-containing system, showed the highest inhibitory activity, being 192-fold more potent than 1. In the present study, the most potent inhibitors were always methyl derivatives 3-5, endowed with a nanomolar range potency, whereas the ethyl ones were 40 times less potent. A reasonable explanation for this finding might be a steric hindrance effect between the ethyl group of 1 and His440 in the active site, as already suggested by the crystal structure of the complex AChE/1. The unfavorable influence of the carbamic N-alkyl chain on AChE inhibition is less striking when considering BChE inhibition, since BChE is characterized by a bigger acyl binding pocket than AChE. In fact, methyl carbamates 3-5 did not show AChE/BChE selectivity, whereas compounds 6-9 were significantly more potent in inhibiting BChE than AChE activity. At 100 microM, 5 was found to inhibit the AChE-induced aggregation only by 19% likely because it is not able to strongly interact with the peripheral anionic site of AChE, which plays an essential role in the Abeta aggregation mediated by the enzyme but is lacking in BChE structure.
|
Inhibitory concentration against human plasma Butyrylcholinesterase
|
Homo sapiens
|
37.0
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.
|
In vitro inhibitory concentration against butyrylcholinesterase was determined using rat serum homogenate
|
Rattus norvegicus
|
350.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis, and evaluation of 2-phenoxy-indan-1-one derivatives as acetylcholinesterase inhibitors.
Year : 2005
Volume : 15
Issue : 17
First Page : 3834
Last Page : 3837
Authors : Sheng R, Lin X, Li J, Jiang Y, Shang Z, Hu Y.
Abstract : A series of 2-phenoxy-indan-1-one derivatives have been designed, synthesized, and tested as acetylcholinesterase inhibitors. The most potent compound exhibited high AChE inhibitory activity (IC50 = 50 nM), and the molecular docking study indicated that it was nicely accommodated by AChE.
|
Anticholinesterase activity against human plasma BChE
|
Homo sapiens
|
37.0
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 human recombinant butyrylcholinesterase
|
Homo sapiens
|
30.1
nM
|
|
Journal : J. Med. Chem.
Title : Novel class of quinone-bearing polyamines as multi-target-directed ligands to combat Alzheimer's disease.
Year : 2007
Volume : 50
Issue : 20
First Page : 4882
Last Page : 4897
Authors : Bolognesi ML, Banzi R, Bartolini M, Cavalli A, Tarozzi A, Andrisano V, Minarini A, Rosini M, Tumiatti V, Bergamini C, Fato R, Lenaz G, Hrelia P, Cattaneo A, Recanatini M, Melchiorre C.
Abstract : One of the characteristics of Alzheimer's disease (AD) that hinders the discovery of effective disease-modifying therapies is the multifactorial nature of its etiopathology. To circumvent this drawback, the use of multi-target-directed ligands (MTDLs) has recently been proposed as a means of simultaneously hitting several targets involved in the development of the AD syndrome. In this paper, a new class of MTDLs based on a polyamine-quinone skeleton, whose lead (memoquin, 2) showed promising properties in preclinical investigations (Cavalli et al. Angew. Chem., Int. Ed. 2007, 46, 3689-3692), is described. 3-29 were tested in vitro against a number of isolated AD-related targets, namely, AChE and BChE, and Abeta aggregation (both AChE-mediated and self-induced). Furthermore, the ability of the compounds to counteract the oxidative stress in a human neuronal-like cellular system (SH-SY5Y cells) was assayed, in both the presence and absence of NQO1, an enzyme able to generate and maintain the reduced form of quinone.
|
Inhibition of human AChE-induced amyloid beta (1-40) aggregation at 100 uM
|
Homo sapiens
|
5.0
%
|
|
Journal : J. Med. Chem.
Title : Novel class of quinone-bearing polyamines as multi-target-directed ligands to combat Alzheimer's disease.
Year : 2007
Volume : 50
Issue : 20
First Page : 4882
Last Page : 4897
Authors : Bolognesi ML, Banzi R, Bartolini M, Cavalli A, Tarozzi A, Andrisano V, Minarini A, Rosini M, Tumiatti V, Bergamini C, Fato R, Lenaz G, Hrelia P, Cattaneo A, Recanatini M, Melchiorre C.
Abstract : One of the characteristics of Alzheimer's disease (AD) that hinders the discovery of effective disease-modifying therapies is the multifactorial nature of its etiopathology. To circumvent this drawback, the use of multi-target-directed ligands (MTDLs) has recently been proposed as a means of simultaneously hitting several targets involved in the development of the AD syndrome. In this paper, a new class of MTDLs based on a polyamine-quinone skeleton, whose lead (memoquin, 2) showed promising properties in preclinical investigations (Cavalli et al. Angew. Chem., Int. Ed. 2007, 46, 3689-3692), is described. 3-29 were tested in vitro against a number of isolated AD-related targets, namely, AChE and BChE, and Abeta aggregation (both AChE-mediated and self-induced). Furthermore, the ability of the compounds to counteract the oxidative stress in a human neuronal-like cellular system (SH-SY5Y cells) was assayed, in both the presence and absence of NQO1, an enzyme able to generate and maintain the reduced form of quinone.
|
Inhibition of self-induced amyloid beta (1-40) aggregation at 10 uM by thioflavin T based fluorometric assay
|
Homo sapiens
|
17.8
%
|
|
Journal : J. Med. Chem.
Title : Novel class of quinone-bearing polyamines as multi-target-directed ligands to combat Alzheimer's disease.
Year : 2007
Volume : 50
Issue : 20
First Page : 4882
Last Page : 4897
Authors : Bolognesi ML, Banzi R, Bartolini M, Cavalli A, Tarozzi A, Andrisano V, Minarini A, Rosini M, Tumiatti V, Bergamini C, Fato R, Lenaz G, Hrelia P, Cattaneo A, Recanatini M, Melchiorre C.
Abstract : One of the characteristics of Alzheimer's disease (AD) that hinders the discovery of effective disease-modifying therapies is the multifactorial nature of its etiopathology. To circumvent this drawback, the use of multi-target-directed ligands (MTDLs) has recently been proposed as a means of simultaneously hitting several targets involved in the development of the AD syndrome. In this paper, a new class of MTDLs based on a polyamine-quinone skeleton, whose lead (memoquin, 2) showed promising properties in preclinical investigations (Cavalli et al. Angew. Chem., Int. Ed. 2007, 46, 3689-3692), is described. 3-29 were tested in vitro against a number of isolated AD-related targets, namely, AChE and BChE, and Abeta aggregation (both AChE-mediated and self-induced). Furthermore, the ability of the compounds to counteract the oxidative stress in a human neuronal-like cellular system (SH-SY5Y cells) was assayed, in both the presence and absence of NQO1, an enzyme able to generate and maintain the reduced form of quinone.
|
Inhibition of human AchE
|
Homo sapiens
|
920.0
nM
|
|
Journal : J. Med. Chem.
Title : Multi-target-directed ligands to combat neurodegenerative diseases.
Year : 2008
Volume : 51
Issue : 3
First Page : 347
Last Page : 372
Authors : Cavalli A, Bolognesi ML, Minarini A, Rosini M, Tumiatti V, Recanatini M, Melchiorre C.
|
Inhibition of Torpedo californica AChE assessed as carbamylation
|
Torpedo californica
|
2.0
/min/M
|
|
Journal : J. Med. Chem.
Title : Exploiting protein fluctuations at the active-site gorge of human cholinesterases: further optimization of the design strategy to develop extremely potent inhibitors.
Year : 2008
Volume : 51
Issue : 11
First Page : 3154
Last Page : 3170
Authors : Butini S, Campiani G, Borriello M, Gemma S, Panico A, Persico M, Catalanotti B, Ros S, Brindisi M, Agnusdei M, Fiorini I, Nacci V, Novellino E, Belinskaya T, Saxena A, Fattorusso C.
Abstract : Protein conformational fluctuations are critical for biological functions, although the relationship between protein motion and function has yet to be fully explored. By a thorough bioinformatics analysis of cholinesterases (ChEs), we identified specific hot spots, responsible for protein fluctuations and functions, and those active-site residues that play a role in modulating the cooperative network among the key substructures. This drew the optimization of our design strategy to discover potent and reversible inhibitors of human acetylcholinesterase and butyrylcholinesterase (hAChE and hBuChE) that selectively interact with specific protein substructures. Accordingly, two tricyclic moieties differently spaced by functionalized linkers were investigated as molecular yardsticks to probe the finest interactions with specific hot spots in the hChE gorge. A number of SAR trends were identified, and the multisite inhibitors 3a and 3d were found to be the most potent inhibitors of hBuChE and hAChE known to date.
|
Inhibition of human serum BuchE after 20 mins by Ellman's method
|
Homo sapiens
|
300.0
nM
|
|
Journal : J. Med. Chem.
Title : Benzofuran-based hybrid compounds for the inhibition of cholinesterase activity, beta amyloid aggregation, and abeta neurotoxicity.
Year : 2008
Volume : 51
Issue : 10
First Page : 2883
Last Page : 2886
Authors : Rizzo S, Rivière C, Piazzi L, Bisi A, Gobbi S, Bartolini M, Andrisano V, Morroni F, Tarozzi A, Monti JP, Rampa A.
Abstract : The complex etiology of Alzheimer's disease (AD) prompts scientists to develop multitarget strategies to combat causes and symptoms. We therefore designed, synthesized, and tested new hybrid molecules linking a benzofuran ring to a N-methyl- N-benzylamine through a heptyloxy chain, affording a series of potential multifunctional drugs for AD. The cholinesterase inhibitory activity was extended to the inhibition of Abeta fibril formation for 1, 3, and 5. Compound 3 showed an additional neuroprotective effect.
|
Inhibition of BChE in human serum assessed as hydrolysis of butyrylthiocholine by Ellman's method
|
Homo sapiens
|
170.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis of novel purine nucleosides towards a selective inhibition of human butyrylcholinesterase.
Year : 2009
Volume : 17
Issue : 14
First Page : 5106
Last Page : 5116
Authors : Marcelo F, Silva FV, Goulart M, Justino J, Sinaÿ P, Blériot Y, Rauter AP.
Abstract : The search for new and potent cholinesterase inhibitors is an ongoing quest mobilizing many organic chemistry groups around the world as these molecules have been shown to treat the late symptoms of Alzheimer's disease as well as to act as neuroprotecting agents. In this work, we disclose the synthesis of novel 2-acetamidopurine nucleosides and, for the first time, regioselective N(7)-glycosylation with 2-acetamido-6-chloropurine, promoted by trimethylsilyl triflate, was accomplished by tuning the reaction conditions (acetonitrile as solvent, 65 degrees C, 5h) starting from 1-acetoxy bicyclic glycosyl donors, or by direct coupling of a methyl glucopyranoside with the nucleobase to obtain only N(7) nucleosides in reasonable yield (55-60%). The nucleosides as well as their sugar precursors were screened for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition. While none of the compounds tested inhibited AChE, remarkably, some of the N(7) nucleosides and sugar bicyclic derivatives showed potent inhibition towards BChE. Nanomolar inhibition was obtained for one compound competing well with rivastigmine, a drug currently in use for the treatment of Alzheimer's disease. Experimental results showed that the presence of benzyl groups on the carbohydrate scaffold and the N(7)-linked purine nucleobase were necessary for strong BChE inactivation. A preliminary evaluation of the acute cytotoxicity of the elongated bicyclic sugar precursors and nucleosides was performed indicating low values, in the same order of magnitude as those of rivastigmine.
|
Inhibition of BChE in human serum assessed as hydrolysis of butyrylthiocholine at 100 ug/mL by Ellman's method
|
Homo sapiens
|
100.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis of novel purine nucleosides towards a selective inhibition of human butyrylcholinesterase.
