|
Percent inhibition of the enzyme Alcohol dehydrogenase was measured in rats which are treated with phenobarbital (PB)
|
None
|
90.0
%
|
|
Journal : J. Med. Chem.
Title : Metabolic depropargylation and its relationship to aldehyde dehydrogenase inhibition in vivo.
Year : 1980
Volume : 23
Issue : 6
First Page : 669
Last Page : 673
Authors : Shirota FN, DeMaster EG, Elberling JA, Nagasawa HT.
Abstract : The relationship between metabolic depropargylation in vitro to inhibition of the low Km aldehyde dehydrogenase (AIDH) of rat liver mitochondria in vivo was determined for a number of compounds bearing a propargyl substituent on nitrogen or oxygen. Only those compounds which enzymatically released the highly reactive alpha, beta-acetylenic aldehyde, propioladehyde, when incubated in vitro with phenobarbital-induced rat liver microsomes, e.g., tripropargylamine (4), pargyline (1a), and N-propargylbenzylamine (1b), significantly elevated blood acetaldehyde levels when administered in vivo. Mitochondrial AIDH activity in these animals was corresponding reduced to less than or equal to 20% that of control animals. Compounds that did not inhibit mitochondrial AlDH activity to this degree did not produce significant levels of propiolaldehyde when incubated with microsomes. Thus, for this series of compounds, metabolic depropargylation is a requirement for AlDH inhibitory activity in vivo.
|
Percent inhibition of the enzyme Alcohol dehydrogenase was measured in rats which are untreated with phenobarbital (PB)
|
None
|
88.0
%
|
|
Journal : J. Med. Chem.
Title : Metabolic depropargylation and its relationship to aldehyde dehydrogenase inhibition in vivo.
Year : 1980
Volume : 23
Issue : 6
First Page : 669
Last Page : 673
Authors : Shirota FN, DeMaster EG, Elberling JA, Nagasawa HT.
Abstract : The relationship between metabolic depropargylation in vitro to inhibition of the low Km aldehyde dehydrogenase (AIDH) of rat liver mitochondria in vivo was determined for a number of compounds bearing a propargyl substituent on nitrogen or oxygen. Only those compounds which enzymatically released the highly reactive alpha, beta-acetylenic aldehyde, propioladehyde, when incubated in vitro with phenobarbital-induced rat liver microsomes, e.g., tripropargylamine (4), pargyline (1a), and N-propargylbenzylamine (1b), significantly elevated blood acetaldehyde levels when administered in vivo. Mitochondrial AIDH activity in these animals was corresponding reduced to less than or equal to 20% that of control animals. Compounds that did not inhibit mitochondrial AlDH activity to this degree did not produce significant levels of propiolaldehyde when incubated with microsomes. Thus, for this series of compounds, metabolic depropargylation is a requirement for AlDH inhibitory activity in vivo.
|
Inhibition of monoamine oxidase A at 10 uM
|
None
|
60.0
%
|
|
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 monoamine oxidase B at 10 uM
|
None
|
98.2
%
|
|
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.
|
Irreversible inhibition of recombinant human MAO-B using p-tyramine substrate preincubated at 200 nM for 15 mins before substrate addition measured after repeated wash-out by fluorescence assay
|
Homo sapiens
|
56.6
%
|
|
Journal : Eur. J. Med. Chem.
Title : A novel series of tacrine-selegiline hybrids with cholinesterase and monoamine oxidase inhibition activities for the treatment of Alzheimer's disease.
Year : 2013
Volume : 62
First Page : 745
Last Page : 753
Authors : Lu C, Zhou Q, Yan J, Du Z, Huang L, Li X.
Abstract : A novel series of tacrine-selegiline hybrids was synthesised and evaluated for application as inhibitors of cholinesterase (AChE/BuChE) and monoamine oxidase (MAO-A/B). The results demonstrate that most of the synthesised compounds exhibit high inhibitory activity. Among these compounds, compound 8g provided a good balance of activity towards all targets (with IC50 values of 22.6 nM, 9.37 nM, 0.3724 μM, and 0.1810 μM for AChE, BuChE, MAO-A and MAO-B, respectively). These results indicated that 8g has the potential to be a multi-functional candidate for Alzheimer's disease.
|
Irreversible inhibition of recombinant human MAO-B using p-tyramine substrate preincubated at 200 nM for 15 mins before substrate addition measured after 20 mins by fluorescence assay
|
Homo sapiens
|
60.3
%
|
|
Journal : Eur. J. Med. Chem.
Title : A novel series of tacrine-selegiline hybrids with cholinesterase and monoamine oxidase inhibition activities for the treatment of Alzheimer's disease.
Year : 2013
Volume : 62
First Page : 745
Last Page : 753
Authors : Lu C, Zhou Q, Yan J, Du Z, Huang L, Li X.
Abstract : A novel series of tacrine-selegiline hybrids was synthesised and evaluated for application as inhibitors of cholinesterase (AChE/BuChE) and monoamine oxidase (MAO-A/B). The results demonstrate that most of the synthesised compounds exhibit high inhibitory activity. Among these compounds, compound 8g provided a good balance of activity towards all targets (with IC50 values of 22.6 nM, 9.37 nM, 0.3724 μM, and 0.1810 μM for AChE, BuChE, MAO-A and MAO-B, respectively). These results indicated that 8g has the potential to be a multi-functional candidate for Alzheimer's disease.
|
Inhibition of recombinant human MAO-B using p-benzylamine substrate preincubated for 15 mins before substrate addition measured after 20 mins by fluorescence assay
|
Homo sapiens
|
188.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : A novel series of tacrine-selegiline hybrids with cholinesterase and monoamine oxidase inhibition activities for the treatment of Alzheimer's disease.
Year : 2013
Volume : 62
First Page : 745
Last Page : 753
Authors : Lu C, Zhou Q, Yan J, Du Z, Huang L, Li X.
Abstract : A novel series of tacrine-selegiline hybrids was synthesised and evaluated for application as inhibitors of cholinesterase (AChE/BuChE) and monoamine oxidase (MAO-A/B). The results demonstrate that most of the synthesised compounds exhibit high inhibitory activity. Among these compounds, compound 8g provided a good balance of activity towards all targets (with IC50 values of 22.6 nM, 9.37 nM, 0.3724 μM, and 0.1810 μM for AChE, BuChE, MAO-A and MAO-B, respectively). These results indicated that 8g has the potential to be a multi-functional candidate for Alzheimer's disease.
|
Inhibition of MAOB (unknown origin) using kynuramine as substrate after 1 hr by fluorescence assay
|
Homo sapiens
|
130.0
nM
|
|
Journal : J. Med. Chem.
Title : Nonpeptidic propargylamines as inhibitors of lysine specific demethylase 1 (LSD1) with cellular activity.
Year : 2013
Volume : 56
Issue : 18
First Page : 7334
Last Page : 7342
Authors : Schmitt ML, Hauser AT, Carlino L, Pippel M, Schulz-Fincke J, Metzger E, Willmann D, Yiu T, Barton M, Schüle R, Sippl W, Jung M.
Abstract : Lysine demethylases play an important role in epigenetic regulation and thus in the development of diseases like cancer or neurodegenerative disorders. As the lysine specific demethylase 1 (LSD1/KDM1) has been strongly connected to androgen and estrogen dependent gene expression, it serves as a promising target for the therapy of hormone dependent cancer. Here, we report on the discovery of new small molecule inhibitors of LSD1 containing a propargylamine warhead, starting out from lysine containing substrate analogues. On the basis of these substrate mimicking inhibitors, we were able to increase potency by a combination of similarity-based virtual screening and subsequent synthetic optimization resulting in more druglike LSD1 inhibitors that led to histone hypermethylation in breast cancer cells.
|
Inhibition of LSD1 (unknown origin) expressed in Sf9 cells using H3K4(me2) as substrate at 100 uM preincubated for 30 mins prior to substrate addition measured after 90 mins by horseradish peroxidase assay relative to control
|
Homo sapiens
|
23.0
%
|
|
Journal : J. Med. Chem.
Title : Nonpeptidic propargylamines as inhibitors of lysine specific demethylase 1 (LSD1) with cellular activity.
