|
Compound was assessed for in vitro inhibition of Acetylcholinesterase isolated from Electrophorus electricus
|
Electrophorus electricus
|
360.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Potent acetylcholinesterase inhibitors: design, synthesis and structure-activity relationships of alkylene linked bis-galanthamine and galanthamine-galanthaminium salts.
Year : 2000
Volume : 10
Issue : 7
First Page : 637
Last Page : 639
Authors : Guillou C, Mary A, Renko DZ, Gras E, Thal C.
Abstract : The syntheses, the anticholinesterase activities and structure-activity relationships of homodimeric (3a-c) and heterodimeric (6a-c) alkylene linked bis-galanthamine are reported. Compounds 6b-c were found to be more potent than galanthamine and tacrine in inhibiting AChE.
|
Inhibitory activity against acetylcholinesterase (AChE) from Torpedo californica (Reversible type of inhibition)
|
Torpedo californica
|
360.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis, anticholinesterase activity and structure-activity relationships of m-Aminobenzoic acid derivatives.
Year : 2003
Volume : 13
Issue : 10
First Page : 1825
Last Page : 1827
Authors : Trujillo-Ferrara J, Montoya Cano L, Espinoza-Fonseca M.
Abstract : The synthesis, acetylcholinesterase inhibitory capacity and structure-activity relationships of simple-structured m-Aminobenzoic acid derivatives are reported. Compound 1b was found to be more potent than galanthamine and tacrine in inhibiting acetylcholinesterase.
|
Inhibitory activity against acetylcholinesterase in human RBC
|
None
|
100.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Acetylcholinesterase inhibition by fused dihydroquinazoline compounds
Year : 1996
Volume : 6
Issue : 6
First Page : 737
Last Page : 742
Authors : Jaen JC, Gregor VE, Lee C, Davis R, Emmerling M
|
In vitro inhibition of human recombinant AChE.
|
None
|
500.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Quaternary salts of E2020 analogues as acetylcholinesterase inhibitors for the reversal of neuromuscular block.
Year : 2002
Volume : 12
Issue : 18
First Page : 2565
Last Page : 2568
Authors : Clark JK, Cowley P, Muir AW, Palin R, Pow E, Prosser AB, Taylor R, Zhang MQ.
Abstract : A series benzylpiperidinium and benzylpyridinium quaternary salts have been synthesised and tested for inhibition of acetylcholinesterase and reversal of neuromuscular block induced by vecuronium. Several potent reversal agents have been identified and their haemodynamic effects measured.
|
Ex vivo inhibition of human erythrocyte Acetylcholinesterase.
|
None
|
800.0
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.
|
In vitro inhibitory effect on rat Acetylcholinesterase
|
None
|
538.0
nM
|
|
Journal : J. Med. Chem.
Title : Flexible 1-[(2-aminoethoxy)alkyl]-3-ar(o)yl(thio)ureas as novel acetylcholinesterase inhibitors. Synthesis and biochemical evaluation.
Year : 1995
Volume : 38
Issue : 15
First Page : 2969
Last Page : 2973
Authors : Vidaluc JL, Calmel F, Bigg DC, Carilla E, Briley M.
Abstract : A series of flexible 1-(2-aminoethoxy)-3-ar(o)yl(thio)ureas was synthesized and assessed for antiacetylcholinesterase activity. This series was designed in order to optimize the spacer length linking the two pharmacophoric moieties, i.e., the basic nitrogen and the ar(o)yl(thio)-urea unit, and to test compounds with greater conformational flexibility. Thus, the replacement of the previously described spacer, 4-piperidinylethyl, by a linear ethoxyethyl chain gave compounds of slightly comparable potency, providing that they were correctly substituted. The results show that this new flexible spacer is compatible with high inhibitory activities. The optimal chain length corresponds to five methylene groups, allowing an efficient interaction between the two pharmacophoric units and the two reported hypothetical enzyme hydrophobic binding sites. Moreover, the initially optimized benzyl group, attached to the basic nitrogen, was found to be advantageously replaced by a cyclohexyl group, showing that an aromatic residue does not represent a prerequisite for activity.
|
Inhibition against acetylcholinesterase (AChE)
|
None
|
750.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel [2-(4-piperidinyl)ethyl](thio)ureas: synthesis and antiacetylcholinesterase activity.
Year : 1994
Volume : 37
Issue : 5
First Page : 689
Last Page : 695
Authors : Vidaluc JL, Calmel F, Bigg D, Carilla E, Stenger A, Chopin P, Briley M.
Abstract : A series of 1-ar(o)yl-3-[2-(1-benzyl-4-piperidinyl)ethyl](thio)urea derivatives was synthesized and evaluated for antiacetylcholinesterase activity. Most aroyl(thio)urea derivatives showed potent inhibitory activity in the sub-micromolar range. A comparable potency was obtained with the aryl(thio)urea analogues by replacing the phenyl with a 2-pyridyl group. The substituted guanidine variations proved to be almost inactive whereas the nitroethylene analogues appeared to be quite efficient. These results were interpreted in terms of the preferential cis-trans conformation of the aroyl(thio)urea and 2-pyridyl(thio)urea moieties involving the existence of hydrogen bonding. In vivo experiments showed that compound 7m had maximal antiamnestic activity at 0.03 mg/kg with a therapeutic ratio greater than 1000, while cholinergic side effects were only seen at doses 100-fold the maximally effective antiamnestic dose. Compound 7m represents a potentially interesting antidementia agent.
|
Acetylcholinesterase inhibitory activity in rat striatal homogenates
|
None
|
630.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and evaluation of 5-amino-5,6,7,8-tetrahydroquinolinones as potential agents for the treatment of Alzheimer's disease.
Year : 1995
Volume : 38
Issue : 18
First Page : 3645
Last Page : 3651
Authors : Fink DM, Bores GM, Effland RC, Huger FP, Kurys BE, Rush DK, Selk DE.
Abstract : A series of 5-amino-5,6,7,8-tetrahydroquinolinones was designed and synthesized as acetylcholinesterase inhibitors. The compounds are related to hyperzine A, a naturally occurring cholinesterase inhibitor. They inhibit acetylcholinesterase in vitro, and many are active in vivo in reversing a scopolamine-induced impairment of 24 h memory in a passive avoidance paradigm. Although these compounds were designed as partial structures of huperzine A, it is unlikely that they bind to the enzyme in a similar fashion, since they lack the unsaturated three-carbon bridge of huperzine A and both the quinolinone nitrogen and the amino group must be substituted in order to obtain good enzyme affinity.
|
Inhibitory concentration against human erythrocyte Acetylcholinesterase
|
Homo sapiens
|
800.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel anticholinesterases based on the molecular skeletons of furobenzofuran and methanobenzodioxepine.
Year : 2005
Volume : 48
Issue : 4
First Page : 986
Last Page : 994
Authors : Luo W, Yu QS, Zhan M, Parrish D, Deschamps JR, Kulkarni SS, Holloway HW, Alley GM, Lahiri DK, Brossi A, Greig NH.
Abstract : Reductive cyclization of 5-hydroxy-3-methyl-3-methoxycarbonylmethylenebenzofuran-2(3H)-one (4) gave 5-hydroxy-3a-methyl-2,3,3a,8a-tatrahydrofuro[2,3-b]benzofuran (5) and the rearrangement product 7-hydroxy-4,5-dihydro-2,5-methano-1,3-benzodioxepine (6). Reaction of compounds 5 and 6 with different isocyanates provided two series novel carbamates (7-12) whose structures were confirmed by X-ray crystallography. These were assessed for anticholinesterase action against freshly prepared human enzyme and proved to be potent inhibitors of either acetyl- (AChE) or butyrylcholinesterase (BChE) with specific compounds exhibiting remarkable selectivity. Because the two series of carbamates (7-12) differ in their phenolic moieties, their respective potency and selectivity for AChE versus BChE was governed by their N-substituted groups. This same characteristic was also present in a series of physovenine analogues (1, 13, 15, 17) and physostigmine analogues (2, 14, 16, 18). These structure-activity relations proved valuable in elucidating the mechanisms underpinning the interaction between carbamate-based cholinesterase inhibitors and their enzyme target. In addition, because physostigmine analogues have demonstrated activity in lowering the Alzheimer's disease protein, amyloid precursor protein (APP), examples of the two new series of carbamates were characterized in culture assays of quantifying cell viability and synthesis of APP.
|
Inhibitory activity against AChE from electric eel
|
Electrophorus electricus
|
500.0
nM
|
|
Inhibitory activity against AChE from electric eel
|
Electrophorus electricus
|
440.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Isolation and cholinesterase-inhibition studies of sterols from Haloxylon recurvum.
Year : 2006
Volume : 16
Issue : 3
First Page : 573
Last Page : 580
Authors : Ahmed E, Nawaz SA, Malik A, Choudhary MI.
Abstract : Haloxysterols A-D (1-4), new C-24 alkylated sterols, have been isolated from the chloroform soluble fraction of Haloxylon recurvum, along with five known sterols 5-9, which are reported for the first time from this species. Their structures were determined by means of 1D- and 2D-NMR techniques. Compounds 1-9 inhibited cholinesterase enzymes in a concentration-dependent manner with K(i) values ranging between 0.85-25.5 and 1.0-19.0 microM against acetylcholinesterase (AChE; EC 3.1.1.7) and butyrylcholinesterase (BChE; EC 3.1.1.8) enzymes, respectively. Lineweaver-Burk, Dixon plots and their secondary replots indicated that compounds 1-9 are non-competitive inhibitors of both AChE and BChE enzymes.
|
Anticholinesterase activity against human erythrocyte AChE
|
Homo sapiens
|
800.0
nM
|
|
Journal : J. Med. Chem.
Title : Inhibition of human acetyl- and butyrylcholinesterase by novel carbamates of (-)- and (+)-tetrahydrofurobenzofuran and methanobenzodioxepine.
Year : 2006
Volume : 49
Issue : 7
First Page : 2174
Last Page : 2185
Authors : Luo W, Yu QS, Kulkarni SS, Parrish DA, Holloway HW, Tweedie D, Shafferman A, Lahiri DK, Brossi A, Greig NH.
Abstract : A new enantiomeric synthesis utilizing classical resolution provided two novel series of optically active inhibitors of cholinesterase: (-)- and (+)-O-carbamoyl phenols of tetrahydrofurobenzofuran and methanobenzodioxepine. An additional two series of (-)- and (+)-O-carbamoyl phenols of pyrroloindole and furoindole were obtained by known procedures, and their anticholinesterase actions were similarly quantified against freshly prepared human acetyl- (AChE) and butyrylcholinesterase (BChE). Both enantiomeric forms of each series demonstrated potent cholinesterase inhibitory activity (with IC(50) values as low as 10 nM for AChE and 3 nM for BChE), with the exception of the (+)-O-carbamoyl phenols of pyrroloindole, which lacked activity (IC(50) values >1 microM). Based on the biological data of these four series, a structure-activity relationship (SAR) analysis was provided by molecular volume calculations. In addition, a probable transition-state model was established according to the known X-ray structure of a transition-state complex of Torpedo californica AChE-m-(N,N,N-trimethylammonio)-2,2,2-trifluoroacetophenone (TcAChE-TMTFA). This model proved valuable in explaining the enantioselectivity and enzyme subtype selectivity of each series. These carbamates are more potent than, or similarly potent to, anticholinesterases in current clinical use, providing not only inhibitors of potential clinical relevance but also pharmacological tools to define drug-enzyme binding interactions within an enzyme crucial in the maintenance of cognition and numerous systemic physiological functions in health, aging, and disease.
|
Inhibition of AChE activity
|
Homo sapiens
|
590.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Isoquinoline derivatives as potential acetylcholinesterase inhibitors.
Year : 2006
Volume : 16
Issue : 8
First Page : 2170
Last Page : 2172
Authors : Markmee S, Ruchirawat S, Prachyawarakorn V, Ingkaninan K, Khorana N.
Abstract : Several bisbenzylisoquinoline alkaloid derivatives showed the inhibitory activity at acetylcholinesterase enzyme (AChE) in micromolar range. It is possible that monomeric moiety of bisbenzylisoquinoline alkaloid might be required for acetylcholinesterase enzyme inhibition. AChE inhibitory activity of related monomeric 1-benzylisoquinolines was examined by using Ellman colorimetric assay with galanthamine as a reference standard.
|
Inhibition of electric eel AChE
|
Electrophorus electricus
|
640.0
nM
|
|
Inhibition of electric eel AChE
|
Electrophorus electricus
|
635.33
nM
|
|
Journal : J. Med. Chem.
Title : Homobivalent quinazolinimines as novel nanomolar inhibitors of cholinesterases with dirigible selectivity toward butyrylcholinesterase.
Year : 2006
Volume : 49
Issue : 18
First Page : 5411
Last Page : 5413
Authors : Decker M.
Abstract : Homobivalent dimers of quinazolinimines, which bridge the imine nitrogen atoms via a hepta- and an octamethylene spacer, with different ring sizes of the alicycles were synthesized from the corresponding quinazolinethiones. The resulting compounds show >100-fold increase of inhibitory activities compared to related monomeric compounds yielding low-nanomolar inhibitors. For heptamethylene dimers, mixed inhibition profiles were obtained, whereas for the octamethylene compounds selectivity toward butyrylcholinesterase (>180) can be achieved with an eight-membered alicycle.
|
Inhibition of AChE
|
Homo sapiens
|
600.0
nM
|
|
Inhibition of AChE
|
Homo sapiens
|
635.33
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 6-Hydroxy- and 6-methoxy-beta-carbolines as acetyl- and butyrylcholinesterase inhibitors.
Year : 2006
Volume : 16
Issue : 22
First Page : 5840
Last Page : 5843
Authors : Schott Y, Decker M, Rommelspacher H, Lehmann J.
Abstract : In the course of studies directed toward the discovery of novel acetyl- and butyrylcholinesterase (AChE and BChE) inhibitors for the treatment of Alzheimer's disease, we focused on beta-carbolines (BCs). 6-Oxygenated beta-carboline and beta-carbolinium derivatives based on the serotonin template were synthesized and tested in vitro for their ability to inhibit AChE and BChE, respectively. Particularly the carbolinium salts, which can be formed by intracerebral methylation out of the tertiary-BC prodrugs, show inhibitory activity levels reaching those of galantamine, physostigmine, and rivastigmine.
|
Inhibition of AChE
|
None
|
550.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Methyl 2-(2-(4-formylphenoxy)acetamido)-2-substituted acetate derivatives: a new class of acetylcholinesterase inhibitors.
Year : 2007
Volume : 17
Issue : 8
First Page : 2123
Last Page : 2125
Authors : Wen H, Zhou Y, Lin C, Ge H, Ma L, Wang Z, Peng W, Song H.
Abstract : A new class of inhibitors of acetylcholinesterase (methyl 2-(2-(4-formylphenoxy)acetamido)-2-substituted acetate derivatives) is described. Compounds 4b and 4i were found to be more potent than galanthamine in inhibiting acetylcholinesterase.
|
Inhibition of human AChE-induced amyloid beta (1-40) aggregation at 100 uM
|
Homo sapiens
|
17.9
%
|
|
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
|
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 Electrophorus electricus AChE by Ellman's method
|
Electrophorus electricus
|
360.0
nM
|
|
Journal : J. Med. Chem.
Title : New potent acetylcholinesterase inhibitors in the tetracyclic triterpene series.
Year : 2007
Volume : 50
Issue : 22
First Page : 5311
Last Page : 5323
Authors : Sauvaître T, Barlier M, Herlem D, Gresh N, Chiaroni A, Guenard D, Guillou C.
Abstract : A new highly selective inhibitor of acetylcholinesterase (AChE) was discovered by high-throughput screening. Compound 1 was synthesized from a natural product, the N-3-isobutyrylcycloxobuxidine-F 2. A new extraction protocol of this compound is described. The hemisynthesis and optimization of 1 are reported. The analogs of 1 were tested in vitro for the inhibition of both cholinesterases (AChE and BuChE). These compounds selectively inhibited AChE. Extensive molecular docking studies were performed with 2 and AChE employing Discover Biosym software to rationalize the binding interaction. The results suggested that ligand 2 binds simultaneously to both catalytic and peripheral sites of AChE.
|
Inhibition of electric eel AChE
|
Electrophorus electricus
|
550.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Derivatives of oxoisoaporphine alkaloids: a novel class of selective acetylcholinesterase inhibitors.
Year : 2007
Volume : 17
Issue : 13
First Page : 3765
Last Page : 3768
Authors : Tang H, Ning FX, Wei YB, Huang SL, Huang ZS, Chan AS, Gu LQ.
Abstract : A series of 9-aminoalkanamido-1-azabenzanthrones derviatives (3a-i Ar-NHCO(CH(2))(n)NR(1)R(2)) and their quaternary methiodide salts (4a-g Ar-NHCO(CH(2))(n)N(+)(CH(3))R(1)R(2)I(-)) were designed and synthesized as acetylcholinesterase (AChE) or butyrylcholinesterase (BuChE) inhibitors. The synthetic compounds exhibited high AChE inhibitory activity with IC(50) values in the nanomolar range and high selectivity for AChE over BuChE (45- to 1980-fold). The structure-activity relationships (SARs) were discussed.
|
Inhibition of rat brain acetylcholinesterase by colorimetric method
|
Rattus norvegicus
|
920.0
nM
|
|
Journal : J. Nat. Prod.
Title : Indole glucoalkaloids from Chimarrhis turbinata and their evaluation as antioxidant agents and acetylcholinesterase inhibitors.
Year : 2004
Volume : 67
Issue : 11
First Page : 1882
Last Page : 1885
Authors : Cardoso CL, Castro-Gamboa I, Silva DH, Furlan M, Epifanio Rde A, Pinto Ada C, Moraes de Rezende C, Lima JA, Bolzani Vda S.
Abstract : As part of our study on bioactive agents from Brazilian rainforest plants, two new glucoalkaloids, 3,4-dehydro-strictosidine (1) and 3,4-dehydro-strictosidinic acid (2), were isolated from Chimarrhis turbinata, along with seven known glucoalkaloids, cordifoline (3), strictosidinic acid (4), strictosidine (5), 5 alpha-carboxystrictosidine (6), turbinatine (7), desoxycordifoline (8), and harman-3-carboxylic acid (9). The structures of the new alkaloids were established on the basis of comprehensive spectral analysis, mainly 1D and 2D NMR experiments, as well as high-resolution HRESIMS. Alkaloid 3 showed strong free-radical scavenging activity against 1,1-diphenyl-2-picrylhydrazyl (DPPH) as well as pronounced antioxidant activity evidenced by redox properties measured by ElCD-HPLC. Additionally, alkaloids 1-9 were submitted to TLC screening for acetylcholinesterase inhibitors. Both 7 and 8 were shown to be moderate acetylcholinesterase inhibitors at a concentration of 0.1 and 1.0 microM, respectively. In an in vitro rat brain assay, 7 showed moderate activity (IC(50) 1.86 microM), compared to the standard compound, galanthamine (IC(50) 0.92 microM).
|
Inhibition of acetylcholinesterase-mediated hydrolysis of acetylcholine at 0.16 mg/mL relative to galanthamine
|
None
|
99.7
%
|
|
Journal : J. Nat. Prod.
Title : Bioactive constituents from Iryanthera megistophylla.
Year : 2002
Volume : 65
Issue : 10
First Page : 1412
Last Page : 1416
Authors : Ming DS, López A, Hillhouse BJ, French CJ, Hudson JB, Towers GH.
Abstract : Activity-guided fractionation of the 95% ethanol extract from the stem bark of Iryanthera megistophylla led to the isolation of two new compounds, named megislignan [2,3-dimethyl-4-(4-methoxyphenyl)-6-hydroxynaphthalene] (1) and megislactone [(2R,3R,4R)-3-hydroxy-4-methyl-2-(hexacos-17-enyl)butanolide] (2), along with seven known compounds, grandinolide (3), iryantherin K (4), iryantherin L (5), cinchonain I b (6), cinchonain I a (7), procyanidin B-2 (8), and cinchonain IIa (9). The structures of the new compounds were elucidated by spectral data interpretation. Isolates were evaluated for their antibacterial, antifungal, antiviral, and antiacetylcholinesterase activities.
|
Inhibition of Torpedo californica AchE activity by Ellman's assay
|
Torpedo californica
|
590.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Petrosamine, a potent anticholinesterase pyridoacridine alkaloid from a Thai marine sponge Petrosia n. sp.
Year : 2008
Volume : 16
Issue : 13
First Page : 6560
Last Page : 6567
Authors : Nukoolkarn VS, Saen-oon S, Rungrotmongkol T, Hannongbua S, Ingkaninan K, Suwanborirux K.
