|
Inhibition of rat brain mitochondria MAOB by radioenzymatic assay
|
Rattus norvegicus
|
98.0
nM
|
|
Journal : J. Med. Chem.
Title : Solid-phase synthesis and insights into structure-activity relationships of safinamide analogues as potent and selective inhibitors of type B monoamine oxidase.
Year : 2007
Volume : 50
Issue : 20
First Page : 4909
Last Page : 4916
Authors : Leonetti F, Capaldi C, Pisani L, Nicolotti O, Muncipinto G, Stefanachi A, Cellamare S, Caccia C, Carotti A.
Abstract : Safinamide, (S)-N2-{4-[(3-fluorobenzyl)oxy]benzyl}alaninamide methanesulfonate, which is in phase III clinical trials as an anti-Parkinson drug, and a library of alkanamidic analogues were prepared through an expeditious solid-phase synthesis and evaluated for their monoamine oxidase B (MAO-B) and monoamine oxidase A (MAO-A) inhibitory activity and selectivity. (S)-3-Chlorobenzyloxyalaninamide (8) and (S)-3-chlorobenzyloxyserinamide (13) derivatives proved to be more potent MAO-B inhibitors than safinamide (IC50 = 33 and 43 nM, respectively, vs 98 nM) but with a lower MAO-B selectivity (SI = 3455 and 1967, respectively, vs 5918). The highest MAO-B inhibitory potency (IC50 = 17 nM) and a good selectivity (SI = 2941) were displayed by (R)-21, a tetrahydroisoquinoline analogue of safinamide. Structure-affinity relationships and docking simulations pointed out strong negative steric effects of alpha-aminoamide side chains and para substituents of the benzyloxy groups and favorable hydrophobic interactions of meta substituents. The significantly diverse MAO-B affinities of a number of R and S alpha-aminoamide enantiomers, including the two rigid analogues (21) of safinamide, indicated likely enantioselective interactions at the enzymatic binding sites.
|
Inhibition of human recombinant MAOB expressed in Pichia pastoris
|
Homo sapiens
|
450.0
nM
|
|
Journal : J. Med. Chem.
Title : Structures of human monoamine oxidase B complexes with selective noncovalent inhibitors: safinamide and coumarin analogs.
Year : 2007
Volume : 50
Issue : 23
First Page : 5848
Last Page : 5852
Authors : Binda C, Wang J, Pisani L, Caccia C, Carotti A, Salvati P, Edmondson DE, Mattevi A.
Abstract : Structures of human monoamine oxidase B (MAO B) in complex with safinamide and two coumarin derivatives, all sharing a common benzyloxy substituent, were determined by X-ray crystallography. These compounds competitively inhibit MAO B with Ki values in the 0.1-0.5 microM range that are 30-700-fold lower than those observed with MAO A. The inhibitors bind noncovalently to MAO B, occupying both the entrance and the substrate cavities and showing a similarly oriented benzyloxy substituent.
|
Inhibition of MAOB
|
None
|
80.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Knowledge based identification of MAO-B selective inhibitors using pharmacophore and structure based virtual screening models.
Year : 2009
Volume : 44
Issue : 9
First Page : 3584
Last Page : 3590
Authors : Boppana K, Dubey PK, Jagarlapudi SA, Vadivelan S, Rambabu G.
Abstract : Monoamine Oxidase B interaction with known ligands was investigated using combined pharmacophore and structure based modeling approach. The docking results suggested that the pharmacophore and docking models are in good agreement and are used to identify the selective MAO-B inhibitors. The best model, Hypo2 consists of three pharmacophore features, i.e., one hydrogen bond acceptor, one hydrogen bond donor and one ring aromatic. The Hypo2 model was used to screen an in-house database of 80,000 molecules and have resulted in 5500 compounds. Docking studies were performed, subsequently, on the cluster representatives of 530 hits from 5500 compounds. Based on the structural novelty and selectivity index, we have suggested 15 selective MAO-B inhibitors for further synthesis and pharmacological screening.
|
Inhibition of recombinant human MAO-B expressed in baculovirus-infected insect cells using p-tyramine as substrate incubated for 30 mins prior to substrate addition measured for 45 mins by amplex red reagent-based microplate fluorescence reader analysis
|
Homo sapiens
|
7.67
nM
|
|
Journal : J. Med. Chem.
Title : Dual targeting of adenosine A(2A) receptors and monoamine oxidase B by 4H-3,1-benzothiazin-4-ones.
Year : 2013
Volume : 56
Issue : 11
First Page : 4580
Last Page : 4596
Authors : Stössel A, Schlenk M, Hinz S, Küppers P, Heer J, Gütschow M, Müller CE.
Abstract : Blockade of A2A adenosine receptors (A2AARs) and inhibition of monoamine oxidase B (MAO-B) in the brain are considered attractive strategies for the treatment of neurodegenerative diseases such as Parkinson's disease (PD). In the present study, benzothiazinones, e.g., 2-(3-chlorophenoxy)-N-(4-oxo-4H-3,1-benzothiazin-2-yl)acetamide (13), were identified as a novel class of potent MAO-B inhibitors (IC50 human MAO-B: 1.63 nM). Benzothiazinones with large substituents in the 2-position, e.g., methoxycinnamoylamino, phenylbutyrylamino, or chlorobenzylpiperazinylbenzamido residues (14, 17, 27, and 28), showed high affinity and selectivity for A2AARs (Ki human A2AAR: 39.5-69.5 nM). By optimizing benzothiazinones for both targets, the first potent, dual-acting A2AAR/MAO-B inhibitors with a nonxanthine structure were developed. The best derivative was N-(4-oxo-4H-3,1-benzothiazin-2-yl)-4-phenylbutanamide (17, Ki human A2A, 39.5 nM; IC50 human MAO-B, 34.9 nM; selective versus other AR subtypes and MAO-A), which inhibited A2AAR-induced cAMP accumulation and showed competitive, reversible MAO-B inhibition. The new compounds may be useful tools for validating the A2AAR/MAO-B dual target approach in PD.
|
Inhibition of MAO-B in mitochondria-enriched Sprague-Dawley rat liver fractions using p-tyramine as substrate incubated for 30 mins prior to substrate addition measured for 45 mins by amplex red reagent-based microplate fluorescence reader analysis
|
Rattus norvegicus
|
25.8
nM
|
|
Journal : J. Med. Chem.
Title : Dual targeting of adenosine A(2A) receptors and monoamine oxidase B by 4H-3,1-benzothiazin-4-ones.
Year : 2013
Volume : 56
Issue : 11
First Page : 4580
Last Page : 4596
Authors : Stössel A, Schlenk M, Hinz S, Küppers P, Heer J, Gütschow M, Müller CE.