Year : 2013
Volume : 56
Issue : 18
First Page : 7334
Last Page : 7342
Authors : Schmitt ML, Hauser AT, Carlino L, Pippel M, Schulz-Fincke J, Metzger E, Willmann D, Yiu T, Barton M, Schüle R, Sippl W, Jung M.
Abstract : Lysine demethylases play an important role in epigenetic regulation and thus in the development of diseases like cancer or neurodegenerative disorders. As the lysine specific demethylase 1 (LSD1/KDM1) has been strongly connected to androgen and estrogen dependent gene expression, it serves as a promising target for the therapy of hormone dependent cancer. Here, we report on the discovery of new small molecule inhibitors of LSD1 containing a propargylamine warhead, starting out from lysine containing substrate analogues. On the basis of these substrate mimicking inhibitors, we were able to increase potency by a combination of similarity-based virtual screening and subsequent synthetic optimization resulting in more druglike LSD1 inhibitors that led to histone hypermethylation in breast cancer cells.
|
Irreversible inhibition of human recombinant MAO-B at 200 nM preincubated for 15 mins followed by repeated washing by centrifugation-ultrafiltration method relative to control
|
Homo sapiens
|
56.6
%
|
|
Journal : Bioorg. Med. Chem.
Title : Inhibition of cholinesterase and monoamine oxidase-B activity by Tacrine-Homoisoflavonoid hybrids.
Year : 2013
Volume : 21
Issue : 23
First Page : 7406
Last Page : 7417
Authors : Sun Y, Chen J, Chen X, Huang L, Li X.
Abstract : A series of Tacrine-Homoisoflavonoid hybrids were designed, synthesised and evaluated as inhibitors of cholinesterases (ChEs) and human monoamine oxidases (MAOs). Most of the compounds were found to be potent against both ChEs and MAO-B. Among these hybrids, compound 8b, with a 6 carbon linker between tacrine and (E)-7-hydroxy-3-(4-methoxybenzylidene)chroman-4-one, proved to be the most potent against AChE and MAO-B with IC50 values of 67.9 nM and 0.401 μM, respectively. This compound was observed to cross the blood-brain barrier (BBB) in a parallel artificial membrane permeation assay for the BBB (PAMPA-BBB). The results indicated that compound 8b is an excellent multifunctional promising compound for development of novel drugs for Alzheimer's disease (AD).
|
Inhibition of human recombinant MAO-B at 200 nM incubated for 15 mins prior to washing relative to control
|
Homo sapiens
|
60.3
%
|
|
Journal : Bioorg. Med. Chem.
Title : Inhibition of cholinesterase and monoamine oxidase-B activity by Tacrine-Homoisoflavonoid hybrids.
Year : 2013
Volume : 21
Issue : 23
First Page : 7406
Last Page : 7417
Authors : Sun Y, Chen J, Chen X, Huang L, Li X.
Abstract : A series of Tacrine-Homoisoflavonoid hybrids were designed, synthesised and evaluated as inhibitors of cholinesterases (ChEs) and human monoamine oxidases (MAOs). Most of the compounds were found to be potent against both ChEs and MAO-B. Among these hybrids, compound 8b, with a 6 carbon linker between tacrine and (E)-7-hydroxy-3-(4-methoxybenzylidene)chroman-4-one, proved to be the most potent against AChE and MAO-B with IC50 values of 67.9 nM and 0.401 μM, respectively. This compound was observed to cross the blood-brain barrier (BBB) in a parallel artificial membrane permeation assay for the BBB (PAMPA-BBB). The results indicated that compound 8b is an excellent multifunctional promising compound for development of novel drugs for Alzheimer's disease (AD).
|
Inhibition of human recombinant MAO-B using benzylamine as substrate preincubated for 15 mins under dark condition followed by substrate addition measured after 20 mins by fluorescence assay
|
Homo sapiens
|
188.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Inhibition of cholinesterase and monoamine oxidase-B activity by Tacrine-Homoisoflavonoid hybrids.
Year : 2013
Volume : 21
Issue : 23
First Page : 7406
Last Page : 7417
Authors : Sun Y, Chen J, Chen X, Huang L, Li X.
Abstract : A series of Tacrine-Homoisoflavonoid hybrids were designed, synthesised and evaluated as inhibitors of cholinesterases (ChEs) and human monoamine oxidases (MAOs). Most of the compounds were found to be potent against both ChEs and MAO-B. Among these hybrids, compound 8b, with a 6 carbon linker between tacrine and (E)-7-hydroxy-3-(4-methoxybenzylidene)chroman-4-one, proved to be the most potent against AChE and MAO-B with IC50 values of 67.9 nM and 0.401 μM, respectively. This compound was observed to cross the blood-brain barrier (BBB) in a parallel artificial membrane permeation assay for the BBB (PAMPA-BBB). The results indicated that compound 8b is an excellent multifunctional promising compound for development of novel drugs for Alzheimer's disease (AD).
|
Inhibition of LSD1 (unknown origin) at 10 uM relative to control
|
Homo sapiens
|
69.8
%
|
|
Journal : MedChemComm
Title : Polyamine-based small molecule epigenetic modulators.
Year : 2012
Volume : 3
Issue : 1
First Page : 14
Last Page : 21
Authors : Sharma SK, Hazeldine S, Crowley ML, Hanson A, Beattie R, Varghese S, Senanayake TM, Hirata A, Hirata F, Huang Y, Wu Y, Steinbergs N, Murray-Stewart T, Bytheway I, Casero RA, Woster PM.
Abstract : Chromatin remodelling enzymes such as the histone deacetylases (HDACs) and histone demethylases such as lysine-specific demethylase 1 (LSD1) have been validated as targets for cancer drug discovery. Although a number of HDAC inhibitors have been marketed or are in human clinical trials, the search for isoform-specific HDAC inhibitors is an ongoing effort. In addition, the discovery and development of compounds targeting histone demethylases are in their early stages. Epigenetic modulators used in combination with traditional antitumor agents such as 5-azacytidine represent an exciting new approach to cancer chemotherapy. We have developed multiple series of HDAC inhibitors and LSD1 inhibitors that promote the re-expression of aberrantly silenced genes that are important in human cancer. The design, synthesis and biological activity of these analogues is described herein.
|
Antidepressant activity in mouse assessed as antagonism of tetrabenazine-induced symptoms at 10 mg/kg, ip administered 30 mins before 35 mg/kg, ip tetrabenazine challenge measured after 30 mins by arousal test
|
Mus musculus
|
60.0
%
|
|
Journal : J. Med. Chem.
Title : 2-(Alkoxyaryl)-2-imidazoline monoamine oxidase inhibitors with antidepressant activity.
Year : 1978
Volume : 21
Issue : 4
First Page : 405
Last Page : 409
Authors : Harfenist M, Soroko FE, McKenzie GM.
Abstract : Unlike the related noncyclic amidines which are broad-spectrum cestocides, a number of 2-imidazolines substituted in the 2 position by alkoxyaryl groups were not highly active in screening tests against the mouse tapeworms Hymenolepsis nana and Oochoristica symmetrica. Certain of the 2-(4-alkoxynaphthyl)-2-imidazolines and 2-(6-alkoxy-2-naphthyl)-2-imidzolines, however, had activity interpreted as antidepressant in the mouse. This activity paralleled in vitro irreversible inhibitory activity against mouse brain MAO for those where no substitution is present on the imidazoline ring. This irreversibility probably has a different origin from that postulated to explain the irreversible MAO inhibition of proparglic, cyclopropyl, and other "chemically reactive" MAO inhibitors.
|
Inhibition of human recombinant MAO-B using p-tyramine as substrate assessed as H2O2 production after 15 mins by fluorescence assay
|
Homo sapiens
|
192.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Multifunctional coumarin derivatives: monoamine oxidase B (MAO-B) inhibition, anti-β-amyloid (Aβ) aggregation and metal chelation properties against Alzheimer's disease.
Year : 2015
Volume : 25
Issue : 3
First Page : 508
Last Page : 513
Authors : Huang M, Xie SS, Jiang N, Lan JS, Kong LY, Wang XB.