Year : 2009
Volume : 17
Issue : 14
First Page : 5106
Last Page : 5116
Authors : Marcelo F, Silva FV, Goulart M, Justino J, Sinaÿ P, Blériot Y, Rauter AP.
Abstract : The search for new and potent cholinesterase inhibitors is an ongoing quest mobilizing many organic chemistry groups around the world as these molecules have been shown to treat the late symptoms of Alzheimer's disease as well as to act as neuroprotecting agents. In this work, we disclose the synthesis of novel 2-acetamidopurine nucleosides and, for the first time, regioselective N(7)-glycosylation with 2-acetamido-6-chloropurine, promoted by trimethylsilyl triflate, was accomplished by tuning the reaction conditions (acetonitrile as solvent, 65 degrees C, 5h) starting from 1-acetoxy bicyclic glycosyl donors, or by direct coupling of a methyl glucopyranoside with the nucleobase to obtain only N(7) nucleosides in reasonable yield (55-60%). The nucleosides as well as their sugar precursors were screened for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition. While none of the compounds tested inhibited AChE, remarkably, some of the N(7) nucleosides and sugar bicyclic derivatives showed potent inhibition towards BChE. Nanomolar inhibition was obtained for one compound competing well with rivastigmine, a drug currently in use for the treatment of Alzheimer's disease. Experimental results showed that the presence of benzyl groups on the carbohydrate scaffold and the N(7)-linked purine nucleobase were necessary for strong BChE inactivation. A preliminary evaluation of the acute cytotoxicity of the elongated bicyclic sugar precursors and nucleosides was performed indicating low values, in the same order of magnitude as those of rivastigmine.
|
Inhibition of BChE in human serum assessed as hydrolysis of butyrylthiocholine at 10 ug/mL by Ellman's method
|
Homo sapiens
|
100.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis of novel purine nucleosides towards a selective inhibition of human butyrylcholinesterase.
Year : 2009
Volume : 17
Issue : 14
First Page : 5106
Last Page : 5116
Authors : Marcelo F, Silva FV, Goulart M, Justino J, Sinaÿ P, Blériot Y, Rauter AP.
Abstract : The search for new and potent cholinesterase inhibitors is an ongoing quest mobilizing many organic chemistry groups around the world as these molecules have been shown to treat the late symptoms of Alzheimer's disease as well as to act as neuroprotecting agents. In this work, we disclose the synthesis of novel 2-acetamidopurine nucleosides and, for the first time, regioselective N(7)-glycosylation with 2-acetamido-6-chloropurine, promoted by trimethylsilyl triflate, was accomplished by tuning the reaction conditions (acetonitrile as solvent, 65 degrees C, 5h) starting from 1-acetoxy bicyclic glycosyl donors, or by direct coupling of a methyl glucopyranoside with the nucleobase to obtain only N(7) nucleosides in reasonable yield (55-60%). The nucleosides as well as their sugar precursors were screened for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition. While none of the compounds tested inhibited AChE, remarkably, some of the N(7) nucleosides and sugar bicyclic derivatives showed potent inhibition towards BChE. Nanomolar inhibition was obtained for one compound competing well with rivastigmine, a drug currently in use for the treatment of Alzheimer's disease. Experimental results showed that the presence of benzyl groups on the carbohydrate scaffold and the N(7)-linked purine nucleobase were necessary for strong BChE inactivation. A preliminary evaluation of the acute cytotoxicity of the elongated bicyclic sugar precursors and nucleosides was performed indicating low values, in the same order of magnitude as those of rivastigmine.
|
Inhibition of BChE in human serum assessed as hydrolysis of butyrylthiocholine at 1 ug/mL by Ellman's method
|
Homo sapiens
|
100.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis of novel purine nucleosides towards a selective inhibition of human butyrylcholinesterase.
Year : 2009
Volume : 17
Issue : 14
First Page : 5106
Last Page : 5116
Authors : Marcelo F, Silva FV, Goulart M, Justino J, Sinaÿ P, Blériot Y, Rauter AP.
Abstract : The search for new and potent cholinesterase inhibitors is an ongoing quest mobilizing many organic chemistry groups around the world as these molecules have been shown to treat the late symptoms of Alzheimer's disease as well as to act as neuroprotecting agents. In this work, we disclose the synthesis of novel 2-acetamidopurine nucleosides and, for the first time, regioselective N(7)-glycosylation with 2-acetamido-6-chloropurine, promoted by trimethylsilyl triflate, was accomplished by tuning the reaction conditions (acetonitrile as solvent, 65 degrees C, 5h) starting from 1-acetoxy bicyclic glycosyl donors, or by direct coupling of a methyl glucopyranoside with the nucleobase to obtain only N(7) nucleosides in reasonable yield (55-60%). The nucleosides as well as their sugar precursors were screened for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition. While none of the compounds tested inhibited AChE, remarkably, some of the N(7) nucleosides and sugar bicyclic derivatives showed potent inhibition towards BChE. Nanomolar inhibition was obtained for one compound competing well with rivastigmine, a drug currently in use for the treatment of Alzheimer's disease. Experimental results showed that the presence of benzyl groups on the carbohydrate scaffold and the N(7)-linked purine nucleobase were necessary for strong BChE inactivation. A preliminary evaluation of the acute cytotoxicity of the elongated bicyclic sugar precursors and nucleosides was performed indicating low values, in the same order of magnitude as those of rivastigmine.
|
Inhibition of BChE in human serum assessed as hydrolysis of butyrylthiocholine at 0.1 ug/mL by Ellman's method
|
Homo sapiens
|
76.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis of novel purine nucleosides towards a selective inhibition of human butyrylcholinesterase.
Year : 2009
Volume : 17
Issue : 14
First Page : 5106
Last Page : 5116
Authors : Marcelo F, Silva FV, Goulart M, Justino J, Sinaÿ P, Blériot Y, Rauter AP.
Abstract : The search for new and potent cholinesterase inhibitors is an ongoing quest mobilizing many organic chemistry groups around the world as these molecules have been shown to treat the late symptoms of Alzheimer's disease as well as to act as neuroprotecting agents. In this work, we disclose the synthesis of novel 2-acetamidopurine nucleosides and, for the first time, regioselective N(7)-glycosylation with 2-acetamido-6-chloropurine, promoted by trimethylsilyl triflate, was accomplished by tuning the reaction conditions (acetonitrile as solvent, 65 degrees C, 5h) starting from 1-acetoxy bicyclic glycosyl donors, or by direct coupling of a methyl glucopyranoside with the nucleobase to obtain only N(7) nucleosides in reasonable yield (55-60%). The nucleosides as well as their sugar precursors were screened for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition. While none of the compounds tested inhibited AChE, remarkably, some of the N(7) nucleosides and sugar bicyclic derivatives showed potent inhibition towards BChE. Nanomolar inhibition was obtained for one compound competing well with rivastigmine, a drug currently in use for the treatment of Alzheimer's disease. Experimental results showed that the presence of benzyl groups on the carbohydrate scaffold and the N(7)-linked purine nucleobase were necessary for strong BChE inactivation. A preliminary evaluation of the acute cytotoxicity of the elongated bicyclic sugar precursors and nucleosides was performed indicating low values, in the same order of magnitude as those of rivastigmine.
|
Inhibition of BuChE
|
None
|
37.0
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 horse serum BChE preincubated for 5 mins by Ellman's method
|
Equus caballus
|
831.76
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Novel alkyl- and arylcarbamate derivatives with N-benzylpiperidine and N-benzylpiperazine moieties as cholinesterases inhibitors.
Year : 2010
Volume : 45
Issue : 12
First Page : 5602
Last Page : 5611
Authors : Więckowska A, Bajda M, Guzior N, Malawska B.
Abstract : The study presents synthesis and biological activity of novel alkyl- and arylcarbamate derivatives with N-benzylpiperidine and N-benzylpiperazine moieties designed as cholinesterases inhibitors. These fragments turned out to determine compounds' selectivity between AChE and BuChE. Derivatives of N-benzylpiperazine (16-25) were selective BuChE inhibitors with 3-(2-(4-benzylpiperazin-1-yl)-2-oxoethyl)-phenyl butylcarbamate (22) being the most potent compound (pIC50=5.00) while a series of carbamate derivatives of N-benzylpiperidine (5-14) displayed non-selective BuChE/AChE inhibitory activity. Molecular modelling studies point out significant differences between orientations of these two groups of compounds in the active site of AChE, which can be an explanation of their different biological activity.
|
Inhibition of AChE-induced amyloid beta aggregation
|
None
|
54.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : (+)-Arisugacin A--computational evidence of a dual binding site covalent inhibitor of acetylcholinesterase.
Year : 2011
Volume : 21
Issue : 9
First Page : 2687
Last Page : 2691
Authors : Al-Rashid ZF, Hsung RP.
Abstract : A computation docking study of the highly potent, non-nitrogen containing, acetylcholinesterase inhibitor (+)-arisugacin A is presented. The model suggests that (+)-arisugacin A is a dual binding site covalent inhibitor of AChE. These findings are examined in the context of Alzheimer's disease-modifying therapeutic design. (+)-Arisugacin A's revealed mode of action is unique, and may serve as a basis for the development of AD therapeutics capable of treating the symptomatic aspects of AD, while being neuroprotective with long term efficacy.
|
Inhibition of BChE
|
None
|
49.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : (+)-Arisugacin A--computational evidence of a dual binding site covalent inhibitor of acetylcholinesterase.
Year : 2011
Volume : 21
Issue : 9
First Page : 2687
Last Page : 2691
Authors : Al-Rashid ZF, Hsung RP.
Abstract : A computation docking study of the highly potent, non-nitrogen containing, acetylcholinesterase inhibitor (+)-arisugacin A is presented. The model suggests that (+)-arisugacin A is a dual binding site covalent inhibitor of AChE. These findings are examined in the context of Alzheimer's disease-modifying therapeutic design. (+)-Arisugacin A's revealed mode of action is unique, and may serve as a basis for the development of AD therapeutics capable of treating the symptomatic aspects of AD, while being neuroprotective with long term efficacy.
|
Inhibition of purified human plasma BuChE preincubated for 30 mins before DTNB substrate addition by spectrophotometric assay based Ellman's method
|
Homo sapiens
|
179.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel carbamate cholinesterase inhibitors that release biologically active amines following enzyme inhibition.
Year : 2009
Volume : 19
Issue : 12
First Page : 3243
Last Page : 3246
Authors : Verheijen JC, Wiig KA, Du S, Connors SL, Martin AN, Ferreira JP, Slepnev VI, Kochendörfer U.
Abstract : Conjugation of the phenol derived from rivastigmine with amphetamines gave access to novel carbamate cholinesterase inhibitors. All compounds possessed increased affinity and selectivity for AChE compared to rivastigmine and were orally bioavailable. Compound 4a, incorporating d-amphetamine, caused significant inhibition of cholinesterase in vivo at doses that were well tolerated. Release of amphetamine from 4a was demonstrated following in vitro and in vivo inhibition of cholinesterase. Compound 4a was also effective in alleviating scopolamine induced amnesia in a rat passive avoidance model.
|
Inhibition of total plasma cholinesterase in rat at 5 mg/kg, po measured 30 to 180 mins post dose
|
Rattus norvegicus
|
39.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel carbamate cholinesterase inhibitors that release biologically active amines following enzyme inhibition.