Abstract : Blockade of A2A adenosine receptors (A2AARs) and inhibition of monoamine oxidase B (MAO-B) in the brain are considered attractive strategies for the treatment of neurodegenerative diseases such as Parkinson's disease (PD). In the present study, benzothiazinones, e.g., 2-(3-chlorophenoxy)-N-(4-oxo-4H-3,1-benzothiazin-2-yl)acetamide (13), were identified as a novel class of potent MAO-B inhibitors (IC50 human MAO-B: 1.63 nM). Benzothiazinones with large substituents in the 2-position, e.g., methoxycinnamoylamino, phenylbutyrylamino, or chlorobenzylpiperazinylbenzamido residues (14, 17, 27, and 28), showed high affinity and selectivity for A2AARs (Ki human A2AAR: 39.5-69.5 nM). By optimizing benzothiazinones for both targets, the first potent, dual-acting A2AAR/MAO-B inhibitors with a nonxanthine structure were developed. The best derivative was N-(4-oxo-4H-3,1-benzothiazin-2-yl)-4-phenylbutanamide (17, Ki human A2A, 39.5 nM; IC50 human MAO-B, 34.9 nM; selective versus other AR subtypes and MAO-A), which inhibited A2AAR-induced cAMP accumulation and showed competitive, reversible MAO-B inhibition. The new compounds may be useful tools for validating the A2AAR/MAO-B dual target approach in PD.
|
Inhibition of human MAO-B
|
Homo sapiens
|
7.67
nM
|
|
Journal : Bioorg. Med. Chem.
Title : 1,3-Dialkyl-substituted tetrahydropyrimido[1,2-f]purine-2,4-diones as multiple target drugs for the potential treatment of neurodegenerative diseases.
Year : 2013
Volume : 21
Issue : 23
First Page : 7435
Last Page : 7452
Authors : Koch P, Akkari R, Brunschweiger A, Borrmann T, Schlenk M, Küppers P, Köse M, Radjainia H, Hockemeyer J, Drabczyńska A, Kieć-Kononowicz K, Müller CE.
Abstract : Adenosine receptors and monoamine oxidases are drug targets for neurodegenerative diseases such as Parkinson's and Alzheimer's disease. In the present study we prepared a library of 55 mostly novel tetrahydropyrimido[2,1-f]purinediones with various substituents in the 1- and 3-position (1,3-dimethyl, 1,3-diethyl, 1,3-dipropyl, 1-methyl-3-propargyl) and broad variation in the 9-position. A synthetic strategy to obtain 3-propargyl-substituted tetrahydropyrimido[2,1-f]purinedione derivatives was developed. The new compounds were evaluated for their interaction with all four adenosine receptor subtypes and for their ability to inhibit monoamine oxidases (MAO). Introduction of mono- or di-chloro-substituted phenyl, benzyl or phenethyl residues at N9 of the 1,3-dimethyl series led to the discovery of a novel class of potent MAO-B inhibitors, the most potent compound being 9-(3,4-dichlorobenzyl)-1,3-dimethyl-6,7,8,9-tetrahydropyrimido[1,2-f]purine-2,4(1H,3H)-dione (21g, IC(50) human MAO-B: 0.0629 μM), which displayed high selectivity versus the other investigated targets. Potent dually active A1/A2A adenosine receptor antagonists were identified, for example, 9-benzyl-1-methyl-3-propargyl-6,7,8,9-tetrahydropyrimido[1,2-f]purine-2,4(1H,3H)dione (19f, Ki, human receptors, A1: 0.249 μM, A2A: 0.253 μM). Several compounds showed triple-target inhibition, the best compound being 9-(2-methoxybenzyl)-1-methyl-3-(prop-2-ynyl)-6,7,8,9-tetrahydro pyrimido [1,2-f]purine-2,4(1H,3H)-dione (19g, Ki A1: 0.605 μM, Ki A2A: 0.417 μM, IC(50) MAO-B: 1.80 μM). Compounds inhibiting several different targets involved in neurodegeneration may exhibit additive or even synergistic effects in vivo.
|
Inhibition of human brain MAO-B using [14C]-phenylethylamine substrate after 20 mins
|
Homo sapiens
|
9.0
nM
|
|
Journal : J. Med. Chem.
Title : Indazole- and indole-5-carboxamides: selective and reversible monoamine oxidase B inhibitors with subnanomolar potency.
Year : 2014
Volume : 57
Issue : 15
First Page : 6679
Last Page : 6703
Authors : Tzvetkov NT, Hinz S, Küppers P, Gastreich M, Müller CE.
Abstract : Indazole- and indole-carboxamides were discovered as highly potent, selective, competitive, and reversible inhibitors of monoamine oxidase B (MAO-B). The compounds are easily accessible by standard synthetic procedures with high overall yields. The most potent derivatives were N-(3,4-dichlorophenyl)-1-methyl-1H-indazole-5-carboxamide (38a, PSB-1491, IC50 human MAO-B 0.386 nM, >25000-fold selective versus MAO-A) and N-(3,4-dichlorophenyl)-1H-indole-5-carboxamide (53, PSB-1410, IC50 human MAO-B 0.227 nM, >5700-fold selective versus MAO-A). Replacement of the carboxamide linker with a methanimine spacer leading to (E)-N-(3,4-dichlorophenyl)-1-(1H-indazol-5-yl)methanimine (58) represents a further novel class of highly potent and selective MAO-B inhibitors (IC50 human MAO-B 0.612 nM, >16000-fold selective versus MAO-A). In N-(3,4-difluorophenyl-1H-indazole-5-carboxamide (30, PSB-1434, IC50 human MAO-B 1.59 nM, selectivity versus MAO-A>6000-fold), high potency and selectivity are optimally combined with superior physicochemical properties. Computational docking studies provided insights into the inhibitors' interaction with the enzyme binding site and a rationale for their high potency despite their small molecular size.
|
Inhibition of rat brain MAO-B using [14C]-phenylethylamine substrate after 20 mins
|
Rattus norvegicus
|
98.0
nM
|
|
Journal : J. Med. Chem.
Title : Indazole- and indole-5-carboxamides: selective and reversible monoamine oxidase B inhibitors with subnanomolar potency.
Year : 2014
Volume : 57
Issue : 15
First Page : 6679
Last Page : 6703
Authors : Tzvetkov NT, Hinz S, Küppers P, Gastreich M, Müller CE.