Abstract : A series of coumarin derivatives were designed, synthesized, and evaluated as novel multifunctional agents against Alzheimer's disease (AD). In vitro studies showed that most of these compounds exhibited significant potency to inhibit hMAO-B selectively and self-induced Aβ1-42 aggregation. In particular, compound 13 presented the greatest potential to inhibit hMAO-B (IC50=0.081μM, SI >1234) and good inhibition of Aβ1-42 aggregation (52.9% at 20μM). Moreover, compound 13 could function as a metal-chelator, penetrate the blood-brain barrier (BBB) and show low cell toxicity in rat pheochromocytoma (PC12) and SH-SY5Y cells. Taken together, these results suggested that compound 13 might be a promising multifunctional agent for AD treatment.
|
Inhibition of human recombinant microsomal MAO-B expressed in Pichia pastoris incubated for 30 mins prior to substrate addition measured after 60 mins by MAO-Glo assay
|
Homo sapiens
|
20.3
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Reversible and irreversible small molecule inhibitors of monoamine oxidase B (MAO-B) investigated by biophysical techniques.
Year : 2015
Volume : 23
Issue : 4
First Page : 770
Last Page : 778
Authors : Rojas RJ, Edmondson DE, Almos T, Scott R, Massari ME.
Abstract : Monoamine oxidase B (MAO-B) plays a key role in the metabolism of dopamine, a neurotransmitter critical for the maintenance of cognitive function. Consequently, MAO-B is an important therapeutic target for disorders characterized by a decline in dopaminergic neurotransmission, including Parkinson's disease (PD). An emerging strategy in drug discovery is to utilize the biophysical approaches of thermal shift and isothermal titration calorimetry (ITC) to gain insight into binding modality and identify thermodynamically privileged chemical scaffolds. Described here is the development of such approaches for reversible and irreversible small molecule inhibitors of MAO-B. Investigation of soluble recombinant MAO-B revealed mechanism-based differences in the thermal shift and binding thermodynamic profiles of MAO-B inhibitors. Irreversible inhibitors demonstrated biphasic protein melt curves, large enthalpically favorable and entropically unfavorable binding, in contrast to reversible compounds, which were characterized by a dose-dependent increase in thermal stability and enthalpically-driven binding. The biophysical approaches described here aim to facilitate the discovery of next-generation MAO-B inhibitors.
|
Inhibition of human recombinant soluble MAO-B expressed in Pichia pastoris incubated for 30 mins prior to substrate addition measured after 60 mins by MAO-Glo assay
|
Homo sapiens
|
49.5
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Reversible and irreversible small molecule inhibitors of monoamine oxidase B (MAO-B) investigated by biophysical techniques.
Year : 2015
Volume : 23
Issue : 4
First Page : 770
Last Page : 778
Authors : Rojas RJ, Edmondson DE, Almos T, Scott R, Massari ME.
Abstract : Monoamine oxidase B (MAO-B) plays a key role in the metabolism of dopamine, a neurotransmitter critical for the maintenance of cognitive function. Consequently, MAO-B is an important therapeutic target for disorders characterized by a decline in dopaminergic neurotransmission, including Parkinson's disease (PD). An emerging strategy in drug discovery is to utilize the biophysical approaches of thermal shift and isothermal titration calorimetry (ITC) to gain insight into binding modality and identify thermodynamically privileged chemical scaffolds. Described here is the development of such approaches for reversible and irreversible small molecule inhibitors of MAO-B. Investigation of soluble recombinant MAO-B revealed mechanism-based differences in the thermal shift and binding thermodynamic profiles of MAO-B inhibitors. Irreversible inhibitors demonstrated biphasic protein melt curves, large enthalpically favorable and entropically unfavorable binding, in contrast to reversible compounds, which were characterized by a dose-dependent increase in thermal stability and enthalpically-driven binding. The biophysical approaches described here aim to facilitate the discovery of next-generation MAO-B inhibitors.
|
Binding affinity to human recombinant microsomal MAO-B by ITC
|
Homo sapiens
|
275.4
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Reversible and irreversible small molecule inhibitors of monoamine oxidase B (MAO-B) investigated by biophysical techniques.
Year : 2015
Volume : 23
Issue : 4
First Page : 770
Last Page : 778
Authors : Rojas RJ, Edmondson DE, Almos T, Scott R, Massari ME.
Abstract : Monoamine oxidase B (MAO-B) plays a key role in the metabolism of dopamine, a neurotransmitter critical for the maintenance of cognitive function. Consequently, MAO-B is an important therapeutic target for disorders characterized by a decline in dopaminergic neurotransmission, including Parkinson's disease (PD). An emerging strategy in drug discovery is to utilize the biophysical approaches of thermal shift and isothermal titration calorimetry (ITC) to gain insight into binding modality and identify thermodynamically privileged chemical scaffolds. Described here is the development of such approaches for reversible and irreversible small molecule inhibitors of MAO-B. Investigation of soluble recombinant MAO-B revealed mechanism-based differences in the thermal shift and binding thermodynamic profiles of MAO-B inhibitors. Irreversible inhibitors demonstrated biphasic protein melt curves, large enthalpically favorable and entropically unfavorable binding, in contrast to reversible compounds, which were characterized by a dose-dependent increase in thermal stability and enthalpically-driven binding. The biophysical approaches described here aim to facilitate the discovery of next-generation MAO-B inhibitors.
|
Reversible inhibition of human MAO-B at 10 times IC50 incubated for 30 mins followed by 100 fold dilution to 0.1 times IC50 by dilution assay relative to control
|
Homo sapiens
|
10.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Multi-target tacrine-coumarin hybrids: cholinesterase and monoamine oxidase B inhibition properties against Alzheimer's disease.
Year : 2015
Volume : 95
First Page : 153
Last Page : 165
Authors : Xie SS, Wang X, Jiang N, Yu W, Wang KD, Lan JS, Li ZR, Kong LY.
Abstract : A series of novel tacrine-coumarin hybrids were designed, synthesized and evaluated as multi-target agents against Alzheimer's disease. The biological assays indicated that most of compounds displayed potent inhibitory activity toward AChE and BuChE, and clearly selective inhibition for MAO-B. Among these compounds, 14c exhibited strong inhibitory activity for AChE (IC50 values of 33.63 nM for eeAChE and 16.11 nM for hAChE) and BuChE (IC50 values of 80.72 nM for eqBuChE and 112.72 nM for hBuChE), and the highest inhibitory activity against hMAO-B (IC50 value of 0.24 μM). Kinetic and molecular modeling studies revealed that 14c was a mixed-type inhibitor, binding simultaneously to catalytic, peripheral and mid-gorge sites of AChE. It was also a competitive inhibitor, which covered the substrate and entrance cavities of MAO-B. Moreover, 14c could penetrate the CNS and show low cell toxicity. Overall, these results suggested that 14c might be an excellent multi-target agent for AD treatment.
|
Inhibition of human recombinant MAO-B using benzylamine as substrate incubated for 15 mins prior to substrate addition measured after 20 mins by fluorescence plate reader analysis
|
Homo sapiens
|
188.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and evaluation of selegiline derivatives as monoamine oxidase inhibitor, antioxidant and metal chelator against Alzheimer's disease.
Year : 2015
Volume : 23
Issue : 13
First Page : 3722
Last Page : 3729
Authors : Xie S, Chen J, Li X, Su T, Wang Y, Wang Z, Huang L, Li X.
Abstract : A series of compounds with monoamine oxidase inhibition and biometal chelation activities were designed, synthesised and evaluated as agents against Alzheimer's disease. The in vitro assay shows that most target compounds exhibit good MAO-B activities with submicromolar IC50 values and antioxidant activity (1.49-5.67 ORAC-FL values). The selected compounds were used to determine the biometal chelating ability using UV-vis spectrometry and high-resolution mass spectrometry, which confirm that they can effectively interact with copper(II), iron(II) and zinc(II). The ThT fluorescence binding assay indicates that the synthetic compounds can inhibit Cu(II)-induced Aβ1-42 aggregation. The parallel artificial membrane permeation assay shows that most target compounds can cross the BBB. Based on these results, compound 8a was selected as a potential multifunctional agent for the treatment of AD.
|
Inhibition of human recombinant MAO-B using kynuramine substrate by spectrophotometric assay
|
Homo sapiens
|
130.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure-Based Design and Optimization of Multitarget-Directed 2H-Chromen-2-one Derivatives as Potent Inhibitors of Monoamine Oxidase B and Cholinesterases.