Abstract : Two pyridoacridine alkaloids, including a known petrosamine and a new 2-bromoamphimedine were isolated from a Thai marine sponge Petrosia n. sp. The alkaloids were characterized on the basis of 1D and 2D NMR, MS, and IR spectroscopy. Only petrosamine showed strong acetylcholinesterase inhibitory activity approximately six times higher than that of the reference galanthamine. A computational docking study of petrosamine with the enzyme from the electric eel Torpedo californica (TcAChE) showed the major contribution to the petrosamine-TcAChE interaction to be arising from the quaternary ammonium group of petrosamine.
|
Inhibition of human recombinant AChE-induced amyloid beta (1-40) aggregation at 100 uM by thioflavin T formation assay
|
Homo sapiens
|
17.9
%
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationships of acetylcholinesterase noncovalent inhibitors based on a polyamine backbone. 4. Further investigation on the inner spacer.
Year : 2008
Volume : 51
Issue : 22
First Page : 7308
Last Page : 7312
Authors : Tumiatti V, Milelli A, Minarini A, Rosini M, Bolognesi ML, Micco M, Andrisano V, Bartolini M, Mancini F, Recanatini M, Cavalli A, Melchiorre C.
Abstract : Novel multi-target-directed ligands were designed by replacing the inner dipiperidino function of 3 with less flexible or completely rigid moieties to obtain compounds endowed with multiple biological properties that might be relevant to Alzheimer's disease. 15 was the most interesting, inhibiting AChE in the nanomolar range and inhibiting AChE-induced and self-promoted beta-amyloid aggregation in the micromolar range.
|
Inhibition of self-induced amyloid beta (1-40) aggregation at 10 uM by thioflavin T formation assay
|
None
|
5.0
%
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationships of acetylcholinesterase noncovalent inhibitors based on a polyamine backbone. 4. Further investigation on the inner spacer.
Year : 2008
Volume : 51
Issue : 22
First Page : 7308
Last Page : 7312
Authors : Tumiatti V, Milelli A, Minarini A, Rosini M, Bolognesi ML, Micco M, Andrisano V, Bartolini M, Mancini F, Recanatini M, Cavalli A, Melchiorre C.
Abstract : Novel multi-target-directed ligands were designed by replacing the inner dipiperidino function of 3 with less flexible or completely rigid moieties to obtain compounds endowed with multiple biological properties that might be relevant to Alzheimer's disease. 15 was the most interesting, inhibiting AChE in the nanomolar range and inhibiting AChE-induced and self-promoted beta-amyloid aggregation in the micromolar range.
|
Inhibition of acetylcholinesterase
|
None
|
500.0
nM
|
|
Journal : J. Nat. Prod.
Title : Bioactive 5alpha-pregnane-type steroidal alkaloids from Sarcococca hookeriana.
Year : 2008
Volume : 71
Issue : 8
First Page : 1481
Last Page : 1484
Authors : Devkota KP, Lenta BN, Wansi JD, Choudhary MI, Kisangau DP, Naz Q, Samreen, Sewald N.
Abstract : The bioassay-guided phytochemical investigation of Sarcococca hookeriana with respect to cholinesterase inhibitory properties has yielded two new 5alpha-pregnane-type steroidal alkaloids, hookerianamides J (1) and K (2), along with eight known compounds (3-10). The structures of 1 and 2 were elucidated by spectroscopic methods. These compounds displayed good to moderate activities in vitro against the enzymes acetylcholinesterase (IC 50 8.1-48.5 microM) and butyrylcholinesterase (IC 50 0.4-4.0 microM). Compounds 1-10 were also tested in vitro for their leishmanicidal activity against Leishmania major and for their antibacterial activities against Bacillus subtilis, Micrococcus luteus, Streptococcus faecalis, and Pseudomonas pallida.
|
Inhibition of AchE
|
None
|
500.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Solid-phase synthesis and biological evaluation of a parallel library of 2,3-dihydro-1,5-benzothiazepines.
Year : 2008
Volume : 16
Issue : 16
First Page : 7691
Last Page : 7697
Authors : Ansari FL, Iftikhar F, Ihsan-Ul-Haq, Mirza B, Baseer M, Rashid U.
Abstract : Solid-phase synthesis of a parallel library of 3'-hydroxy-2,3-dihydrobenzothiazepines has been carried out through [4+3] annulation of alpha,beta-unsaturated ketones with aminothiophenol, using Wang resin as solid support. The synthesized compounds were evaluated for their potential as antibacterial, tumor inhibitors as well as acetyl- and butyrylcholinesterase inhibitors. None of the compounds showed any significant antibacterial activity. However, quite a few compounds showed significant potential as crown gall tumor inhibitors. These results reflect a strong exploratory potential in search of new benzothiazepines as source of anticancer agents. The results of the inhibition of cholinesterase revealed that benzothiazepines have a greater potential as butyrylcholinesterase inhibitors as compared to acetylcholinesterase. Moreover, the substitution of hydroxy group at C-3 in ring A led to increased activity when compared to unsubstituted- and 2'-OH substituted benzothiazepines.
|
Inhibition of human AChE at 100 uM by Ellman's assay
|
Homo sapiens
|
97.66
%
|
|
Journal : J. Nat. Prod.
Title : Taspine: bioactivity-guided isolation and molecular ligand-target insight of a potent acetylcholinesterase inhibitor from Magnolia x soulangiana.
Year : 2006
Volume : 69
Issue : 9
First Page : 1341
Last Page : 1346
Authors : Rollinger JM, Schuster D, Baier E, Ellmerer EP, Langer T, Stuppner H.
Abstract : A bioactivity-guided approach was taken to identify the acetylcholinesterase (AChE, EC 3.1.1.7) inhibitory agent in a Magnolia x soulangiana extract using a microplate enzyme assay with Ellman's reagent. This permitted the isolation of the alkaloids taspine (1) and (-)-asimilobine (2), which were detected for the first time in this species. Compound 1 showed a significantly higher effect on AChE than the positive control galanthamine and selectively inhibited the enzyme in a long-lasting and concentration-dependent fashion with an IC(50) value of 0.33 +/- 0.07 muM. Extensive molecular docking studies were performed with human and Torpedo californica-AChE employing Gold software to rationalize the binding interaction. The results suggested ligand 1 to bind in an alternative binding orientation when compared to galanthamine. While this is located in close vicinity to the catalytic amino acid triad, the 1-AChE complex was found to be stabilized by (i) sandwich-like pi-stacking interactions between the planar aromatic ligand (1) and the Trp84 and Phe330 of the enzyme, (ii) an esteratic site anchoring with the amino side chain, and (iii) a hydrogen-bonding network.
|
Inhibition of AChE by microplate assay
|
None
|
980.0
nM
|
|
Journal : J. Nat. Prod.
Title : The application of HPLC with on-line coupled UV/MS-biochemical detection for isolation of an acetylcholinesterase inhibitor from narcissus 'Sir Winston Churchill'.
Year : 2000
Volume : 63
Issue : 6
First Page : 803
Last Page : 806
Authors : Ingkaninan K, Hazekamp A, de Best CM, Irth H, Tjaden UR, van der Heijden R, van der Greef J, Verpoorte R.
Abstract : An HPLC with on-line coupled UV/MS-biochemical detection method for acetylcholinesterase (AChE) inhibitors in natural sources has been developed. The potential of this method is shown by the isolation of a new AChE inhibitor from the alcoholic extract of Narcissus 'Sir Winston Churchill'. Combining a prefractionation technique using centrifugal partition chromatography with the on-line HPLC-UV/MS-biochemical detection resulted in the isolation of the active compound that was identified as ungiminorine. This alkaloid shows a mild inhibitory effect on AChE.
|
Inhibition of acetylcholinesterase at 10 uM by Ellman's method
|
None
|
96.82
%
|
|
Journal : J. Nat. Prod.
Title : Xanthones from Gentianella amarella ssp. acuta with acetylcholinesterase and monoamine oxidase inhibitory activities.
Year : 2008
Volume : 71
Issue : 5
First Page : 895
Last Page : 897
Authors : Urbain A, Marston A, Grilo LS, Bravo J, Purev O, Purevsuren B, Batsuren D, Reist M, Carrupt PA, Hostettmann K.
Abstract : Two new xanthone glycosides, corymbiferin 3-O-beta-D-glucopyranoside (1) and swertiabisxanthone-I 8'-O-beta- d-glucopyranoside (2), were isolated from Gentianella amarella ssp. acuta, along with eight known xanthones: triptexanthoside C, veratriloside, corymbiferin 1-O-glucoside, swertianolin, norswertianolin, swertiabisxanthone-I, bellidin, and bellidifolin, four of them identified for the first time in G. amarella ssp. acuta. The isolation was conducted mainly by centrifugal partition chromatography, and the structures of the isolated compounds were established on the basis of spectrometric data including 2D NMR and mass spectrometry. Xanthones were weakly active against acetylcholinesterase (AChE), except triptexanthoside C, which inhibited AChE with an IC(50) of 13.8 +/- 1.6 microM. Some compounds were active against monoamine oxidases (MAO): bellidin and bellidifolin showed interesting inhibitory activity of MAO A, while swertianolin, the 8-O-glucopyranoside form of bellidifolin, gave 93.6% inhibition of MAO B activity at 10(-5) M.
|
Inhibition of electric eel AChE type 6S by Ellman's assay
|
Electrophorus electricus
|
640.0
nM
|
|
Inhibition of electric eel AChE type 6S by Ellman's assay
|
Electrophorus electricus
|
635.33
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis and pharmacological evaluation of hybrid molecules out of quinazolinimines and lipoic acid lead to highly potent and selective butyrylcholinesterase inhibitors with antioxidant properties.
Year : 2008
Volume : 16
Issue : 8
First Page : 4252
Last Page : 4261
Authors : Decker M, Kraus B, Heilmann J.
Abstract : A set of hybrid molecules were synthesized out of lipoic acid, alpha,omega-diamines of different lengths serving as spacers, and cholinesterase (ChE) inhibiting [2,1-b]quinazolinimines. Depending on the length of the alkylene spacer the amide hybrids are inhibitors of acetylcholinesterase (AChE) with inhibitory activities of 0.5-4.6microM and inhibitors of butyrylcholinesterase (BChE) with activities down to 5.7nM, therefore greatly exceeding the inhibitory activities of the parent quinazolinimines by factors of up to 1000. Due to increasing activity at BChE with increasing length of the alkylene spacer approximately 100-fold selectivity toward BChE is reached with a hepta- and an octamethylene spacer. Kinetic measurements reveal competitive and reversible inhibition of both ChEs by the hybrids. Furthermore, cell viability and antioxidant activity (using the ORAC-fluorescein assay) of several hybrids were evaluated, showing cytotoxicity at concentrations from 3.7 to 10.2microM and antioxidant properties are in the range of 0.4-0.8 Trolox equivalents (lipoic acid=0.6).
|
Inhibition of Torpedo californica AChE
|
Torpedo californica
|
652.0
nM
|
|
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 AChE
|
Homo sapiens
|
350.0
nM
|
|
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 electric eel AChE by Ellman's method
|
Electrophorus electricus
|
550.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis, biological evaluation and molecular modeling of oxoisoaporphine and oxoaporphine derivatives as new dual inhibitors of acetylcholinesterase/butyrylcholinesterase.
Year : 2009
Volume : 44
Issue : 6
First Page : 2523
Last Page : 2532
Authors : Tang H, Wei YB, Zhang C, Ning FX, Qiao W, Huang SL, Ma L, Huang ZS, Gu LQ.
Abstract : Aporphine alkaloids, isolated from Chinese medicinal herb, are important natural products. We recently reported that synthetic derivatives of oxoisoaporphine alkaloids exhibited high acetylcholinesterase inhibitory activity and high selectivity for AChE over BuChE (Bioorg. Med. Chem. Lett. 2007, 17, 3765-3768). In this paper, further research results were presented. A series of novel derivatives of oxoaporphine alkaloids (5a-j, 4-carboxylic amide-7-oxo-7H-dibenzo[de,g]quinoline, Ar-CONH(CH(2))(n)NR) and their quaternary methiodide salts (6a-h, Ar-CONH(CH(2))(n)N(+)(CH(3))RI(-)) were designed and synthesized as acetylcholinesterase (AChE) and/or butyrylcholinesterase (BuChE) inhibitors. The AChE inhibition potency of synthetic oxoaporphine derivatives was decreased about 2-3 orders of magnitude as compared with that of oxoisoaporphine derivatives. Non-competitive binding mode was found for both kinds of derivatives. Molecular docking simulations on the oxoisoaporphine derivatives 7 series and oxoaporphine derivatives 6 series with AChE from Torpedo californica have demonstrated that the ligands bound to the dual-site of the enzyme.
|
Antioxidant activity in Wistar rat brain assessed as inhibition of lipid peroxidation
|
Rattus norvegicus
|
4.93
ug.mL-1
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis, spectral characterization and biological evaluation of phosphorylated derivatives of galanthamine.
Year : 2010
Volume : 45
Issue : 1
First Page : 203
Last Page : 209
Authors : Koteswara Rao V, Janardhan Rao A, Subba Reddy S, Naga Raju C, Visweswara Rao P, Ghosh SK.
Abstract : A series of novel phosphorylated derivatives of galanthamine 6-11 and 12-17 were synthesized in two step process with high yields. In the first step galanthamine 1 was reacted with bis (2-chloroethyl) phosphoramidic dichloride 2/4-nitrophenyl phosphorodichloridate 3 in presence of triethylamine (TEA) in dry tetrahydrofuran (THF) yielded the intermediates 4/5. They were further reacted with various compounds like 2-aminoethanol, ethyleneglycol, ethylenediamine, 2-aminoethanethiol, 2-hydroxyethanethiol, monopotassium dihydrogenphosphate to obtain the title compounds 6-11 and 12-17. The title compounds showed promising antimicrobial, antioxidant activities and was greatly influenced by the presence of different bioactive groups.
|
Antioxidant activity in Wistar rat brain assessed as reduction in glutathione content
|
Rattus norvegicus
|
4.21
ug.mL-1
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis, spectral characterization and biological evaluation of phosphorylated derivatives of galanthamine.
Year : 2010
Volume : 45
Issue : 1
First Page : 203
Last Page : 209
Authors : Koteswara Rao V, Janardhan Rao A, Subba Reddy S, Naga Raju C, Visweswara Rao P, Ghosh SK.
Abstract : A series of novel phosphorylated derivatives of galanthamine 6-11 and 12-17 were synthesized in two step process with high yields. In the first step galanthamine 1 was reacted with bis (2-chloroethyl) phosphoramidic dichloride 2/4-nitrophenyl phosphorodichloridate 3 in presence of triethylamine (TEA) in dry tetrahydrofuran (THF) yielded the intermediates 4/5. They were further reacted with various compounds like 2-aminoethanol, ethyleneglycol, ethylenediamine, 2-aminoethanethiol, 2-hydroxyethanethiol, monopotassium dihydrogenphosphate to obtain the title compounds 6-11 and 12-17. The title compounds showed promising antimicrobial, antioxidant activities and was greatly influenced by the presence of different bioactive groups.
|
Inhibition of superoxide dismutase in Wistar rat brain
|
Rattus norvegicus
|
3.84
ug.mL-1
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis, spectral characterization and biological evaluation of phosphorylated derivatives of galanthamine.
Year : 2010
Volume : 45
Issue : 1
First Page : 203
Last Page : 209
Authors : Koteswara Rao V, Janardhan Rao A, Subba Reddy S, Naga Raju C, Visweswara Rao P, Ghosh SK.
Abstract : A series of novel phosphorylated derivatives of galanthamine 6-11 and 12-17 were synthesized in two step process with high yields. In the first step galanthamine 1 was reacted with bis (2-chloroethyl) phosphoramidic dichloride 2/4-nitrophenyl phosphorodichloridate 3 in presence of triethylamine (TEA) in dry tetrahydrofuran (THF) yielded the intermediates 4/5. They were further reacted with various compounds like 2-aminoethanol, ethyleneglycol, ethylenediamine, 2-aminoethanethiol, 2-hydroxyethanethiol, monopotassium dihydrogenphosphate to obtain the title compounds 6-11 and 12-17. The title compounds showed promising antimicrobial, antioxidant activities and was greatly influenced by the presence of different bioactive groups.
|
Inhibition of catalase in Wistar rat brain
|
Rattus norvegicus
|
5.06
ug.mL-1
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis, spectral characterization and biological evaluation of phosphorylated derivatives of galanthamine.
Year : 2010
Volume : 45
Issue : 1
First Page : 203
Last Page : 209
Authors : Koteswara Rao V, Janardhan Rao A, Subba Reddy S, Naga Raju C, Visweswara Rao P, Ghosh SK.
Abstract : A series of novel phosphorylated derivatives of galanthamine 6-11 and 12-17 were synthesized in two step process with high yields. In the first step galanthamine 1 was reacted with bis (2-chloroethyl) phosphoramidic dichloride 2/4-nitrophenyl phosphorodichloridate 3 in presence of triethylamine (TEA) in dry tetrahydrofuran (THF) yielded the intermediates 4/5. They were further reacted with various compounds like 2-aminoethanol, ethyleneglycol, ethylenediamine, 2-aminoethanethiol, 2-hydroxyethanethiol, monopotassium dihydrogenphosphate to obtain the title compounds 6-11 and 12-17. The title compounds showed promising antimicrobial, antioxidant activities and was greatly influenced by the presence of different bioactive groups.
|
Inhibition of electric eel AChE by modified Ellman method
|
Electrophorus electricus
|
623.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis, biological evaluation, and molecular modeling of berberine derivatives as potent acetylcholinesterase inhibitors.
Year : 2010
Volume : 18
Issue : 3
First Page : 1244
Last Page : 1251
Authors : Huang L, Shi A, He F, Li X.
Abstract : By targeting the dual active sites of acetylcholinesterase (AChE), a new series of berberine derivatives was designed, synthesized, and evaluated as AChE inhibitors. Most of the derivatives inhibited AChE in the sub-micromolar range. Compound 8c, berberine linked with phenol by a 4-carbon spacer, showed the most potent inhibition of AChE. A kinetic study of AChE and BuChE indicated that a mix-competitive binding mode existed for these berberine derivatives. Molecular modeling studies confirmed that these hybrids target both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. This is the first report where AChE inhibitory activity has been associated with berberine as a lead molecule.
|
Inhibition of Electric eel AChE after 2 mins by colorimetric Ellman assay
|
Electrophorus electricus
|
640.0
nM
|
|
Inhibition of Electric eel AChE after 2 mins by colorimetric Ellman assay
|
Electrophorus electricus
|
635.33
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Bivalent 5,8,9,13b-tetrahydro-6H-isoquino[1,2-a]isoquinolines and -isoquinolinium salts: novel heterocyclic templates for butyrylcholinesterase inhibitors.
Year : 2010
Volume : 20
Issue : 9
First Page : 2946
Last Page : 2949
Authors : Schulze M, Siol O, Decker M, Lehmann J.
Abstract : Three different types of homobivalent compounds, 5,8,9,13b-tetrahydro-6H-isoqino[1,2-a]isoquinolines bearing tertiary N-atoms, their quaternary ammonium salts and their dibenzazecine analogues, connected by alkylene spacers of various lengths were synthesized. Compared to the therapeutically used inhibitor galanthamine, some of the bivalent compounds showed much higher inhibitory activities at both cholinesterases in the Ellman test. Surprisingly, not only the quaternary salts, but also the uncharged tertiary compounds exhibited IC(50) values at butyrylcholinesterase in the nanomolar range. Selectivity toward BChE of up to 76-fold was observed.
|
Inhibition of electric eel AChE by modified Ellman's method
|
Electrophorus electricus
|
635.33
nM
|
|
Inhibition of electric eel AChE by modified Ellman's method
|
Electrophorus electricus
|
636.0
nM
|
|
Journal : J. Med. Chem.
Title : Bivalent beta-carbolines as potential multitarget anti-Alzheimer agents.
Year : 2010
Volume : 53
Issue : 9
First Page : 3611
Last Page : 3617
Authors : Rook Y, Schmidtke KU, Gaube F, Schepmann D, Wünsch B, Heilmann J, Lehmann J, Winckler T.
Abstract : Alzheimer's disease (AD) is a prevalent neurodegenerative disorder with multifactorial causes that requires multitargeted treatment. Inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) improve cholinergic signaling in the central nervous system and thus AChE inhibitors are well established in the therapy of AD to improve memory disturbances and other cognitive symptoms. On the other hand, AD patients benefit from reduction of pathologic glutamate-induced, Ca(2+)-mediated excitotoxicity by the N-methyl-d-aspartate receptor (NR) antagonist memantine. New drugs that simultaneously affect both cholinergic transmission and glutamate-induced excitotoxicity may further improve AD treatment. While connecting beta-carboline units by alkylene spacers in two different series of compounds and subsequent evaluation of their AChE/BChE-inhibitory potential, we found that several of these bivalent beta-carbolines were potent NR blockers. The most promising compound was a N(9)-homobivalent beta-carboline with a nonylene spacer, which displayed IC(50) values of 0.5 nM for AChE, 5.7 nM for BChE, and 1.4 microM for NR, respectively.
|
Inhibition of AChE in human erythrocytes by Ellman's method
|
Homo sapiens
|
600.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis, inhibitory activity of cholinesterases, and neuroprotective profile of novel 1,8-naphthyridine derivatives.