Abstract : Indazole- and indole-carboxamides were discovered as highly potent, selective, competitive, and reversible inhibitors of monoamine oxidase B (MAO-B). The compounds are easily accessible by standard synthetic procedures with high overall yields. The most potent derivatives were N-(3,4-dichlorophenyl)-1-methyl-1H-indazole-5-carboxamide (38a, PSB-1491, IC50 human MAO-B 0.386 nM, >25000-fold selective versus MAO-A) and N-(3,4-dichlorophenyl)-1H-indole-5-carboxamide (53, PSB-1410, IC50 human MAO-B 0.227 nM, >5700-fold selective versus MAO-A). Replacement of the carboxamide linker with a methanimine spacer leading to (E)-N-(3,4-dichlorophenyl)-1-(1H-indazol-5-yl)methanimine (58) represents a further novel class of highly potent and selective MAO-B inhibitors (IC50 human MAO-B 0.612 nM, >16000-fold selective versus MAO-A). In N-(3,4-difluorophenyl-1H-indazole-5-carboxamide (30, PSB-1434, IC50 human MAO-B 1.59 nM, selectivity versus MAO-A>6000-fold), high potency and selectivity are optimally combined with superior physicochemical properties. Computational docking studies provided insights into the inhibitors' interaction with the enzyme binding site and a rationale for their high potency despite their small molecular size.
|
Inhibition of human recombinant MAO-B expressed in baculovirus-infected insect cells using p-tyraimne substrate
|
Homo sapiens
|
5.18
nM
|
|
Journal : J. Med. Chem.
Title : Indazole- and indole-5-carboxamides: selective and reversible monoamine oxidase B inhibitors with subnanomolar potency.
Year : 2014
Volume : 57
Issue : 15
First Page : 6679
Last Page : 6703
Authors : Tzvetkov NT, Hinz S, Küppers P, Gastreich M, Müller CE.
Abstract : Indazole- and indole-carboxamides were discovered as highly potent, selective, competitive, and reversible inhibitors of monoamine oxidase B (MAO-B). The compounds are easily accessible by standard synthetic procedures with high overall yields. The most potent derivatives were N-(3,4-dichlorophenyl)-1-methyl-1H-indazole-5-carboxamide (38a, PSB-1491, IC50 human MAO-B 0.386 nM, >25000-fold selective versus MAO-A) and N-(3,4-dichlorophenyl)-1H-indole-5-carboxamide (53, PSB-1410, IC50 human MAO-B 0.227 nM, >5700-fold selective versus MAO-A). Replacement of the carboxamide linker with a methanimine spacer leading to (E)-N-(3,4-dichlorophenyl)-1-(1H-indazol-5-yl)methanimine (58) represents a further novel class of highly potent and selective MAO-B inhibitors (IC50 human MAO-B 0.612 nM, >16000-fold selective versus MAO-A). In N-(3,4-difluorophenyl-1H-indazole-5-carboxamide (30, PSB-1434, IC50 human MAO-B 1.59 nM, selectivity versus MAO-A>6000-fold), high potency and selectivity are optimally combined with superior physicochemical properties. Computational docking studies provided insights into the inhibitors' interaction with the enzyme binding site and a rationale for their high potency despite their small molecular size.
|
Inhibition of rat recombinant MAO-B expressed in baculovirus-infected insect cells using p-tyraimne substrate
|
Rattus norvegicus
|
18.0
nM
|
|
Journal : J. Med. Chem.
Title : Indazole- and indole-5-carboxamides: selective and reversible monoamine oxidase B inhibitors with subnanomolar potency.
Year : 2014
Volume : 57
Issue : 15
First Page : 6679
Last Page : 6703
Authors : Tzvetkov NT, Hinz S, Küppers P, Gastreich M, Müller CE.
Abstract : Indazole- and indole-carboxamides were discovered as highly potent, selective, competitive, and reversible inhibitors of monoamine oxidase B (MAO-B). The compounds are easily accessible by standard synthetic procedures with high overall yields. The most potent derivatives were N-(3,4-dichlorophenyl)-1-methyl-1H-indazole-5-carboxamide (38a, PSB-1491, IC50 human MAO-B 0.386 nM, >25000-fold selective versus MAO-A) and N-(3,4-dichlorophenyl)-1H-indole-5-carboxamide (53, PSB-1410, IC50 human MAO-B 0.227 nM, >5700-fold selective versus MAO-A). Replacement of the carboxamide linker with a methanimine spacer leading to (E)-N-(3,4-dichlorophenyl)-1-(1H-indazol-5-yl)methanimine (58) represents a further novel class of highly potent and selective MAO-B inhibitors (IC50 human MAO-B 0.612 nM, >16000-fold selective versus MAO-A). In N-(3,4-difluorophenyl-1H-indazole-5-carboxamide (30, PSB-1434, IC50 human MAO-B 1.59 nM, selectivity versus MAO-A>6000-fold), high potency and selectivity are optimally combined with superior physicochemical properties. Computational docking studies provided insights into the inhibitors' interaction with the enzyme binding site and a rationale for their high potency despite their small molecular size.
|
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
|
16.7
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
|
5.4
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.
|
Binding affinity to human recombinant microsomal MAO-B by ITC
|
Homo sapiens
|
187.2
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 recombinant human MAOB using benzylamine as substrate after 30 mins by Amplex red based spectrophotometric analysis
|
Homo sapiens
|
112.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis of a series of unsaturated ketone derivatives as selective and reversible monoamine oxidase inhibitors.
Year : 2015
Volume : 23
Issue : 19
First Page : 6486
Last Page : 6496
Authors : Choi JW, Jang BK, Cho NC, Park JH, Yeon SK, Ju EJ, Lee YS, Han G, Pae AN, Kim DJ, Park KD.
Abstract : We have synthesized three categories of α,β-unsaturated carbonyl derivatives and evaluated their MAO-A and MAO-B inhibitory activities. Among them, compound 10b including α,β-unsaturated ketone group showed the most potent and selective MAO-B inhibitory activity (IC₅₀ human MAO-B 16 nM, >6000-fold selective vs MAO-A) and compound 10b exhibited good reversibility compared with selegiline, a well-known irreversible MAO-B inhibitor. However, both α,β-unsaturated amide and ester derivatives exhibited weaker MAO-B inhibition potencies. The docking studies provided insights into the possible binding modes and the key interaction sites of the synthesized MAO-B inhibitors.
|
Radioenzymatic Assay: The enzyme activity was assessed with a radioenzymatic assay using the substrate 14C-phenylethylamine (PEA) specific for MAO-B.The mitochondrial pellet (500 μg protein) was resuspended in 0.1 M phosphate buffer (pH 7.4). 200 μl of the suspension were added to a 50 μl solution of the test compound or buffer, and incubated for 30 min at 37° C. (preincubation) then the substrate (50 μl) was added. The incubation was carried out for 10 minutes at 37° C. (14C-PEA, 0.5 μM).The reaction was stopped by adding 0.2 ml of perchloric acid. After centrifugation, the deaminated metabolites were extracted with 3 ml of toluene and the radioactive organic phase containing the neutral and/or acidic metabolites formed as a result of MAO-B activity was measured by liquid scintillation spectrometry at 90% efficiency.
|
Rattus norvegicus
|
100.0
nM
|
|
Title : Substituted 2-[2-(phenyl) ethylamino] alkaneamide derivatives and their use as sodium and/or calcium channel modulators
Year : 2015
|
Inhibition of recombinant human MAO-B after 20 mins using 50 uM kynuramine as substrate by fluorescence spectrophotometry
|
Homo sapiens
|
48.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Inhibition of monoamine oxidase by benzoxathiolone analogues.