Year : 2009
Volume : 19
Issue : 12
First Page : 3243
Last Page : 3246
Authors : Verheijen JC, Wiig KA, Du S, Connors SL, Martin AN, Ferreira JP, Slepnev VI, Kochendörfer U.
Abstract : Conjugation of the phenol derived from rivastigmine with amphetamines gave access to novel carbamate cholinesterase inhibitors. All compounds possessed increased affinity and selectivity for AChE compared to rivastigmine and were orally bioavailable. Compound 4a, incorporating d-amphetamine, caused significant inhibition of cholinesterase in vivo at doses that were well tolerated. Release of amphetamine from 4a was demonstrated following in vitro and in vivo inhibition of cholinesterase. Compound 4a was also effective in alleviating scopolamine induced amnesia in a rat passive avoidance model.
|
Inhibition of total brain cholinesterase activity in rat at 5 mg/kg, po measured 30 to 180 mins post dose
|
Rattus norvegicus
|
56.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel carbamate cholinesterase inhibitors that release biologically active amines following enzyme inhibition.
Year : 2009
Volume : 19
Issue : 12
First Page : 3243
Last Page : 3246
Authors : Verheijen JC, Wiig KA, Du S, Connors SL, Martin AN, Ferreira JP, Slepnev VI, Kochendörfer U.
Abstract : Conjugation of the phenol derived from rivastigmine with amphetamines gave access to novel carbamate cholinesterase inhibitors. All compounds possessed increased affinity and selectivity for AChE compared to rivastigmine and were orally bioavailable. Compound 4a, incorporating d-amphetamine, caused significant inhibition of cholinesterase in vivo at doses that were well tolerated. Release of amphetamine from 4a was demonstrated following in vitro and in vivo inhibition of cholinesterase. Compound 4a was also effective in alleviating scopolamine induced amnesia in a rat passive avoidance model.
|
Inhibition of human erythrocytes BChE
|
Homo sapiens
|
37.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Quinolizidinyl derivatives of bi- and tricyclic systems as potent inhibitors of acetyl- and butyrylcholinesterase with potential in Alzheimer's disease.
Year : 2011
Volume : 46
Issue : 6
First Page : 2170
Last Page : 2184
Authors : Tasso B, Catto M, Nicolotti O, Novelli F, Tonelli M, Giangreco I, Pisani L, Sparatore A, Boido V, Carotti A, Sparatore F.
Abstract : On the pattern of the potent and selective butyrylcholinesterase (BChE) inhibitors ethopropazine and Astra1397, sets of quinolizidinyl derivatives of bi- and tricyclic (hetero)aromatic systems were studied as dual, or BChE-selective inhibitors. All compounds exhibited activity against both cholinesterases, but inhibition of BChE was generally stronger, with submicromolar IC50 values for most of them (e.g. 15: IC50 versus BChE=0.15 μM; SI=47). However, in a subset of quinolizidinyl derivatives of 6-hydroxycoumarin an inverted selectivity for acetylcholinesterase (AChE) was observed (e.g. 46: IC50 versus AChE=0.35 μM; SI=0.06). Docking studies furnished a sound interpretation of the observed different enzyme activity. Several of the studied compounds have shown, in the past, additional pharmacological properties (as antagonism on presynaptic muscarinic autoreceptor; inhibition of enkephaline aminopeptidase and antipsychotic activity) of some relevance in Alzheimer's disease, and may, therefore, represent hits for the development of interesting single-entity multi-target drugs.
|
Inhibition of human plasma BChE
|
Homo sapiens
|
37.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Quinolizidinyl derivatives of bi- and tricyclic systems as potent inhibitors of acetyl- and butyrylcholinesterase with potential in Alzheimer's disease.
Year : 2011
Volume : 46
Issue : 6
First Page : 2170
Last Page : 2184
Authors : Tasso B, Catto M, Nicolotti O, Novelli F, Tonelli M, Giangreco I, Pisani L, Sparatore A, Boido V, Carotti A, Sparatore F.
Abstract : On the pattern of the potent and selective butyrylcholinesterase (BChE) inhibitors ethopropazine and Astra1397, sets of quinolizidinyl derivatives of bi- and tricyclic (hetero)aromatic systems were studied as dual, or BChE-selective inhibitors. All compounds exhibited activity against both cholinesterases, but inhibition of BChE was generally stronger, with submicromolar IC50 values for most of them (e.g. 15: IC50 versus BChE=0.15 μM; SI=47). However, in a subset of quinolizidinyl derivatives of 6-hydroxycoumarin an inverted selectivity for acetylcholinesterase (AChE) was observed (e.g. 46: IC50 versus AChE=0.35 μM; SI=0.06). Docking studies furnished a sound interpretation of the observed different enzyme activity. Several of the studied compounds have shown, in the past, additional pharmacological properties (as antagonism on presynaptic muscarinic autoreceptor; inhibition of enkephaline aminopeptidase and antipsychotic activity) of some relevance in Alzheimer's disease, and may, therefore, represent hits for the development of interesting single-entity multi-target drugs.
|
Inhibition of human serum recombinant BChE after 20 mins using butyrylthiocholine iodide as a substrate by Ellman's assay
|
Homo sapiens
|
301.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Exploiting the lipoic acid structure in the search for novel multitarget ligands against Alzheimer's disease.
Year : 2011
Volume : 46
Issue : 11
First Page : 5435
Last Page : 5442
Authors : Rosini M, Simoni E, Bartolini M, Tarozzi A, Matera R, Milelli A, Hrelia P, Andrisano V, Bolognesi ML, Melchiorre C.
Abstract : Lipoic acid (LA) is a natural antioxidant. Its structure was previously combined with that of the acetylcholinesterase inhibitor tacrine to give lipocrine (1), a lead compound multitargeted against Alzheimer's disease (AD). Herein, we further explore LA as a privileged structure for developing multimodal compounds to investigate AD. First, we studied the effect of LA chirality by evaluating the cholinesterase profile of 1's enantiomers. Then, a new series of LA hybrids was designed and synthesized by combining racemic LA with motifs of other known anticholinesterase agents (rivastigmine and memoquin). This afforded 4, which represents a step forward in the search for balanced anticholinesterase and antioxidant capacities.
|
Inhibition of human serum BuChE using butyrylthiocholine iodide as substrate preincubated for 90 mins before substrate addition by Ellman's method
|
Homo sapiens
|
301.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : The First Dual ChE/FAAH Inhibitors: New Perspectives for Alzheimer's Disease?
Year : 2012
Volume : 3
Issue : 3
First Page : 182
Last Page : 186
Authors : Rampa A, Bartolini M, Bisi A, Belluti F, Gobbi S, Andrisano V, Ligresti A, Di Marzo V.
Abstract : The treatment of Alzheimer's disease (AD) still remains an area of significant unmet need, with drugs that only target the symptoms of the disease. Therefore, there is considerable need for disease-modifying therapies. The complex etiology of AD prompts scientists to develop multitarget strategies to combat causes and symptoms. To this aim, we designed, synthesized, and tested four new carbamates as dual cholinesterase-FAAH inhibitors. The dual activity of these compounds could lead to a potentially more effective treatment for the counteraction of AD progression, because they would allow regulation of both ACh and eCB signaling and improve neuronal transmission and/or counteract neuroinflammation.
|
Inhibition of equine BuChE after 120 mins by Ellman's method
|
Equus caballus
|
160.0
nM
|
|
Journal : J. Med. Chem.
Title : Carbamate derivatives of indolines as cholinesterase inhibitors and antioxidants for the treatment of Alzheimer's disease.
Year : 2012
Volume : 55
Issue : 23
First Page : 10700
Last Page : 10715
Authors : Yanovsky I, Finkin-Groner E, Zaikin A, Lerman L, Shalom H, Zeeli S, Weill T, Ginsburg I, Nudelman A, Weinstock M.
Abstract : The cascade of events that occurs in Alzheimer's disease involving oxidative stress and the reduction in cholinergic transmission can be better addressed by multifunctional drugs than cholinesterase inhibitors alone. For this purpose, we prepared a large number of derivatives of indoline-3-propionic acids and esters. They showed scavenging activity against different radicals in solution and significant protection against cytotoxicity in cardiomyocytes and primary cultures of neuronal cells exposed to H2O2 species and serum deprivation at concentrations ranging from 1 nM to 10 μM depending on the compound. For most of the indoline-3-propionic acid derivatives, introduction of N-methyl-N-ethyl or N-methyl-N-(4-methoxyphenyl) carbamate moieties at positions 4, 6, or 7 conferred both acetyl (AChE) and butyryl (BuChE) cholinesterase inhibitory activities at similar concentrations to those that showed antioxidant activity. The most potent AChE inhibitors were 120 (3-(2-aminoethyl) indolin-4-yl ethyl(methyl)carbamate dihydrochloride) and 94 (3-(3-methoxy-3-oxopropyl)-4-(((4-methoxyphenyl)(methyl) carbamoyl)oxy)indolin-1-ium hydrochloride) with IC50s of 0.4 and 1.2 μM, respectively.
|
Inhibition of bovine AChE after 120 mins by Ellman's method
|
Bos taurus
|
620.0
nM
|
|
Journal : J. Med. Chem.
Title : Carbamate derivatives of indolines as cholinesterase inhibitors and antioxidants for the treatment of Alzheimer's disease.
Year : 2012
Volume : 55
Issue : 23
First Page : 10700
Last Page : 10715
Authors : Yanovsky I, Finkin-Groner E, Zaikin A, Lerman L, Shalom H, Zeeli S, Weill T, Ginsburg I, Nudelman A, Weinstock M.
Abstract : The cascade of events that occurs in Alzheimer's disease involving oxidative stress and the reduction in cholinergic transmission can be better addressed by multifunctional drugs than cholinesterase inhibitors alone. For this purpose, we prepared a large number of derivatives of indoline-3-propionic acids and esters. They showed scavenging activity against different radicals in solution and significant protection against cytotoxicity in cardiomyocytes and primary cultures of neuronal cells exposed to H2O2 species and serum deprivation at concentrations ranging from 1 nM to 10 μM depending on the compound. For most of the indoline-3-propionic acid derivatives, introduction of N-methyl-N-ethyl or N-methyl-N-(4-methoxyphenyl) carbamate moieties at positions 4, 6, or 7 conferred both acetyl (AChE) and butyryl (BuChE) cholinesterase inhibitory activities at similar concentrations to those that showed antioxidant activity. The most potent AChE inhibitors were 120 (3-(2-aminoethyl) indolin-4-yl ethyl(methyl)carbamate dihydrochloride) and 94 (3-(3-methoxy-3-oxopropyl)-4-(((4-methoxyphenyl)(methyl) carbamoyl)oxy)indolin-1-ium hydrochloride) with IC50s of 0.4 and 1.2 μM, respectively.
|
Inhibition of butyrylcholinesterase (unknown origin)
|
Homo sapiens
|
300.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis and biological evaluation of coumarin alkylamines as potent and selective dual binding site inhibitors of acetylcholinesterase.
Year : 2013
Volume : 21
Issue : 1
First Page : 146
Last Page : 152
Authors : Catto M, Pisani L, Leonetti F, Nicolotti O, Pesce P, Stefanachi A, Cellamare S, Carotti A.