Year : 2010
Volume : 53
Issue : 14
First Page : 5129
Last Page : 5143
Authors : de Los Ríos C, Egea J, Marco-Contelles J, León R, Samadi A, Iriepa I, Moraleda I, Gálvez E, García AG, López MG, Villarroya M, Romero A.
Abstract : 1,8-Naphthyridine derivatives related to 17 (ITH4012), a neuroprotective compound reported by our research group, have been synthesized. In general, they have shown better inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) than most tacrine derivatives previously synthesized in our laboratory. The compounds presented an interesting neuroprotective profile in SH-SY5Y neuroblastoma cells stressed with rotenone/oligomycin A. Moreover, compound 14 (ethyl 5-amino-2-methyl-6,7,8,9-tetrahydrobenzo[b][1,8]naphthyridine-3-carboxylate) also caused protection in cells stressed with okadaic acid (OA) or amyloid beta 1-42 peptide (Abeta(1-42)). Interestingly, compound 14 prevented the OA-induced PP2A inhibition, one of the enzymes implicated in tau dephosphorylation. This compound also exhibited neuroprotection against neurotoxicity elicited by oxygen and glucose deprivation in hippocampal slices. Because these stressors caused neuronal damage related to physiopathological hallmarks found in the brain of Alzheimer's disease (AD) patients, we conclude that compound 14 deserves further in vivo studies in AD models to test its therapeutic potential in this disease.
|
Inhibition of electric eel AChE by Ellman's method
|
Electrophorus electricus
|
560.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis, inhibitory activity of cholinesterases, and neuroprotective profile of novel 1,8-naphthyridine derivatives.
Year : 2010
Volume : 53
Issue : 14
First Page : 5129
Last Page : 5143
Authors : de Los Ríos C, Egea J, Marco-Contelles J, León R, Samadi A, Iriepa I, Moraleda I, Gálvez E, García AG, López MG, Villarroya M, Romero A.
Abstract : 1,8-Naphthyridine derivatives related to 17 (ITH4012), a neuroprotective compound reported by our research group, have been synthesized. In general, they have shown better inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) than most tacrine derivatives previously synthesized in our laboratory. The compounds presented an interesting neuroprotective profile in SH-SY5Y neuroblastoma cells stressed with rotenone/oligomycin A. Moreover, compound 14 (ethyl 5-amino-2-methyl-6,7,8,9-tetrahydrobenzo[b][1,8]naphthyridine-3-carboxylate) also caused protection in cells stressed with okadaic acid (OA) or amyloid beta 1-42 peptide (Abeta(1-42)). Interestingly, compound 14 prevented the OA-induced PP2A inhibition, one of the enzymes implicated in tau dephosphorylation. This compound also exhibited neuroprotection against neurotoxicity elicited by oxygen and glucose deprivation in hippocampal slices. Because these stressors caused neuronal damage related to physiopathological hallmarks found in the brain of Alzheimer's disease (AD) patients, we conclude that compound 14 deserves further in vivo studies in AD models to test its therapeutic potential in this disease.
|
Inhibition of electric eel AChE by Ellman's assay
|
Electrophorus electricus
|
623.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and biological evaluation of a new series of berberine derivatives as dual inhibitors of acetylcholinesterase and butyrylcholinesterase.
Year : 2010
Volume : 18
Issue : 12
First Page : 4475
Last Page : 4484
Authors : Huang L, Luo Z, He F, Lu J, Li X.
Abstract : A series of novel berberine derivatives were designed, synthesized, and biologically evaluated as inhibitors of both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Among these derivatives, compound 48a, berberine linked with 3-methylpyridinium by a 2-carbon spacer, was found to be a potent inhibitor of AChE, with an IC(50) value of 0.048 microM and compound 40c, berberine linked with 2-thionaphthol by a 4-carbon spacer, acted as the most potent inhibitor for BuChE with an IC(50) value of 0.078 microM. Kinetic studies and molecular modeling simulations of the AChE-inhibitor complex indicated that a mixed-competitive binding mode existed for these berberine derivatives.
|
Antimalarial activity against Plasmodium falciparum K1
|
Plasmodium falciparum K1
|
4.38
ug.mL-1
|
|
Journal : Bioorg. Med. Chem.
Title : Antimalarials from nature.
Year : 2009
Volume : 17
Issue : 9
First Page : 3229
Last Page : 3256
Authors : Kaur K, Jain M, Kaur T, Jain R.
Abstract : Malaria is a major public health problem mainly due to the development of resistance by the most lethal causative parasitic species, Plasmodium falciparum to the mainstay drugs like chloroquine. New drugs with unique structures and mechanism of action are urgently required to treat sensitive and drug-resistant strains of malaria. Historically, compounds containing novel structure from natural origin represent a major source for the discovery and development of new drugs for several diseases. This review presents recent advances in antimalarial drug discovery from natural sources, including plant extracts, and compounds isolated from plants, bacteria, fungi and marine organisms. These compounds offer new and novel scaffolds for development as antimalarials. The literature from 1998 to October 2008 is reviewed. The review present literature compilation from plant and marine extracts, alkaloids (naphthylisoquinolines, bisbenzylisoquinolines, protoberberines and aporphines, indoles, manzamines, and miscellaneous alkaloids) terpenes (sesquiterpenes, triterpenes, diterpenes, and miscellaneous terpenes) quassinoids, flavonoids, limonoids, chalcones, peptides, xanthones, quinones and coumarines, and miscellaneous antimalarials from nature. The review also provides an outlook to recent semisynthetic approaches to antimalarial drugs discovered from natural sources.
|
Competitive inhibition of Electrophorus electricus AChE by Lineweaver-Burke plot analysis
|
Electrophorus electricus
|
428.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Multipotent drugs with cholinergic and neuroprotective properties for the treatment of Alzheimer and neuronal vascular diseases. I. Synthesis, biological assessment, and molecular modeling of simple and readily available 2-aminopyridine-, and 2-chloropyridine-3,5-dicarbonitriles.
Year : 2010
Volume : 18
Issue : 16
First Page : 5861
Last Page : 5872
Authors : Samadi A, Marco-Contelles J, Soriano E, Alvarez-Pérez M, Chioua M, Romero A, González-Lafuente L, Gandía L, Roda JM, López MG, Villarroya M, García AG, Ríos Cde L.
Abstract : The synthesis, molecular modeling, and pharmacological analysis of new multipotent simple, and readily available 2-aminopyridine-3,5-dicarbonitriles (3-20), and 2-chloropyridine-3,5-dicarbonitriles (21-28), prepared from 2-amino-6-chloropyridine-3,5-dicarbonitrile (1) and 2-amino-6-chloro-4-phenylpyridine-3,5-dicarbonitrile (2) is described. The biological evaluation showed that some of these molecules were modest inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), in the micromolar range. The 2-amino (3, 4), and 2-chloro derivatives 21-23, 25, 26 were AChE selective inhibitors, whereas 2-amino derivatives 5, 14 proved to be selective for BuChE. Only inhibitor 24 was equipotent for both cholinesterases. Kinetic studies on compound 23 showed that this compound is a mixed-type inhibitor of AChE showing a K(i) of 6.33 microM. No clear SAR can be obtained form these data, but apparently, compounds bearing small groups such as the N,N'-dimethylamino or the pyrrolidino, regardless of the presence of a 2-amino, or 6-chloro substituent in the pyridine ring, preferentially inhibit AChE. Molecular modeling on inhibitors 4, 5, 22, and 23 has been carried out to give a better insight into the binding mode on the catalytic active site (CAS), and peripheral anionic site (PAS) of AChE. The most important differences in the observed binding relay on the modifications of the group at C2, as the amino group forms two hydrogen bonds that direct the binding mode, while in the case of compounds with a chlorine atom, this is not possible. The neuroprotective profile of these molecules has been investigated. In the LDH test, only compounds 26, 3, 22, and 24 showed neuroprotection with values in the range 37.8-31.6% in SH-SY5Y neuroblastoma cells stressed with a mixture of oligomycin-A/rotenone, but in the MTT test only compound 17 (32.9%) showed a similar profile. Consequently, these compounds can be considered as attractive multipotent therapeutic molecules on two key pharmacological receptors playing key roles in the progress of Alzheimer, that is, cholinergic dysfunction and oxidative stress, and neuronal vascular diseases.
|
Inhibition of AChE by Ellman's assay
|
None
|
300.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Structure-activity studies on acetylcholinesterase inhibition in the lycorine series of Amaryllidaceae alkaloids.
Year : 2010
Volume : 20
Issue : 17
First Page : 5290
Last Page : 5294
Authors : McNulty J, Nair JJ, Little JR, Brennan JD, Bastida J.
Abstract : The synthesis of differentially functionalized analogs of the Amaryllidaceae alkaloid lycorine, accessed via a concise chemoselective silylation strategy, is described uncovering two of the most potent inhibitors of acetylcholinesterase (AChE) identified to date in this series. Important elements of this novel pharmacophore were elucidated through structure-activity relationship (SAR) studies.
|
Inhibition of AChE by Ellman's method
|
None
|
530.0
nM
|
|
Journal : J. Nat. Prod.
Title : Triterpenoidal alkaloids from Buxus natalensis and their acetylcholinesterase inhibitory activity.
Year : 2010
Volume : 73
Issue : 11
First Page : 1858
Last Page : 1862
Authors : Matochko WL, James A, Lam CW, Kozera DJ, Ata A, Gengan RM.
Abstract : Acetylcholinesterase (AChE) inhibition-directed phytochemical studies on the methanolic extract of Buxus natalensis, collected in South Africa, resulted in the isolation of 12 compounds: O(2)-natafuranamine (1), O(10)-natafuranamine (2), cyclonataminol (3), 31-demethylbuxaminol A (4), buxaminol A (5), buxafuranamide (6), buxalongifolamidine (7), buxamine A (8), cyclobuxophylline K (9), buxaminol C (10), methyl syringate (11), and p-coumaroylputrescine (12). Compounds 1-4 were new alkaloids, and compound 5 was isolated for the first time as a natural product. Their structures were elucidated with the aid of extensive NMR and mass spectroscopic studies. Compounds 1 and 2 are members of a rarely occurring class of Buxus alkaloids, having a tetrahydrofuran ring incorporated in their structures. Compounds 1-12 exhibited strong to moderate AChE inhibitory activity.
|
Inhibition of electric eel AChE by Ellman's method
|
Electrophorus electricus
|
640.0
nM
|
|
Inhibition of electric eel AChE by Ellman's method
|
Electrophorus electricus
|
635.33
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Probing the mid-gorge of cholinesterases with spacer-modified bivalent quinazolinimines leads to highly potent and selective butyrylcholinesterase inhibitors.
Year : 2011
Volume : 19
Issue : 3
First Page : 1222
Last Page : 1235
Authors : Chen X, Tikhonova IG, Decker M.
Abstract : The spacer structure of homobivalent quinazolinimes acting as potent acetyl-(AChE)- and butyrylcholinesterase (BChE) inhibitors was chemically modified introducing tertiary amine and acyl-amide moieties, and the activities at both ChEs were evaluated. Molecular docking was applied to explain the data and probe the capacity of the mid-gorge site of both ChEs. The novel spacer structures considerably alter the biological profile of bivalent quinazolinimines with regard to both inhibitory activity and selectivity. Mutual interaction of binding to the various sites of the enzymes was further investigated by applying also different spacer lengths and ring sizes of the alicycle of the tricyclic quinazolinimines. In order to achieve selectivity toward BChE and to improve inhibitory activities, the spacer structure was optimized and identified a highly potent and selective BChE inhibitor.
|
Inhibition of electric eel Acetylcholinesterase
|
Electrophorus electricus
|
623.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis, biological evaluation and molecular modeling of novel triazole-containing berberine derivatives as acetylcholinesterase and β-amyloid aggregation inhibitors.
Year : 2011
Volume : 19
Issue : 7
First Page : 2298
Last Page : 2305
Authors : Shi A, Huang L, Lu C, He F, Li X.
Abstract : A series of novel triazole-containing berberine derivatives were synthesized via the azide-alkyne cycloaddition reaction. Their biological activity as inhibitors of both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) were evaluated. Among them, compound 16d, which featured a diisopropylamino substitution at the 4-position of triazole ring, was found to be a potent inhibitor of AChE, with IC(50) value of 0.044 μM. Compound 18d, which beares a butyl at the 4-position of the triazole ring, showed the highest potency of β-amyloid aggregation inhibition (77.9% at 20 μM). Molecular modeling studies indicated that the triazole moiety of berberine derivatives displayed a face-to-face π-π stacking interaction in a 'sandwich' form with the Trp84 (4.09 Å) and Phe330 (4.33 Å) in catalytic sites of AChE.
|
Inhibition of AChE-induced amyloid beta aggregation
|
None
|
350.0
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 human erythrocytes AChE
|
Homo sapiens
|
800.0
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 AChE
|
Homo sapiens
|
800.0
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 electric eel AChE by colorimetric Ellman's assay
|
Electrophorus electricus
|
640.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Mycobacterium tuberculosis and cholinesterase inhibitors from Voacanga globosa.
Year : 2011
Volume : 46
Issue : 7
First Page : 3118
Last Page : 3123
Authors : Macabeo AP, Vidar WS, Chen X, Decker M, Heilmann J, Wan B, Franzblau SG, Galvez EV, Aguinaldo MA, Cordell GA.
Abstract : Globospiramine (1), a new spirobisindole alkaloid possessing an Aspidosperma-Aspidosperma skeleton, together with deoxyvobtusine (2), deoxyvobtusine lactone (3), vobtusine lactone (4) and lupeol (5), were isolated and identified from Voacanga globosa through a bioassay-guided purification. The gross structure and absolute stereochemistry of 1 were established by circular dichroism spectroscopy, HR-MS and unambiguous NMR spectroscopic experiments. In addition, a new biogenetic pathway for the formation of the spiro-Aspidosperma-Aspidosperma skeleton is proposed. Alkaloid 1 showed potent antituberculosis activity against Mycobacterium tuberculosis H(37)Rv as evidenced in microplate Alamar blue assay (MIC = 4 μg/mL) and low-oxygen recovery assay (LORA (MIC = 5.2 μg/mL). The bisindole alkaloids also exhibited promising activity against acetylcholinesterase and, especially butyrylcholinesterase, with deoxyvobtusine (2) (IC(50) = 6.2 μM) as the most strongly inhibiting compound. This study extends the variety of alkaloid structural platforms which exhibit antimycobacterial and anticholinesterase activity.
|
Inhibition of electric eel AChE at 10'-4.3 M by colorimetric Ellman's assay
|
Electrophorus electricus
|
6.197
%
|
|
Journal : Eur. J. Med. Chem.
Title : Mycobacterium tuberculosis and cholinesterase inhibitors from Voacanga globosa.
Year : 2011
Volume : 46
Issue : 7
First Page : 3118
Last Page : 3123
Authors : Macabeo AP, Vidar WS, Chen X, Decker M, Heilmann J, Wan B, Franzblau SG, Galvez EV, Aguinaldo MA, Cordell GA.
Abstract : Globospiramine (1), a new spirobisindole alkaloid possessing an Aspidosperma-Aspidosperma skeleton, together with deoxyvobtusine (2), deoxyvobtusine lactone (3), vobtusine lactone (4) and lupeol (5), were isolated and identified from Voacanga globosa through a bioassay-guided purification. The gross structure and absolute stereochemistry of 1 were established by circular dichroism spectroscopy, HR-MS and unambiguous NMR spectroscopic experiments. In addition, a new biogenetic pathway for the formation of the spiro-Aspidosperma-Aspidosperma skeleton is proposed. Alkaloid 1 showed potent antituberculosis activity against Mycobacterium tuberculosis H(37)Rv as evidenced in microplate Alamar blue assay (MIC = 4 μg/mL) and low-oxygen recovery assay (LORA (MIC = 5.2 μg/mL). The bisindole alkaloids also exhibited promising activity against acetylcholinesterase and, especially butyrylcholinesterase, with deoxyvobtusine (2) (IC(50) = 6.2 μM) as the most strongly inhibiting compound. This study extends the variety of alkaloid structural platforms which exhibit antimycobacterial and anticholinesterase activity.
|
Inhibition of electric eel AChE using acetylcholine chloride as substrate preincubated for 15 mins by Ellman's method
|
Electrophorus electricus
|
623.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Benzenediol-berberine hybrids: multifunctional agents for Alzheimer's disease.
Year : 2011
Volume : 19
Issue : 23
First Page : 7228
Last Page : 7235
Authors : Jiang H, Wang X, Huang L, Luo Z, Su T, Ding K, Ding K, Li X.
Abstract : We designed and synthesized a series of hybrid molecules, in an effort to identify novel multifunctional drug candidates for Alzheimer's disease (AD), by reacting berberine with benzenediol, melatonin, and ferulic acid. The products were evaluated for: (i) the ability to inhibit multiple cholinesterases (ChEs); (ii) the capacity to prevent amyloid β (Aβ) aggregation; and (iii) antioxidant activity. All of the derivatives were better antioxidants, and inhibited Aβ aggregation to a greater extent, than the lead compound, berberine. Two of the hybrids, in particular, have the potential to be excellent candidates for AD therapy: the berberine-pyrocatechol hybrid (compound 8) was a much better inhibitor of acetylcholinesterase (AChE) than unconjugated berberine (IC(50): 0.123 vs 0.374 μM); and the berberine-hydroquinone hybrid (compound 12) displayed high antioxidant activity, could inhibit AChE (IC(50) of 0.460 μM), and had the greatest ability to inhibit Aβ aggregation.
|
Inhibition of electric eel AChE using acetylcholine iodide as substrate measured every 5 sec for 2 mins by Ellman's method
|
Electrophorus electricus
|
600.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Prospective acetylcholinesterase inhibitory activity of indole and its analogs.
Year : 2012
Volume : 22
Issue : 8
First Page : 2885
Last Page : 2888
Authors : Khorana N, Changwichit K, Ingkaninan K, Utsintong M.
Abstract : Acetylcholinesterase (AChE) inhibitory activity is one of the proposed targets for indole analogs. Simple indoles with substitution of methoxy, carboxy or hydroxy at the benzene ring showed a low percent of inhibitory activity in eel-AChE. Adding a side chain at the pyrrole ring, such as serotonin, β-carbolines and quinolines (the bioisostere of indole), improved the inhibitory activity significantly. However, proper substitution and conformation of the ring were required for good binding. The result of inhibition in human-AChE of serotonin, β-carbolines and quinolines showed similar profile as eel-AChE with lower magnitude. The data from molecular docking showed that they shared the same binding site as galantamine.
|
Inhibition of electric eel AChE using acetylcholine iodide as substrate at 3.4 X 10'-4 M measured every 5 sec for 2 mins by Ellman's method
|
Electrophorus electricus
|
100.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Prospective acetylcholinesterase inhibitory activity of indole and its analogs.
Year : 2012
Volume : 22
Issue : 8
First Page : 2885
Last Page : 2888
Authors : Khorana N, Changwichit K, Ingkaninan K, Utsintong M.
Abstract : Acetylcholinesterase (AChE) inhibitory activity is one of the proposed targets for indole analogs. Simple indoles with substitution of methoxy, carboxy or hydroxy at the benzene ring showed a low percent of inhibitory activity in eel-AChE. Adding a side chain at the pyrrole ring, such as serotonin, β-carbolines and quinolines (the bioisostere of indole), improved the inhibitory activity significantly. However, proper substitution and conformation of the ring were required for good binding. The result of inhibition in human-AChE of serotonin, β-carbolines and quinolines showed similar profile as eel-AChE with lower magnitude. The data from molecular docking showed that they shared the same binding site as galantamine.
|
Inhibition of human AChE by Ellman's method
|
Homo sapiens
|
300.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Prospective acetylcholinesterase inhibitory activity of indole and its analogs.
Year : 2012
Volume : 22
Issue : 8
First Page : 2885
Last Page : 2888
Authors : Khorana N, Changwichit K, Ingkaninan K, Utsintong M.
Abstract : Acetylcholinesterase (AChE) inhibitory activity is one of the proposed targets for indole analogs. Simple indoles with substitution of methoxy, carboxy or hydroxy at the benzene ring showed a low percent of inhibitory activity in eel-AChE. Adding a side chain at the pyrrole ring, such as serotonin, β-carbolines and quinolines (the bioisostere of indole), improved the inhibitory activity significantly. However, proper substitution and conformation of the ring were required for good binding. The result of inhibition in human-AChE of serotonin, β-carbolines and quinolines showed similar profile as eel-AChE with lower magnitude. The data from molecular docking showed that they shared the same binding site as galantamine.
|
Inhibition of electric eel acetylcholine esterase using acetylcholine chloride as substrate incubated for 15 mins prior to substrate addition measured every 1 min by Ellman's assay
|
Electrophorus electricus
|
623.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis, and evaluation of indanone derivatives as acetylcholinesterase inhibitors and metal-chelating agents.