Year : 2016
Volume : 26
Issue : 4
First Page : 1200
Last Page : 1204
Authors : Mostert S, Petzer A, Petzer JP.
Abstract : Inhibitors of the monoamine oxidase (MAO) enzymes are considered useful therapeutic agents, and are used in the clinic for the treatment of depressive illness and Parkinson's disease. In addition, MAO inhibitors are also under investigation for the treatment of certain cardiovascular pathologies and as possible aids to smoking cessation. In an attempt to discover novel classes of compounds that inhibit the MAOs, the current study examines the human MAO inhibitory properties of a small series of 2H-1,3-benzoxathiol-2-one analogues. The results show that the benzoxathiolones are potent MAO-B inhibitors with IC50 values ranging from 0.003 to 0.051 μM. Although the benzoxathiolones are selective for the MAO-B isoform, two compounds display good MAO-A inhibition with IC50 values of 0.189 and 0.424 μM. Dialysis studies show that a selected compound inhibits the MAOs reversibly. It may thus be concluded that the benzoxathiolone class is suitable for the design and development of MAO-B inhibitors, and that in some instances good MAO-A inhibition may also be achieved.
|
Inhibition of human MAOA using p-tyramine as substrate at 100 uM after 15 mins by Amplex Red MAO assay
|
Homo sapiens
|
9.74
%
|
|
Journal : MedChemComm
Title : Acetophenone derivatives: novel and potent small molecule inhibitors of monoamine oxidase B
Year : 2015
Volume : 6
Issue : 12
First Page : 2146
Last Page : 2157
Authors : Wang Z, Li X, Xu W, Li F, Wang J, Kong L, Wang X
|
Inhibition of MAOB (unknown origin)
|
Homo sapiens
|
450.0
nM
|
|
Journal : MedChemComm
Title : Acetophenone derivatives: novel and potent small molecule inhibitors of monoamine oxidase B
Year : 2015
Volume : 6
Issue : 12
First Page : 2146
Last Page : 2157
Authors : Wang Z, Li X, Xu W, Li F, Wang J, Kong L, Wang X
|
Inhibition of human MAOB using p-tyramine as substrate at 100 uM after 15 mins by Amplex Red MAO assay
|
Homo sapiens
|
15.4
%
|
|
Journal : MedChemComm
Title : Acetophenone derivatives: novel and potent small molecule inhibitors of monoamine oxidase B
Year : 2015
Volume : 6
Issue : 12
First Page : 2146
Last Page : 2157
Authors : Wang Z, Li X, Xu W, Li F, Wang J, Kong L, Wang X
|
Inhibition of human recombinant MAO-B using kynuramine as substrate incubated for 20 mins by fluorescence spectrophotometric analysis
|
Homo sapiens
|
48.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : An evaluation of synthetic indole derivatives as inhibitors of monoamine oxidase.
Year : 2016
Volume : 26
Issue : 9
First Page : 2214
Last Page : 2219
Authors : Chirkova ZV, Kabanova MV, Filimonov SI, Abramov IG, Petzer A, Petzer JP, Suponitsky KY.
Abstract : In a recent study we have shown that several indole-5,6-dicarbonitrile derivatives are potent inhibitors of human monoamine oxidase (MAO) A and B. To expand on these results and to further determine structure-activity relationships (SARs) for MAO inhibition by this chemical class, the present study investigates the MAO inhibition properties of additional indole-5,6-dicarbonitriles and related indole-5,6-dicarboxylic acid and pyrrolo[3,4-f]indole-5,7-dione derivatives. Among the active compounds two pyrrolo[3,4-f]indole-5,7-dione derivatives inhibited MAO-A (4 g) and MAO-B (4d) with IC50 values of 0.250 and 0.581 μM, respectively. In general indole-5,6-dicarbonitriles, however, exhibit higher MAO inhibition potencies while indole-5,6-dicarboxylic acids are weak MAO inhibitors. Active MAO inhibitors such as 4 g and 4d may be used as leads for the development of drugs for the treatment of disease states such as Parkinson's disease and depression. MAO inhibitors are also under investigation as potential agents for the treatment of prostate cancer, certain types of cardiomyopathies and Alzheimer's disease.
|
Inhibition of recombinant human MAO-B expressed in baculovirus infected BTI insect cells assessed as reduction in H2O2 production using p-tyramine as substrate pretreated for 30 mins followed by substrate addition after 30 mins by Amplex red reagent based assay
|
Homo sapiens
|
6.0
nM
|
|
Journal : Eur J Med Chem
Title : Discovery of highly selective and potent monoamine oxidase B inhibitors: Contribution of additional phenyl rings introduced into 2-aryl-1,3,4-oxadiazin-5(6H)-one.
Year : 2017
Volume : 130
First Page : 365
Last Page : 378
Authors : Lee J, Lee Y, Park SJ, Lee J, Kim YS, Suh YG, Lee J.
Abstract : Monoamine oxidase B (MAO-B) is a flavin adenine dinucleotide (FAD)-containing enzyme that plays a major role in the oxidative deamination of biogenic amines and neurotransmitters. Inhibiting MAO-B activity is a promising approach in the treatment of neurological disorders. Here, we report a series of 2-aryl-1,3,4-oxadiazin-5(6H)-one derivatives as highly selective and potent MAO-B inhibitors. Analysis of the binding sites of hMAO-A and hMAO-B led to design of linear analogs of 2-aryl-1,3,4-oxadiazin-5(6H)-one with an additional phenyl ring. Biological evaluation of the 26 new derivatives resulted in the identification of highly potent and selective inhibitors with optimal physicochemical properties to potentially cross the blood-brain barrier (BBB). Compounds 18a, 18b, 18e and 25b potently inhibited MAO-B, with IC50 values of 4-25 nM and excellent SI over MAO-A (18a > 25000, 18b > 8333 and 18e > 4000 and 25b > 4545). Docking results suggest that an optimal linker between two aromatic rings on the 2-aryl-1,3,4-oxadiazin-5(6H)-one scaffold is a key element in the binding and inhibition of MAO-B.
|
Inhibition of human recombinant microsomal MAOB expressed in baculovirus infected BTI-TN-5B1- 4 cells using p-tyramine as substrate assessed as decrease in H2O2 production after 15 mins by amplex red-based fluorescence assay
|
Homo sapiens
|
23.07
nM
|
|
Journal : J Med Chem
Title : Coumarin versus Chromone Monoamine Oxidase B Inhibitors: Quo Vadis?