Abstract : Acetylcholinesterase inhibitors (AChEIs) are currently the drugs of choice, although only symptomatic and palliative, for the treatment of Alzheimer's disease (AD). Donepezil is one of most used AChEIs in AD therapy, acting as a dual binding site, reversible inhibitor of AChE with high selectivity over butyrylcholinesterase (BChE). Through a combined target- and ligand-based approach, a series of coumarin alkylamines matching the structural determinants of donepezil were designed and prepared. 6,7-Dimethoxycoumarin derivatives carrying a protonatable benzylamino group, linked to position 3 by suitable linkers, exhibited fairly good AChE inhibitory activity and a high selectivity over BChE. The inhibitory potency was strongly influenced by the length and shape of the spacer and by the methoxy substituents on the coumarin scaffold. The inhibition mechanism, assessed for the most active compound 13 (IC(50) 7.6 nM) resulted in a mixed-type, thus confirming its binding at both the catalytic and peripheral binding sites of AChE.
|
Inhibition of acetylcholinesterase (unknown origin)
|
Homo sapiens
|
700.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis and biological evaluation of coumarin alkylamines as potent and selective dual binding site inhibitors of acetylcholinesterase.
Year : 2013
Volume : 21
Issue : 1
First Page : 146
Last Page : 152
Authors : Catto M, Pisani L, Leonetti F, Nicolotti O, Pesce P, Stefanachi A, Cellamare S, Carotti A.
Abstract : Acetylcholinesterase inhibitors (AChEIs) are currently the drugs of choice, although only symptomatic and palliative, for the treatment of Alzheimer's disease (AD). Donepezil is one of most used AChEIs in AD therapy, acting as a dual binding site, reversible inhibitor of AChE with high selectivity over butyrylcholinesterase (BChE). Through a combined target- and ligand-based approach, a series of coumarin alkylamines matching the structural determinants of donepezil were designed and prepared. 6,7-Dimethoxycoumarin derivatives carrying a protonatable benzylamino group, linked to position 3 by suitable linkers, exhibited fairly good AChE inhibitory activity and a high selectivity over BChE. The inhibitory potency was strongly influenced by the length and shape of the spacer and by the methoxy substituents on the coumarin scaffold. The inhibition mechanism, assessed for the most active compound 13 (IC(50) 7.6 nM) resulted in a mixed-type, thus confirming its binding at both the catalytic and peripheral binding sites of AChE.
|
Inhibition of human BuChE using butyrylthiocholine as substrate by Ellman's method
|
Homo sapiens
|
300.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Cannabinoid agonists showing BuChE inhibition as potential therapeutic agents for Alzheimer's disease.
Year : 2014
Volume : 73
First Page : 56
Last Page : 72
Authors : González-Naranjo P, Pérez-Macias N, Campillo NE, Pérez C, Arán VJ, Girón R, Sánchez-Robles E, Martín MI, Gómez-Cañas M, García-Arencibia M, Fernández-Ruiz J, Páez JA.
Abstract : Designing drugs with a specific multi-target profile is a promising approach against multifactorial illnesses as Alzheimer's disease. In this work, new indazole ethers that possess dual activity as both cannabinoid agonists CB2 and inhibitors of BuChE have been designed by computational methods. On the basis of this knowledge, the synthesis, pharmacological evaluation and docking studies of a new class of indazoles has been performed. Pharmacological evaluation includes radioligand binding assays with [(3)H]-CP55940 for CB1R and CB2R and functional activity for cannabinoid receptors on isolated tissue. Additionally, in vitro inhibitory assays of AChE/BuChE and the corresponding competition studies have been carried out. The results of pharmacological tests have revealed that three of these derivatives behave as CB2 cannabinoid agonists and simultaneously show BuChE inhibition. In particular, compounds 3 and 24 have emerged as promising candidates as novel cannabinoids that inhibit BuChE by a non-competitive or mixed mechanism, respectively. On the other hand, both molecules show antioxidant properties.
|
Inhibition of BuChE (unknown origin) using butyrylthiocholine iodide as substrate incubated for 25 mins by Ellman's method
|
Homo sapiens
|
260.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis and pharmacological evaluation of chalcone derivatives as acetylcholinesterase inhibitors.
Year : 2014
Volume : 22
Issue : 21
First Page : 6124
Last Page : 6133
Authors : Liu HR, Liu XJ, Fan HQ, Tang JJ, Gao XH, Liu WK.
Abstract : A novel series of chalcone derivatives (4a-8d) were designed, synthesized, and evaluated for the inhibition activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The logP values of the compounds were shown to range from 1.49 to 2.19, which suggested that they were possible to pass blood brain barriers in vivo. The most promising compound 4a (IC50: 4.68 μmol/L) was 2-fold more potent than Rivastigmine against AChE (IC50: 10.54 μmol/L) and showed a high selectivity for AChE over BuChE (ratio: 4.35). Enzyme kinetic study suggested that the inhibition mechanism of compound 4a was a mixed-type inhibition. Meanwhile, the result of molecular docking showed its potent inhibition of AChE and high selectivity for AChE over BuChE.
|
Inhibition of recombinant human BChE by Ellman method
|
Homo sapiens
|
30.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery, biological evaluation, and crystal structure of a novel nanomolar selective butyrylcholinesterase inhibitor.
Year : 2014
Volume : 57
Issue : 19
First Page : 8167
Last Page : 8179
Authors : Brus B, Košak U, Turk S, Pišlar A, Coquelle N, Kos J, Stojan J, Colletier JP, Gobec S.
Abstract : Butyrylcholinesterase (BChE) is regarded as a promising drug target as its levels and activity significantly increase in the late stages of Alzheimer's disease. To discover novel BChE inhibitors, we used a hierarchical virtual screening protocol followed by biochemical evaluation of 40 highest scoring hit compounds. Three of the compounds identified showed significant inhibitory activities against BChE. The most potent, compound 1 (IC50 = 21.3 nM), was resynthesized and resolved into its pure enantiomers. A high degree of stereoselective activity was revealed, and a dissociation constant of 2.7 nM was determined for the most potent stereoisomer (+)-1. The crystal structure of human BChE in complex with compound (+)-1 was solved, revealing the binding mode and providing clues for potential optimization. Additionally, compound 1 inhibited amyloid β(1-42) peptide self-induced aggregation into fibrils (by 61.7% at 10 μM) and protected cultured SH-SY5Y cells against amyloid-β-induced toxicity. These data suggest that compound 1 represents a promising candidate for hit-to-lead follow-up in the drug-discovery process against Alzheimer's disease.
|
Inhibition of BChE in rat serum using butyrylthiocholine iodide substrate incubated for 15 mins by UV spectroscopy based Ellman's method
|
Rattus norvegicus
|
370.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis and evaluation of rivastigmine and curcumin hybrids as site-activated multitarget-directed ligands for Alzheimer's disease therapy.
Year : 2014
Volume : 22
Issue : 17
First Page : 4717
Last Page : 4725
Authors : Li Y, Peng P, Tang L, Hu Y, Hu Y, Sheng R.
Abstract : A series of novel 2-methoxy-phenyl dimethyl-carbamate derivatives were designed, synthesized and evaluated as site-activated MTDLs based on rivastigmine and curcumin. Most of them exhibited good to excellent AChE and BuChE inhibitory activities with sub-micromolar IC50 values. Among all the compounds, 6a demonstrated the most potent AChE inhibition with IC50 value of 0.097μM, which is about 20-fold than that of rivastigmine. In addition, the three selected compounds 5a, 6a and 6e demonstrated inhibitory activity against Aβ self-aggregation similar to cucurmin in TEM assay, which is obviously different from the weak activity of rivastigmine. Moreover, the hydrolysate of 6a (compound 7) also showed potent ABTS(+) scavenging and moderate copper ion chelating activity in vitro.
|
Inhibition of AChE (unknown origin)
|
Homo sapiens
|
54.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A computational view on the significance of E-ring in binding of (+)-arisugacin A to acetylcholinesterase.
Year : 2015
Volume : 25
Issue : 21
First Page : 4848
Last Page : 4853
Authors : Al-Rashid ZF, Hsung RP.
Abstract : A computational docking study of a series of de novo structural analogs of the highly potent, non-nitrogen containing, acetylcholinesterase inhibitor (+)-arisugacin A is presented. In direct comparison to the recently reported X-ray single-crystal structure of (+)-territrem B bound hAChE, the modeling suggests that there is a unique conformational preference for the E-ring that is responsible for the superior inhibitory activity of (+)-arisugacin A against hAChE relative to (+)-territrem B, and that substitutions on the E-ring also play an important role in the protein-ligand interaction.
|
Pseudo-irreversible inhibition of Torpedo californica AChE using acetylthiocholine as substrate by cornish bowden plot analysis
|
Torpedo californica
|
2.0
/M/min
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis, structural characterization, docking, lipophilicity and cytotoxicity of 1-[(1R)-1-(6-fluoro-1,3-benzothiazol-2-yl)ethyl]-3-alkyl carbamates, novel acetylcholinesterase and butyrylcholinesterase pseudo-irreversible inhibitors.
Year : 2016
Volume : 24
Issue : 7
First Page : 1560
Last Page : 1572
Authors : Pejchal V, Štěpánková Š, Pejchalová M, Královec K, Havelek R, Růžičková Z, Ajani H, Lo R, Lepšík M.
Abstract : In the current study, sixteen novel derivatives of (R)-1-(6-fluorobenzo[d]thiazol-2-yl)ethanamine were synthesized as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. Chemical structures together with purity of the synthesized compounds were substantiated by IR, (1)H, (13)C, (19)F NMR, high resolution mass spectrometry and elemental analysis. The optical activities were confirmed by optical rotation measurements. The synthesized compounds were evaluated for their AChE and BChE inhibitory activities. In addition, the cytotoxicity of the most active compounds was investigated against human cell lines employing XTT tetrazolium salt reduction assay and xCELLigence system allowing a label-free assessment of the cells proliferation. Our results demonstrated that the inhibitory mechanism was confirmed to be pseudo-irreversible, in line with previous studies on carbamates. Compounds indicated as 3b, 3d, 3l and 3n showed the best AChE inhibitory activity of all the evaluated compounds and were up to tenfold more potent than standard drug rivastigmine. The binding mode was determined using state-of-the-art covalent docking and scoring methodology. The obtained data clearly demonstrated that 3b, 3d, 3l and 3n benzothiazole carbamates possess high inhibitory activity against AChE and BChE and concurrently negligible cytotoxicity. In conclusion, our results indicate, that these derivatives could be promising in an effective therapeutic intervention for Alzheimer's disease.
|
Inhibition of human serum BuChE using acetylthiocholine iodide as substrate preincubated for 20 to 60 mins followed by substrate addition by Ellman's method
|
Homo sapiens
|
301.0
nM
|
|
Journal : J. Med. Chem.
Title : Fatty Acid Amide Hydrolase (FAAH), Acetylcholinesterase (AChE), and Butyrylcholinesterase (BuChE): Networked Targets for the Development of Carbamates as Potential Anti-Alzheimer's Disease Agents.
Year : 2016
Volume : 59
Issue : 13
First Page : 6387
Last Page : 6406
Authors : Montanari S, Scalvini L, Bartolini M, Belluti F, Gobbi S, Andrisano V, Ligresti A, Di Marzo V, Rivara S, Mor M, Bisi A, Rampa A.