Year : 2015
Volume : 58
Issue : 14
First Page : 5561
Last Page : 5578
Authors : Farina R, Pisani L, Catto M, Nicolotti O, Gadaleta D, Denora N, Soto-Otero R, Mendez-Alvarez E, Passos CS, Muncipinto G, Altomare CD, Nurisso A, Carrupt PA, Carotti A.
Abstract : The multifactorial nature of Alzheimer's disease calls for the development of multitarget agents addressing key pathogenic processes. To this end, by following a docking-assisted hybridization strategy, a number of aminocoumarins were designed, prepared, and tested as monoamine oxidases (MAOs) and acetyl- and butyryl-cholinesterase (AChE and BChE) inhibitors. Highly flexible N-benzyl-N-alkyloxy coumarins 2-12 showed good inhibitory activities at MAO-B, AChE, and BChE but low selectivity. More rigid inhibitors, bearing meta- and para-xylyl linkers, displayed good inhibitory activities and high MAO-B selectivity. Compounds 21, 24, 37, and 39, the last two featuring an improved hydrophilic/lipophilic balance, exhibited excellent activity profiles with nanomolar inhibitory potency toward hMAO-B, high hMAO-B over hMAO-A selectivity and submicromolar potency at hAChE. Cell-based assays of BBB permeation, neurotoxicity, and neuroprotection supported the potential of compound 37 as a BBB-permeant neuroprotective agent against H2O2-induced oxidative stress with poor interaction as P-gp substrate and very low cytotoxicity.
|
Inhibition of human MAO-B using p-tyramine as substrate assessed as production of H2O2 from p-tyramine incubated for 15 mins by Amplex Red MAO assay
|
Homo sapiens
|
198.5
nM
|
|
Journal : MedChemComm
Title : Chromanones: selective and reversible monoamine oxidase B inhibitors with nanomolar potency
Year : 2015
Volume : 6
Issue : 7
First Page : 1293
Last Page : 1302
Authors : Lan J, Xie S, Huang M, Hu Y, Kong L, Wang X
|
Inhibition of human recombinant microsomal MAO-B expressed in baculovirus-infected insect cells using p-tyramine as substrate preincubated for 15 mins followed by substrate addition measured for 20 mins by amplex red assay
|
Homo sapiens
|
195.0
nM
|
|
Journal : Bioorg Med Chem
Title : N-Propargylpiperidines with naphthalene-2-carboxamide or naphthalene-2-sulfonamide moieties: Potential multifunctional anti-Alzheimer's agents.
Year : 2017
Volume : 25
Issue : 2
First Page : 633
Last Page : 645
Authors : Košak U, Knez D, Coquelle N, Brus B, Pišlar A, Nachon F, Brazzolotto X, Kos J, Colletier JP, Gobec S.
Abstract : In the brains of patients with Alzheimer's disease, the enzymatic activities of butyrylcholinesterase (BChE) and monoamine oxidase B (MAO-B) are increased. While BChE is a viable therapeutic target for alleviation of symptoms caused by cholinergic hypofunction, MAO-B is a potential therapeutic target for prevention of neurodegeneration in Alzheimer's disease. Starting with piperidine-based selective human (h)BChE inhibitors and propargylamine-based MAO inhibitors, we have designed, synthesized and biochemically evaluated a series of N-propargylpiperidines. All of these compounds inhibited hBChE with good selectivity over the related enzyme, acetylcholinesterase, and crossed the blood-brain barrier in a parallel artificial membrane permeation assay. The crystal structure of one of the inhibitors (compound 3) in complex with hBChE revealed its binding mode. Three compounds (4, 5, 6) showed concomitant inhibition of MAO-B. Additionally, the most potent hBChE inhibitor 7 and dual BChE and MAO-B inhibitor 6 were non-cytotoxic and protected neuronal SH-SY5Y cells from toxic amyloid β-peptide species.
|
Irreversible inhibition of recombinant human MAO-A expressed in baculovirus infected BTI insect cell microsomes assessed as residual activity using kynuramine as substrate at 13 uM preincubated for 15 mins with subsequent dialysis for 24 hrs followed by substrate addition measured after 20 mins by fluorescence spectroscopy relative to negative control
|
Homo sapiens
|
0.1
%
|
|
Journal : Eur J Med Chem
Title : The evaluation of 1,4-benzoquinones as inhibitors of human monoamine oxidase.
Year : 2017
Volume : 135
First Page : 196
Last Page : 203
Authors : Mostert S, Petzer A, Petzer JP.
Abstract : The monoamine oxidase (MAO) enzymes are of considerable pharmacological interest and inhibitors are used in the clinic for the treatment of major depressive disorder and Parkinson's disease. A limited number of studies have shown that the quinone class of compounds possesses MAO inhibition properties. Most notable among these is a report that 2,3,6-trimethyl-1,4-naphthoquinone (TMN), present in extracts of cured tobacco leafs, is a non-selective inhibitor of both MAO isoforms. An older study reports that 1,4-benzoquinone inhibits MAO-A and MAO-B from human synaptosomes. Both 1,4-naphthoquinones and 1,4-benzoquinone are reported to inhibit the MAOs with a reversible mode of action. Since the MAO inhibition properties of additional members of the 1,4-benzoquinone class of compounds have not yet been explored, the present study investigates a small series of four 1,4-benzoquinones which incorporate phenyl, benzyl, benzyloxy and cyclopentyl monosubstitution on C2. The 1,4-benzoquinones were found to be moderately potent MAO inhibitors with IC50 values of 5.03-13.2 μM (MAO-A) and 3.69-23.2 μM (MAO-B). These values are comparable to those recorded for 1,4-benzoquinone of 4.82 μM (MAO-A) and 10.2 μM (MAO-B). Of interest however, is the finding that the 1,4-benzoquinones are irreversible inhibitors of MAO-A since prolonged incubation results in near complete inhibition, and enzyme activity is not recovered by dialysis. MAO-B is much less sensitive to inactivation by the 1,4-benzoquinones. These findings are discussed with reference to a possible mechanism by which irreversible inhibition occurs. It may be concluded that irreversible 1,4-benzoquinone-derived inhibitors may act as probes for investigating quinone reactive sites in the MAOs.
|
Inhibition of recombinant human MAOB using benzylamine as substrate preincubated for 15 mins followed by substrate addition measured after 15 mins by Amplex red reagent based fluorescence assay
|
Homo sapiens
|
188.0
nM
|
|
Journal : Eur J Med Chem
Title : Discovery of novel propargylamine-modified 4-aminoalkyl imidazole substituted pyrimidinylthiourea derivatives as multifunctional agents for the treatment of Alzheimer's disease.
Year : 2018
Volume : 143
First Page : 33
Last Page : 47
Authors : Xu YX, Wang H, Li XK, Dong SN, Liu WW, Gong Q, Wang TD, Tang Y, Zhu J, Li J, Zhang HY, Mao F.
Abstract : A series of novel propargylamine-modified pyrimidinylthiourea derivatives (1-3) were designed and synthesized as multifunctional agents for Alzheimer's disease (AD) therapy, and their potential was evaluated through various biological experiments. Among these derivatives, compound 1b displayed good selective inhibitory activity against AChE (vs BuChE, IC50 = 0.324 μM, SI > 123) and MAO-B (vs MAO-A, IC50 = 1.427 μM, SI > 35). Molecular docking study showed that the pyrimidinylthiourea moiety of 1b could bind to the catalytic active site (CAS) of AChE, and the propargylamine moiety interacted directly with the flavin adenine dinucleotide (FAD) of MAO-B. Moreover, 1b demonstrated mild antioxidant ability, good copper chelating property, effective inhibitory activity against Cu2+-induced Aβ1-42 aggregation, moderate neuroprotection, low cytotoxicity, and appropriate blood-brain barrier (BBB) permeability in vitro and was capable of ameliorating scopolamine-induced cognitive impairment in mice. These results indicated that 1b has the potential to be a multifunctional candidate for the treatment of Alzheimer's disease.
|
Inhibition of human MAO-B using p-tyramine as substrate preincubated for 15 mins followed by substrate addition measured after 20 mins by fluorescence-based Amplex Red MAO assay
|
Homo sapiens
|
200.0
nM
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis, and evaluation of salicyladimine derivatives as multitarget-directed ligands against Alzheimer's disease.
Year : 2017
Volume : 25
Issue : 21
First Page : 5917
Last Page : 5928
Authors : Yang HL, Cai P, Liu QH, Yang XL, Fang SQ, Tang YW, Wang C, Wang XB, Kong LY.