Year : 2017
Volume : 60
Issue : 16
First Page : 7206
Last Page : 7212
Authors : Fonseca A, Reis J, Silva T, Matos MJ, Bagetta D, Ortuso F, Alcaro S, Uriarte E, Borges F.
Abstract : Because of the lack of significant disease-modifying drugs for neurodegenerative disorders, a pressing need for new chemical entities endowed with IMAO-B still exists. Within this framework, and for the first time, a study was performed to compare coumarin- and chomone-3-phenylcarboxamide scaffolds. Compounds 10a and 10b were the most potent, selective, and reversible noncompetitive IMAO-B. The benzopyrone sp2 oxygen atom was found to be position independent and a productive contributor for the ligand-enzyme complex stability.
|
Inhibition of recombinant human MAO-B expressed in baculovirus infected BTI insect cell microsomes using kynuramine as substrate after 20 mins by fluorescence spectroscopy
|
Homo sapiens
|
48.0
nM
|
|
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 MAO-B using benzylamine as substrate preincubated for 15 mins followed by substrate addition measured after 20 mins by amplex red reagent based spectrophotometric assay
|
Homo sapiens
|
17.0
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis and evaluation of biaryl derivatives for structural characterization of selective monoamine oxidase B inhibitors toward Parkinson's disease therapy.
Year : 2018
Volume : 26
Issue : 1
First Page : 232
Last Page : 244
Authors : Yeon SK, Choi JW, Park JH, Lee YR, Kim HJ, Shin SJ, Jang BK, Kim S, Bahn YS, Han G, Lee YS, Pae AN, Park KD.
Abstract : Benzyloxyphenyl moiety is a common structure of highly potent, selective and reversible inhibitors of monoamine oxidase B (MAO-B), safinamide and sembragiline. We synthesized 4-(benzyloxy)phenyl and biphenyl-4-yl derivatives including halogen substituents on the terminal aryl unit. In addition, we modified the carbon linker between amine group and the biaryl linked unit. Among synthesized compounds, 12c exhibited the most potent and selective MAO-B inhibitory effect (hMAO-B IC50: 8.9 nM; >10,000-fold selectivity over MAO-A) as a competitive inhibitor. In addition, 12c showed greater MAO-B inhibitory activity and selectivity compared to well-known MAO-B inhibitors such as selegiline, safinamide and sembragiline. In the MPTP-induced mouse model of Parkinson's disease (PD), 12c significantly protected the tyrosine hydroxylase (TH)-immunopositive DAergic neurons and attenuated the PD-associated behavioral deficits. This study suggests characteristic structures as a MAO-B inhibitor that may provide a good insight for the development of therapeutic agents for PD.
|
Inhibition of human MAO-B expressed in baculovirus infected insect cell membranes using kynuramine as substrate preincubated for 30 mins followed by substrate addition measured after 15 to 20 mins by discontinuous fluorimetric method
|
Homo sapiens
|
21.0
nM
|
|
Journal : Eur J Med Chem
Title : Novel indanone derivatives as MAO B/H3R dual-targeting ligands for treatment of Parkinson's disease.
Year : 2018
Volume : 148
First Page : 487
Last Page : 497
Authors : Affini A, Hagenow S, Zivkovic A, Marco-Contelles J, Stark H.
Abstract : The design of multi-targeting ligands was developed in the last decades as an innovative therapeutic concept for Parkinson's disease (PD) and other neurodegenerative disorders. As the monoamine oxidase B (MAO B) and the histamine H3 receptor (H3R) are promising targets for dopaminergic regulation, we synthetized dual-targeting ligands (DTLs) as non-dopaminergic receptor approach for the treatment of PD. Three series of compounds were developed by attaching the H3R pharmacophore to indanone-related MAO B motifs, leading to development of MAO B/H3R DTLs. Among synthesized indanone DTLs, compounds bearing the 2-benzylidene-1-indanone core structure showed MAO B preferring inhibition capabilities along with nanomolar hH3R affinity. Substitution of C5 and C6 position of the 2-benzylidene-1-indanones with lipophilic substituents revealed three promising candidates exhibiting inhibitory potencies for MAO B with IC50 values ranging from 1931 nM to 276 nM and high affinities at hH3R (Ki < 50 nM). Compound 3f ((E)-5-((4-bromobenzyl)oxy)-2-(4-(3-(piperidin-1-yl)propoxy)benzylidene)-2,3-dihydro-1H-inden-1-one, MAO B IC50 = 276 nM, hH3R Ki = 6.5 nM) showed highest preference for MAO B over MAO A (SI > 36). Interestingly, IC50 determinations after preincubation of enzyme and DTLs revealed also nanomolar MAO B potency for 3e (MAO B IC50 = 232 nM), a structural isomer of 3f, and 3d (MAO B IC50 = 541 nM), suggesting time-dependent inhibition modes. Reversibility of inhibition for all three compounds were confirmed by dilution studies in excess of substrate. Thus, indanone-substituted derivatives are promising lead structures for the design of MAO B/hH3R DTLs as novel therapeutic approach of PD therapy.
|
Inhibition of human MAO-B expressed in baculovirus infected insect cell membranes using kynuramine as substrate after 15 to 20 mins by discontinuous fluorimetric method
|
Homo sapiens
|
53.0
nM
|
|
Journal : Eur J Med Chem
Title : Novel indanone derivatives as MAO B/H3R dual-targeting ligands for treatment of Parkinson's disease.
Year : 2018
Volume : 148
First Page : 487
Last Page : 497
Authors : Affini A, Hagenow S, Zivkovic A, Marco-Contelles J, Stark H.