Abstract : The modulation of the endocannabinoid system is emerging as a viable avenue for the treatment of neurodegeneration, being involved in neuroprotective and anti-inflammatory processes. In particular, indirectly enhancing endocannabinoid signaling to therapeutic levels through FAAH inhibition might be beneficial for neurodegenerative disorders such as Alzheimer's disease, effectively preventing or slowing the progression of the disease. Hence, in the search for a more effective treatment for Alzheimer's disease, in this paper, the multitarget-directed ligand paradigm was applied to the design of carbamates able to simultaneously target the recently proposed endocannabinoid system and the classic cholinesterase system, and achieve effective dual FAAH/cholinesterase inhibitors. Among the two series of synthesized compounds, while some derivatives proved to be extremely potent on a single target, compounds 9 and 19 were identified as effective dual FAAH/ChE inhibitors, with well-balanced nanomolar activities. Thus, 9 and 19 might be considered as new promising candidates for Alzheimer's disease treatment.
|
Inhibition of human serum BChE using S-Butyrylthiocholine iodide as substrate preincubated for 15 mins followed by substrate addition by Ellman's method
|
Homo sapiens
|
380.0
nM
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis, biological evaluation, and molecular modeling studies of chalcone-rivastigmine hybrids as cholinesterase inhibitors.
Year : 2017
Volume : 25
Issue : 1
First Page : 360
Last Page : 371
Authors : Wang L, Wang Y, Tian Y, Shang J, Sun X, Chen H, Wang H, Tan W.
Abstract : A series of novel chalcone-rivastigmine hybrids were designed, synthesized, and tested in vitro for their ability to inhibit human acetylcholinesterase and butyrylcholinesterase. Most of the target compounds showed hBChE selective activity in the micro- and submicromolar ranges. The most potent compound 3 exhibited comparable IC50 to the commercially available drug (rivastigmine). To better understand their structure activity relationships (SAR) and mechanisms of enzyme-inhibitor interactions, kinetic and molecular modeling studies including molecular docking and molecular dynamics (MD) simulations were carried out. Furthermore, compound 3 blocks the formation of reactive oxygen species (ROS) in SH-SY5Y cells and shows the required druggability and low cytotoxicity, suggesting this hybrid is a promising multifunctional drug candidate for Alzheimer's disease (AD) treatment.
|
Inhibition of AChE (unknown origin) at 1 uM using acetylthiocholine iodide as substrate preincubated for 60 mins followed by substrate addition measured after 5 mins by Ellman's method relative to control
|
Homo sapiens
|
6.77
%
|
|
Journal : Eur J Med Chem
Title : Discovery of novel rivastigmine-hydroxycinnamic acid hybrids as multi-targeted agents for Alzheimer's disease.
Year : 2017
Volume : 125
First Page : 784
Last Page : 792
Authors : Chen Z, Digiacomo M, Tu Y, Gu Q, Wang S, Yang X, Chu J, Chen Q, Han Y, Chen J, Nesi G, Sestito S, Macchia M, Rapposelli S, Pi R.
Abstract : A series of rivastigmine-caffeic acid and rivastigmine-ferulic acid hybrids were designed, synthesized, and evaluated as multifunctional agents for Alzheimer's disease (AD) in vitro. The new compounds exerted antioxidant neuroprotective properties and good cholinesterases (ChE) inhibitory activities. Some of them also inhibited amyloid protein (Aβ) aggregation. In particular, compound 5 emerged as promising drug candidates endowed with neuroprotective potential, ChE inhibitory, Aβ self-aggregation inhibitory and copper chelation properties. These data suggest that compound 5 offers an attractive starting point for further lead optimization in the drug-discovery process against AD.
|
Inhibition of AChE (unknown origin) at 5 uM using acetylthiocholine iodide as substrate preincubated for 60 mins followed by substrate addition measured after 5 mins by Ellman's method relative to control
|
Homo sapiens
|
15.56
%
|
|
Journal : Eur J Med Chem
Title : Discovery of novel rivastigmine-hydroxycinnamic acid hybrids as multi-targeted agents for Alzheimer's disease.
Year : 2017
Volume : 125
First Page : 784
Last Page : 792
Authors : Chen Z, Digiacomo M, Tu Y, Gu Q, Wang S, Yang X, Chu J, Chen Q, Han Y, Chen J, Nesi G, Sestito S, Macchia M, Rapposelli S, Pi R.
Abstract : A series of rivastigmine-caffeic acid and rivastigmine-ferulic acid hybrids were designed, synthesized, and evaluated as multifunctional agents for Alzheimer's disease (AD) in vitro. The new compounds exerted antioxidant neuroprotective properties and good cholinesterases (ChE) inhibitory activities. Some of them also inhibited amyloid protein (Aβ) aggregation. In particular, compound 5 emerged as promising drug candidates endowed with neuroprotective potential, ChE inhibitory, Aβ self-aggregation inhibitory and copper chelation properties. These data suggest that compound 5 offers an attractive starting point for further lead optimization in the drug-discovery process against AD.
|
Inhibition of BuChE (unknown origin) at 1 uM using acetylthiocholine iodide as substrate preincubated for 60 mins followed by substrate addition measured after 5 mins by Ellman's method relative to control
|
Homo sapiens
|
61.04
%
|
|
Journal : Eur J Med Chem
Title : Discovery of novel rivastigmine-hydroxycinnamic acid hybrids as multi-targeted agents for Alzheimer's disease.
Year : 2017
Volume : 125
First Page : 784
Last Page : 792
Authors : Chen Z, Digiacomo M, Tu Y, Gu Q, Wang S, Yang X, Chu J, Chen Q, Han Y, Chen J, Nesi G, Sestito S, Macchia M, Rapposelli S, Pi R.
Abstract : A series of rivastigmine-caffeic acid and rivastigmine-ferulic acid hybrids were designed, synthesized, and evaluated as multifunctional agents for Alzheimer's disease (AD) in vitro. The new compounds exerted antioxidant neuroprotective properties and good cholinesterases (ChE) inhibitory activities. Some of them also inhibited amyloid protein (Aβ) aggregation. In particular, compound 5 emerged as promising drug candidates endowed with neuroprotective potential, ChE inhibitory, Aβ self-aggregation inhibitory and copper chelation properties. These data suggest that compound 5 offers an attractive starting point for further lead optimization in the drug-discovery process against AD.
|
Inhibition of BuChE (unknown origin) at 5 uM using acetylthiocholine iodide as substrate preincubated for 60 mins followed by substrate addition measured after 5 mins by Ellman's method relative to control
|
Homo sapiens
|
92.99
%
|
|
Journal : Eur J Med Chem
Title : Discovery of novel rivastigmine-hydroxycinnamic acid hybrids as multi-targeted agents for Alzheimer's disease.
Year : 2017
Volume : 125
First Page : 784
Last Page : 792
Authors : Chen Z, Digiacomo M, Tu Y, Gu Q, Wang S, Yang X, Chu J, Chen Q, Han Y, Chen J, Nesi G, Sestito S, Macchia M, Rapposelli S, Pi R.
Abstract : A series of rivastigmine-caffeic acid and rivastigmine-ferulic acid hybrids were designed, synthesized, and evaluated as multifunctional agents for Alzheimer's disease (AD) in vitro. The new compounds exerted antioxidant neuroprotective properties and good cholinesterases (ChE) inhibitory activities. Some of them also inhibited amyloid protein (Aβ) aggregation. In particular, compound 5 emerged as promising drug candidates endowed with neuroprotective potential, ChE inhibitory, Aβ self-aggregation inhibitory and copper chelation properties. These data suggest that compound 5 offers an attractive starting point for further lead optimization in the drug-discovery process against AD.
|
Inhibition of butyrylcholinesterase (unknown origin) using butyrylthiocholine iodide as substrate after 25 mins by Ellmann method
|
Homo sapiens
|
260.0
nM
|
|
Journal : Eur J Med Chem
Title : Novel ferulic amide derivatives with tertiary amine side chain as acetylcholinesterase and butyrylcholinesterase inhibitors: The influence of carbon spacer length, alkylamine and aromatic group.
Year : 2017
Volume : 126
First Page : 810
Last Page : 822
Authors : Liu H, Liu L, Gao X, Liu Y, Xu W, He W, Jiang H, Tang J, Fan H, Xia X.
Abstract : Based on our recent investigations on chalcone derivatives as AChE inhibitors, a series of ferulic acid (FA) tertiary amine derivatives similar to chalcone compounds were designed and synthesized. The results of bioactivity evaluation revealed that most of new synthesized compounds had comparable or more potent AChE inhibitory activity than the control drug Rivastigmine. The alteration of carbon chain linking tertiary amine groups and ferulic acid scaffold markedly influenced the inhibition activity against AChE. Among them the inhibitory activity of compound 6d (IC50: 0.71 ± 0.09 μmol/L) and 6e (IC50: 1.11 ± 0.17 μmol/L) was equal to 15-fold and 9-fold than that of Rivastigmine against AChE (IC50: 10.54 ± 0.86 μmol/L), respectively. Moreover, compound 6d shows the highest selectivity for AChE over butyrylcholinesterase(BuChE) (ratio: 18.3). The kinetic study suggested that compound 6d revealed a mixed-type inhibition against AChE. The result of molecular docking showed that compound 6d combines to AChE with three amino acid sites(Trp84, Tyr334 and Trp279), while combines to BuChE with two amino acid sites (Tyr67 and Gly66) in enzyme domains, respectively. Compound 6d might act as a potential agent for the treatment of Alzheimer's diseases (AD).
|
Inhibition of human BuChE using butyrylthiocholine as substrate after 1 min by Ellman's method
|
Homo sapiens
|
370.0
nM
|
|
Journal : J Med Chem
Title : The Magic of Crystal Structure-Based Inhibitor Optimization: Development of a Butyrylcholinesterase Inhibitor with Picomolar Affinity and in Vivo Activity.
Year : 2018
Volume : 61
Issue : 1
First Page : 119
Last Page : 139
Authors : Košak U, Brus B, Knez D, Žakelj S, Trontelj J, Pišlar A, Šink R, Jukič M, Živin M, Podkowa A, Nachon F, Brazzolotto X, Stojan J, Kos J, Coquelle N, Sałat K, Colletier JP, Gobec S.
Abstract : The enzymatic activity of butyrylcholinesterase (BChE) in the brain increases with the progression of Alzheimer's disease, thus classifying BChE as a promising drug target in advanced Alzheimer's disease. We used structure-based drug discovery approaches to develop potent, selective, and reversible human BChE inhibitors. The most potent, compound 3, had a picomolar inhibition constant versus BChE due to strong cation-π interactions, as revealed by the solved crystal structure of its complex with human BChE. Additionally, compound 3 inhibits BChE ex vivo and is noncytotoxic. In vitro pharmacokinetic experiments show that compound 3 is highly protein bound, highly permeable, and metabolically stable. Finally, compound 3 crosses the blood-brain barrier, and it improves memory, cognitive functions, and learning abilities of mice in a scopolamine model of dementia. Compound 3 is thus a promising advanced lead compound for the development of drugs for alleviating symptoms of cholinergic hypofunction in patients with advanced Alzheimer's disease.
|
Inhibition of BuChE (unknown origin) at 500 nM pre-incubated for 20 mins before S-Butyrylthiocholine iodide substrate addition by Ellman reagent based spectrophotometry
|
Homo sapiens
|
30.08
%
|
|
Journal : Eur J Med Chem
Title : Nature-based molecules combined with rivastigmine: A symbiotic approach for the synthesis of new agents against Alzheimer's disease.
Year : 2017
Volume : 141
First Page : 232
Last Page : 239
Authors : Nesi G, Chen Q, Sestito S, Digiacomo M, Yang X, Wang S, Pi R, Rapposelli S.