Abstract : A series of salicyladimine derivatives were designed, synthesized and evaluated as multi-target-directed ligands for the treatment of Alzheimer's disease (AD). Biological activity results demonstrated that some derivatives possessed significant inhibitory activities against amyloid-β (Aβ) aggregation and human monoamine oxidase B (hMAO-B) as well as remarkable antioxidant effects and low cell toxicity. The optimal compound, 5, exhibited excellent potency for inhibition of self-induced Aβ1-42 aggregation (91.3±2.1%, 25μM), inhibition of hMAO-B (IC50, 1.73±0.39μM), antioxidant effects (43.4±2.6μM of IC50 by DPPH method, 0.67±0.06 trolox equivalent by ABTS method), metal chelation and BBB penetration. Furthermore, compound 5 had neuroprotective effects against ROS generation, H2O2-induced apoptosis, 6-OHDA-induced cell injury, and a significant in vitro anti-inflammatory activity. Collectively, these findings highlighted that compound 5 was a potential balanced multifunctional neuroprotective agent for the development of anti-AD drugs.
|
Inhibition of human recombinant MAOB using benzylamine as substrate preincubated for 30 mins followed by substrate addition
|
Homo sapiens
|
120.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Selective inhibition of monoamine oxidase A by hispidol.
Year : 2018
Volume : 28
Issue : 4
First Page : 584
Last Page : 588
Authors : Baek SC, Lee HW, Ryu HW, Kang MG, Park D, Kim SH, Cho ML, Oh SR, Kim H.
Abstract : Hispidol, an aurone, isolated from Glycine max Merrill, was found to potently and selectively inhibit an isoform of recombinant human monoamine oxidase-A (MAO-A), with an IC50 value of 0.26 µM, and to inhibit MAO-B, but with lower potency (IC50 = 2.45 µM). Hispidol reversibly and competitively inhibited MAO-A with a Ki value of 0.10 µM with a potency much greater than toloxatone (IC50 = 1.10 µM), a marketed drug. It also reversibly and competitively inhibited MAO-B (Ki = 0.51 µM). Sulfuretin, an analog of hispidol, effectively inhibited MAO-A (IC50 = 4.16 µM) but not MAO-B (IC50 > 80 µM). A comparison of their chemical structures showed that the 3'-hydroxyl group of sulfuretin might reduce its inhibitory activities against MAO-A and MAO-B. Flexible docking simulation revealed that the binding affinity of hispidol for MAO-A (-9.1 kcal/mol) was greater than its affinity for MAO-B (-8.7 kcal/mol). The docking simulation showed hispidol binds to the major pocket of MAO-A or MAO-B. The findings suggest hispidol is a potent, selective, reversible inhibitor of MAO-A, and that it be considered a novel lead compound for development of novel reversible inhibitors of MAO-A.
|
Inhibition of recombinant human MAO-B using p-tyramine as substrate preincubated for 15 mins followed by substrate addition measured after 20 mins by amplex red reagent based fluorescence assay
|
Homo sapiens
|
194.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and evaluation of coumarin-pargyline hybrids as novel dual inhibitors of monoamine oxidases and amyloid-β aggregation for the treatment of Alzheimer's disease.
Year : 2017
Volume : 138
First Page : 715
Last Page : 728
Authors : Yang HL, Cai P, Liu QH, Yang XL, Li F, Wang J, Wu JJ, Wang XB, Kong LY.
Abstract : A series of coumarin-pargyline hybrids (4a-x) have been designed, synthesized and evaluated as novel dual inhibitors of Alzheimer's disease (AD). Most of the compounds exhibited a potent ability to inhibit amyloid-β (Aβ) aggregation and monoamine oxidases. In particular, compound 4x exhibited remarkable inhibitory activities against monoamine oxidases (IC50, 0.027 ± 0.004 μM for MAO-B; 3.275 ± 0.040 μM for MAO-A) and Aβ1-42 aggregation (54.0 ± 1.1%, 25 μM). Moreover, compound 4x showed low toxicity according to in vitro cell toxicity test. The results of the parallel artificial membrane permeability assay for blood-brain barrier indicated that compound 4x would be potent to cross the blood-brain barrier. Collectively, these findings demonstrate that compound 4x was an effective and promising candidate for AD therapy.
|
Inhibition of MAO-A (unknown origin)
|
Homo sapiens
|
11.52
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and evaluation of coumarin-pargyline hybrids as novel dual inhibitors of monoamine oxidases and amyloid-β aggregation for the treatment of Alzheimer's disease.
Year : 2017
Volume : 138
First Page : 715
Last Page : 728
Authors : Yang HL, Cai P, Liu QH, Yang XL, Li F, Wang J, Wu JJ, Wang XB, Kong LY.
Abstract : A series of coumarin-pargyline hybrids (4a-x) have been designed, synthesized and evaluated as novel dual inhibitors of Alzheimer's disease (AD). Most of the compounds exhibited a potent ability to inhibit amyloid-β (Aβ) aggregation and monoamine oxidases. In particular, compound 4x exhibited remarkable inhibitory activities against monoamine oxidases (IC50, 0.027 ± 0.004 μM for MAO-B; 3.275 ± 0.040 μM for MAO-A) and Aβ1-42 aggregation (54.0 ± 1.1%, 25 μM). Moreover, compound 4x showed low toxicity according to in vitro cell toxicity test. The results of the parallel artificial membrane permeability assay for blood-brain barrier indicated that compound 4x would be potent to cross the blood-brain barrier. Collectively, these findings demonstrate that compound 4x was an effective and promising candidate for AD therapy.
|
Inhibition of MAO-B (unknown origin)
|
Homo sapiens
|
8.2
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and evaluation of coumarin-pargyline hybrids as novel dual inhibitors of monoamine oxidases and amyloid-β aggregation for the treatment of Alzheimer's disease.
Year : 2017
Volume : 138
First Page : 715
Last Page : 728
Authors : Yang HL, Cai P, Liu QH, Yang XL, Li F, Wang J, Wu JJ, Wang XB, Kong LY.
Abstract : A series of coumarin-pargyline hybrids (4a-x) have been designed, synthesized and evaluated as novel dual inhibitors of Alzheimer's disease (AD). Most of the compounds exhibited a potent ability to inhibit amyloid-β (Aβ) aggregation and monoamine oxidases. In particular, compound 4x exhibited remarkable inhibitory activities against monoamine oxidases (IC50, 0.027 ± 0.004 μM for MAO-B; 3.275 ± 0.040 μM for MAO-A) and Aβ1-42 aggregation (54.0 ± 1.1%, 25 μM). Moreover, compound 4x showed low toxicity according to in vitro cell toxicity test. The results of the parallel artificial membrane permeability assay for blood-brain barrier indicated that compound 4x would be potent to cross the blood-brain barrier. Collectively, these findings demonstrate that compound 4x was an effective and promising candidate for AD therapy.
|
Inhibition of recombinant human MAO-B assessed as reduction in H2O2 production using p-tyramine as substrate preincubated for 15 mins followed by substrate addition by Amplex red reagent based fluorescence assay
|
Homo sapiens
|
75.2
nM
|
|
Journal : MedChemComm
Title : Synthesis and pharmacological evaluation of multi-functional homoisoflavonoid derivatives as potent inhibitors of monoamine oxidase B and cholinesterase for the treatment of Alzheimer's disease.
Year : 2017
Volume : 8
Issue : 7
First Page : 1459
Last Page : 1467
Authors : Liu QH, Wu JJ, Li F, Cai P, Yang XL, Kong LY, Wang XB.