Abstract : The design of multi-targeting ligands was developed in the last decades as an innovative therapeutic concept for Parkinson's disease (PD) and other neurodegenerative disorders. As the monoamine oxidase B (MAO B) and the histamine H3 receptor (H3R) are promising targets for dopaminergic regulation, we synthetized dual-targeting ligands (DTLs) as non-dopaminergic receptor approach for the treatment of PD. Three series of compounds were developed by attaching the H3R pharmacophore to indanone-related MAO B motifs, leading to development of MAO B/H3R DTLs. Among synthesized indanone DTLs, compounds bearing the 2-benzylidene-1-indanone core structure showed MAO B preferring inhibition capabilities along with nanomolar hH3R affinity. Substitution of C5 and C6 position of the 2-benzylidene-1-indanones with lipophilic substituents revealed three promising candidates exhibiting inhibitory potencies for MAO B with IC50 values ranging from 1931 nM to 276 nM and high affinities at hH3R (Ki < 50 nM). Compound 3f ((E)-5-((4-bromobenzyl)oxy)-2-(4-(3-(piperidin-1-yl)propoxy)benzylidene)-2,3-dihydro-1H-inden-1-one, MAO B IC50 = 276 nM, hH3R Ki = 6.5 nM) showed highest preference for MAO B over MAO A (SI > 36). Interestingly, IC50 determinations after preincubation of enzyme and DTLs revealed also nanomolar MAO B potency for 3e (MAO B IC50 = 232 nM), a structural isomer of 3f, and 3d (MAO B IC50 = 541 nM), suggesting time-dependent inhibition modes. Reversibility of inhibition for all three compounds were confirmed by dilution studies in excess of substrate. Thus, indanone-substituted derivatives are promising lead structures for the design of MAO B/hH3R DTLs as novel therapeutic approach of PD therapy.
|
Inhibition of human recombinant MAO-B expressed in baculovirus infected BTI-TN-5B1-4 insect cells using benzylamine as substrate preincubated for 1 hr followed by substrate addition and measured after 30 mins by resazurin dye-based fluorescence assay
|
Homo sapiens
|
24.0
nM
|
|
Journal : J Med Chem
Title : Development of Novel Monoamine Oxidase-B (MAO-B) Inhibitors with Reduced Blood-Brain Barrier Permeability for the Potential Management of Noncentral Nervous System (CNS) Diseases.
Year : 2018
Volume : 61
Issue : 16
First Page : 7043
Last Page : 7064
Authors : Gealageas R, Devineau A, So PPL, Kim CMJ, Surendradoss J, Buchwalder C, Heller M, Goebeler V, Dullaghan EM, Grierson DS, Putnins EE.
Abstract : Studies indicate that MAO-B is induced in peripheral inflammatory diseases. To target peripheral tissues using MAO-B inhibitors that do not permeate the blood-brain barrier (BBB) the MAO-B-selective inhibitor deprenyl was remodeled by replacing the terminal acetylene with a CO2H function, and incorporating a para-OCH2Ar motif (compounds 10a-s). Further, in compound 32 the C-2 side chain corresponded to CH2CN. In vitro, 10c, 10j, 10k, and 32 were identified as potent reversible MAO-B inhibitors, and all four compounds were more stable than deprenyl in plasma, liver microsomal, and hepatocyte stability assays. In vivo, they demonstrated greater plasma bioavailability. Assessment of in vitro BBB permeability showed that compound 10k is a P-glycoprotein (P-gp) substrate and 10j displayed mild interaction. Importantly, compounds 10c, 10j, 10k, and 32 displayed significantly reduced BBB permeability after intravenous, subcutaneous, and oral administration. These polar MAO-B inhibitors are pertinent leads for evaluation of efficacy in noncentral nervous system (CNS) inflammatory disease models.
|
Inhibition of human recombinant MAOB expressed in baculovirus infected BTI-TN-5B1- 4 cells using p-tyramine as substrate assessed as decrease in H2O2 production by amplex red-based fluorescence assay
|
Homo sapiens
|
23.0
nM
|
|
Journal : Eur J Med Chem
Title : Multi-target-directed ligands for Alzheimer's disease: Discovery of chromone-based monoamine oxidase/cholinesterase inhibitors.
Year : 2018
Volume : 158
First Page : 781
Last Page : 800
Authors : Reis J, Cagide F, Valencia ME, Teixeira J, Bagetta D, Pérez C, Uriarte E, Oliveira PJ, Ortuso F, Alcaro S, Rodríguez-Franco MI, Borges F.
Abstract : There has been a substantial research effort to design multi-target ligands for the treatment of Alzheimer's disease (AD), an approach that is moved by the knowledge that AD is a complex and multifactorial disease affecting many linked to pathological pathways. Accordingly, we have devoted efforts to develop multi-target ligands based on the chromone scaffold. As a result, a small library of chromone derivatives was synthesized and screened towards human cholinesterases and monoamine oxidases. Compounds 2-(dimethylamino)ethyl (E)-3-(4-oxo-2-(p-methylphenlcarbamoyl)-4H-chromen-6-yl)acrylate (9a) and 2-(dimethylamino)ethyl (E)-3-(4-oxo-3-(phenylcarbamoyl)-4H-chromen-6-yl)acrylate (23a) were identified as the most promising multi-target inhibitors of the series. Compound 9a acted as a potent, selective and bifunctional AChEI (IC50 = 0.21 μM, Ki = 0.19 μM) and displayed dual hMAO inhibitory activity (hMAO-A IC50 = 0.94 μM, Ki = 0.057 μM and hMAO-B IC50 = 3.81 μM, Ki = 0.48 μM). Compound 23a acted as a selective IMAO-B (IC50 = 0.63 μM, Ki = 0.34 μM) while still displaying hChE inhibitory and bifunctional activity in the low micromolar range. Overall, these two compounds stand out as reversible multi-target inhibitors with favourable permeability, toxicological and drug-like profiles, thus being valid candidates for subsequent optimization and pre-clinical studies.
|
Inhibition of recombinant human MAOB expressed in insect cell microsomes using kynuramine as substrate measured after 20 mins by fluorescence spectrophotometry
|
Homo sapiens
|
48.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Novel monoamine oxidase inhibitors based on the privileged 2-imidazoline molecular framework.
Year : 2019
Volume : 29
Issue : 1
First Page : 40
Last Page : 46
Authors : Shetnev A, Osipyan A, Baykov S, Sapegin A, Chirkova Z, Korsakov M, Petzer A, Engelbrecht I, Petzer JP.