Abstract : Starting from nature as original source, new potential agents with pleiotropic activities have been synthesized and evaluated as neuroprotective agents. In this work, novel nature-based hybrids, combining antioxidant motifs with rivastigmine, have been designed and synthesized. The biological results revealed that the new compounds inhibit both AChE and BuChE. In particular, lipoic acid hybrids LA1, LA2, LA3 resulted to be the most potent inhibitors of BuChE showing IC50 values ranging from 340 to 378 nM. Analogously, all the compounds were able to inhibit the self β-amyloid1-42 aggregation. The gallic acid hybrid GA2 as well as the 2-chromonecarboxylic acid hybrids CA1 and CA2 prevented the self-mediated Aβ aggregation with percentages of inhibition ranging from 53% to 59%. Finally, some of them also show potent neuroprotective effects against glutamate-induced cell death and low toxicity in HT22 cells.
|
Inhibition of AChE (unknown origin) at 500 nM pre-incubated for 20 mins before acetylthiocholine iodide substrate addition by Ellman reagent based spectrophotometry
|
Homo sapiens
|
1.92
%
|
|
Journal : Eur J Med Chem
Title : Nature-based molecules combined with rivastigmine: A symbiotic approach for the synthesis of new agents against Alzheimer's disease.
Year : 2017
Volume : 141
First Page : 232
Last Page : 239
Authors : Nesi G, Chen Q, Sestito S, Digiacomo M, Yang X, Wang S, Pi R, Rapposelli S.
Abstract : Starting from nature as original source, new potential agents with pleiotropic activities have been synthesized and evaluated as neuroprotective agents. In this work, novel nature-based hybrids, combining antioxidant motifs with rivastigmine, have been designed and synthesized. The biological results revealed that the new compounds inhibit both AChE and BuChE. In particular, lipoic acid hybrids LA1, LA2, LA3 resulted to be the most potent inhibitors of BuChE showing IC50 values ranging from 340 to 378 nM. Analogously, all the compounds were able to inhibit the self β-amyloid1-42 aggregation. The gallic acid hybrid GA2 as well as the 2-chromonecarboxylic acid hybrids CA1 and CA2 prevented the self-mediated Aβ aggregation with percentages of inhibition ranging from 53% to 59%. Finally, some of them also show potent neuroprotective effects against glutamate-induced cell death and low toxicity in HT22 cells.
|
Inhibition of BuChE (unknown origin) pre-incubated for 20 mins before S-Butyrylthiocholine iodide substrate addition by Ellman reagent based spectrophotometry
|
Homo sapiens
|
678.0
nM
|
|
Journal : Eur J Med Chem
Title : Nature-based molecules combined with rivastigmine: A symbiotic approach for the synthesis of new agents against Alzheimer's disease.
Year : 2017
Volume : 141
First Page : 232
Last Page : 239
Authors : Nesi G, Chen Q, Sestito S, Digiacomo M, Yang X, Wang S, Pi R, Rapposelli S.
Abstract : Starting from nature as original source, new potential agents with pleiotropic activities have been synthesized and evaluated as neuroprotective agents. In this work, novel nature-based hybrids, combining antioxidant motifs with rivastigmine, have been designed and synthesized. The biological results revealed that the new compounds inhibit both AChE and BuChE. In particular, lipoic acid hybrids LA1, LA2, LA3 resulted to be the most potent inhibitors of BuChE showing IC50 values ranging from 340 to 378 nM. Analogously, all the compounds were able to inhibit the self β-amyloid1-42 aggregation. The gallic acid hybrid GA2 as well as the 2-chromonecarboxylic acid hybrids CA1 and CA2 prevented the self-mediated Aβ aggregation with percentages of inhibition ranging from 53% to 59%. Finally, some of them also show potent neuroprotective effects against glutamate-induced cell death and low toxicity in HT22 cells.
|
Inhibition of BChE (unknown origin)
|
Homo sapiens
|
30.0
nM
|
|
Journal : Eur J Med Chem
Title : Multi-target-directed ligands for treating Alzheimer's disease: Butyrylcholinesterase inhibitors displaying antioxidant and neuroprotective activities.
Year : 2018
Volume : 156
First Page : 598
Last Page : 617
Authors : Knez D, Coquelle N, Pišlar A, Žakelj S, Jukič M, Sova M, Mravljak J, Nachon F, Brazzolotto X, Kos J, Colletier JP, Gobec S.
Abstract : The limited clinical efficacy of current symptomatic treatment and minute effect on progression of Alzheimer's disease has shifted the research focus from single targets towards multi-target-directed ligands. Here, a potent selective inhibitor of human butyrylcholinesterase was used as the starting point to develop a new series of multifunctional ligands. A focused library of derivatives was designed and synthesised that showed both butyrylcholinesterase inhibition and good antioxidant activity as determined by the DPPH assay. The crystal structure of compound 11 in complex with butyrylcholinesterase revealed the molecular basis for its low nanomolar inhibition of butyrylcholinesterase (Ki = 1.09 ± 0.12 nM). In addition, compounds 8 and 11 show metal-chelating properties, and reduce the redox activity of chelated Cu2+ ions in a Cu-ascorbate redox system. Compounds 8 and 11 decrease intracellular levels of reactive oxygen species, and are not substrates of the active efflux transport system, as determined in Caco2 cells. Compound 11 also protects neuroblastoma SH-SY5Y cells from toxic Aβ1-42 species. These data indicate that compounds 8 and 11 are promising multifunctional lead ligands for treatment of Alzheimer's disease.
|
Inhibition of AChE in human erythrocytes preincubated for 60 mins followed by substrate addition by Ellman's method
|
Homo sapiens
|
920.0
nM
|
|
Journal : J Med Chem
Title : Rational Design of Multitarget-Directed Ligands: Strategies and Emerging Paradigms.
Year : 2019
Volume : 62
Issue : 20
First Page : 8881
Last Page : 8914
Authors : Zhou J, Jiang X, He S, Jiang H, Feng F, Liu W, Qu W, Sun H.
Abstract : Due to the complexity of multifactorial diseases, single-target drugs do not always exhibit satisfactory efficacy. Recently, increasing evidence indicates that simultaneous modulation of multiple targets may improve both therapeutic safety and efficacy, compared with single-target drugs. However, few multitarget drugs are on market or in clinical trials, despite the best efforts of medicinal chemists. This article discusses the systematic establishment of target combination, lead generation, and optimization of multitarget-directed ligands (MTDLs). Moreover, we analyze some MTDLs research cases for several complex diseases in recent years and the physicochemical properties of 117 clinical multitarget drugs, with the aim to reveal the trends and insights of the potential use of MTDLs.
|
Inhibition of human serum BChE using butyrylthiocholine iodide as substrate preincubated for 20 to 60 mins followed by substrate addition by Ellman's method
|
Homo sapiens
|
301.0
nM
|
|
Journal : J Med Chem
Title : Highly Selective Butyrylcholinesterase Inhibitors with Tunable Duration of Action by Chemical Modification of Transferable Carbamate Units Exhibit Pronounced Neuroprotective Effect in an Alzheimer's Disease Mouse Model.
Year : 2019
Volume : 62
Issue : 20
First Page : 9116
Last Page : 9140
Authors : Hoffmann M, Stiller C, Endres E, Scheiner M, Gunesch S, Sotriffer C, Maurice T, Decker M.
Abstract : In this study, the carbamate structure of pseudo-irreversible butyrylcholinesterase (BChE) inhibitors was optimized with regard to a longer binding to the enzyme. A set of compounds bearing different heterocycles (e.g., morpholine, tetrahydroisoquinoline, benzimidazole, piperidine) and alkylene spacers (2 to 10 methylene groups between carbamate and heterocycle) in the carbamate residue was synthesized and characterized in vitro for their binding affinity, binding kinetics, and carbamate hydrolysis. These novel BChE inhibitors are highly selective for <i>h</i>BChE over human acetycholinesterase (<i>h</i>AChE), yielding short-, medium-, and long-acting nanomolar <i>h</i>BChE inhibitors (with a half-life of the carbamoylated enzyme ranging from 1 to 28 h). The inhibitors show neuroprotective properties in a murine hippocampal cell line and a pharmacological mouse model of Alzheimer's disease (AD), suggesting a significant benefit of BChE inhibition for a disease-modifying treatment of AD.
|
Inhibition of electric eel AChE at 50 nM using acetylthiocholine iodide as substrate preincubated for 60 mins followed by substrate addition measured for 5 mins by Ellman's method
|
Electrophorus electricus
|
2.59
%
|
|
Journal : Eur J Med Chem
Title : Multi-targeted ChEI-copper chelating molecules as neuroprotective agents.
Year : 2019
Volume : 174
First Page : 216
Last Page : 225
Authors : Sestito S, Wang S, Chen Q, Lu J, Bertini S, Pomelli C, Chiellini G, He X, Pi R, Rapposelli S.
Abstract : The identification of a valid therapeutic treatment for Alzheimer's disease (AD) represents nowadays an urgent and still unmet medical need, since currently available anti-AD drugs only relieve symptoms and show a modest efficacy. Recent evidence indicates that multi-target-directed ligands (MTDLs) can potentially provide an effective strategy to develop innovative therapies directed towards the onset and progression of this multifactorial neurodegenerative disorder. In this work we designed, synthesized and evaluated a new series of MTDLs bearing the rivastigmine skeleton (ChE-inhibitor) linked to known metal-chelating moieties with linkers of different length. For all the novel derivatives, AChE/BuChE inhibitory activity, ROS scavenging activity and potential cytotoxicity have been assessed. For the best compound (4), copper chelating properties and neuroprotective effects were also evaluated. Our data demonstrated that hybrid derivative 4 is able to effectively inhibit AChE and BuChE and to chelate copper, showing a protective action on neurons. These results, although preliminary, indicate that compound 4 can be considered as a possible hit molecule for the development of new anti-AD MTDLs.
|
Inhibition of equine serum BChE at 50 nM using acetylthiocholine iodide as substrate preincubated for 60 mins followed by substrate addition measured for 5 mins by Ellman's method
|
Equus caballus
|
54.66
%
|
|
Journal : Eur J Med Chem
Title : Multi-targeted ChEI-copper chelating molecules as neuroprotective agents.
Year : 2019
Volume : 174
First Page : 216
Last Page : 225
Authors : Sestito S, Wang S, Chen Q, Lu J, Bertini S, Pomelli C, Chiellini G, He X, Pi R, Rapposelli S.
Abstract : The identification of a valid therapeutic treatment for Alzheimer's disease (AD) represents nowadays an urgent and still unmet medical need, since currently available anti-AD drugs only relieve symptoms and show a modest efficacy. Recent evidence indicates that multi-target-directed ligands (MTDLs) can potentially provide an effective strategy to develop innovative therapies directed towards the onset and progression of this multifactorial neurodegenerative disorder. In this work we designed, synthesized and evaluated a new series of MTDLs bearing the rivastigmine skeleton (ChE-inhibitor) linked to known metal-chelating moieties with linkers of different length. For all the novel derivatives, AChE/BuChE inhibitory activity, ROS scavenging activity and potential cytotoxicity have been assessed. For the best compound (4), copper chelating properties and neuroprotective effects were also evaluated. Our data demonstrated that hybrid derivative 4 is able to effectively inhibit AChE and BuChE and to chelate copper, showing a protective action on neurons. These results, although preliminary, indicate that compound 4 can be considered as a possible hit molecule for the development of new anti-AD MTDLs.
|
Inhibition of human serum BChE using butyrylthiocholine as substrate by Ellman's assay
|
Homo sapiens
|
300.0
nM
|
|
Journal : Eur J Med Chem
Title : Indazolylketones as new multitarget cannabinoid drugs.