Abstract : A series of homoisoflavonoid derivatives was designed, synthesized and evaluated as potential multi-functional anti-Alzheimer's agents for their inhibitory activity on cholinesterase and monoamine oxidase. Among them, compound <b>16</b> showed moderate acetylcholinesterase (AChE) inhibitory activity (eeAChE IC<sub>50</sub> = 0.89 ± 0.02 μM; hAChE IC<sub>50</sub> = 0.657 ± 0.002 μM) and significant monoamine oxidase B (MAO-B) inhibitory activity (hMAO-B IC<sub>50</sub> = 0.0372 ± 0.0002 μM). Kinetic analysis of AChE, MAO-B inhibition and molecular modeling studies revealed that compound <b>16</b> is a dual binding site inhibitor of AChE and noncompetitive inhibitor of MAO-B. Furthermore, <b>16</b> could penetrate through the blood-brain barrier (BBB) <i>in vitro</i>. Most importantly, oral administration of <b>16</b> demonstrated no marked signs of acute toxicity and it could significantly reverse scopolamine-induced memory impairment in mice. These results suggested that compound <b>16</b> is a promising multifunctional drug candidate with potential effect for the treatment of Alzheimer's disease.
|
Inhibition of recombinant human microsomal MAOB expressed in baculovirus infected BTI insect cells using p-tyramine as substrate preincubated for 15 mins followed by substrate addition and measured over 20 mins by amplex red reagent-based horseradish peroxidase-coupled fluorometric assay
|
Homo sapiens
|
195.5
nM
|
|
Journal : J Med Chem
Title : Stereoselective Activity of 1-Propargyl-4-styrylpiperidine-like Analogues That Can Discriminate between Monoamine Oxidase Isoforms A and B.
Year : 2020
Volume : 63
Issue : 3
First Page : 1361
Last Page : 1387
Authors : Knez D, Colettis N, Iacovino LG, Sova M, Pišlar A, Konc J, Lešnik S, Higgs J, Kamecki F, Mangialavori I, Dolšak A, Žakelj S, Trontelj J, Kos J, Binda C, Marder M, Gobec S.
Abstract : The resurgence of interest in monoamine oxidases (MAOs) has been fueled by recent correlations of this enzymatic activity with cardiovascular, neurological, and oncological disorders. This has promoted increased research into selective MAO-A and MAO-B inhibitors. Here, we shed light on how selective inhibition of MAO-A and MAO-B can be achieved by geometric isomers of cis- and trans-1-propargyl-4-styrylpiperidines. While the cis isomers are potent human MAO-A inhibitors, the trans analogues selectively target only the MAO-B isoform. The inhibition was studied by kinetic analysis, UV-vis spectrum measurements, and X-ray crystallography. The selective inhibition of the MAO-A and MAO-B isoforms was confirmed ex vivo in mouse brain homogenates, and additional in vivo studies in mice show the therapeutic potential of 1-propargyl-4-styrylpiperidines for central nervous system disorders. This study represents a unique case of stereoselective activity of cis/trans isomers that can discriminate between structurally related enzyme isoforms.
|
Inhibition of human recombinant microsomal MAO-B expressed in baculovirus infected BTI-TN-5B1-4 cells assessed as reduction in production of H202 using p-tyramine as substrate incubated for 30 mins followed by substrate addition by horse radish peroxidase/Amplex red reagent based fluorescence assay
|
Homo sapiens
|
150.0
nM
|
|
Journal : Eur J Med Chem
Title : Dipropargyl substituted diphenylpyrimidines as dual inhibitors of monoamine oxidase and acetylcholinesterase.
Year : 2019
Volume : 177
First Page : 221
Last Page : 234
Authors : Kumar B, Kumar V, Prashar V, Saini S, Dwivedi AR, Bajaj B, Mehta D, Parkash J, Kumar V.
Abstract : Alzheimer's disease (AD) is a multifactorial neurological disorder involving complex pathogenesis. Single target directed drugs proved ineffective and since last few years' different pharmacological strategies including multi-targeting agents are being explored for the effective drug development for AD. A total of 19 dipropargyl substituted diphenylpyrimidines have been synthesized and evaluated for the monoamine oxidase (MAO) and acetylcholinesterase (AChE) inhibition potential. All the compounds were found to be selective and reversible inhibitors of MAO-B isoform. These compounds also displayed good AChE inhibition potential with IC<sub>50</sub> values in low micromolar range. AVB4 was found to be the most potent MAO-B inhibitor with IC<sub>50</sub> value of 1.49 ± 0.09 μM and AVB1 was found to be the most potent AChE inhibitor with IC<sub>50</sub> value of 1.35 ± 0.03 μM. In the ROS protection inhibition studies, AVB1 and AVB4 displayed weak but interesting activity in SH-SY5Y cells. In the cytotoxicity studies involving SH-SY5Y cells, both AVB1 and AVB4 were found to be non-toxic to the tissue cells. In the molecular dynamic simulation studies of 30 ns, the potent compounds were found to be quite stable in the active site of MAO-B and AChE. The results suggested that AVB1 and AVB4 are promising dual inhibitors and have the potential to be developed as anti-Alzheimer's drug.
|
Inhibition of recombinant human MAO-B expressed in baculovirus infected BTI insect cells incubated for 15 mins with substrate p-Tyramine by fluorescence assay
|
Homo sapiens
|
85.8
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and biological evaluation of hydroxypyridinone-coumarin hybrids as multimodal monoamine oxidase B inhibitors and iron chelates against Alzheimer's disease.
Year : 2019
Volume : 180
First Page : 367
Last Page : 382
Authors : Zhang C, Yang K, Yu S, Su J, Yuan S, Han J, Chen Y, Gu J, Zhou T, Bai R, Xie Y.
Abstract : A series of hybrids of hydroxypyridinone and coumarin were rationally designed, synthesized and biologically evaluated for their iron ion chelating and MAO-B inhibitory activities. Most of the compounds displayed excellent iron ion chelating effects and moderate to good anti-MAO-B activities. Compound 27a exhibited the most potent activity against MAO-B, with an IC<sub>50</sub> value of 14.7 nM. Importantly, 27a showed good U251 cell protective effect and significantly ameliorated the cognitive dysfunction of scopolamine-induced AD mice. Moreover, molecular docking was performed to elucidate the probable ligand-receptor interaction, and the structure-activity relationships were also summarized.
|
Inhibition of MAOB (unknown origin) using benzylamine as substrate preincubated for 30 mins followed by substrate addition
|
Homo sapiens
|
91.0
nM
|
|
Journal : MedChemComm
Title : Selected aryl thiosemicarbazones as a new class of multi-targeted monoamine oxidase inhibitors.
Year : 2018
Volume : 9
Issue : 11
First Page : 1871
Last Page : 1881
Authors : Mathew B, Baek SC, Grace Thomas Parambi D, Pil Lee J, Joy M, Annie Rilda PR, Randev RV, Nithyamol P, Vijayan V, Inasu ST, Mathew GE, Lohidakshan KK, Kumar Krishnan G, Kim H.
Abstract : A series of 13 phenyl substituted thiosemicarbazones (<b>SB1-SB13</b>) were synthesized and evaluated for their inhibitory potential towards human recombinant monoamine oxidase A and B (MAO-A and MAO-B, respectively) and acetylcholinesterase. The solid state structure of <b>SB4</b> was ascertained by the single X-ray diffraction technique. Compounds <b>SB5</b> and <b>SB11</b> were potent for MAO-A (IC<sub>50</sub> 1.82 ± 0.14) and MAO-B (IC<sub>50</sub> 0.27 ± 0.015 μM), respectively. Furthermore, <b>SB11</b> showed a high selectivity index (SI > 37.0) for MAO-B. The effects of fluorine orientation revealed that <b>SB11</b> (<i>m</i>-fluorine) showed 28.2 times higher inhibitory activity than <b>SB12</b> (<i>o</i>-fluorine) against MAO-B. Furthermore, inhibitions by <b>SB5</b> and <b>SB11</b> against MAO-A and MAO-B, respectively, were recovered to near reference levels in reversibility experiments. Both <b>SB5</b> and <b>SB11</b> showed competitive inhibition modes, with <i>K</i> <sub>i</sub> values of 0.97 ± 0.042 and 0.12 ± 0.006 μM, respectively. These results indicate that <b>SB5</b> and <b>SB11</b> are selective, reversible and competitive inhibitors of MAO-A and MAO-B, respectively. Compounds <b>SB5</b>, <b>SB7</b> and <b>SB11</b> showed moderate inhibition against acetylcholinesterase with IC<sub>50</sub> values of 35.35 ± 0.47, 15.61 ± 0.057 and 26.61 ± 0.338 μM, respectively. Blood-brain barrier (BBB) permeation was studied using the parallel artificial membrane permeation assay (PAMPA) method. Molecular docking studies were carried out using AutoDock 4.2.
|
Inhibition of PYCR1 in human SUM159PT cells assessed as reduction proline content at 100 uM by LC-MS analysis relative to control
|
Homo sapiens
|
50.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : A fragment-like approach to PYCR1 inhibition.