Year : 2012
Volume : 22
Issue : 13
First Page : 4462
Last Page : 4466
Authors : Meng FC, Mao F, Shan WJ, Qin F, Huang L, Li XS.
Abstract : A series of novel indanone derivatives was designed, synthesised and evaluated as potential agents for Alzheimer's disease. Among them, compound 6a, with a piperidine group linked to indone by a two-carbon spacer, exhibited the most potent inhibitor activity, with an IC(50) of 0.0018 μM for AChE; the inhibitory activity of this compound was 14-fold more potent than that of donepezil. Furthermore, these compounds also exhibited good metal-chelating ability.
|
Inhibition of self-induced amyloid beta (1 to 40) aggregation at 100 uM after 24 hrs by thioflavin T-based fluorescence analysis
|
None
|
48.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Development and evaluation of multifunctional agents for potential treatment of Alzheimer's disease: application to a pyrimidine-2,4-diamine template.
Year : 2012
Volume : 22
Issue : 14
First Page : 4707
Last Page : 4712
Authors : Mohamed T, Yeung JC, Vasefi MS, Beazely MA, Rao PP.
Abstract : We investigated a group of 2-benzylpiperidin-N-benzylpyrimidin-4-amines with various electron-withdrawing or electron-donating groups (EWGs or EDGs, respectively) as multi-targeted Alzheimer's disease (AD) therapeutics. The synthesized derivatives were screened for anti-cholinesterase (AChE and BuChE), anti-Aβ-aggregation (AChE- and self-induced) and anti-β-secretase (BACE-1) activities in an effort to identify lead, multifunctional candidates as part of our multi-targeted approach to treat AD. Biological assessment revealed that the nature of the substituent on the C-4 benzylamine group (e.g., halogen vs methoxy-based) greatly affected the biological profile. In vitro screening identified N(2)-(1-benzylpiperidin-4-yl)-N(4)-(3,4-dimethoxybenzyl)pyrimidine-2,4-diamine (7h) as the lead candidate with a dual ChE (AChE IC(50)=9.9 μM; BuChE IC(50)=11.4 μM), Aβ-aggregation (AChE-induced=59.3%; self-induced=17.4% at 100 μM) and BACE-1 (34% inhibition at 10 μM) inhibitory profile along with good cell viability (% neuroblastoma cell viability at 40 μM=81.0%). Molecular modeling studies indicate that a central pyrimidine-2,4-diamine ring serves as a suitable template to develop novel small molecule candidates to target multiple pathological routes in AD.
|
Inhibition of human recombinant AChE using acetylthiocholine as substrate
|
Homo sapiens
|
61.96
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis, and bioevaluation of benzamides: novel acetylcholinesterase inhibitors with multi-functions on butylcholinesterase, Aβ aggregation, and β-secretase.
Year : 2012
Volume : 20
Issue : 22
First Page : 6739
Last Page : 6750
Authors : Peng DY, Sun Q, Zhu XL, Lin HY, Chen Q, Yu NX, Yang WC, Yang GF.
Abstract : Alzheimer's disease (AD) is a multifactorial syndrome with several target proteins contributing to its etiology. In this study, we conducted a structure-based design and successfully produced a series of new multi-site AChE inhibitors with a novel framework. Compound 2e, characterized by a central benzamide moiety linked to an isoquinoline at one side and acetophenone at the other, was the most potent candidate with K(i) of 6.47nM against human AChE. Particularly, it showed simultaneous inhibitory effects against BChE, Aβ aggregation, and β-secretase. We therefore conclude that compound 2e is a very promising multi-function lead for the treatment of AD.
|
Inhibition of human recombinant BChE using acetylthiocholine as substrate
|
Homo sapiens
|
192.47
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis, and bioevaluation of benzamides: novel acetylcholinesterase inhibitors with multi-functions on butylcholinesterase, Aβ aggregation, and β-secretase.
Year : 2012
Volume : 20
Issue : 22
First Page : 6739
Last Page : 6750
Authors : Peng DY, Sun Q, Zhu XL, Lin HY, Chen Q, Yu NX, Yang WC, Yang GF.
Abstract : Alzheimer's disease (AD) is a multifactorial syndrome with several target proteins contributing to its etiology. In this study, we conducted a structure-based design and successfully produced a series of new multi-site AChE inhibitors with a novel framework. Compound 2e, characterized by a central benzamide moiety linked to an isoquinoline at one side and acetophenone at the other, was the most potent candidate with K(i) of 6.47nM against human AChE. Particularly, it showed simultaneous inhibitory effects against BChE, Aβ aggregation, and β-secretase. We therefore conclude that compound 2e is a very promising multi-function lead for the treatment of AD.
|
Neuroprotective activity in human SH-SY5Y cells assessed as protection against NMDA-induced cell death after 6 hrs by MTS assay
|
Homo sapiens
|
747.0
nM
|
|
Journal : J. Med. Chem.
Title : Combining galantamine and memantine in multitargeted, new chemical entities potentially useful in Alzheimer's disease.
Year : 2012
Volume : 55
Issue : 22
First Page : 9708
Last Page : 9721
Authors : Simoni E, Daniele S, Bottegoni G, Pizzirani D, Trincavelli ML, Goldoni L, Tarozzo G, Reggiani A, Martini C, Piomelli D, Melchiorre C, Rosini M, Cavalli A.
Abstract : Herein we report on a novel series of multitargeted compounds obtained by linking together galantamine and memantine. The compounds were designed by taking advantage of the crystal structures of acetylcholinesterase (AChE) in complex with galantamine derivatives. Sixteen novel derivatives were synthesized, using spacers of different lengths and chemical composition. The molecules were then tested as inhibitors of AChE and as binders of the N-methyl-d-aspartate (NMDA) receptor (NMDAR). Some of the new compounds were nanomolar inhibitors of AChE and showed micromolar affinities for NMDAR. All compounds were also tested for selectivity toward NMDAR containing the 2B subunit (NR2B). Some of the new derivatives showed a micromolar affinity for NR2B. Finally, selected compounds were tested using a cell-based assay to measure their neuroprotective activity. Three of them showed a remarkable neuroprotective profile, inhibiting the NMDA-induced neurotoxicity at subnanomolar concentrations (e.g., 5, named memagal, IC(50) = 0.28 nM).
|
Inhibition of Electrophorus electricus (electric eel) acetylcholinesterase (AChE) using acetylthiocholine iodide as substrate preincubated for 15 min
|
Electrophorus electricus
|
500.0
nM
|
|
Journal : Med Chem Res
Title : In silico studies on 2,3-dihydro-1,5-benzothiazepines as cholinesterase inhibitors
Year : 2012
Volume : 21
Issue : 9
First Page : 2329
Last Page : 2339
Authors : Ansari FL, Kalsoom S, Zaheer-ul-Haq, Ali Z, Jabeen F
|
Inhibition of butyrylcholinesterase (unknown origin) using butyrylthiocholine chloride as substrate incubated for 15 min prior to substrate addition measured for 15 min by spectrophotometric analysis
|
Homo sapiens
|
170.0
nM
|
|
Journal : Med Chem Res
Title : Synthesis and enzyme inhibitory activities of some new pyrazole-based heterocyclic compounds
Year : 2012
Volume : 21
Issue : 10
First Page : 2772
Last Page : 2778
Authors : Harit T, Malek F, Bali BE, Khan A, Dalvandi K, Marasini BP, Noreen S, Malik R, Khan S, Iqbal Choudhary M
|
Inhibition of acetylcholinesterase (unknown origin) using acetylthiocholine iodide as substrate incubated for 15 min prior to substrate addition measured for 15 min by spectrophotometric analysis
|
Homo sapiens
|
500.0
nM
|
|
Journal : Med Chem Res
Title : Synthesis and enzyme inhibitory activities of some new pyrazole-based heterocyclic compounds
Year : 2012
Volume : 21
Issue : 10
First Page : 2772
Last Page : 2778
Authors : Harit T, Malek F, Bali BE, Khan A, Dalvandi K, Marasini BP, Noreen S, Malik R, Khan S, Iqbal Choudhary M
|
Inhibition of Electrophorus electricus (electric eel) acetylcholinesterase (AChE) using acetylcholine iodide as substrate at 10 '-4 M by Ellman method
|
Electrophorus electricus
|
0.6
%
|
|
Journal : Med Chem Res
Title : Evaluation of a new lead for acetylcholinesterase inhibition
Year : 2009
Volume : 18
Issue : 3
First Page : 231
Last Page : 241
Authors : Khorana N, Markmee S, Ingkaninan K, Ruchirawat S, Kitbunnadaj R, Pullagurla MR
|
Inhibition of acetylcholinesterase (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 ICR mouse brain AChE using acetylthiocholine iodide as substrate at 100 uM incubated 10 mins prior to substrate addition measured after 10 mins by Ellman's method
|
Mus musculus
|
91.94
%
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis of aminoalkyl-substituted coumarin derivatives as acetylcholinesterase inhibitors.
Year : 2014
Volume : 22
Issue : 4
First Page : 1262
Last Page : 1267
Authors : Nam SO, Park DH, Lee YH, Ryu JH, Lee YS.
Abstract : Alzheimer's disease, one of the most common forms of dementia, is a progressive neurodegenerative disorder symptomatically characterized by declines in memory and cognitive abilities. To date, the successful therapeutic strategy to treat AD is maintaining levels of acetylcholine by inhibiting acetylcholinesterase (AChE). In the present study, coumarin derivatives were designed and synthesized as AChE inhibitors based on the lead structure of scopoletin. Of those synthesized, pyrrolidine-substituted coumarins 3b and 3f showed ca. 160-fold higher AChE inhibitory activities than scopoletin. These compounds also ameliorated scopolamine-induced memory deficit in mice when administered orally at the dose of 1 and 2 mg/kg.
|
Inhibition of AChE (unknown origin) using acetylthiocholine as substrate at 5 uM preincubated for 15 mins measured after 30 mins by Ellman's method
|
Homo sapiens
|
61.44
%
|
|
Journal : J. Nat. Prod.
Title : Marsupellins A-F, ent-longipinane-type sesquiterpenoids from the Chinese liverwort Marsupella alpine with acetylcholinesterase inhibitory activity.
Year : 2014
Volume : 77
Issue : 4
First Page : 1031
Last Page : 1036
Authors : Zhang J, Fan P, Zhu R, Li R, Lin Z, Sun B, Zhang C, Zhou J, Lou H.
Abstract : Acetylcholinesterase (AChE) inhibitory activity-guided fractionation of the Chinese liverwort Marsupella alpine afforded six new [marsupellins A-F (1-6)] and three known (7-9) ent-longipinane-type sesquiterpenoids. The structures were determined from MS and NMR spectroscopic data, single-crystal X-ray diffraction, and electronic circular dichroism calculations. Compounds 1-9 exhibited moderate to weak AChE inhibitory activity.
|
Inhibition of human AChE by spectrophotometry
|
Homo sapiens
|
550.0
nM
|
|
Journal : J. Nat. Prod.
Title : Alkaloids from the roots of Stichoneuron caudatum and their acetylcholinesterase inhibitory activities.
Year : 2014
Volume : 77
Issue : 4
First Page : 894
Last Page : 901
Authors : Ramli RA, Lie W, Pyne SG.
Abstract : Four new stichoneurine-type alkaloids, stichoneurines F and G (1-2) and sessilistemonamines E and F (3-4), have been isolated from the root extracts of Stichoneuron caudatum. The structures and relative configurations of these alkaloids have been determined by spectroscopic methods and molecular modeling experiments. Compounds 1-4 were tested for their acetylcholinesterase (AChE) inhibitory activities against human AChE. Compound 3 showed significant inhibitory activity with an IC50 value of 9.1±0.15 μM.
|
Inhibition of human recombinant AChE using acetylthiocholine iodide substrate incubated for 15 mins by spectrophotometry based Ellman's method
|
Homo sapiens
|
700.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis and biological evaluation of novel 6H-benzo[c]chromen-6-one, and 7,8,9,10-tetrahydro-benzo[c]chromen-6-one derivatives as potential cholinesterase inhibitors.
Year : 2014
Volume : 22
Issue : 19
First Page : 5141
Last Page : 5154
Authors : Gulcan HO, Unlu S, Esiringu I, Ercetin T, Sahin Y, Oz D, Sahin MF.
Abstract : Hydroxylated 6H-benzo[c]chromen-6-one derivatives (i.e., urolithins) are the main bioavailable metabolites, and biomarkers of ellagitannins present in various nutrition. Although these dietaries, the sources of urolithins, are employed in folk medicine as cognitive enhancer in the treatment of Alzheimer's Disease, urolithins have negligible potential to inhibit acetylcholinesterase and butyrylcholinesterase enzymes, the validated targets of Alzheimer's Disease. Therefore, within this research, a series of 6H-benzo[c]chromen-6-one, and 7,8,9,10-tetrahydro-benzo[c]chromen-6-one derivatives has been designed, synthesized, and their biological activities were evaluated as potential acetylcholinesterase and butyrylcholinesterase inhibitors. The compounds synthesized exerted comparable activity in comparison to rivastigmine, galantamine, and donepezil both in in vitro and in vivo studies.
|
Inhibition of AChE (unknown origin) assessed as reduction in acetylthiocholine iodide hydrolysis at 2 uM after 15 mins by Ellman method
|
Homo sapiens
|
54.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Sulfonamides as multifunctional agents for Alzheimer's disease.
Year : 2015
Volume : 25
Issue : 3
First Page : 626
Last Page : 630
Authors : Bag S, Tulsan R, Sood A, Cho H, Redjeb H, Zhou W, LeVine H, Török B, Török M.
Abstract : Sulfonamide linker-based inhibitors with extended linear structure were designed and synthesized with the aim of producing multifunctional agents against several processes involved in the pathology of Alzheimer's disease (AD). The potency of the compounds were assessed in the inhibition of Aβ self-assembly (fibril and oligomer formation), in modulating cholinesterase (AChE, BuChE) activity, and scavenging free radicals. Several compounds exhibited promising Aβ self-assembly and cholinesterase inhibition and in parallel, showed good free radical scavenging properties. The investigation of the scaffold described in this study resulted in the identification of three compounds (14, 19 and 26) as promising leads for the further design of multifunctional drug candidates for AD.
|
Inhibition of BuChE (unknown origin) assessed as reduction in S-butyrylthiocholine chloride hydrolysis at 10 uM after 15 mins by Ellman method
|
Homo sapiens
|
40.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Sulfonamides as multifunctional agents for Alzheimer's disease.
Year : 2015
Volume : 25
Issue : 3
First Page : 626
Last Page : 630
Authors : Bag S, Tulsan R, Sood A, Cho H, Redjeb H, Zhou W, LeVine H, Török B, Török M.
Abstract : Sulfonamide linker-based inhibitors with extended linear structure were designed and synthesized with the aim of producing multifunctional agents against several processes involved in the pathology of Alzheimer's disease (AD). The potency of the compounds were assessed in the inhibition of Aβ self-assembly (fibril and oligomer formation), in modulating cholinesterase (AChE, BuChE) activity, and scavenging free radicals. Several compounds exhibited promising Aβ self-assembly and cholinesterase inhibition and in parallel, showed good free radical scavenging properties. The investigation of the scaffold described in this study resulted in the identification of three compounds (14, 19 and 26) as promising leads for the further design of multifunctional drug candidates for AD.
|
Inhibition of human AChE assessed as acetylthiocholine hydrolysis
|
Homo sapiens
|
61.9
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Syntheses of coumarin-tacrine hybrids as dual-site acetylcholinesterase inhibitors and their activity against butylcholinesterase, Aβ aggregation, and β-secretase.
Year : 2014
Volume : 22
Issue : 17
First Page : 4784
Last Page : 4791
Authors : Sun Q, Peng DY, Yang SG, Zhu XL, Yang WC, Yang GF.
Abstract : Exploring small-molecule acetylcholinesterase (AChE) inhibitors to slow the breakdown of acetylcholine (Ach) represents the mainstream direction for Alzheimer's disease (AD) therapy. As the first acetylcholinesterase inhibitor approved for the clinical treatment of AD, tacrine has been widely used as a pharmacophore to design hybrid compounds in order to combine its potent AChE inhibition with other multi-target profiles. In present study, a series of novel tacrine-coumarin hybrids were designed, synthesized and evaluated as potent dual-site AChE inhibitors. Moreover, compound 1g was identified as the most potent candidate with about 2-fold higher potency (Ki=16.7nM) against human AChE and about 2-fold lower potency (Ki=16.1nM) against BChE than tacrine (Ki=35.7nM for AChE, Ki=8.7nM for BChE), respectively. In addition, some of the tacrine-coumarin hybrids showed simultaneous inhibitory effects against both Aβ aggregation and β-secretase. We therefore conclude that tacrine-coumarin hybrid is an interesting multifunctional lead for the AD drug discovery.
|
Inhibition of human BChE assessed as acetylthiocholine hydrolysis
|
Homo sapiens
|
192.5
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Syntheses of coumarin-tacrine hybrids as dual-site acetylcholinesterase inhibitors and their activity against butylcholinesterase, Aβ aggregation, and β-secretase.
Year : 2014
Volume : 22
Issue : 17
First Page : 4784
Last Page : 4791
Authors : Sun Q, Peng DY, Yang SG, Zhu XL, Yang WC, Yang GF.
Abstract : Exploring small-molecule acetylcholinesterase (AChE) inhibitors to slow the breakdown of acetylcholine (Ach) represents the mainstream direction for Alzheimer's disease (AD) therapy. As the first acetylcholinesterase inhibitor approved for the clinical treatment of AD, tacrine has been widely used as a pharmacophore to design hybrid compounds in order to combine its potent AChE inhibition with other multi-target profiles. In present study, a series of novel tacrine-coumarin hybrids were designed, synthesized and evaluated as potent dual-site AChE inhibitors. Moreover, compound 1g was identified as the most potent candidate with about 2-fold higher potency (Ki=16.7nM) against human AChE and about 2-fold lower potency (Ki=16.1nM) against BChE than tacrine (Ki=35.7nM for AChE, Ki=8.7nM for BChE), respectively. In addition, some of the tacrine-coumarin hybrids showed simultaneous inhibitory effects against both Aβ aggregation and β-secretase. We therefore conclude that tacrine-coumarin hybrid is an interesting multifunctional lead for the AD drug discovery.
|
Inhibition of BchE in human plasma incubated for 30 mins using butyrylthiocholine substrate at 37 degC by DTNB dye based spectrophotometry
|
Homo sapiens
|
0.38
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : New septanoside and 20-hydroxyecdysone septanoside derivative from Atriplex portulacoides roots with preliminary biological activities.
Year : 2015
Volume : 25
Issue : 8
First Page : 1665
Last Page : 1670
Authors : Ben Nejma A, Nguir A, Ben Jannet H, Hamza MA, Daïch A, Othman M, Lawson AM.
Abstract : The phytochemical investigation of a Tunisian plant Atriplex portulacoides (Chenopodiaceae) led to the isolation of two new compounds designated as portulasoid (2) and septanoecdysone (3) along with the known 20-hydroxyecdysone (20HE) (1). Their chemical structures were elucidated on the basis of extensive spectroscopic methods including ES-HRMS, 1D and 2D-NMR. The isolated compounds were finally tested for their antioxidant activity by using DPPH, ABTS(+), Fe(3+) and catalase assays and also for their antibacterial and anticholinesterase activities.
|
Inhibition of acetylcholinesterase (unknown origin) assessed as AChI hydrolysis using AChI and DTNB as substrate by Ellman's method
|
Homo sapiens
|
250.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Discovery of potent carbonic anhydrase and acetylcholine esterase inhibitors: novel sulfamoylcarbamates and sulfamides derived from acetophenones.
Year : 2015
Volume : 23
Issue : 13
First Page : 3592
Last Page : 3602
Authors : Akıncıoğlu A, Akıncıoğlu H, Gülçin İ, Durdagi S, Supuran CT, Göksu S.
Abstract : In this study, several novel sulfamides were synthesized and evaluated for their acetylcholine esterase (AChE) and human carbonic anhydrase I, and II isoenzymes (hCA I and II) inhibition profiles. Reductive amination of methoxyacetophenones was used for the synthesis of amines. Amines were converted to sulfamoylcarbamates with chlorosulfonyl isocyanate (CSI) in the presence of BnOH. Pd-C catalyzed hydrogenolysis of sulfamoylcarbamates afforded sulfamides. These novel compounds were good inhibitors of the cytosolic hCA I, and hCA II with Ki values in the range of 45.9±8.9-687.5±84.3 pM for hCA I, and 48.80±8.2-672.2±71.9pM for hCA II. The inhibitory effects of the synthesized novel compounds on AChE were also investigated. The Ki values of these compounds were in the range of 4.52±0.61-38.28±6.84pM for AChE. These results show that hCA I, II, and AChE were effectively inhibited by the novel sulfamoylcarbamates 17-21 and sulfamide derivatives 22-26. All investigated compounds were docked within the active sites of the corresponding enzymes revealing the reasons of the effective inhibitory activity.
|
Inhibition of AChE (unknown origin)
|
Homo sapiens
|
350.0
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.
|
Inhibition of electric eel AChE using acetylthiocholine iodide as substrate preincubated for 5 mins followed by substrate addition measured after 5 mins by Ellman's method
|
Electrophorus electricus
|
665.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis, pharmacological assessment, molecular modeling and in silico studies of fused tricyclic coumarin derivatives as a new family of multifunctional anti-Alzheimer agents.