Abstract : Series of structurally diverse 2-imidazoline derivatives have been synthesized by condensation of substituted aldehydes with ethylenediamine, Pd-catalyzed N-arylation of 2-imidazolines and by the formation of 1,2,4-oxadiazoles and benzoxazepines from 2-imidazoline-containing precursors. The 2-imidazoline derivatives were evaluated as potential inhibitors of human monoamine oxidase (MAO) A and B. Among the 2-imidazolines, good potency inhibitors were discovered with compound 9p (IC<sub>50</sub> = 0.012 µM) being the most potent MAO-B inhibitor, while compound 9d (IC<sub>50</sub> = 0.751 µM) was the most potent MAO-A inhibitor of the series. These potencies are in the same range as those of reference MAO inhibitors used in the clinic. Among 33 compounds evaluated, 13 exhibited IC<sub>50</sub> values in the submicromolar range for the inhibition of an MAO isoform. It is postulated that the imidazoline moieties of some of these inhibitors may be recognized by the imidazoline I<sub>2</sub>-binding site of MAO. Good potency MAO inhibitors may be useful for the treatment of neuropsychiatric and neurodegenerative disorders such as depression and Parkinson's disease, and future application for the treatment of prostate cancer, congestive heart failure and Alzheimer's disease. In addition, high potency 2-imidazoline-derived MAO inhibitors may be used as potential probes for the imidazoline binding sites of the MAOs, as well as to determine alternative binding regions of imidazoline within the MAO active site.
|
Inhibition of human microsomal MAO-B expressed in baculovirus infected BTI-TN-5B1-4 cells assessed as reduction in 4-hydroxyquinoline formation using kynuramine as substrate preincubated with substrate for 10 mins followed by enzyme addition by spectrophotometric analysis
|
Homo sapiens
|
23.1
nM
|
|
Journal : Eur J Med Chem
Title : Design of novel monoamine oxidase-B inhibitors based on piperine scaffold: Structure-activity-toxicity, drug-likeness and efflux transport studies.
Year : 2020
Volume : 185
First Page : 111770
Last Page : 111770
Authors : Chavarria D, Fernandes C, Silva V, Silva C, Gil-Martins E, Soares P, Silva T, Silva R, Remião F, Oliveira PJ, Borges F.
Abstract : Piperine has been associated with neuroprotective effects and monoamine oxidase (MAO) inhibition, thus being an attractive scaffold to develop new antiparkinsonian agents. Accordingly, we prepared a small library of piperine derivatives and screened the inhibitory activities towards human MAO isoforms (hMAO-A and hMAO-B). Structure-activity relationship (SAR) studies pointed out that the combination of α-cyano and benzyl ester groups increased both potency and selectivity towards hMAO-B. Kinetic experiments with compounds 7, 10 and 15 indicated a competitive hMAO-B inhibition mechanism. Compounds 15 and 16, at 10 μM, caused a small but significant decrease in P-gp efflux activity in Caco-2 cells. Compound 15 stands out as the most potent piperine-based hMAO-B inhibitor (IC<sub>50</sub> = 47.4 nM), displaying favourable drug-like properties and a broad safety window. Compound 15 is thus a suitable candidate for lead optimization and the development of multitarget-directed ligands.
|
Inhibition of human microsomal MAO-A expressed in baculovirus infected BTI-TN-5B1-4 cells assessed as reduction in 4-hydroxyquinoline formation at 10 uM using kynuramine as substrate preincubated with substrate for 10 mins followed by enzyme inhibition by spectrophotometric analysis
|
Homo sapiens
|
50.0
%
|
|
Journal : Eur J Med Chem
Title : Design of novel monoamine oxidase-B inhibitors based on piperine scaffold: Structure-activity-toxicity, drug-likeness and efflux transport studies.
Year : 2020
Volume : 185
First Page : 111770
Last Page : 111770
Authors : Chavarria D, Fernandes C, Silva V, Silva C, Gil-Martins E, Soares P, Silva T, Silva R, Remião F, Oliveira PJ, Borges F.
Abstract : Piperine has been associated with neuroprotective effects and monoamine oxidase (MAO) inhibition, thus being an attractive scaffold to develop new antiparkinsonian agents. Accordingly, we prepared a small library of piperine derivatives and screened the inhibitory activities towards human MAO isoforms (hMAO-A and hMAO-B). Structure-activity relationship (SAR) studies pointed out that the combination of α-cyano and benzyl ester groups increased both potency and selectivity towards hMAO-B. Kinetic experiments with compounds 7, 10 and 15 indicated a competitive hMAO-B inhibition mechanism. Compounds 15 and 16, at 10 μM, caused a small but significant decrease in P-gp efflux activity in Caco-2 cells. Compound 15 stands out as the most potent piperine-based hMAO-B inhibitor (IC<sub>50</sub> = 47.4 nM), displaying favourable drug-like properties and a broad safety window. Compound 15 is thus a suitable candidate for lead optimization and the development of multitarget-directed ligands.
|
Inhibition of recombinant human MAO-A expressed in baculovirus infected insect cell microsomes at 10 uM using kynuramine as substrate measured after 30 mins by fluorescence based assay relative to control
|
Homo sapiens
|
20.0
%
|
|
Journal : Eur J Med Chem
Title : Investigating alkyl nitrates as nitric oxide releasing precursors of multitarget acetylcholinesterase-monoamine oxidase B inhibitors.
Year : 2019
Volume : 161
First Page : 292
Last Page : 309
Authors : Pisani L, Iacobazzi RM, Catto M, Rullo M, Farina R, Denora N, Cellamare S, Altomare CD.
Abstract : Herein we envisaged the possibility of exploiting alkyl nitrates as precursors of alcohol-bearing dual inhibitors targeting acetylcholinesterase (AChE) and monoamine oxidase B (MAO B), key enzymes in neurodegenerative syndromes such as Alzheimer's disease (AD), through biotransformation unmasking an alcoholic function upon nitric oxide (NO) release. The cooperation to neuroprotection of low fluxes of NO and target enzymes' inhibition by the alcohol metabolites might return a multitargeting effect. The in vitro screening towards ChEs and MAOs of a collection of 21 primary alcohols disclosed a subset of dual inhibitors, among which three diverse chemotypes were selected to study the corresponding nitrates. Nitrate 14 proved to be a brain permeant, potent AChE-MAO B inhibitor by itself. Moreover, it protected human SH-SY5Y lines against rotenone and hydrogen peroxide with a poor inherent cytotoxicity and showed a slow conversion profile to its alcohol metabolite 9d that still behaved as bimodal and neuroprotective molecule.
|
Inhibition of recombinant human MAO-B expressed in baculovirus infected insect cell microsomes using kynuramine as substrate measured after 30 mins by fluorescence based assay
|
Homo sapiens
|
18.0
nM
|
|
Journal : Eur J Med Chem
Title : Investigating alkyl nitrates as nitric oxide releasing precursors of multitarget acetylcholinesterase-monoamine oxidase B inhibitors.
Year : 2019
Volume : 161
First Page : 292
Last Page : 309
Authors : Pisani L, Iacobazzi RM, Catto M, Rullo M, Farina R, Denora N, Cellamare S, Altomare CD.