Year : 2019
Volume : 29
Issue : 18
First Page : 2626
Last Page : 2631
Authors : Milne K, Sun J, Zaal EA, Mowat J, Celie PHN, Fish A, Berkers CR, Forlani G, Loayza-Puch F, Jamieson C, Agami R.
Abstract : Pyrroline-5-carboxylate reductase 1 (PYCR1) is the final enzyme involved in the biosynthesis of proline and has been found to be upregulated in various forms of cancer. Due to the role of proline in maintaining the redox balance of cells and preventing apoptosis, PYCR1 is emerging as an attractive oncology target. Previous PYCR1 knockout studies led to a reduction in tumor growth. Accordingly, a small molecule inhibitor of PYCR1 could lead to new treatments for cancer, and a focused screening effort identified pargyline as a fragment-like hit. We report the design and synthesis of the first tool compounds as PYCR1 inhibitors, derived from pargyline, which were assayed to assess their ability to attenuate the production of proline. Structural activity studies have revealed the key determinants of activity, with the most potent compound (4) showing improved activity in vitro in enzyme (IC<sub>50</sub> = 8.8 µM) and pathway relevant effects in cell-based assays.
|
Inhibition of human recombinant MAO-B expressed in baculovirus infected BTI insect cells using benzylamine as substrate after 30 mins by spectrophotometric analysis
|
Homo sapiens
|
100.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Osthenol, a prenylated coumarin, as a monoamine oxidase A inhibitor with high selectivity.
Year : 2019
Volume : 29
Issue : 6
First Page : 839
Last Page : 843
Authors : Baek SC, Kang MG, Park JE, Lee JP, Lee H, Ryu HW, Park CM, Park D, Cho ML, Oh SR, Kim H.
Abstract : Osthenol (6), a prenylated coumarin isolated from the dried roots of Angelica pubescens, potently and selectively inhibited recombinant human monoamine oxidase-A (hMAO-A) with an IC50 value of 0.74 µM and showed a high selectivity index (SI > 81.1) for hMAO-A versus hMAO-B. Compound 6 was a reversible competitive hMAO-A inhibitor (Ki = 0.26 µM) with a potency greater than toloxatone (IC50 = 0.93 µM), a marketed drug. Isopsoralen (3) and bakuchicin (1), furanocoumarin derivatives isolated from Psoralea corylifolia L., showed slightly higher IC50 values (0.88 and 1.78 µM, respectively) for hMAO-A than 6, but had low SI values (3.1 for both). Other coumarins tested did not effectively inhibit hMAO-A or hMAO-B. A structural comparison suggested that the 8-(3,3-dimethylallyl) group of 6 increased its inhibitory activity against hMAO-A compared with the 6-methoxy group of scopoletin (4). Molecular docking simulations revealed that the binding affinity of 6 for hMAO-A (-8.5 kcal/mol) was greater than that for hMAO-B (-5.6 kcal/mol) and that of 4 for hMAO-A (-7.3 kcal/mol). Docking simulations also implied that 6 interacted with hMAO-A at Phe208 and with hMAO-B at Ile199 by carbon hydrogen bondings. Our findings suggest that osthenol, derived from natural products, is a selective and potent reversible inhibitor of MAO-A, and can be regarded a potential lead compound for the design of novel reversible MAO-A inhibitors.
|
Inhibition of recombinant human MAO-B expressed in baculovirus infected BTI insect cells preincubated for 10 mins followed by addition of benzylamine as substrate
|
Homo sapiens
|
103.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Potent selective monoamine oxidase B inhibition by maackiain, a pterocarpan from the roots of Sophora flavescens.
Year : 2016
Volume : 26
Issue : 19
First Page : 4714
Last Page : 4719
Authors : Lee HW, Ryu HW, Kang MG, Park D, Oh SR, Kim H.
Abstract : Monoamine oxidase (MAO) catalyzes the oxidation of monoamines and its two isoforms, MAO-A and MAO-B, break down neurotransmitter amines. Of the compounds isolated from the roots of Sophora flavescens, (-)-maackiain (4), a pterocarpan, was found to potently and selectively inhibit human MAO-B, with an IC50 of 0.68μM, and to have a selectivity index of 126.2 for MAO-B. As compared with other herbal natural products, the IC50 value of 4 for MAO-B is one of the lowest reported to date. Genistein (1) highly, effectively and non-selectively inhibited MAO-A and MAO-B with IC50 values of 3.9μM and 4.1μM, respectively. (-)-4-Hydroxy-3-methoxy-8,9-methylenedioxypterocarpan (2) effectively and non-selectively inhibited MAO-A and MAO-B with IC50 values of 20.3μM and 10.3μM, respectively. In addition, compound 4 reversibly and competitively inhibited MAO-B with a Ki value of 0.054μM. Molecular docking simulation revealed that the binding affinity of 4 for MAO-B (-26.6kcal/mol) was greater than its affinity for MAO-A (-8.3kcal/mol), which was in-line with our inhibitory activity findings. Furthermore, Cys172 of MAO-B was found to be a key residue for hydrogen bonding with compound 4. The findings of this study suggest compound 4 be viewed as a new potent, selective, and reversible MAO-B inhibitor, and that compounds 1 and 2 be considered useful lead compounds for the developments of nonselective and reversible MAO inhibitors for the treatment of disorders like Parkinson's disease, Alzheimer disease, and depression.
|
Inhibition of Wistar rat brain MAOB using kynuramine as substrate preincubated for 15 mins followed by substrate addition and measured after 15 mins by fluorescence assay
|
Rattus norvegicus
|
220.0
nM
|
|
Journal : J Nat Prod
Title : Bioactive Dimeric Acylphloroglucinols from the Mexican Fern Elaphoglossum paleaceum.
Year : 2019
Volume : 82
Issue : 4
First Page : 785
Last Page : 791
Authors : Arvizu-Espinosa MG, von Poser GL, Henriques AT, Mendoza-Ruiz A, Cardador-Martínez A, Gesto-Borroto R, Núñez-Aragón PN, Villarreal-Ortega ML, Sharma A, Cardoso-Taketa A.
Abstract : Two new prenylated acylphloroglucinols, paleacenins A (1) and B (2), were isolated from the rhizome n-hexane and chloroform extracts of the fern Elaphoglossum paleaceum. Both compounds were found to possess the same geranylated filicinic acid moiety but have a different phloroglucinol ring substituent. Their structures were determined using 1H and 13C NMR spectroscopic, HRMS, and ECD analysis. The plant extracts and purified compounds were assayed for inhibition of monoamine oxidase (MAO) activity, and the n-hexane and chloroform extracts displayed 25.0% and 26.5% inhibition of MAO-A, respectively, as well as 42.5% and 23.7% inhibition of MAO-B, respectively. Compounds 1 and 2 exhibited IC50 values of 31.0 (1.3) μM for MAO-A and 4.7 (4.4) μM for MAO-B. Paleacenin A (1) showed a higher selective index (SI) toward MAO-B (SIMAO-B/MAO-A 0.1), and paleacenin B (2) exhibited selectivity to MAO-A (SIMAO-B/MAO-A, 3.5). The extracts showed cytotoxicity against a panel of prostate, cervix, breast, and colon cancer cell lines (IC50 values between 1.7 and 10.6 μg/mL); the pure compounds were more active against the prostate, cervix, and colon cancer cell lines. Paleacenins A (1) and B (2), with IC50 values of 46 and 41 μM, respectively, inhibited nitric oxide production by the RAW264.7 murine macrophage model.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
13.6
%
|
|
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.
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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
|
0.44
%
|
|
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
|
0.44
%
|
|
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.
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Inhibition of recombinant human MAO-B expressed in baculovirus infected BTI insect cells assessed as reduction in formation of 4-quinolinol using kynuramine as substrate preincubated with substrate for 10 mins followed by enzyme addition and measured after 20 mins by fluorescence based microplate reader assay
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Homo sapiens
|
220.0
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis of natural product-like polyprenylated phenols and quinones: Evaluation of their neuroprotective activities.
Year : 2020
Volume : 28
Issue : 1
First Page : 115156
Last Page : 115156
Authors : Kamauchi H, Oda T, Horiuchi K, Takao K, Sugita Y.