Year : 2016
Volume : 107
First Page : 219
Last Page : 232
Authors : Shaik JB, Palaka BK, Penumala M, Kotapati KV, Devineni SR, Eadlapalli S, Darla MM, Ampasala DR, Vadde R, Amooru GD.
Abstract : A series of fused tricyclic coumarin derivatives bearing iminopyran ring connected to various amido moieties were developed as potential multifunctional anti-Alzheimer agents for their cholinesterase inhibitory and radical scavenging activities. In vitro studies revealed that most of these compounds exhibited high inhibitory activity on acetylcholinesterase (AChE), with IC50 values ranging from 0.003 to 0.357 μM which is 2-220 folds more potent than the positive control, galantamine. Their inhibition selectivity against AChE over butyrylcholinesterase (BuChE) has increased about 194 fold compared with galantamine. The developed compounds also showed potent ABTS radical scavenging activity (IC50 7.98-15.99 μM). Specifically, the most potent AChE inhibitor 6n (IC50 0.003 ± 0.0007 μM) has an excellent antioxidant profile as determined by the ABTS method (IC50 7.98 ± 0.77 μM). Moreover, cell viability studies in SK N SH cells showed that the compounds 6m-q have significant neuroprotective effects against H2O2-induced cell death, and are not neurotoxic at all concentrations except 6n and 6q. The kinetic analysis of compound 6n proved that it is a mixed-type inhibitor for EeAChE (Ki1 0.0103 μM and Ki2 0.0193 μM). Accordingly, the molecular modeling study demonstrated that 6m-q with substituted benzyl amido moiety possessed an optimal docking pose with interactions at catalytic active site (CAS) and peripheral anionic site (PAS) of AChE simultaneously and thereby they might prevent aggregation of Aβ induced by AChE. Furthermore, in silico ADMET prediction studies indicated that these compounds satisfied all the characteristics of CNS acting drugs. Most active inhibitor 6n is permeable to BBB as determined in the in vivo brain AChE activity. To sum up, the multipotent therapuetic profile of these novel tricyclic coumarins makes them promising leads for developing anti-Alzheimer agents.
|
Inhibition of electric eel AChE using acetylthiocholine iodide as substrate at by Ellman spectrophotometric method
|
Electrophorus electricus
|
0.45
ug.mL-1
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and evaluation of bis-thiazole derivatives as new anticancer agents.
Year : 2016
Volume : 107
First Page : 288
Last Page : 294
Authors : Turan-Zitouni G, Altıntop MD, Özdemir A, Kaplancıklı ZA, Çiftçi GA, Temel HE.
Abstract : New bis-thiazole derivatives (1-10) were synthesized via the ring closure of 1,1'-(3,3'-dimethoxybiphenyl-4,4'-diyl)bis(thiourea) with phenacyl bromides and evaluated for their cytotoxic effects on A549 human lung adenocarcinoma, C6 rat glioma, 5RP7 H-ras oncogene transformed rat embryonic fibroblast and NIH/3T3 mouse embryonic fibroblast cell lines using MTT assay. DNA synthesis inhibitory effects of these compounds were investigated. Each derivative was also evaluated for its ability to inhibit AChE and BuChE using a modification of Ellman's spectrophotometric method. Among these compounds, 3,3'-dimethoxy-N(4),N(4)'-bis(4-(4-bromophenyl)thiazol-2-yl)-[1,1'-biphenyl]-4,4'-diamine (5) can be identified as the most promising anticancer agent due to its notable inhibitory effects on A549 and C6 cell lines and low toxicity to NIH/3T3 cell lines. Compound 5 exhibited anticancer activity against A549 and C6 cell lines with IC50 values of 37.3 ± 6.8 μg/mL and 11.3 ± 1.2 μg/mL, whereas mitoxantrone showed anticancer activity against A549 and C6 cell lines with IC50 values of 15.7 ± 4.0 μg/mL and 11.0 ± 1.7 μg/mL, respectively. Furthermore, compound 5 showed DNA synthesis inhibitory activity against A549 cell line.
|
Inhibition of BuChE (unknown origin) using butyrylthiocholine iodide as substrate by Ellman spectrophotometric method
|
Homo sapiens
|
6.34
ug.mL-1
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and evaluation of bis-thiazole derivatives as new anticancer agents.
Year : 2016
Volume : 107
First Page : 288
Last Page : 294
Authors : Turan-Zitouni G, Altıntop MD, Özdemir A, Kaplancıklı ZA, Çiftçi GA, Temel HE.
Abstract : New bis-thiazole derivatives (1-10) were synthesized via the ring closure of 1,1'-(3,3'-dimethoxybiphenyl-4,4'-diyl)bis(thiourea) with phenacyl bromides and evaluated for their cytotoxic effects on A549 human lung adenocarcinoma, C6 rat glioma, 5RP7 H-ras oncogene transformed rat embryonic fibroblast and NIH/3T3 mouse embryonic fibroblast cell lines using MTT assay. DNA synthesis inhibitory effects of these compounds were investigated. Each derivative was also evaluated for its ability to inhibit AChE and BuChE using a modification of Ellman's spectrophotometric method. Among these compounds, 3,3'-dimethoxy-N(4),N(4)'-bis(4-(4-bromophenyl)thiazol-2-yl)-[1,1'-biphenyl]-4,4'-diamine (5) can be identified as the most promising anticancer agent due to its notable inhibitory effects on A549 and C6 cell lines and low toxicity to NIH/3T3 cell lines. Compound 5 exhibited anticancer activity against A549 and C6 cell lines with IC50 values of 37.3 ± 6.8 μg/mL and 11.3 ± 1.2 μg/mL, whereas mitoxantrone showed anticancer activity against A549 and C6 cell lines with IC50 values of 15.7 ± 4.0 μg/mL and 11.0 ± 1.7 μg/mL, respectively. Furthermore, compound 5 showed DNA synthesis inhibitory activity against A549 cell line.
|
Inhibition AChE (unknown origin) using ATCI as substrate assessed as hydrolysis of ATCI at 5 uM measured every 1 min for 10 times
|
Homo sapiens
|
90.0
%
|
|
Journal : J. Nat. Prod.
Title : Bioactive Constituents of Glycyrrhiza uralensis (Licorice): Discovery of the Effective Components of a Traditional Herbal Medicine.
Year : 2016
Volume : 79
Issue : 2
First Page : 281
Last Page : 292
Authors : Ji S, Li Z, Song W, Wang Y, Liang W, Li K, Tang S, Wang Q, Qiao X, Zhou D, Yu S, Ye M.
Abstract : Traditional herbal medicines have been reported to possess significant bioactivities. In this investigation, a combined strategy using both phytochemical and biological approaches was conducted to discern the effective components of licorice, a widely used herbal medicine. Altogether, 122 compounds (1-122), including six new structures (1-6), were isolated and identified from the roots and rhizomes of Glycyrrhiza uralensis (licorice). These compounds were then screened using 11 cell- and enzyme-based bioassay methods, including Nrf2 activation, NO inhibition, NF-κB inhibition, H1N1 virus inhibition, cytotoxicity for cancer cells (HepG2, SW480, A549, MCF7), PTP1B inhibition, tyrosinase inhibition, and AChE inhibition. A number of bioactive compounds, particularly isoprenylated phenolics, were found for the first time. Echinatin (7), a potent Nrf2 activator, was selected as an example for further biological work. It attenuated CCl4-induced liver damage in mice (5 or 10 mg/kg, ip) and thus is responsible, at least in part, for the hepatoprotective activity of licorice.
|
Inhibition AChE (unknown origin) using ATCI as substrate assessed as hydrolysis of ATCI after 10 mins measured every 1 min for 10 times
|
Homo sapiens
|
300.0
nM
|
|
Journal : J. Nat. Prod.
Title : Bioactive Constituents of Glycyrrhiza uralensis (Licorice): Discovery of the Effective Components of a Traditional Herbal Medicine.
Year : 2016
Volume : 79
Issue : 2
First Page : 281
Last Page : 292
Authors : Ji S, Li Z, Song W, Wang Y, Liang W, Li K, Tang S, Wang Q, Qiao X, Zhou D, Yu S, Ye M.
Abstract : Traditional herbal medicines have been reported to possess significant bioactivities. In this investigation, a combined strategy using both phytochemical and biological approaches was conducted to discern the effective components of licorice, a widely used herbal medicine. Altogether, 122 compounds (1-122), including six new structures (1-6), were isolated and identified from the roots and rhizomes of Glycyrrhiza uralensis (licorice). These compounds were then screened using 11 cell- and enzyme-based bioassay methods, including Nrf2 activation, NO inhibition, NF-κB inhibition, H1N1 virus inhibition, cytotoxicity for cancer cells (HepG2, SW480, A549, MCF7), PTP1B inhibition, tyrosinase inhibition, and AChE inhibition. A number of bioactive compounds, particularly isoprenylated phenolics, were found for the first time. Echinatin (7), a potent Nrf2 activator, was selected as an example for further biological work. It attenuated CCl4-induced liver damage in mice (5 or 10 mg/kg, ip) and thus is responsible, at least in part, for the hepatoprotective activity of licorice.
|
Inhibition of electric eel AChE using ATCI as substrate preincubated for 30 mins followed by substrate addition measured after 5 mins by DTNB-based spectrophotometric analysis
|
Electrophorus electricus
|
480.0
nM
|
|
Journal : J Nat Prod
Title : Alkaloids from Hippeastrum argentinum and Their Cholinesterase-Inhibitory Activities: An in Vitro and in Silico Study.
Year : 2016
Volume : 79
Issue : 5
First Page : 1241
Last Page : 1248
Authors : Ortiz JE, Pigni NB, Andujar SA, Roitman G, Suvire FD, Enriz RD, Tapia A, Bastida J, Feresin GE.
Abstract : Two new alkaloids, 4-O-methylnangustine (1) and 7-hydroxyclivonine (2) (montanine and homolycorine types, respectively), and four known alkaloids were isolated from the bulbs of Hippeastrum argentinum, and their cholinesterase-inhibitory activities were evaluated. These compounds were identified using GC-MS, and their structures were defined by physical data analysis. Compound 2 showed weak butyrylcholinesterase (BuChE)-inhibitory activity, with a half-maximal inhibitory concentration (IC50) value of 67.3 ± 0.09 μM. To better understand the experimental results, a molecular modeling study was also performed. The combination of a docking study, molecular dynamics simulations, and quantum theory of atoms in molecules calculations provides new insight into the molecular interactions of compound 2 with BuChE, which were compared to those of galantamine.
|
Inhibition of Electrophorus electricus AChE using acetylthiocholine iodide as substrate incubated for 15 mins followed by substrate addition by Ellman's method
|
Electrophorus electricus
|
610.0
nM
|
|
Journal : Eur J Med Chem
Title : Avarol derivatives as competitive AChE inhibitors, non hepatotoxic and neuroprotective agents for Alzheimer's disease.
Year : 2016
Volume : 122
First Page : 326
Last Page : 338
Authors : Tommonaro G, García-Font N, Vitale RM, Pejin B, Iodice C, Cañadas S, Marco-Contelles J, Oset-Gasque MJ.
Abstract : Avarol is a marine sesquiterpenoid hydroquinone, previously isolated from the marine sponge Dysidea avara Schmidt (Dictyoceratida), with antiinflammatory, antitumor, antioxidant, antiplatelet, anti-HIV, and antipsoriatic effects. Recent findings indicate that some thio-avarol derivatives exhibit acetylcholinesterase (AChE) inhibitory activity. The multiple pharmacological properties of avarol, thio-avarol and/or their derivatives prompted us to continue the in vitro screening, focusing on their AChE inhibitory and neuroprotective effects. Due to the complex nature of Alzheimer's disease (AD), there is a renewed search for new, non hepatotoxic anticholinesterasic compounds. This paper describes the synthesis and in vitro biological evaluation of avarol-3'-thiosalicylate (TAVA) and thiosalycil-prenyl-hydroquinones (TPHs), as non hepatotoxic anticholinesterasic agents, showing a good neuroprotective effect on the decreased viability of SHSY5Y human neuroblastoma cells induced by oligomycin A/rotenone and okadaic acid. A molecular modeling study was also undertaken on the most promising molecules within the series to elucidate their AChE binding modes and in particular the role played by the carboxylate group in enzyme inhibition. Among them, TPH4, bearing a geranylgeraniol substituent, is the most significant Electrophorus electricus AChE (EeAChE) inhibitor (IC50 = 6.77 ± 0.24 μM), also endowed with a moderate serum horse butyrylcholinesterase (eqBuChE) inhibitory activity, being also the least hepatotoxic and the best neuroprotective compound of the series. Thus, TPHs represents a new family of synthetic compounds, chemically related to the natural compound avarol, which has been discovered for the potential treatment of AD. Findings prove the relevance of TPHs as a new possible generation of competitive AChE inhibitors pointing out the importance of the salycilic substituents on the hydroquinone ring. Since these compounds do not belong to the class of alkaloids, which are notorious for their capability to inhibit AChE while exhibiting side effects, they may constitute novel active AChE inhibitors with fewer side effects.
|
Inhibition of BuChE (unknown origin) at 10 uM by spectrophotometric analysis based Ellman's assay
|
Homo sapiens
|
29.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Synthesis and application of β-carbolines as novel multi-functional anti-Alzheimer's disease agents.
Year : 2017
Volume : 27
Issue : 2
First Page : 232
Last Page : 236
Authors : Horton W, Sood A, Peerannawar S, Kugyela N, Kulkarni A, Tulsan R, Tran CD, Soule J, LeVine H, Török B, Török M.
Abstract : The design, synthesis and assessment of β-carboline core-based compounds as potential multifunctional agents against several processes that are believed to play a significant role in Alzheimer's disease (AD) pathology, are described. The activity of the compounds was determined in Aβ self-assembly (fibril and oligomer formation) and cholinesterase (AChE, BuChE) activity inhibition, and their antioxidant properties were also assessed. To obtain insight into the mode of action of the compounds, HR-MS studies were carried out on the inhibitor-Aβ complex formation and molecular docking was performed on inhibitor-BuChE interactions. While several compounds exhibited strong activities in individual assays, compound 14 emerged as a promising multi-target lead for the further structure-activity relationship studies.
|
Inhibition of electric eel AChE at 2 uM by spectrophotometric analysis based Ellman's assay
|
Electrophorus electricus
|
50.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Synthesis and application of β-carbolines as novel multi-functional anti-Alzheimer's disease agents.
Year : 2017
Volume : 27
Issue : 2
First Page : 232
Last Page : 236
Authors : Horton W, Sood A, Peerannawar S, Kugyela N, Kulkarni A, Tulsan R, Tran CD, Soule J, LeVine H, Török B, Török M.
Abstract : The design, synthesis and assessment of β-carboline core-based compounds as potential multifunctional agents against several processes that are believed to play a significant role in Alzheimer's disease (AD) pathology, are described. The activity of the compounds was determined in Aβ self-assembly (fibril and oligomer formation) and cholinesterase (AChE, BuChE) activity inhibition, and their antioxidant properties were also assessed. To obtain insight into the mode of action of the compounds, HR-MS studies were carried out on the inhibitor-Aβ complex formation and molecular docking was performed on inhibitor-BuChE interactions. While several compounds exhibited strong activities in individual assays, compound 14 emerged as a promising multi-target lead for the further structure-activity relationship studies.
|
Inhibition of electric eel AChE pretreated for 20 mins followed by acetylthiocholine iodide substrate addition measured for 5 mins by Ellman's method
|
Electrophorus electricus
|
560.0
nM
|
|
Journal : Eur J Med Chem
Title : New azepino[4,3-b]indole derivatives as nanomolar selective inhibitors of human butyrylcholinesterase showing protective effects against NMDA-induced neurotoxicity.
Year : 2017
Volume : 125
First Page : 288
Last Page : 298
Authors : de Candia M, Zaetta G, Denora N, Tricarico D, Majellaro M, Cellamare S, Altomare CD.
Abstract : Several 6-substituted 3,4,5,6-tetrahydroazepino[4,3-b]indol-1(2H)-one (THAI) derivatives were synthesized and evaluated for their activity as cholinesterase (ChE) inhibitors. The most potent inhibitors were identified among 6-(2-phenylethyl)-THAI derivatives, and in particular compounds 12b and 12d proved to be very active against human BChE (IC50 = 13 and 1.8 nM, respectively), with 1000-fold selectivity over AChE. Structure-activity relationships highlighted critical features (e.g., ring fusion [4,3-b], integrity of the lactam CONH function) and favorable physicochemical properties of the 6-(2-phenylethyl) group (i.e., optimal position, size and lipophilicity of phenyl substituents). The effects of a number of compounds against NMDA-induced SH-SY5Y neuronal cell injury were also evaluated. Treatment with 12b increased cell viability in SH-SY5Y cells pretreated with 250 μM NMDA, with significant effects (P < 0.05) at concentrations between 0.5 and 5 μM. These findings suggest that THAI can be used as a scaffold for developing new drug leads for the treatment of Alzheimer-type neurodegeneration syndrome.
|
Inhibition of acetylcholinesterase (unknown origin) using acetylthiocholine as substrate preincubated for 20 mins followed by substrate addition by Ellmans method
|
Homo sapiens
|
600.0
nM
|
|
Journal : Bioorg Med Chem
Title : Green synthesis of novel spiro-indenoquinoxaline derivatives and their cholinesterases inhibition activity.
Year : 2017
Volume : 25
Issue : 7
First Page : 2057
Last Page : 2064
Authors : Maryamabadi A, Hasaninejad A, Nowrouzi N, Mohebbi G.
Abstract : A convenient synthesis of substituted spiroindenoquinoxalines at mild and green conditions was developed. Multicomponent reaction of substituted phenylene diamines, ninhydrin, malononitrile and N,N'-substituted-2-nitroethene-1,1-diamines produced the target compounds. Twelve new spiroindenoquinoxalines were obtained, and their ability in inhibition of acetyl and butyrylcholinesterases were investigated both in vitro and in silico. All compounds showed moderate level activity against both acetyl and butyrylcholinesterases.
|
Inhibition of electric eel AChE using acetylthiocholine iodide as substrate preincubated for 15 mins followed by substrate addition by spectrophotometric analysis
|
Electrophorus electricus
|
623.0
nM
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis, and evaluation of multitarget-directed ligands against Alzheimer's disease based on the fusion of donepezil and curcumin.
Year : 2017
Volume : 25
Issue : 12
First Page : 2946
Last Page : 2955
Authors : Yan J, Hu J, Liu A, He L, Li X, Wei H.
Abstract : By fusing donepezil and curcumin, a novel series of compounds were obtained as multitarget-directed ligands against Alzheimer's disease. Among them, compound 11b displayed potent acetylcholinesterase (AChE) inhibition (IC50=187nM) and the highest BuChE/AChE selectivity (66.3). Compound 11b also inhibited 45.3% Aβ1-42 self-aggregation at 20μM and displayed remarkable antioxidant effects. The metal-chelating property of compound 11b was elucidated by determining the 1:1 stoichiometry for the 11b-Cu(II) complex. The excellent blood-brain barrier permeability of 11b also indicated the potential for the compound to penetrate the central nervous system.
|
Inhibition of AChE (unknown origin)
|
Homo sapiens
|
355.0
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 electric eel AChE at 0.781 ug using acetylthiocholine iodide as substrate preincubated for 15 mins followed by substrate addition measured every 5 mins for 15 mins by spectrophotometric method relative to control
|
Electrophorus electricus
|
43.77
%
|
|
Journal : Bioorg Med Chem Lett
Title : A cascade synthesis, in vitro cholinesterases inhibitory activity and docking studies of novel Tacrine-pyranopyrazole derivatives.
Year : 2018
Volume : 28
Issue : 14
First Page : 2481
Last Page : 2484
Authors : Derabli C, Boualia I, Abdelwahab AB, Boulcina R, Bensouici C, Kirsch G, Debache A.