Year : 2019
Volume : 166
First Page : 90
Last Page : 107
Authors : González-Naranjo P, Pérez-Macias N, Pérez C, Roca C, Vaca G, Girón R, Sánchez-Robles E, Martín-Fontelles MI, de Ceballos ML, Martin-Requero A, Campillo NE, Páez JA.
Abstract : Multitarget cannabinoids could be a promising therapeutic strategic to fight against Alzheimer's disease. In this sense, our group has developed a new family of indazolylketones with multitarget profile including cannabinoids, cholinesterase and BACE-1 activity. A medicinal chemistry program that includes computational design, synthesis and in vitro and cellular evaluation has allowed to us to achieve lead compounds. In this work, the synthesis and evaluation of a new class of indazolylketones have been performed. Pharmacological evaluation includes functional activity for cannabinoid receptors on isolated tissue. In addition, in vitro inhibitory assays in AChE/BuChE enzymes and BACE-1 have been carried out. Furthermore, studies of neuroprotective effects in human neuroblastoma SH-SY5Y cells and studies of the mechanisms of survival/death in lymphoblasts of patients with Alzheimer's disease have been achieved. The results of pharmacological tests have revealed that some of these derivatives (5, 6) behave as CB2 cannabinoid agonists and simultaneously show BuChE and/or BACE-1 inhibition.
|
Inhibition of equine serum BuChE using butyrylthiocholine iodide as substrate preincubated with enzyme for 20 mins followed by substrate addition by Ellman's method
|
Equus caballus
|
560.0
nM
|
|
Journal : Eur J Med Chem
Title : Discovery of δ-sultone-fused pyrazoles for treating Alzheimer's disease: Design, synthesis, biological evaluation and SAR studies.
Year : 2019
Volume : 181
First Page : 111598
Last Page : 111598
Authors : Xu Y, Zhang Z, Jiang X, Chen X, Wang Z, Alsulami H, Qin HL, Tang W.
Abstract : A class of novel δ-sulfonolactone-fused pyrazole scaffold was prepared via sulfur (VI) fluoride exchange (SuFEx) chemistry using aryl sulfonyl fluorides and pyrazolones. Enzyme screening revealed their cholinesterase inhibitory activity, among them, compounds 4a, 5a and 5d were identified as highly selective submicromolar BuChE inhibitors (IC<sub>50</sub> = 0.20, 0.46 and 0.42 μM, respectively), which exhibited nontoxicity, lipophilicity and remarkable neuroprotective activity. Kinetic studies showed that BuChE inhibition of compounds 5a and 5d was reversible, mixed-type and non-competitive inhibition against BuChE (K<sub>i</sub> = 145 nM and 60 nM, respectively). Compound 5d can be accommodated into hBuChE via π-S interaction and hydrophobic interactions. The title compounds are potentially symptomatic treatment in progressive Alzheimer's disease.
|
Inhibition of equine BuChE using ACTI as substrate preincubated for 29 mins followed by substrate addition measured at 1 min intervals for 10 mins by Ellman's assay
|
Equus caballus
|
495.0
nM
|
|
Journal : J Med Chem
Title : Discovery and Structure-Activity Relationships of a Highly Selective Butyrylcholinesterase Inhibitor by Structure-Based Virtual Screening.
Year : 2016
Volume : 59
Issue : 16
First Page : 7683
Last Page : 7689
Authors : Dighe SN, Deora GS, De la Mora E, Nachon F, Chan S, Parat MO, Brazzolotto X, Ross BP.
Abstract : Structure-based virtual screening of two libraries containing 567 981 molecules was used to discover novel, selective BuChE inhibitors, which are potentially superior symptomatic treatments in late-stage Alzheimer's disease. Compound 16 was identified as a highly selective submicromolar inhibitor of BuChE (huBuChE IC50 = 0.443 μM) with high permeability in the PAMPA-BBB model. The X-ray crystal structure of huBuChE in complex with 16 revealed the atomic-level interactions and offers opportunities for further development of the series.
|
Inhibition of human BuChE using ACTI as substrate incubated for 40 mins measured at 1 min intervals for 10 mins by Ellman's assay
|
Homo sapiens
|
803.0
nM
|
|
Journal : J Med Chem
Title : Discovery and Structure-Activity Relationships of a Highly Selective Butyrylcholinesterase Inhibitor by Structure-Based Virtual Screening.
Year : 2016
Volume : 59
Issue : 16
First Page : 7683
Last Page : 7689
Authors : Dighe SN, Deora GS, De la Mora E, Nachon F, Chan S, Parat MO, Brazzolotto X, Ross BP.
Abstract : Structure-based virtual screening of two libraries containing 567 981 molecules was used to discover novel, selective BuChE inhibitors, which are potentially superior symptomatic treatments in late-stage Alzheimer's disease. Compound 16 was identified as a highly selective submicromolar inhibitor of BuChE (huBuChE IC50 = 0.443 μM) with high permeability in the PAMPA-BBB model. The X-ray crystal structure of huBuChE in complex with 16 revealed the atomic-level interactions and offers opportunities for further development of the series.
|
Inhibition of mouse plasma BuChE using S-butyrylacetylthiocholine iodide as substrate at 10 uM measured after 30 mins by Ellman's method relative to control
|
Mus musculus
|
93.15
%
|
|
Journal : Eur J Med Chem
Title : Design, synthesis, and evaluation of isoflavone analogs as multifunctional agents for the treatment of Alzheimer's disease.
Year : 2019
Volume : 168
First Page : 207
Last Page : 220
Authors : Wang D, Hu M, Li X, Zhang D, Chen C, Fu J, Shao S, Shi G, Zhou Y, Wu S, Zhang T.
Abstract : A series of novel isoflavone analogs were designed, synthesized, and evaluated as multitarget-directed ligands for the treatment of Alzheimer's disease. In vitro evaluations revealed that some ligands had multifunctional profiles, including potent blockage of histamine 3 receptor (H3R), excellent inhibition of acetylcholinesterase (AChE), neuroprotective effects and anti-neuroinflammatory properties. Among these derivatives, compound 9b exhibited the highest ability to block H3R (IC50 = 0.27 μM) and good inhibitory activity against AChE (IC50 = 0.08 μM). Additionally, compound 9b showed obvious neuroprotective effect on SH-SY5Y by preventing copper-induced neuronal damage and potent anti-neuroinflammatory activity by inhibiting the production of inflammatory factors on BV-2 cells. A molecular modeling study revealed that 9b acts as a mixed-type inhibitor that interacts simultaneously with H3R and AChE. Moreover, in vivo data revealed that compound 9b did not cause acute toxicity in mice at doses up to 1000 mg/kg, and had desirable pharmacokinetic properties, as well as a good blood-brain barrier (BBB) permeability (log BB = 1.24 ± 0.07). Further studies demonstrated that chronic oral treatment with 9b significantly improved cognitive dysfunction in scopolamine-induced AD mice in the step-down passive avoidance test. Taken together, the present study showed that compound 9b is a promising multifunctional drug candidate for the treatment of Alzheimer's disease.
|
Inhibition of mouse plasma BuChE using S-butyrylacetylthiocholine iodide as substrate measured after 30 mins by Ellman's method relative to control
|
Mus musculus
|
58.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis, and evaluation of isoflavone analogs as multifunctional agents for the treatment of Alzheimer's disease.
Year : 2019
Volume : 168
First Page : 207
Last Page : 220
Authors : Wang D, Hu M, Li X, Zhang D, Chen C, Fu J, Shao S, Shi G, Zhou Y, Wu S, Zhang T.
Abstract : A series of novel isoflavone analogs were designed, synthesized, and evaluated as multitarget-directed ligands for the treatment of Alzheimer's disease. In vitro evaluations revealed that some ligands had multifunctional profiles, including potent blockage of histamine 3 receptor (H3R), excellent inhibition of acetylcholinesterase (AChE), neuroprotective effects and anti-neuroinflammatory properties. Among these derivatives, compound 9b exhibited the highest ability to block H3R (IC50 = 0.27 μM) and good inhibitory activity against AChE (IC50 = 0.08 μM). Additionally, compound 9b showed obvious neuroprotective effect on SH-SY5Y by preventing copper-induced neuronal damage and potent anti-neuroinflammatory activity by inhibiting the production of inflammatory factors on BV-2 cells. A molecular modeling study revealed that 9b acts as a mixed-type inhibitor that interacts simultaneously with H3R and AChE. Moreover, in vivo data revealed that compound 9b did not cause acute toxicity in mice at doses up to 1000 mg/kg, and had desirable pharmacokinetic properties, as well as a good blood-brain barrier (BBB) permeability (log BB = 1.24 ± 0.07). Further studies demonstrated that chronic oral treatment with 9b significantly improved cognitive dysfunction in scopolamine-induced AD mice in the step-down passive avoidance test. Taken together, the present study showed that compound 9b is a promising multifunctional drug candidate for the treatment of Alzheimer's disease.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
9.94
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.03
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.03
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
|
In-vivo inhibition of AChE in human brain at 0.6 mg/kg, ip relative to control
|
Homo sapiens
|
40.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Propargylamine-derived multi-target directed ligands for Alzheimer's disease therapy.
Year : 2020
Volume : 30
Issue : 3
First Page : 126880
Last Page : 126880
Authors : do Carmo Carreiras M, Ismaili L, Marco-Contelles J.
Abstract : Current options for the treatment of Alzheimeŕs disease have been restricted to prescription of acetylcholinesterase inhibitors or N-methyl-d-aspartate receptor antagonist, memantine. Propargylamine-derived multi-target directed ligands, such as ladostigil, M30, ASS234 and contilisant, involve different pathways. Apart from acting as inhibitors of both cholinesterases and monoamine oxidases, they show improvement of cognitive impairment, antioxidant activities, enhancement of iron-chelating activities, protect against tau hyperphosphorylation, block metal-associated oxidative stress, regulate APP and Aβ expression processing by the non-amyloidogenic α-secretase pathway, suppress mitochondrial permeability transition pore opening, and coordinate protein kinase C signaling and Bcl-2 family proteins. Other hybrid propargylamine derivatives are also reported.
|
In-vivo inhibition of BuChE in human brain at 0.6 mg/kg, ip relative to control
|
Homo sapiens
|
25.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Propargylamine-derived multi-target directed ligands for Alzheimer's disease therapy.
Year : 2020
Volume : 30
Issue : 3
First Page : 126880
Last Page : 126880
Authors : do Carmo Carreiras M, Ismaili L, Marco-Contelles J.
Abstract : Current options for the treatment of Alzheimeŕs disease have been restricted to prescription of acetylcholinesterase inhibitors or N-methyl-d-aspartate receptor antagonist, memantine. Propargylamine-derived multi-target directed ligands, such as ladostigil, M30, ASS234 and contilisant, involve different pathways. Apart from acting as inhibitors of both cholinesterases and monoamine oxidases, they show improvement of cognitive impairment, antioxidant activities, enhancement of iron-chelating activities, protect against tau hyperphosphorylation, block metal-associated oxidative stress, regulate APP and Aβ expression processing by the non-amyloidogenic α-secretase pathway, suppress mitochondrial permeability transition pore opening, and coordinate protein kinase C signaling and Bcl-2 family proteins. Other hybrid propargylamine derivatives are also reported.
|
Inhibition of equine serum BChE using S-butyrylthiocholine iodide as substrate preincubated for 60 mins followed by substrate addition and measured for 5 mins by Ellman's method
|
Equus caballus
|
785.0
nM
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis and biological evaluation of novel carbamates as potential inhibitors of acetylcholinesterase and butyrylcholinesterase.