Abstract : Twenty-seven natural product-like polyprenylated phenols and quinones were synthesized and their neuroprotective activity was tested using human monoamine oxidase B (MAO-B) and SH-SY5Y cells. Eight compounds inhibited MAO-B (IC<sub>50</sub> values < 25 μM) and the inhibition mode and molecular docking of two (8c and 16c) were investigated. Compounds inhibiting MAO-B activity were additionally tested for their ability to protect SH-SY5Y cells from peroxide injury. Three derivatives (3c, 8c and 16c) exhibited both MAO-B inhibitory and neuroprotective activity. A structure activity-relationship study showed that a phenolic hydroxyl group and a longer side chain are important for both activities.
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Inhibition of recombinant human MAO-B at 10 uM incubated for 30 mins by fluorescence-based method
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Homo sapiens
|
0.14
%
|
|
Journal : J Nat Prod
Title : Bioactive Azepine-Indole Alkaloids from <i>Psychotria nemorosa</i>.
Year : 2020
Volume : 83
Issue : 4
First Page : 852
Last Page : 863
Authors : Klein-Júnior LC, Cretton S, Vander Heyden Y, Gasper AL, Nejad-Ebrahimi S, Christen P, Henriques AT.
Abstract : Phytochemical investigation of the alkaloid extract of the aerial parts of <i>Psychotria nemorosa</i> led to the isolation and characterization of 10 azepine-indole alkaloids, i.e., cimitrypazepine (<b>1</b>), fargesine (<b>2</b>), nemorosines A (<b>3</b>), and B (<b>12</b>), nemorosinosides A-F (<b>4</b>-<b>9</b>), as well as two β-carboline derivatives, 10-hydroxyisodolichantoside (<b>10</b>) and 10-hydroxydolichantoside (<b>11</b>), an isoxazole alkaloid, nemorosinoside G (<b>13</b>), serotonin (<b>14</b>), bufotenine (<b>15</b>), and (<i>S</i>)-gentianol (<b>16</b>). Compounds <b>3</b>-<b>13</b> have not yet been described. These compounds were isolated by semipreparative HPLC, and their structures were determined by means of HRMS, NMR, and ECD measurements. In addition, the monoamine oxidase-A (MAO-A), MAO-B, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) inhibitory activities were evaluated. Alkaloids <b>1</b>-<b>3</b> inhibited the MAO-A activity with IC<sub>50</sub> values of 1.4, 1.4, and 0.9 μM, respectively.
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Inhibition of human recombinant MAO-B expressed in baculovirus infected BTI insect cells using kynuramine as substrate at 100 nM incubated for 10 mins followed by substrate addition by fluorimetric analysis relative to control
|
Homo sapiens
|
53.0
%
|
|
Journal : Bioorg Med Chem
Title : Rational design, synthesis and biological evaluation of novel multitargeting anti-AD iron chelators with potent MAO-B inhibitory and antioxidant activity.
Year : 2020
Volume : 28
Issue : 12
First Page : 115550
Last Page : 115550
Authors : Jiang X, Guo J, Lv Y, Yao C, Zhang C, Mi Z, Shi Y, Gu J, Zhou T, Bai R, Xie Y.
Abstract : A series of (3-hydroxypyridin-4-one)-coumarin hybrids were developed and investigated as potential multitargeting candidates for the treatment of Alzheimer's disease (AD) through the incorporation of iron-chelating and monoamine oxidase B (MAO-B) inhibition. This combination endowed the hybrids with good capacity to inhibit MAO-B as well as excellent iron-chelating effects. The pFe<sup>3+</sup> values of the compounds were ranging from 16.91 to 20.16, comparable to more potent than the reference drug deferiprone (DFP). Among them, compound 18d exhibited the most promising activity against MAO-B, with an IC<sub>50</sub> value of 87.9 nM. Moreover, compound 18d exerted favorable antioxidant activity, significantly reversed the amyloid-β<sub>1-42</sub> (Aβ<sub>1-42</sub>) induced PC12 cell damage. More importantly, 18d remarkably ameliorated the cognitive dysfunction in a scopolamine-induced mice AD model. In brief, a series of hybrids with potential anti-AD effect were successfully obtained, indicating that the design of iron chelators with MAO-B inhibitory and antioxidant activities is an attractive strategy against AD progression.
|
Inhibition of human recombinant MAO-B expressed in baculovirus infected BTI insect cells using kynuramine as substrate incubated for 10 mins followed by substrate addition by fluorimetric analysis
|
Homo sapiens
|
107.3
nM
|
|
Journal : Bioorg Med Chem
Title : Rational design, synthesis and biological evaluation of novel multitargeting anti-AD iron chelators with potent MAO-B inhibitory and antioxidant activity.
Year : 2020
Volume : 28
Issue : 12
First Page : 115550
Last Page : 115550
Authors : Jiang X, Guo J, Lv Y, Yao C, Zhang C, Mi Z, Shi Y, Gu J, Zhou T, Bai R, Xie Y.
Abstract : A series of (3-hydroxypyridin-4-one)-coumarin hybrids were developed and investigated as potential multitargeting candidates for the treatment of Alzheimer's disease (AD) through the incorporation of iron-chelating and monoamine oxidase B (MAO-B) inhibition. This combination endowed the hybrids with good capacity to inhibit MAO-B as well as excellent iron-chelating effects. The pFe<sup>3+</sup> values of the compounds were ranging from 16.91 to 20.16, comparable to more potent than the reference drug deferiprone (DFP). Among them, compound 18d exhibited the most promising activity against MAO-B, with an IC<sub>50</sub> value of 87.9 nM. Moreover, compound 18d exerted favorable antioxidant activity, significantly reversed the amyloid-β<sub>1-42</sub> (Aβ<sub>1-42</sub>) induced PC12 cell damage. More importantly, 18d remarkably ameliorated the cognitive dysfunction in a scopolamine-induced mice AD model. In brief, a series of hybrids with potential anti-AD effect were successfully obtained, indicating that the design of iron chelators with MAO-B inhibitory and antioxidant activities is an attractive strategy against AD progression.
|
Inhibition of recombinant human MAO-B using p-tyramine as substrate preincubated with enzyme for 15 mins followed incubation with substrate for 20 mins by Amplex red reagent based fluorescence based analysis
|
Homo sapiens
|
120.0
nM
|
|
Journal : RSC Med Chem
Title : Chromone and donepezil hybrids as new multipotent cholinesterase and monoamine oxidase inhibitors for the potential treatment of Alzheimer''s disease
Year : 2020
Volume : 11
Issue : 2
First Page : 225
Last Page : 233
Authors : Wang, Xiao-Bing, Yin, Fu-Cheng, Huang, Ming, Jiang, Neng, Lan, Jin-Shuai, Kong, Ling-Yi
Abstract : A series of chromone and donepezil hybrids were designed, synthesized, and evaluated as multipotent cholinesterase (ChE) and monoamine oxidase (MAO) inhibitors for the potential therapy of Alzheimer's disease (AD). In vitro studies showed that the great majority of these compounds exhibited potent inhibitory activity toward BuChE and AChE and clearly selective inhibition for hMAO-B. In particular, compound 5c presented the most balanced potential for ChE inhibition (BuChE: IC50 = 5.24 microM; AChE: IC50 = 0.37 microM) and hMAO-B selectivity (IC50 = 0.272 microM, SI = 247). Molecular modeling and kinetic studies suggested that 5c was a mixed-type inhibitor, binding simultaneously to peripheral and active sites of AChE. It was also a competitive inhibitor, which occupied the substrate and entrance cavities of MAO-B. Moreover, compound 5c could penetrate the blood-brain barrier (BBB) and showed low toxicity to rat pheochromocytoma (PC12) cells. Altogether, these results indicated that compound 5c might be a hopeful multitarget drug candidate with possible impact on Alzheimer's disease therapy.
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Inhibition of human recombinant MAO-B using kynuramine as substrate incubated for 20 mins measuring increase in emission signal at 400 nm multimode plate reader assay
|
Homo sapiens
|
220.0
nM
|
|
|
Inhibition of human MAO-B preincubated for 5 mins followed by addition of Kynuramine substrate and measured after 30 mins by plate reader method
|
Homo sapiens
|
80.0
nM
|
|