Abstract : In this work, we describe the preparation of some new Tacrine analogues modified with a pyranopyrazole moiety. A one-pot multicomponent reaction of 3-methyl-1H-pyrazol-5(4H)-one, aryl(or hetero)aldehydes, malononitrile and cyclohexanone involving a Friedländer condensation led to the title compounds. The synthesized heterocyclic analogues of this molecule were evaluated in vitro for their AChE and BChE inhibitory activities in search for potent cholinesterase enzyme inhibitors. Most of the synthesized compounds displayed remarkable AChE inhibitory activities with IC50 values ranging from 0.044 to 5.80 µM, wherein compounds 5e and 5j were found to be most active inhibitors against AChE with IC50 values of 0.058 and 0.044 µM respectively. Molecular modeling simulation on AChE and BChE receptors, showed good correlation between IC50 values and binding interaction template of the most active inhibitors docked into the active site of their relevant enzymes.
|
Inhibition of electric eel AChE at 1.563 ug using acetylthiocholine iodide as substrate preincubated for 15 mins followed by substrate addition measured every 5 mins for 15 mins by spectrophotometric method relative to control
|
Electrophorus electricus
|
68.5
%
|
|
Journal : Bioorg Med Chem Lett
Title : A cascade synthesis, in vitro cholinesterases inhibitory activity and docking studies of novel Tacrine-pyranopyrazole derivatives.
Year : 2018
Volume : 28
Issue : 14
First Page : 2481
Last Page : 2484
Authors : Derabli C, Boualia I, Abdelwahab AB, Boulcina R, Bensouici C, Kirsch G, Debache A.
Abstract : In this work, we describe the preparation of some new Tacrine analogues modified with a pyranopyrazole moiety. A one-pot multicomponent reaction of 3-methyl-1H-pyrazol-5(4H)-one, aryl(or hetero)aldehydes, malononitrile and cyclohexanone involving a Friedländer condensation led to the title compounds. The synthesized heterocyclic analogues of this molecule were evaluated in vitro for their AChE and BChE inhibitory activities in search for potent cholinesterase enzyme inhibitors. Most of the synthesized compounds displayed remarkable AChE inhibitory activities with IC50 values ranging from 0.044 to 5.80 µM, wherein compounds 5e and 5j were found to be most active inhibitors against AChE with IC50 values of 0.058 and 0.044 µM respectively. Molecular modeling simulation on AChE and BChE receptors, showed good correlation between IC50 values and binding interaction template of the most active inhibitors docked into the active site of their relevant enzymes.
|
Inhibition of electric eel AChE at 3.125 ug using acetylthiocholine iodide as substrate preincubated for 15 mins followed by substrate addition measured every 5 mins for 15 mins by spectrophotometric method relative to control
|
Electrophorus electricus
|
80.69
%
|
|
Journal : Bioorg Med Chem Lett
Title : A cascade synthesis, in vitro cholinesterases inhibitory activity and docking studies of novel Tacrine-pyranopyrazole derivatives.
Year : 2018
Volume : 28
Issue : 14
First Page : 2481
Last Page : 2484
Authors : Derabli C, Boualia I, Abdelwahab AB, Boulcina R, Bensouici C, Kirsch G, Debache A.
Abstract : In this work, we describe the preparation of some new Tacrine analogues modified with a pyranopyrazole moiety. A one-pot multicomponent reaction of 3-methyl-1H-pyrazol-5(4H)-one, aryl(or hetero)aldehydes, malononitrile and cyclohexanone involving a Friedländer condensation led to the title compounds. The synthesized heterocyclic analogues of this molecule were evaluated in vitro for their AChE and BChE inhibitory activities in search for potent cholinesterase enzyme inhibitors. Most of the synthesized compounds displayed remarkable AChE inhibitory activities with IC50 values ranging from 0.044 to 5.80 µM, wherein compounds 5e and 5j were found to be most active inhibitors against AChE with IC50 values of 0.058 and 0.044 µM respectively. Molecular modeling simulation on AChE and BChE receptors, showed good correlation between IC50 values and binding interaction template of the most active inhibitors docked into the active site of their relevant enzymes.
|
Inhibition of electric eel AChE at 6.25 ug using acetylthiocholine iodide as substrate preincubated for 15 mins followed by substrate addition measured every 5 mins for 15 mins by spectrophotometric method relative to control
|
Electrophorus electricus
|
85.78
%
|
|
Journal : Bioorg Med Chem Lett
Title : A cascade synthesis, in vitro cholinesterases inhibitory activity and docking studies of novel Tacrine-pyranopyrazole derivatives.
Year : 2018
Volume : 28
Issue : 14
First Page : 2481
Last Page : 2484
Authors : Derabli C, Boualia I, Abdelwahab AB, Boulcina R, Bensouici C, Kirsch G, Debache A.
Abstract : In this work, we describe the preparation of some new Tacrine analogues modified with a pyranopyrazole moiety. A one-pot multicomponent reaction of 3-methyl-1H-pyrazol-5(4H)-one, aryl(or hetero)aldehydes, malononitrile and cyclohexanone involving a Friedländer condensation led to the title compounds. The synthesized heterocyclic analogues of this molecule were evaluated in vitro for their AChE and BChE inhibitory activities in search for potent cholinesterase enzyme inhibitors. Most of the synthesized compounds displayed remarkable AChE inhibitory activities with IC50 values ranging from 0.044 to 5.80 µM, wherein compounds 5e and 5j were found to be most active inhibitors against AChE with IC50 values of 0.058 and 0.044 µM respectively. Molecular modeling simulation on AChE and BChE receptors, showed good correlation between IC50 values and binding interaction template of the most active inhibitors docked into the active site of their relevant enzymes.
|
Inhibition of electric eel AChE at 12.5 ug using acetylthiocholine iodide as substrate preincubated for 15 mins followed by substrate addition measured every 5 mins for 15 mins by spectrophotometric method relative to control
|
Electrophorus electricus
|
91.8
%
|
|
Journal : Bioorg Med Chem Lett
Title : A cascade synthesis, in vitro cholinesterases inhibitory activity and docking studies of novel Tacrine-pyranopyrazole derivatives.
Year : 2018
Volume : 28
Issue : 14
First Page : 2481
Last Page : 2484
Authors : Derabli C, Boualia I, Abdelwahab AB, Boulcina R, Bensouici C, Kirsch G, Debache A.
Abstract : In this work, we describe the preparation of some new Tacrine analogues modified with a pyranopyrazole moiety. A one-pot multicomponent reaction of 3-methyl-1H-pyrazol-5(4H)-one, aryl(or hetero)aldehydes, malononitrile and cyclohexanone involving a Friedländer condensation led to the title compounds. The synthesized heterocyclic analogues of this molecule were evaluated in vitro for their AChE and BChE inhibitory activities in search for potent cholinesterase enzyme inhibitors. Most of the synthesized compounds displayed remarkable AChE inhibitory activities with IC50 values ranging from 0.044 to 5.80 µM, wherein compounds 5e and 5j were found to be most active inhibitors against AChE with IC50 values of 0.058 and 0.044 µM respectively. Molecular modeling simulation on AChE and BChE receptors, showed good correlation between IC50 values and binding interaction template of the most active inhibitors docked into the active site of their relevant enzymes.
|
Inhibition of electric eel AChE at 25 ug using acetylthiocholine iodide as substrate preincubated for 15 mins followed by substrate addition measured every 5 mins for 15 mins by spectrophotometric method relative to control
|
Electrophorus electricus
|
94.77
%
|
|
Journal : Bioorg Med Chem Lett
Title : A cascade synthesis, in vitro cholinesterases inhibitory activity and docking studies of novel Tacrine-pyranopyrazole derivatives.
Year : 2018
Volume : 28
Issue : 14
First Page : 2481
Last Page : 2484
Authors : Derabli C, Boualia I, Abdelwahab AB, Boulcina R, Bensouici C, Kirsch G, Debache A.
Abstract : In this work, we describe the preparation of some new Tacrine analogues modified with a pyranopyrazole moiety. A one-pot multicomponent reaction of 3-methyl-1H-pyrazol-5(4H)-one, aryl(or hetero)aldehydes, malononitrile and cyclohexanone involving a Friedländer condensation led to the title compounds. The synthesized heterocyclic analogues of this molecule were evaluated in vitro for their AChE and BChE inhibitory activities in search for potent cholinesterase enzyme inhibitors. Most of the synthesized compounds displayed remarkable AChE inhibitory activities with IC50 values ranging from 0.044 to 5.80 µM, wherein compounds 5e and 5j were found to be most active inhibitors against AChE with IC50 values of 0.058 and 0.044 µM respectively. Molecular modeling simulation on AChE and BChE receptors, showed good correlation between IC50 values and binding interaction template of the most active inhibitors docked into the active site of their relevant enzymes.
|
Inhibition of electric eel AChE at 0.024 ug using acetylthiocholine iodide as substrate preincubated for 15 mins followed by substrate addition measured every 5 mins for 15 mins by spectrophotometric method relative to control
|
Electrophorus electricus
|
35.9
%
|
|
Journal : Bioorg Med Chem Lett
Title : A cascade synthesis, in vitro cholinesterases inhibitory activity and docking studies of novel Tacrine-pyranopyrazole derivatives.
Year : 2018
Volume : 28
Issue : 14
First Page : 2481
Last Page : 2484
Authors : Derabli C, Boualia I, Abdelwahab AB, Boulcina R, Bensouici C, Kirsch G, Debache A.
Abstract : In this work, we describe the preparation of some new Tacrine analogues modified with a pyranopyrazole moiety. A one-pot multicomponent reaction of 3-methyl-1H-pyrazol-5(4H)-one, aryl(or hetero)aldehydes, malononitrile and cyclohexanone involving a Friedländer condensation led to the title compounds. The synthesized heterocyclic analogues of this molecule were evaluated in vitro for their AChE and BChE inhibitory activities in search for potent cholinesterase enzyme inhibitors. Most of the synthesized compounds displayed remarkable AChE inhibitory activities with IC50 values ranging from 0.044 to 5.80 µM, wherein compounds 5e and 5j were found to be most active inhibitors against AChE with IC50 values of 0.058 and 0.044 µM respectively. Molecular modeling simulation on AChE and BChE receptors, showed good correlation between IC50 values and binding interaction template of the most active inhibitors docked into the active site of their relevant enzymes.
|
Inhibition of electric eel AChE at 0.049 ug using acetylthiocholine iodide as substrate preincubated for 15 mins followed by substrate addition measured every 5 mins for 15 mins by spectrophotometric method relative to control
|
Electrophorus electricus
|
43.77
%
|
|
Journal : Bioorg Med Chem Lett
Title : A cascade synthesis, in vitro cholinesterases inhibitory activity and docking studies of novel Tacrine-pyranopyrazole derivatives.
Year : 2018
Volume : 28
Issue : 14
First Page : 2481
Last Page : 2484
Authors : Derabli C, Boualia I, Abdelwahab AB, Boulcina R, Bensouici C, Kirsch G, Debache A.
Abstract : In this work, we describe the preparation of some new Tacrine analogues modified with a pyranopyrazole moiety. A one-pot multicomponent reaction of 3-methyl-1H-pyrazol-5(4H)-one, aryl(or hetero)aldehydes, malononitrile and cyclohexanone involving a Friedländer condensation led to the title compounds. The synthesized heterocyclic analogues of this molecule were evaluated in vitro for their AChE and BChE inhibitory activities in search for potent cholinesterase enzyme inhibitors. Most of the synthesized compounds displayed remarkable AChE inhibitory activities with IC50 values ranging from 0.044 to 5.80 µM, wherein compounds 5e and 5j were found to be most active inhibitors against AChE with IC50 values of 0.058 and 0.044 µM respectively. Molecular modeling simulation on AChE and BChE receptors, showed good correlation between IC50 values and binding interaction template of the most active inhibitors docked into the active site of their relevant enzymes.
|
Inhibition of electric eel AChE at 0.098 ug using acetylthiocholine iodide as substrate preincubated for 15 mins followed by substrate addition measured every 5 mins for 15 mins by spectrophotometric method relative to control
|
Electrophorus electricus
|
68.5
%
|
|
Journal : Bioorg Med Chem Lett
Title : A cascade synthesis, in vitro cholinesterases inhibitory activity and docking studies of novel Tacrine-pyranopyrazole derivatives.
Year : 2018
Volume : 28
Issue : 14
First Page : 2481
Last Page : 2484
Authors : Derabli C, Boualia I, Abdelwahab AB, Boulcina R, Bensouici C, Kirsch G, Debache A.
Abstract : In this work, we describe the preparation of some new Tacrine analogues modified with a pyranopyrazole moiety. A one-pot multicomponent reaction of 3-methyl-1H-pyrazol-5(4H)-one, aryl(or hetero)aldehydes, malononitrile and cyclohexanone involving a Friedländer condensation led to the title compounds. The synthesized heterocyclic analogues of this molecule were evaluated in vitro for their AChE and BChE inhibitory activities in search for potent cholinesterase enzyme inhibitors. Most of the synthesized compounds displayed remarkable AChE inhibitory activities with IC50 values ranging from 0.044 to 5.80 µM, wherein compounds 5e and 5j were found to be most active inhibitors against AChE with IC50 values of 0.058 and 0.044 µM respectively. Molecular modeling simulation on AChE and BChE receptors, showed good correlation between IC50 values and binding interaction template of the most active inhibitors docked into the active site of their relevant enzymes.
|
Inhibition of electric eel AChE at 0.195 ug using acetylthiocholine iodide as substrate preincubated for 15 mins followed by substrate addition measured every 5 mins for 15 mins by spectrophotometric method relative to control
|
Electrophorus electricus
|
80.69
%
|
|
Journal : Bioorg Med Chem Lett
Title : A cascade synthesis, in vitro cholinesterases inhibitory activity and docking studies of novel Tacrine-pyranopyrazole derivatives.
Year : 2018
Volume : 28
Issue : 14
First Page : 2481
Last Page : 2484
Authors : Derabli C, Boualia I, Abdelwahab AB, Boulcina R, Bensouici C, Kirsch G, Debache A.
Abstract : In this work, we describe the preparation of some new Tacrine analogues modified with a pyranopyrazole moiety. A one-pot multicomponent reaction of 3-methyl-1H-pyrazol-5(4H)-one, aryl(or hetero)aldehydes, malononitrile and cyclohexanone involving a Friedländer condensation led to the title compounds. The synthesized heterocyclic analogues of this molecule were evaluated in vitro for their AChE and BChE inhibitory activities in search for potent cholinesterase enzyme inhibitors. Most of the synthesized compounds displayed remarkable AChE inhibitory activities with IC50 values ranging from 0.044 to 5.80 µM, wherein compounds 5e and 5j were found to be most active inhibitors against AChE with IC50 values of 0.058 and 0.044 µM respectively. Molecular modeling simulation on AChE and BChE receptors, showed good correlation between IC50 values and binding interaction template of the most active inhibitors docked into the active site of their relevant enzymes.
|
Inhibition of electric eel AChE at 0.391 ug using acetylthiocholine iodide as substrate preincubated for 15 mins followed by substrate addition measured every 5 mins for 15 mins by spectrophotometric method relative to control
|
Electrophorus electricus
|
35.9
%
|
|
Journal : Bioorg Med Chem Lett
Title : A cascade synthesis, in vitro cholinesterases inhibitory activity and docking studies of novel Tacrine-pyranopyrazole derivatives.
Year : 2018
Volume : 28
Issue : 14
First Page : 2481
Last Page : 2484
Authors : Derabli C, Boualia I, Abdelwahab AB, Boulcina R, Bensouici C, Kirsch G, Debache A.
Abstract : In this work, we describe the preparation of some new Tacrine analogues modified with a pyranopyrazole moiety. A one-pot multicomponent reaction of 3-methyl-1H-pyrazol-5(4H)-one, aryl(or hetero)aldehydes, malononitrile and cyclohexanone involving a Friedländer condensation led to the title compounds. The synthesized heterocyclic analogues of this molecule were evaluated in vitro for their AChE and BChE inhibitory activities in search for potent cholinesterase enzyme inhibitors. Most of the synthesized compounds displayed remarkable AChE inhibitory activities with IC50 values ranging from 0.044 to 5.80 µM, wherein compounds 5e and 5j were found to be most active inhibitors against AChE with IC50 values of 0.058 and 0.044 µM respectively. Molecular modeling simulation on AChE and BChE receptors, showed good correlation between IC50 values and binding interaction template of the most active inhibitors docked into the active site of their relevant enzymes.
|
Inhibition of horse serum BChE at 0.391 ug using butyrylthiocholine chloride as substrate preincubated for 15 mins followed by substrate addition measured every 5 mins for 15 mins by spectrophotometric method relative to control
|
Equus caballus
|
11.13
%
|
|
Journal : Bioorg Med Chem Lett
Title : A cascade synthesis, in vitro cholinesterases inhibitory activity and docking studies of novel Tacrine-pyranopyrazole derivatives.
Year : 2018
Volume : 28
Issue : 14
First Page : 2481
Last Page : 2484
Authors : Derabli C, Boualia I, Abdelwahab AB, Boulcina R, Bensouici C, Kirsch G, Debache A.
Abstract : In this work, we describe the preparation of some new Tacrine analogues modified with a pyranopyrazole moiety. A one-pot multicomponent reaction of 3-methyl-1H-pyrazol-5(4H)-one, aryl(or hetero)aldehydes, malononitrile and cyclohexanone involving a Friedländer condensation led to the title compounds. The synthesized heterocyclic analogues of this molecule were evaluated in vitro for their AChE and BChE inhibitory activities in search for potent cholinesterase enzyme inhibitors. Most of the synthesized compounds displayed remarkable AChE inhibitory activities with IC50 values ranging from 0.044 to 5.80 µM, wherein compounds 5e and 5j were found to be most active inhibitors against AChE with IC50 values of 0.058 and 0.044 µM respectively. Molecular modeling simulation on AChE and BChE receptors, showed good correlation between IC50 values and binding interaction template of the most active inhibitors docked into the active site of their relevant enzymes.
|
Inhibition of horse serum BChE at 0.781 ug using butyrylthiocholine chloride as substrate preincubated for 15 mins followed by substrate addition measured every 5 mins for 15 mins by spectrophotometric method relative to control
|
Equus caballus
|
21.02
%
|
|
Journal : Bioorg Med Chem Lett
Title : A cascade synthesis, in vitro cholinesterases inhibitory activity and docking studies of novel Tacrine-pyranopyrazole derivatives.
Year : 2018
Volume : 28
Issue : 14
First Page : 2481
Last Page : 2484
Authors : Derabli C, Boualia I, Abdelwahab AB, Boulcina R, Bensouici C, Kirsch G, Debache A.
Abstract : In this work, we describe the preparation of some new Tacrine analogues modified with a pyranopyrazole moiety. A one-pot multicomponent reaction of 3-methyl-1H-pyrazol-5(4H)-one, aryl(or hetero)aldehydes, malononitrile and cyclohexanone involving a Friedländer condensation led to the title compounds. The synthesized heterocyclic analogues of this molecule were evaluated in vitro for their AChE and BChE inhibitory activities in search for potent cholinesterase enzyme inhibitors. Most of the synthesized compounds displayed remarkable AChE inhibitory activities with IC50 values ranging from 0.044 to 5.80 µM, wherein compounds 5e and 5j were found to be most active inhibitors against AChE with IC50 values of 0.058 and 0.044 µM respectively. Molecular modeling simulation on AChE and BChE receptors, showed good correlation between IC50 values and binding interaction template of the most active inhibitors docked into the active site of their relevant enzymes.
|
Inhibition of horse serum BChE at 1.563 ug using butyrylthiocholine chloride as substrate preincubated for 15 mins followed by substrate addition measured every 5 mins for 15 mins by spectrophotometric method relative to control
|
Equus caballus
|
55.22
%
|
|
Journal : Bioorg Med Chem Lett
Title : A cascade synthesis, in vitro cholinesterases inhibitory activity and docking studies of novel Tacrine-pyranopyrazole derivatives.
Year : 2018
Volume : 28
Issue : 14
First Page : 2481
Last Page : 2484
Authors : Derabli C, Boualia I, Abdelwahab AB, Boulcina R, Bensouici C, Kirsch G, Debache A.
Abstract : In this work, we describe the preparation of some new Tacrine analogues modified with a pyranopyrazole moiety. A one-pot multicomponent reaction of 3-methyl-1H-pyrazol-5(4H)-one, aryl(or hetero)aldehydes, malononitrile and cyclohexanone involving a Friedländer condensation led to the title compounds. The synthesized heterocyclic analogues of this molecule were evaluated in vitro for their AChE and BChE inhibitory activities in search for potent cholinesterase enzyme inhibitors. Most of the synthesized compounds displayed remarkable AChE inhibitory activities with IC50 values ranging from 0.044 to 5.80 µM, wherein compounds 5e and 5j were found to be most active inhibitors against AChE with IC50 values of 0.058 and 0.044 µM respectively. Molecular modeling simulation on AChE and BChE receptors, showed good correlation between IC50 values and binding interaction template of the most active inhibitors docked into the active site of their relevant enzymes.
|
Inhibition of horse serum BChE at 3.125 ug using butyrylthiocholine chloride as substrate preincubated for 15 mins followed by substrate addition measured every 5 mins for 15 mins by spectrophotometric method relative to control
|
Equus caballus
|
63.87
%
|
|
Journal : Bioorg Med Chem Lett
Title : A cascade synthesis, in vitro cholinesterases inhibitory activity and docking studies of novel Tacrine-pyranopyrazole derivatives.