Year : 2020
Volume : 28
Issue : 5
First Page : 115324
Last Page : 115324
Authors : Wu J, Pistolozzi M, Liu S, Tan W.
Abstract : Rivastigmine, a dual inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), has been approved by U.S. Food and Drug Administration to treat Alzheimer's disease (AD) and Parkinson's disease (PD) dementia. In the current work, a bambuterol derivative lacking one of the carbamoyloxy groups on the benzene ring (BMC-1) and its analogues were synthesized using 1-(3-hydroxyphenyl) ethan-1-one and 1-(4-hydroxyphenyl) ethan-1-one as starting materials. In-vitro cholinesterase assay established that nine compounds were more potent to inhibit both electric eel AChE and equine serum BChE than rivastigmine under the same experimental conditions. Further study confirmed that among the nine carbamates, BMC-3 (IC<sub>50(AChE)</sub> = 792 nM, IC<sub>50(BChE)</sub> = 2.2 nM) and BMC-16 (IC<sub>50(AChE)</sub> = 266 nM, IC<sub>50(BChE)</sub> = 10.6 nM) were excellent cholinesterase inhibitors with potential of permeating through the blood-brain barrier. These carbamates could be used as potential dual inhibitors of AChE and BChE and to discover novel drugs for the treatment of AD and PD dementia.
|
Inhibition of rat bone marrow myeloperoxidase using H2O2 as substrate at 10 uM after 20 mins by TMB based method (Rvb = - 1.4 +/- 12.7%)
|
Rattus norvegicus
|
17.1
%
|
|
Journal : Bioorg Med Chem
Title : Acylhydrazones as isoniazid derivatives with multi-target profiles for the treatment of Alzheimer's disease: Radical scavenging, myeloperoxidase/acetylcholinesterase inhibition and biometal chelation.
Year : 2020
Volume : 28
Issue : 10
First Page : 115470
Last Page : 115470
Authors : Santos DC, Henriques RR, Junior MAAL, Farias AB, Nogueira TLDC, Quimas JVF, Romeiro NC, Silva LLD, Souza ALF.
Abstract : Acylhydrazones 1a-o, derived from isoniazid, were synthesized and evaluated for Myeloperoxidase (MPO) and Acetylcholinesterase (AChE) inhibition, as well as their antioxidant and metal chelating activities, with the purpose of investigating potential multi-target profiles for the treatment of Alzheimer's disease. Synthesized compounds were tested using the 2,2-diphenyl-2-picrylhydrazyl (DPPH) method and 1i, 1j and 1 m showed radical scavenging ability. Compounds 1b, 1 h, 1i, 1 m and 1o inhibited MPO activity (10 μM) at 96.1 ± 5.5%, 90 ± 2.1%, 100.3 ± 1.7%, 80.1 ± 9.4% and 82.2 ± 10.6%, respectively, and only compound 1 m was able to inhibit 54.2 ± 1.7% of AChE activity (100 μM). Docking studies of the most potent compound 1 m were carried out, and the computational results provided the theoretical basis of enzyme inhibition. Furthermore, compound 1 m was able to form complexes with Fe<sup>2+</sup> and Zn<sup>2+</sup> ions in a 2:1 ligand:metal ratio according to the Job Plot method.
|
Inhibition of Electrophorus electricus AChE at 100 uM using acetylthiocholine iodide as substrate preincubated for 30 mins followed by substrate addition and measured after 10 mins by Ellman's method (Rvb = 7 +/- 7.1%)
|
Electrophorus electricus
|
59.6
%
|
|
Journal : Bioorg Med Chem
Title : Acylhydrazones as isoniazid derivatives with multi-target profiles for the treatment of Alzheimer's disease: Radical scavenging, myeloperoxidase/acetylcholinesterase inhibition and biometal chelation.
Year : 2020
Volume : 28
Issue : 10
First Page : 115470
Last Page : 115470
Authors : Santos DC, Henriques RR, Junior MAAL, Farias AB, Nogueira TLDC, Quimas JVF, Romeiro NC, Silva LLD, Souza ALF.
Abstract : Acylhydrazones 1a-o, derived from isoniazid, were synthesized and evaluated for Myeloperoxidase (MPO) and Acetylcholinesterase (AChE) inhibition, as well as their antioxidant and metal chelating activities, with the purpose of investigating potential multi-target profiles for the treatment of Alzheimer's disease. Synthesized compounds were tested using the 2,2-diphenyl-2-picrylhydrazyl (DPPH) method and 1i, 1j and 1 m showed radical scavenging ability. Compounds 1b, 1 h, 1i, 1 m and 1o inhibited MPO activity (10 μM) at 96.1 ± 5.5%, 90 ± 2.1%, 100.3 ± 1.7%, 80.1 ± 9.4% and 82.2 ± 10.6%, respectively, and only compound 1 m was able to inhibit 54.2 ± 1.7% of AChE activity (100 μM). Docking studies of the most potent compound 1 m were carried out, and the computational results provided the theoretical basis of enzyme inhibition. Furthermore, compound 1 m was able to form complexes with Fe<sup>2+</sup> and Zn<sup>2+</sup> ions in a 2:1 ligand:metal ratio according to the Job Plot method.
|
Inhibition of equine serum BuChE using butyrylthiocholine iodide as substrate preincubated with enzyme for 20 mins followed by addition of substrate and measured after 20 mins by DTNB reagent based Ellman's method
|
Equus caballus
|
560.0
nM
|
|
Journal : Eur J Med Chem
Title : The structure-based optimization of δ-sultone-fused pyrazoles as selective BuChE inhibitors.
Year : 2020
Volume : 201
First Page : 112273
Last Page : 112273
Authors : Zhang Z,Min J,Chen M,Jiang X,Xu Y,Qin H,Tang W
Abstract : Structure-based optimization was conducted to improve the potency and selectivity of BuChE inhibitors with δ-sulfonolactone-fused pyrazole scaffold. By mimicking the hydrophobic interactions of donepezil at PAS, the introduction of a tertiary benzylamine at 5-position can significantly increase BuChE inhibitory activity. Compounds C4 and C6 were identified as high selective nanomolar BuChE inhibitors (IC = 8.3 and 7.7 nM, respectively), which exhibited mild antioxidant capacity, nontoxicity, lipophilicity and neuroprotective activity. Kinetic studies showed that BuChE inhibition of compound C6 was mixed-type against BuChE (K = 24 nM) and >2000-fold selectivity for BuChE over AChE. The proposed binding mode of new inhibitors was consistent with the results of structure-activity relationship analysis.
|
In vivo inhibition of AChE in ICR mouse assessed as reduction in enzyme activity in cerebral cortex at 2 mg/kg, ig via gavage measured after 30 mins using acetylthiocholine iodide as substrate by DTNB reagent based assay
|
Mus musculus
|
49.9
%
|
|
Journal : Bioorg Med Chem
Title : Twin drug design, synthesis and evaluation of diosgenin derivatives as multitargeted agents for the treatment of vascular dementia.
Year : 2021
Volume : 37
First Page : 116109
Last Page : 116109
Authors : Yang GX,Sun JM,Zheng LL,Zhang L,Li J,Gan HX,Huang Y,Huang J,Diao XX,Tang Y,Wang R,Ma L
Abstract : A novel series of multitargeted molecules were designed and synthesized by combining the pharmacological role of cholinesterase inhibitor and antioxidant of steroid as potential ligands for the treatment of Vascular Dementia (VD). The oxygen-glucose deprivation (OGD) model was used to evaluate these molecules, among which the most potent compound ML5 showed the highest activity. Firstly, ML5 showed appropriate inhibition of cholinesterases (ChEs) at orally 15 mg/kg in vivo. The further test revealed that ML5 promoted the nuclear translocation of Nrf2. Furthermore, ML5 has significant neuroprotective effect in vivo model of bilateral common carotid artery occlusion (BCCAO), significantly increasing the expression of Nrf2 protein in the cerebral cortex. In the molecular docking research, we predicted the ML5 combined with hAChE and Keap1. Finally, compound ML5 displayed normal oral absorption and it was nontoxic at 500 mg/kg, po, dose. We can draw the conclusion that ML5 could be considered as a new potential compound for VD treatment.
|
Inhibition of human BuChE using S-butyrylthiocholine as substrate preincubated for 30 mins followed by substrate addition and measured after 25 mins by DTNB-reagent based spectrophotometric method
|
Homo sapiens
|
37.0
nM
|
|
Journal : Eur J Med Chem
Title : Pleiotropic prodrugs: Design of a dual butyrylcholinesterase inhibitor and 5-HT receptor antagonist with therapeutic interest in Alzheimer's disease.
Year : 2021
Volume : 210
First Page : 113059
Last Page : 113059
Authors : Toublet FX,Lalut J,Hatat B,Lecoutey C,Davis A,Since M,Corvaisier S,Freret T,Sopková-de Oliveira Santos J,Claeysen S,Boulouard M,Dallemagne P,Rochais C
Abstract : Beside acetylcholinesterase, butyrylcholinesterase could be considered as a putative target of interest for the symptomatic treatment of Alzheimer's disease (AD). As a result of complexity of AD, no molecule has been approved since 2002. Idalopirdine, a 5-HT receptors antagonist, did not show its effectiveness in clinical trial despite its evaluation as adjunct to cholinesterase inhibitors. Pleiotropic molecules, known as multitarget directed ligands (MTDLs) are currently developed to tackle the multifactorial origin of AD. In this context, we have developed a pleiotropic carbamate 7, that behaves as a covalent inhibitor of BuChE (IC = 0.97 μM). The latter will deliver after hydrolysis, compound 6, a potent 5-HT receptors antagonist (K = 11.4 nM) related to idalopirdine. In silico and in vitro evaluation proving our concept were performed completed with first in vivo results that demonstrate great promise in restoring working memory.
|
Inhibition of human recombinant AChE using acetylthiocholine iodide as substrate preincubated with enzyme for 10 mins followed by substrate addition and measured by Ellman's method
|
Homo sapiens
|
60.0
nM
|
|
|
Inhibition of human serum BuChE using butyrylthiocholine iodide as substrate preincubated with enzyme for 10 mins followed by substrate addition and measured by Ellman's method
|
Homo sapiens
|
14.3
nM
|
|
|
Inhibition of recombinant human BuChe using S-butyrylthiocholine iodide as substrate measured after 7 mins by Ellman's method
|
Homo sapiens
|
300.0
nM
|
|
|
Inhibition of human AChE using acetylthiocholine iodide as substrate at 20 uM preincubated with enzyme for 5 mins followed by substrate addition and measured after 5 mins by Ellman's method
|
Homo sapiens
|
12.2
%
|
|
|
Antioxidant activity assessed as DPPH radical scavenging activity at 100 uM incubated for 2 hrs by microplate reader method
|
None
|
2.5
%
|
|
|
Inhibition of equine serum BuChE using butyrylthiocholine iodide as substrate preincubated with enzyme for 20 mins followed by substrate addition and measured after 20 mins by Ellman's method
|
Equus caballus
|
58.0
nM
|
|
|
Inhibition of HFIP-pretreated human recombinant amyloid beta (1 to 42) self aggregation at 10 uM incubated up to 48 hrs under shaking condition and measured every 3 min by Thioflavin T based fluorescence assay relative to control
|
Homo sapiens
|
86.6
%
|
|
|
Primary screen in NF54 nanoGlo assay, in single point, at 2uM, 72h
|
Plasmodium falciparum
|
7.0
%
|
|