Year : 2018
Volume : 28
Issue : 14
First Page : 2481
Last Page : 2484
Authors : Derabli C, Boualia I, Abdelwahab AB, Boulcina R, Bensouici C, Kirsch G, Debache A.
Abstract : In this work, we describe the preparation of some new Tacrine analogues modified with a pyranopyrazole moiety. A one-pot multicomponent reaction of 3-methyl-1H-pyrazol-5(4H)-one, aryl(or hetero)aldehydes, malononitrile and cyclohexanone involving a Friedländer condensation led to the title compounds. The synthesized heterocyclic analogues of this molecule were evaluated in vitro for their AChE and BChE inhibitory activities in search for potent cholinesterase enzyme inhibitors. Most of the synthesized compounds displayed remarkable AChE inhibitory activities with IC50 values ranging from 0.044 to 5.80 µM, wherein compounds 5e and 5j were found to be most active inhibitors against AChE with IC50 values of 0.058 and 0.044 µM respectively. Molecular modeling simulation on AChE and BChE receptors, showed good correlation between IC50 values and binding interaction template of the most active inhibitors docked into the active site of their relevant enzymes.
|
Inhibition of horse serum BChE at 6.25 ug using butyrylthiocholine chloride as substrate preincubated for 15 mins followed by substrate addition measured every 5 mins for 15 mins by spectrophotometric method relative to control
|
Equus caballus
|
78.85
%
|
|
Journal : Bioorg Med Chem Lett
Title : A cascade synthesis, in vitro cholinesterases inhibitory activity and docking studies of novel Tacrine-pyranopyrazole derivatives.
Year : 2018
Volume : 28
Issue : 14
First Page : 2481
Last Page : 2484
Authors : Derabli C, Boualia I, Abdelwahab AB, Boulcina R, Bensouici C, Kirsch G, Debache A.
Abstract : In this work, we describe the preparation of some new Tacrine analogues modified with a pyranopyrazole moiety. A one-pot multicomponent reaction of 3-methyl-1H-pyrazol-5(4H)-one, aryl(or hetero)aldehydes, malononitrile and cyclohexanone involving a Friedländer condensation led to the title compounds. The synthesized heterocyclic analogues of this molecule were evaluated in vitro for their AChE and BChE inhibitory activities in search for potent cholinesterase enzyme inhibitors. Most of the synthesized compounds displayed remarkable AChE inhibitory activities with IC50 values ranging from 0.044 to 5.80 µM, wherein compounds 5e and 5j were found to be most active inhibitors against AChE with IC50 values of 0.058 and 0.044 µM respectively. Molecular modeling simulation on AChE and BChE receptors, showed good correlation between IC50 values and binding interaction template of the most active inhibitors docked into the active site of their relevant enzymes.
|
Inhibition of horse serum BChE at 12.5 ug using butyrylthiocholine chloride as substrate preincubated for 15 mins followed by substrate addition measured every 5 mins for 15 mins by spectrophotometric method relative to control
|
Equus caballus
|
85.71
%
|
|
Journal : Bioorg Med Chem Lett
Title : A cascade synthesis, in vitro cholinesterases inhibitory activity and docking studies of novel Tacrine-pyranopyrazole derivatives.
Year : 2018
Volume : 28
Issue : 14
First Page : 2481
Last Page : 2484
Authors : Derabli C, Boualia I, Abdelwahab AB, Boulcina R, Bensouici C, Kirsch G, Debache A.
Abstract : In this work, we describe the preparation of some new Tacrine analogues modified with a pyranopyrazole moiety. A one-pot multicomponent reaction of 3-methyl-1H-pyrazol-5(4H)-one, aryl(or hetero)aldehydes, malononitrile and cyclohexanone involving a Friedländer condensation led to the title compounds. The synthesized heterocyclic analogues of this molecule were evaluated in vitro for their AChE and BChE inhibitory activities in search for potent cholinesterase enzyme inhibitors. Most of the synthesized compounds displayed remarkable AChE inhibitory activities with IC50 values ranging from 0.044 to 5.80 µM, wherein compounds 5e and 5j were found to be most active inhibitors against AChE with IC50 values of 0.058 and 0.044 µM respectively. Molecular modeling simulation on AChE and BChE receptors, showed good correlation between IC50 values and binding interaction template of the most active inhibitors docked into the active site of their relevant enzymes.
|
Inhibition of horse serum BChE at 25 ug using butyrylthiocholine chloride as substrate preincubated for 15 mins followed by substrate addition measured every 5 mins for 15 mins by spectrophotometric method relative to control
|
Equus caballus
|
96.98
%
|
|
Journal : Bioorg Med Chem Lett
Title : A cascade synthesis, in vitro cholinesterases inhibitory activity and docking studies of novel Tacrine-pyranopyrazole derivatives.
Year : 2018
Volume : 28
Issue : 14
First Page : 2481
Last Page : 2484
Authors : Derabli C, Boualia I, Abdelwahab AB, Boulcina R, Bensouici C, Kirsch G, Debache A.
Abstract : In this work, we describe the preparation of some new Tacrine analogues modified with a pyranopyrazole moiety. A one-pot multicomponent reaction of 3-methyl-1H-pyrazol-5(4H)-one, aryl(or hetero)aldehydes, malononitrile and cyclohexanone involving a Friedländer condensation led to the title compounds. The synthesized heterocyclic analogues of this molecule were evaluated in vitro for their AChE and BChE inhibitory activities in search for potent cholinesterase enzyme inhibitors. Most of the synthesized compounds displayed remarkable AChE inhibitory activities with IC50 values ranging from 0.044 to 5.80 µM, wherein compounds 5e and 5j were found to be most active inhibitors against AChE with IC50 values of 0.058 and 0.044 µM respectively. Molecular modeling simulation on AChE and BChE receptors, showed good correlation between IC50 values and binding interaction template of the most active inhibitors docked into the active site of their relevant enzymes.
|
Inhibition of electric eel AChE
|
Electrophorus electricus
|
250.0
nM
|
|
Journal : Eur J Med Chem
Title : Discorhabdin alkaloids from Antarctic Latrunculia spp. sponges as a new class of cholinesterase inhibitors.
Year : 2017
Volume : 136
First Page : 294
Last Page : 304
Authors : Botić T, Defant A, Zanini P, Žužek MC, Frangež R, Janussen D, Kersken D, Knez Ž, Mancini I, Sepčić K.
Abstract : The brominated pyrroloiminoquinone alkaloids discorhabdins B, L and G and 3-dihydro-7,8- dehydrodiscorhabdin C, isolated from methanol extracts of two specimens of Latrunculia sp. sponges collected near the Antarctic Peninsula, are here demonstrated for the first time to be reversible competitive inhibitors of cholinesterases. They showed Ki for electric eel acetylcholinesterase of 1.6-15.0 μM, for recombinant human acetylcholinesterase of 22.8-98.0 μM, and for horse serum butyrylcholinesterase of 5.0-76.0 μM. These values are promising when compared to the current cholinesterase inhibitors used for treatment of patients with Alzheimer's disease, to counteract the acetylcholine deficiency in the brain. Good correlation was obtained between IC50 data and results by molecular docking calculation on the binding interactions within the acetylcholinesterase active site, which also indicated the moieties in discorhabdin structures involved. To avoid unwanted peripheral side effects that can appear in patients using some acetylcholinesterase inhibitors, electrophysiological experiments were carried out on one of the most active of these compounds, discorhabdin G, which confirmed that it had no detectable undesirable effects on neuromuscular transmission and skeletal muscle function. These findings are promising for development of cholinesterase inhibitors based on the scaffold of discorhabdins, as potential new agents for treatment of patients with Alzheimer's disease.
|
Inhibition of equine serum BChE at 1 mM
|
Equus caballus
|
80.3
%
|
|
Journal : Eur J Med Chem
Title : Discorhabdin alkaloids from Antarctic Latrunculia spp. sponges as a new class of cholinesterase inhibitors.
Year : 2017
Volume : 136
First Page : 294
Last Page : 304
Authors : Botić T, Defant A, Zanini P, Žužek MC, Frangež R, Janussen D, Kersken D, Knez Ž, Mancini I, Sepčić K.
Abstract : The brominated pyrroloiminoquinone alkaloids discorhabdins B, L and G and 3-dihydro-7,8- dehydrodiscorhabdin C, isolated from methanol extracts of two specimens of Latrunculia sp. sponges collected near the Antarctic Peninsula, are here demonstrated for the first time to be reversible competitive inhibitors of cholinesterases. They showed Ki for electric eel acetylcholinesterase of 1.6-15.0 μM, for recombinant human acetylcholinesterase of 22.8-98.0 μM, and for horse serum butyrylcholinesterase of 5.0-76.0 μM. These values are promising when compared to the current cholinesterase inhibitors used for treatment of patients with Alzheimer's disease, to counteract the acetylcholine deficiency in the brain. Good correlation was obtained between IC50 data and results by molecular docking calculation on the binding interactions within the acetylcholinesterase active site, which also indicated the moieties in discorhabdin structures involved. To avoid unwanted peripheral side effects that can appear in patients using some acetylcholinesterase inhibitors, electrophysiological experiments were carried out on one of the most active of these compounds, discorhabdin G, which confirmed that it had no detectable undesirable effects on neuromuscular transmission and skeletal muscle function. These findings are promising for development of cholinesterase inhibitors based on the scaffold of discorhabdins, as potential new agents for treatment of patients with Alzheimer's disease.
|
Inhibition of electric eel AChE at 3 uM using acetylthiocholine iodide as substrate measured for 0.5 to 1.5 mins post substrate addition by spectrophotometry based Ellman's method
|
Electrophorus electricus
|
13.44
%
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and biochemical evaluation of novel multi-target inhibitors as potential anti-Parkinson agents.
Year : 2018
Volume : 143
First Page : 1543
Last Page : 1552
Authors : Carradori S, Ortuso F, Petzer A, Bagetta D, De Monte C, Secci D, De Vita D, Guglielmi P, Zengin G, Aktumsek A, Alcaro S, Petzer JP.
Abstract : New 4-(3-nitrophenyl)thiazol-2-ylhydrazone derivatives are proposed as dual-target-directed monoamine oxidase B (MAO-B) and acetylcholinesterase (AChE) inhibitors, as well as antioxidant agents, for the treatment of neurodegenerative disorders such as Parkinson's disease. Rational molecular design, target recognition and predicted pharmacokinetic properties have been evaluated by means of molecular modelling. Based on these properties, compounds were synthesized and evaluated in vitro as MAO-B and AChE inhibitors, and compared to the activities at their corresponding isozymes, monoamine oxidase A (MAO-A) and butyrylcholinesterase (BuChE), respectively. Anti-oxidant properties, potentially useful in the treatment of neurodegenerative disorders, have been also investigated in vitro. Among the evaluated compounds, three inhibitors may be considered as promising dual inhibitors of MAO-B and AChE, in vitro. MAO-B inhibition was also shown to be competitive and reversible for compound 19.
|
Inhibition of horse serum BuChE at 3 uM using butyrylthiocholine iodide as substrate preincubated for 15 mins followed by substrate addition measured after 10 mins by spectrophotometry based-Ellman's method
|
Equus caballus
|
13.62
%
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and biochemical evaluation of novel multi-target inhibitors as potential anti-Parkinson agents.
Year : 2018
Volume : 143
First Page : 1543
Last Page : 1552
Authors : Carradori S, Ortuso F, Petzer A, Bagetta D, De Monte C, Secci D, De Vita D, Guglielmi P, Zengin G, Aktumsek A, Alcaro S, Petzer JP.
Abstract : New 4-(3-nitrophenyl)thiazol-2-ylhydrazone derivatives are proposed as dual-target-directed monoamine oxidase B (MAO-B) and acetylcholinesterase (AChE) inhibitors, as well as antioxidant agents, for the treatment of neurodegenerative disorders such as Parkinson's disease. Rational molecular design, target recognition and predicted pharmacokinetic properties have been evaluated by means of molecular modelling. Based on these properties, compounds were synthesized and evaluated in vitro as MAO-B and AChE inhibitors, and compared to the activities at their corresponding isozymes, monoamine oxidase A (MAO-A) and butyrylcholinesterase (BuChE), respectively. Anti-oxidant properties, potentially useful in the treatment of neurodegenerative disorders, have been also investigated in vitro. Among the evaluated compounds, three inhibitors may be considered as promising dual inhibitors of MAO-B and AChE, in vitro. MAO-B inhibition was also shown to be competitive and reversible for compound 19.
|
Inhibition of equine serum BChE at 10 uM using S-butyrylthiocholine chloride as substrate preincubated for 15 mins followed by substrate addition and measured for 45 mins by Ellmans microplate assay
|
Equus caballus
|
80.77
%
|
|
Journal : Bioorg Med Chem
Title : In silico studies, synthesis and pharmacological evaluation to explore multi-targeted approach for imidazole analogues as potential cholinesterase inhibitors with neuroprotective role for Alzheimer's disease.
Year : 2018
Volume : 26
Issue : 8
First Page : 1511
Last Page : 1522
Authors : Gurjar AS, Darekar MN, Yeong KY, Ooi L.
Abstract : Alzheimer's disease (AD) is a progressive neurodegenerative disorder with multiple factors associated with its pathogenesis. Our strategy against AD involves design of multi-targeted 2-substituted-4,5-diphenyl-1H-imidazole analogues which can interact and inhibit AChE, thereby, increasing the synaptic availability of ACh, inhibit BuChE, relieve induced oxidative stress and confer a neuroprotective role. Molecular docking was employed to study interactions within the AChE active site. In silico ADME study was performed to estimate pharmacokinetic parameters. Based on computational studies, some analogues were synthesized and subjected to pharmacological evaluation involving antioxidant activity, toxicity and memory model studies in animals followed by detailed mechanistic in vitro cholinesterase inhibition study. Amongst the series, analogue 13 and 20 are the most promising multi-targeted candidates which can potentially increase memory, decrease free radical levels and protect neurons against cognitive deficit.
|
Inhibition of AChE (unknown origin)
|
Homo sapiens
|
300.0
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.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging
|
Homo sapiens
|
1.53
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
|
Inhibition of AChE (unknown origin) at 100 ug/mL using acetylthiocholine iodide as substrate by spectrophotometry based Ellman's method
|
Homo sapiens
|
98.89
%
|
|
Journal : Bioorg Med Chem Lett
Title : Bioactivity-guided identification of flavonoids with cholinesterase and β-amyloid peptide aggregation inhibitory effects from the seeds of Millettia pachycarpa.
Year : 2019
Volume : 29
Issue : 10
First Page : 1194
Last Page : 1198
Authors : Tu Y, Wu C, Kang Y, Li Q, Zhu C, Li Y.
Abstract : Millettia pachycarpa Benth, a widely used anthelminthic drug in folk, is rich in flavonoids with various bioactivities. This study aimed to identify active flavonoids with anti-Alzheimer's disease (AD) effect from its seeds by a bioassay-guided isolation. A novel rotenoid with unusual oxidative ring-opening skeleton (10) and nine known flavonoids (1-9) were obtained, and their structures were elucidated by NMR and HR-ESIMS analysis. Among all isolates, 7 and 8 showed selective butyrylcholinesterase (BChE) inhibitory activities (IC50 = 2.34 and 11.49 μM, respectively), while 3 was classified as a dual-action inhibitor against acetylcholinesterase (AChE) and BChE (IC50 AChE = 17.14 μM, IC50 BChE = 5.68 μM). Further kinetic study revealed that 3, 7, and 8 were mixed-type BChE inhibitors, but 3 was a competitive AChE inhibitor. Their strong binding affinities to BChE were confirmed by fluorescence quenching analysis. Additionally, 3 and 8 exhibited potent inhibitory effects against β-amyloid peptide aggregation. These results revealed M. pachycarpa could be a valuable source for anti-AD leads development, and compounds 3, 7 and 8 were worthy of further study as multifunctional or specific agents for AD treatment.
|
Inhibition of BChE (unknown origin) at 100 ug/mL using butyrylthiocholine iodide as substrate by spectrophotometry based Ellman's method
|
Homo sapiens
|
94.6
%
|
|
Journal : Bioorg Med Chem Lett
Title : Bioactivity-guided identification of flavonoids with cholinesterase and β-amyloid peptide aggregation inhibitory effects from the seeds of Millettia pachycarpa.
Year : 2019
Volume : 29
Issue : 10
First Page : 1194
Last Page : 1198
Authors : Tu Y, Wu C, Kang Y, Li Q, Zhu C, Li Y.
Abstract : Millettia pachycarpa Benth, a widely used anthelminthic drug in folk, is rich in flavonoids with various bioactivities. This study aimed to identify active flavonoids with anti-Alzheimer's disease (AD) effect from its seeds by a bioassay-guided isolation. A novel rotenoid with unusual oxidative ring-opening skeleton (10) and nine known flavonoids (1-9) were obtained, and their structures were elucidated by NMR and HR-ESIMS analysis. Among all isolates, 7 and 8 showed selective butyrylcholinesterase (BChE) inhibitory activities (IC50 = 2.34 and 11.49 μM, respectively), while 3 was classified as a dual-action inhibitor against acetylcholinesterase (AChE) and BChE (IC50 AChE = 17.14 μM, IC50 BChE = 5.68 μM). Further kinetic study revealed that 3, 7, and 8 were mixed-type BChE inhibitors, but 3 was a competitive AChE inhibitor. Their strong binding affinities to BChE were confirmed by fluorescence quenching analysis. Additionally, 3 and 8 exhibited potent inhibitory effects against β-amyloid peptide aggregation. These results revealed M. pachycarpa could be a valuable source for anti-AD leads development, and compounds 3, 7 and 8 were worthy of further study as multifunctional or specific agents for AD treatment.
|
Inhibition of AChE (unknown origin) at 20 ug/mL using acetylthiocholine iodide as substrate by spectrophotometry based Ellman's method
|
Homo sapiens
|
98.89
%
|
|
Journal : Bioorg Med Chem Lett
Title : Bioactivity-guided identification of flavonoids with cholinesterase and β-amyloid peptide aggregation inhibitory effects from the seeds of Millettia pachycarpa.
Year : 2019
Volume : 29
Issue : 10
First Page : 1194
Last Page : 1198
Authors : Tu Y, Wu C, Kang Y, Li Q, Zhu C, Li Y.
Abstract : Millettia pachycarpa Benth, a widely used anthelminthic drug in folk, is rich in flavonoids with various bioactivities. This study aimed to identify active flavonoids with anti-Alzheimer's disease (AD) effect from its seeds by a bioassay-guided isolation. A novel rotenoid with unusual oxidative ring-opening skeleton (10) and nine known flavonoids (1-9) were obtained, and their structures were elucidated by NMR and HR-ESIMS analysis. Among all isolates, 7 and 8 showed selective butyrylcholinesterase (BChE) inhibitory activities (IC50 = 2.34 and 11.49 μM, respectively), while 3 was classified as a dual-action inhibitor against acetylcholinesterase (AChE) and BChE (IC50 AChE = 17.14 μM, IC50 BChE = 5.68 μM). Further kinetic study revealed that 3, 7, and 8 were mixed-type BChE inhibitors, but 3 was a competitive AChE inhibitor. Their strong binding affinities to BChE were confirmed by fluorescence quenching analysis. Additionally, 3 and 8 exhibited potent inhibitory effects against β-amyloid peptide aggregation. These results revealed M. pachycarpa could be a valuable source for anti-AD leads development, and compounds 3, 7 and 8 were worthy of further study as multifunctional or specific agents for AD treatment.
|
Inhibition of BChE (unknown origin) at 20 ug/mL using butyrylthiocholine iodide as substrate by spectrophotometry based Ellman's method
|
Homo sapiens
|
94.6
%
|
|
Journal : Bioorg Med Chem Lett
Title : Bioactivity-guided identification of flavonoids with cholinesterase and β-amyloid peptide aggregation inhibitory effects from the seeds of Millettia pachycarpa.
Year : 2019
Volume : 29
Issue : 10
First Page : 1194
Last Page : 1198
Authors : Tu Y, Wu C, Kang Y, Li Q, Zhu C, Li Y.
Abstract : Millettia pachycarpa Benth, a widely used anthelminthic drug in folk, is rich in flavonoids with various bioactivities. This study aimed to identify active flavonoids with anti-Alzheimer's disease (AD) effect from its seeds by a bioassay-guided isolation. A novel rotenoid with unusual oxidative ring-opening skeleton (10) and nine known flavonoids (1-9) were obtained, and their structures were elucidated by NMR and HR-ESIMS analysis. Among all isolates, 7 and 8 showed selective butyrylcholinesterase (BChE) inhibitory activities (IC50 = 2.34 and 11.49 μM, respectively), while 3 was classified as a dual-action inhibitor against acetylcholinesterase (AChE) and BChE (IC50 AChE = 17.14 μM, IC50 BChE = 5.68 μM). Further kinetic study revealed that 3, 7, and 8 were mixed-type BChE inhibitors, but 3 was a competitive AChE inhibitor. Their strong binding affinities to BChE were confirmed by fluorescence quenching analysis. Additionally, 3 and 8 exhibited potent inhibitory effects against β-amyloid peptide aggregation. These results revealed M. pachycarpa could be a valuable source for anti-AD leads development, and compounds 3, 7 and 8 were worthy of further study as multifunctional or specific agents for AD treatment.
|
Inhibition of human Cholinesterase
|
Homo sapiens
|
575.0
nM
|
|
Journal : Bioorg Med Chem
Title : Anti-cholinesterase hybrids as multi-target-directed ligands against Alzheimer's disease (1998-2018).
Year : 2019
Volume : 27
Issue : 6
First Page : 895
Last Page : 930
Authors : Mishra P, Kumar A, Panda G.
Abstract : Alzheimer's disease (AD) is a genetically complex, progressive and irreversible neurodegenerative disorder of the brain which involves multiple associated etiological targets. The complex pathogenesis of AD gave rise to multi-target-directed ligands (MTDLs) principle to combat this dreaded disease. Within this approach, the design and synthesis of hybrids prevailed greatly because of their capability to simultaneously target the intertwined pathogenesis components of the disease. The hybrids include pharmacophoric hybridization of two or more established chemical scaffolds endowed with the desired pharmacological properties into a single moiety. In AD, the primary foundation of medication therapy and drug design strategies includes the inhibition of cholinesterase (ChE) enzymes. Hence the development of ChE inhibition based hybrids is the central choice of AD medicinal chemistry research. To illustrate the progress of ChE inhibition based hybrids and novel targets, we reviewed the medicinal chemistry and pharmacological properties of the multi-target molecules published since 1998-December 2018. We hope that this article will allow the readers to easily follow the evolution of this prominent medicinal chemistry approach to develop a more efficient inhibitor.
|
Inhibition of AChE in human erythrocytes using acetylthiocholine iodide as substrate at 100 uM preincubated with enzyme for 10 mins followed by substrate addition measured for 15 mins by Ellman's method relative to control
|
Homo sapiens
|
71.2
%
|
|
Journal : Eur J Med Chem
Title : Carboxamides vs. methanimines: Crystal structures, binding interactions, photophysical studies, and biological evaluation of (indazole-5-yl)methanimines as monoamine oxidase B and acetylcholinesterase inhibitors.
Year : 2019
Volume : 179
First Page : 404
Last Page : 422
Authors : Tzvetkov NT, Stammler HG, Georgieva MG, Russo D, Faraone I, Balacheva AA, Hristova S, Atanasov AG, Milella L, Antonov L, Gastreich M.
Abstract : A comprehensive study was performed for the first time to compare two structurally related substance classes, namely indazole-5-carboxamides (11-16) and (indazole-5-yl)methanimines (17-22). Both chemical entities are potent, selective and reversible MAO-B inhibitors and, therefore, may serve as promising lead structures for the development of drug candidates against Parkinson's disease (PD) and other neurological disorders. Compounds 15 (Ki = 170 pM, SI = 25907) and 17 (Ki = 270 pM, SI = 16340) were the most potent and selective MAO-B inhibitors in both series. To investigate the multi-target inhibitory activity, all compounds were further screened for their potency against human AChE and BuChE enzymes. Compound 15 was found to be the most potent and selective AChE inhibitor in all series (hAChE IC50 = 78.3 ± 1.7 μM). Moreover, compounds 11 and 17 showed no risk of drug-induced hepatotoxicity and a wider safety window, as determined in preliminary cytotoxicity screening. Molecular modeling studies into the human MAO-B enzyme-binding site supported by a HYDE analysis suggested that the imine linker similarly contributes to the total binding energy in methanimines 17-22 as the amide spacer in their carboxamide analogs 11-16. Amplified photophysical evaluation of compounds 17 and 20, including single X-ray analysis, photochemical experiments, and quantum-chemical calculations, provided insights into their more favourable isomeric forms and structural features, which contribute to their biologically active form and promising drug-like properties.
|
Inhibition of BuChE in human serum using S-butyrylthiocholine iodide as substrate at 100 uM preincubated with enzyme for 10 mins followed by substrate addition measured for 15 mins by Ellman's method relative to control
|
Homo sapiens
|
38.3
%
|
|
Journal : Eur J Med Chem
Title : Carboxamides vs. methanimines: Crystal structures, binding interactions, photophysical studies, and biological evaluation of (indazole-5-yl)methanimines as monoamine oxidase B and acetylcholinesterase inhibitors.
Year : 2019
Volume : 179
First Page : 404
Last Page : 422
Authors : Tzvetkov NT, Stammler HG, Georgieva MG, Russo D, Faraone I, Balacheva AA, Hristova S, Atanasov AG, Milella L, Antonov L, Gastreich M.
Abstract : A comprehensive study was performed for the first time to compare two structurally related substance classes, namely indazole-5-carboxamides (11-16) and (indazole-5-yl)methanimines (17-22). Both chemical entities are potent, selective and reversible MAO-B inhibitors and, therefore, may serve as promising lead structures for the development of drug candidates against Parkinson's disease (PD) and other neurological disorders. Compounds 15 (Ki = 170 pM, SI = 25907) and 17 (Ki = 270 pM, SI = 16340) were the most potent and selective MAO-B inhibitors in both series. To investigate the multi-target inhibitory activity, all compounds were further screened for their potency against human AChE and BuChE enzymes. Compound 15 was found to be the most potent and selective AChE inhibitor in all series (hAChE IC50 = 78.3 ± 1.7 μM). Moreover, compounds 11 and 17 showed no risk of drug-induced hepatotoxicity and a wider safety window, as determined in preliminary cytotoxicity screening. Molecular modeling studies into the human MAO-B enzyme-binding site supported by a HYDE analysis suggested that the imine linker similarly contributes to the total binding energy in methanimines 17-22 as the amide spacer in their carboxamide analogs 11-16. Amplified photophysical evaluation of compounds 17 and 20, including single X-ray analysis, photochemical experiments, and quantum-chemical calculations, provided insights into their more favourable isomeric forms and structural features, which contribute to their biologically active form and promising drug-like properties.
|
Inhibition of human recombinant AChE at 25 uM using acetylthiocholine iodide as substrate preincubated for 20 mins followed by substrate addition by Ellman's spectrophotometric method relative to control
|
Homo sapiens
|
90.0
%
|
|
Journal : Eur J Med Chem
Title : Discovery of novel benzofuran-based compounds with neuroprotective and immunomodulatory properties for Alzheimer's disease treatment.
Year : 2019
Volume : 178
First Page : 243
Last Page : 258
Authors : Montanari S, Mahmoud AM, Pruccoli L, Rabbito A, Naldi M, Petralla S, Moraleda I, Bartolini M, Monti B, Iriepa I, Belluti F, Gobbi S, Di Marzo V, Bisi A, Tarozzi A, Ligresti A, Rampa A.
Abstract : To address the multifactorial nature of Alzheimer's Disease (AD), a multi-target-directed ligand approach was herein developed. As a follow-up of our previous studies, a small library of newly designed 2-arylbenzofuran derivatives was evaluated towards cholinesterases and cannabinoid receptors. The two most promising compounds, 8 and 10, were then assessed for their neuroprotective activity and for their ability to modulate the microglial phenotype. Compound 8 emerged as able to fight AD from several directions: it restored the cholinergic system by inhibiting butyrylcholinesterase, showed neuroprotective activity against Aβ<sub>1-42</sub> oligomers, was a potent and selective CB<sub>2</sub> ligand and had immunomodulatory effects, switching microglia from the pro-inflammatory M1 to the neuroprotective M2 phenotype. Derivative 10 was a potent CB<sub>2</sub> inverse agonist with promising immunomodulatory properties and could be considered as a tool for investigating the role of CB<sub>2</sub> receptors and for developing potential immunomodulating drugs addressing the endocannabinoid system.
|
Inhibition of human recombinant BuChE at 25 uM using butyrylthiocholine iodide as substrate preincubated for 20 mins followed by substrate addition by Ellman's spectrophotometric method relative to control
|
Homo sapiens
|
54.2
%
|
|
Journal : Eur J Med Chem
Title : Discovery of novel benzofuran-based compounds with neuroprotective and immunomodulatory properties for Alzheimer's disease treatment.
Year : 2019
Volume : 178
First Page : 243
Last Page : 258
Authors : Montanari S, Mahmoud AM, Pruccoli L, Rabbito A, Naldi M, Petralla S, Moraleda I, Bartolini M, Monti B, Iriepa I, Belluti F, Gobbi S, Di Marzo V, Bisi A, Tarozzi A, Ligresti A, Rampa A.
Abstract : To address the multifactorial nature of Alzheimer's Disease (AD), a multi-target-directed ligand approach was herein developed. As a follow-up of our previous studies, a small library of newly designed 2-arylbenzofuran derivatives was evaluated towards cholinesterases and cannabinoid receptors. The two most promising compounds, 8 and 10, were then assessed for their neuroprotective activity and for their ability to modulate the microglial phenotype. Compound 8 emerged as able to fight AD from several directions: it restored the cholinergic system by inhibiting butyrylcholinesterase, showed neuroprotective activity against Aβ<sub>1-42</sub> oligomers, was a potent and selective CB<sub>2</sub> ligand and had immunomodulatory effects, switching microglia from the pro-inflammatory M1 to the neuroprotective M2 phenotype. Derivative 10 was a potent CB<sub>2</sub> inverse agonist with promising immunomodulatory properties and could be considered as a tool for investigating the role of CB<sub>2</sub> receptors and for developing potential immunomodulating drugs addressing the endocannabinoid system.
|
Inhibition of AChE (unknown origin)
|
Homo sapiens
|
0.767
ug.mL-1
|
|
Journal : Eur J Med Chem
Title : Triazole derivatives as inhibitors of Alzheimer's disease: Current developments and structure-activity relationships.
Year : 2019
Volume : 180
First Page : 656
Last Page : 672
Authors : Xu M, Peng Y, Zhu L, Wang S, Ji J, Rakesh KP.
Abstract : Alzheimer's disease (AD) is a well known neurodegenerative disorder alarming millions of people worldwide and the subsequent epidemiological statistics highlights the implication of the disease. AD is a multi-factorial disease, a variety of single-target directed drugs that have reached clinical trials have unsuccessful. Hence, various factors associated without set of AD have been considered in targeted drug discovery and development. Triazoles are five-membered heterocyclic scaffold due to their broad range of biological activities. The present review focuses on the recent developments in the area of medicinal chemistry to explore the diverse chemical structures of potential inhibitors of Alzheimer's disease and also look at its structure-activity relationships (SAR) studies of bioactive compounds for future discovery of suitable drug candidates. The prominence has been given on the major advancements in the medicinal brochure of this pharmacophore for the period during 2012-2019.
|
Antitrypanosomal activity against Trypanosoma cruzi
|
Trypanosoma cruzi
|
30.0
ug.mL-1
|
|
Journal : Bioorg Med Chem Lett
Title : Antiprotozoal alkaloid principles of the plant family Amaryllidaceae.
Year : 2019
Volume : 29
Issue : 20
First Page : 126642
Last Page : 126642
Authors : Nair JJ, van Staden J.
Abstract : Protozoan-borne diseases are prominent amongst diseases caused by parasites. Given their alarming morbidity and mortality statistics, there is ever growing interest in new therapies against these diseases. Whilst synthetic drugs such as benznidazole and melarsoprol have had a profound influence on the clinical setup, there has been significant interest in the phytochemical platform to also deliver such drug candidates. The plant family Amaryllidaceae is recognizable for its isoquinoline alkaloids, which exhibit attractive molecular architectures and interesting biological properties. This survey focuses on the antiprotozoal activities of 73 of such substances described in 18 different species of the Amaryllidaceae. Of these, 2-O-acetyllycorine was identified as the most potent (IC<sub>50</sub> 0.15 μg/mL against Trypansoma brucei brucei). Also considered are structure-activity relationships which have served to modulate activities, as well as the plausible mechanisms that underpin these effects and afford insight to the Amaryllidaceae alkaloid antiprotozoal pharmacophore.
|
Antitrypanosomal activity against Leishmania donovani
|
Leishmania donovani
|
30.0
ug.mL-1
|
|
Journal : Bioorg Med Chem Lett
Title : Antiprotozoal alkaloid principles of the plant family Amaryllidaceae.
Year : 2019
Volume : 29
Issue : 20
First Page : 126642
Last Page : 126642
Authors : Nair JJ, van Staden J.
Abstract : Protozoan-borne diseases are prominent amongst diseases caused by parasites. Given their alarming morbidity and mortality statistics, there is ever growing interest in new therapies against these diseases. Whilst synthetic drugs such as benznidazole and melarsoprol have had a profound influence on the clinical setup, there has been significant interest in the phytochemical platform to also deliver such drug candidates. The plant family Amaryllidaceae is recognizable for its isoquinoline alkaloids, which exhibit attractive molecular architectures and interesting biological properties. This survey focuses on the antiprotozoal activities of 73 of such substances described in 18 different species of the Amaryllidaceae. Of these, 2-O-acetyllycorine was identified as the most potent (IC<sub>50</sub> 0.15 μg/mL against Trypansoma brucei brucei). Also considered are structure-activity relationships which have served to modulate activities, as well as the plausible mechanisms that underpin these effects and afford insight to the Amaryllidaceae alkaloid antiprotozoal pharmacophore.
|
Antitrypanosomal activity against Trypanosoma brucei rhodesiense
|
Trypanosoma brucei rhodesiense
|
30.0
ug.mL-1
|
|
Journal : Bioorg Med Chem Lett
Title : Antiprotozoal alkaloid principles of the plant family Amaryllidaceae.
Year : 2019
Volume : 29
Issue : 20
First Page : 126642
Last Page : 126642
Authors : Nair JJ, van Staden J.
Abstract : Protozoan-borne diseases are prominent amongst diseases caused by parasites. Given their alarming morbidity and mortality statistics, there is ever growing interest in new therapies against these diseases. Whilst synthetic drugs such as benznidazole and melarsoprol have had a profound influence on the clinical setup, there has been significant interest in the phytochemical platform to also deliver such drug candidates. The plant family Amaryllidaceae is recognizable for its isoquinoline alkaloids, which exhibit attractive molecular architectures and interesting biological properties. This survey focuses on the antiprotozoal activities of 73 of such substances described in 18 different species of the Amaryllidaceae. Of these, 2-O-acetyllycorine was identified as the most potent (IC<sub>50</sub> 0.15 μg/mL against Trypansoma brucei brucei). Also considered are structure-activity relationships which have served to modulate activities, as well as the plausible mechanisms that underpin these effects and afford insight to the Amaryllidaceae alkaloid antiprotozoal pharmacophore.
|
Inhibition of electric eel AChE using acetylthiocholine iodide as substrate preincubated for 20 mins followed by substrate addition and measured upto 5 mins by Ellman's method
|
Electrophorus electricus
|
560.0
nM
|
|
Journal : Eur J Med Chem
Title : Investigating 1,2,3,4,5,6-hexahydroazepino[4,3-b]indole as scaffold of butyrylcholinesterase-selective inhibitors with additional neuroprotective activities for Alzheimer's disease.
Year : 2019
Volume : 177
First Page : 414
Last Page : 424
Authors : Purgatorio R, de Candia M, Catto M, Carrieri A, Pisani L, De Palma A, Toma M, Ivanova OA, Voskressensky LG, Altomare CD.
Abstract : Due to the role of butyrylcholinesterase (BChE) in acetylcholine hydrolysis in the late stages of the Alzheimer's disease (AD), inhibitors of butyrylcholinesterase (BChE) have been recently envisaged, besides acetylcholinesterase (AChE) inhibitors, as candidates for treating mild-to-moderate AD. Herein, synthesis and AChE/BChE inhibition activity of some twenty derivatives of 1,2,3,4,5,6-hexahydroazepino[4,3-b]indole (HHAI) is reported. Most of the newly synthesized HHAI derivatives achieved the inhibition of both ChE isoforms with IC<sub>50</sub>s in the micromolar range, with a structure-dependent selectivity toward BChE. Apparently, molecular volume and lipophilicity do increase selectivity toward BChE, and indeed the N<sup>2</sup>-(4-phenylbutyl) HHAI derivative 15d, which behaves as a mixed-type inhibitor, resulted the most potent (IC<sub>50</sub> 0.17 μM) and selective (>100-fold) inhibitor toward either horse serum and human BChE. Moreover, 15d inhibited in vitro self-induced aggregation of neurotoxic amyloid-β (Aβ) peptide and displayed neuroprotective effects in neuroblastoma SH-SY5Y cell line, significantly recovering (P < 0.001) cell viability when impaired by Aβ<sub>1-42</sub> and hydrogen peroxide insults. Overall, this study highlighted HHAI as useful and versatile scaffold for developing new small molecules targeting some enzymes and biochemical pathways involved in the pathogenesis of AD.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
9.86
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
19.34
%
|
|
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
|
-0.05
%
|
|
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
|
-0.14
%
|
|
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
|
-0.14
%
|
|
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
|
-0.05
%
|
|
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.
|
Inhibition of AChE (unknown origin) preincubated for 30 mins followed by substrate addition acetylthiocholineiodide measured after 40 mins by Ellman's method
|
Homo sapiens
|
790.0
nM
|
|
Journal : Eur J Med Chem
Title : Simple analogues of natural product chelerythrine: Discovery of a novel anticholinesterase 2-phenylisoquinolin-2-ium scaffold with excellent potency against acetylcholinesterase.
Year : 2020
Volume : 200
First Page : 112415
Last Page : 112415
Authors : Zhou B,Li H,Cui Z,Li D,Geng H,Gao J,Zhou L
Abstract : As simple analogues of the natural compound chelerythrine, a novel anti-cholinesterase 2-phenylisoquinolin-2-ium scaffold was designed by structure imitation. The activity evaluation led to the discovery of seven compounds with potent anti-acetylcholinesterase activity with IC values of ≤0.72 μM, superior to chelerythrine and standard drugs galantamine. Particularly, compound 8y showed the excellent dual acetylcholinesterase-butyrylcholinesterase inhibition activity, superior to rivastigmine, a dual cholinesterase inhibitor drug. Furthermore, the compounds displayed a competitive anti-acetylcholinesterase mechanism with the substrate and low cytotoxicity. Molecular docking showed that the isoquinoline moiety is embedded in a cavity surrounded by four aromatic residues of acetylcholinesterase by the π-π action. Structure-activity relationship showed that the p-substituents on the C-ring can dramatically improve the anti-acetylcholinesterase activity, while 8-OMe can increase the activity against the two cholinesterases simultaneously. Thus, the title compounds emerged as promising lead compounds for the development of novel cholinesterase inhibitor agents.
|
Inhibition of AChE (unknown origin) at 10 uM preincubated for 30 mins followed by substrate addition acetylthiocholineiodide measured after 40 mins by Ellman's method relative to control
|
Homo sapiens
|
81.4
%
|
|
Journal : Eur J Med Chem
Title : Simple analogues of natural product chelerythrine: Discovery of a novel anticholinesterase 2-phenylisoquinolin-2-ium scaffold with excellent potency against acetylcholinesterase.
Year : 2020
Volume : 200
First Page : 112415
Last Page : 112415
Authors : Zhou B,Li H,Cui Z,Li D,Geng H,Gao J,Zhou L
Abstract : As simple analogues of the natural compound chelerythrine, a novel anti-cholinesterase 2-phenylisoquinolin-2-ium scaffold was designed by structure imitation. The activity evaluation led to the discovery of seven compounds with potent anti-acetylcholinesterase activity with IC values of ≤0.72 μM, superior to chelerythrine and standard drugs galantamine. Particularly, compound 8y showed the excellent dual acetylcholinesterase-butyrylcholinesterase inhibition activity, superior to rivastigmine, a dual cholinesterase inhibitor drug. Furthermore, the compounds displayed a competitive anti-acetylcholinesterase mechanism with the substrate and low cytotoxicity. Molecular docking showed that the isoquinoline moiety is embedded in a cavity surrounded by four aromatic residues of acetylcholinesterase by the π-π action. Structure-activity relationship showed that the p-substituents on the C-ring can dramatically improve the anti-acetylcholinesterase activity, while 8-OMe can increase the activity against the two cholinesterases simultaneously. Thus, the title compounds emerged as promising lead compounds for the development of novel cholinesterase inhibitor agents.
|
Inhibition of human BuChE at 100 uM using butyrylthiocholine chloride as substrate by Ellman's method
|
Homo sapiens
|
68.2
%
|
|