Abstract : Herein we envisaged the possibility of exploiting alkyl nitrates as precursors of alcohol-bearing dual inhibitors targeting acetylcholinesterase (AChE) and monoamine oxidase B (MAO B), key enzymes in neurodegenerative syndromes such as Alzheimer's disease (AD), through biotransformation unmasking an alcoholic function upon nitric oxide (NO) release. The cooperation to neuroprotection of low fluxes of NO and target enzymes' inhibition by the alcohol metabolites might return a multitargeting effect. The in vitro screening towards ChEs and MAOs of a collection of 21 primary alcohols disclosed a subset of dual inhibitors, among which three diverse chemotypes were selected to study the corresponding nitrates. Nitrate 14 proved to be a brain permeant, potent AChE-MAO B inhibitor by itself. Moreover, it protected human SH-SY5Y lines against rotenone and hydrogen peroxide with a poor inherent cytotoxicity and showed a slow conversion profile to its alcohol metabolite 9d that still behaved as bimodal and neuroprotective molecule.
|
Inhibition of recombinant human MAO-B expressed in baculovirus infected insect cell microsomes using kynuramine as substrate measured after 30 mins by spectrophotometric assay
|
Homo sapiens
|
28.0
nM
|
|
Journal : Eur J Med Chem
Title : Investigating alkyl nitrates as nitric oxide releasing precursors of multitarget acetylcholinesterase-monoamine oxidase B inhibitors.
Year : 2019
Volume : 161
First Page : 292
Last Page : 309
Authors : Pisani L, Iacobazzi RM, Catto M, Rullo M, Farina R, Denora N, Cellamare S, Altomare CD.
Abstract : Herein we envisaged the possibility of exploiting alkyl nitrates as precursors of alcohol-bearing dual inhibitors targeting acetylcholinesterase (AChE) and monoamine oxidase B (MAO B), key enzymes in neurodegenerative syndromes such as Alzheimer's disease (AD), through biotransformation unmasking an alcoholic function upon nitric oxide (NO) release. The cooperation to neuroprotection of low fluxes of NO and target enzymes' inhibition by the alcohol metabolites might return a multitargeting effect. The in vitro screening towards ChEs and MAOs of a collection of 21 primary alcohols disclosed a subset of dual inhibitors, among which three diverse chemotypes were selected to study the corresponding nitrates. Nitrate 14 proved to be a brain permeant, potent AChE-MAO B inhibitor by itself. Moreover, it protected human SH-SY5Y lines against rotenone and hydrogen peroxide with a poor inherent cytotoxicity and showed a slow conversion profile to its alcohol metabolite 9d that still behaved as bimodal and neuroprotective molecule.
|
Inhibition of human MAO-B expressed in baculovirus infected BTI insect cells using p-tyramine as substrate preincubated for 30 mins followed by substrate addition and measured after 1 hr by fluorescence-based Amplex Red MAO assay
|
Homo sapiens
|
7.7
nM
|
|
Journal : Bioorg Med Chem Lett
Title : 4-tert-Pentylphenoxyalkyl derivatives - Histamine H<sub>3</sub> receptor ligands and monoamine oxidase B inhibitors.
Year : 2018
Volume : 28
Issue : 23-24
First Page : 3596
Last Page : 3600
Authors : Łażewska D, Olejarz-Maciej A, Kaleta M, Bajda M, Siwek A, Karcz T, Doroz-Płonka A, Cichoń U, Kuder K, Kieć-Kononowicz K.
Abstract : The synthesis and biological activity of 4-tert-pentylphenoxypropyl derivatives are described in this manuscript. All compounds (except one) showed human histamine H<sub>3</sub> receptor affinity with K<sub>i</sub> values below 760 nM. The inhibitory activity toward human monoamine oxidase B (hMAO B) was evaluated using a fluorometric Amplex-Red assay, and most of the compounds were effective in the submicromolar range. Among them, 1-(3-(4-tert-pPentylphenoxy)propyl)pyrrolidine (5) exhibited hMAO B inhibitory activity with an IC<sub>50</sub> value of 4.5 nM. In addition, hMAO B inhibition by 5 was shown to be non-competitive and reversible. Further, recently described potent histamine H<sub>3</sub> receptor ligands - 4-tert-pentylphenoxyalkyl derivatives (with a 4-8 carbon spacer) - were evaluated for hMAO B inhibitory activity, and some of them displayed activity in the submicromolar range. Selected compounds were also tested for human MAO A (hMAO A) inhibitory potencies and exhibited no activity. Moreover, molecular modeling studies were carried out for tested compounds to explain their molecular mechanism of hMAO B inhibition and the selectivity of compounds for hMAO B over hMAO A.
|
Reversible inhibition of human MAOB
|
Homo sapiens
|
9.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : 4-tert-Pentylphenoxyalkyl derivatives - Histamine H<sub>3</sub> receptor ligands and monoamine oxidase B inhibitors.
Year : 2018
Volume : 28
Issue : 23-24
First Page : 3596
Last Page : 3600
Authors : Łażewska D, Olejarz-Maciej A, Kaleta M, Bajda M, Siwek A, Karcz T, Doroz-Płonka A, Cichoń U, Kuder K, Kieć-Kononowicz K.
Abstract : The synthesis and biological activity of 4-tert-pentylphenoxypropyl derivatives are described in this manuscript. All compounds (except one) showed human histamine H<sub>3</sub> receptor affinity with K<sub>i</sub> values below 760 nM. The inhibitory activity toward human monoamine oxidase B (hMAO B) was evaluated using a fluorometric Amplex-Red assay, and most of the compounds were effective in the submicromolar range. Among them, 1-(3-(4-tert-pPentylphenoxy)propyl)pyrrolidine (5) exhibited hMAO B inhibitory activity with an IC<sub>50</sub> value of 4.5 nM. In addition, hMAO B inhibition by 5 was shown to be non-competitive and reversible. Further, recently described potent histamine H<sub>3</sub> receptor ligands - 4-tert-pentylphenoxyalkyl derivatives (with a 4-8 carbon spacer) - were evaluated for hMAO B inhibitory activity, and some of them displayed activity in the submicromolar range. Selected compounds were also tested for human MAO A (hMAO A) inhibitory potencies and exhibited no activity. Moreover, molecular modeling studies were carried out for tested compounds to explain their molecular mechanism of hMAO B inhibition and the selectivity of compounds for hMAO B over hMAO A.
|
Inhibition of human recombinant MAO-B expressed in baculovirus infected BTI-TN-5B1-4 insect cells assessed as decrease in H2O2 production using p-tyramine as substrate incubated for 20 mins by horse-radish peroxidase/amplex red-based fluorescence method
|
Homo sapiens
|
5.18
nM
|
|
Inhibition of human recombinant MAO-B expressed in baculovirus infected BTI-TN-5B1-4 insect cells assessed as decrease in H2O2 production using p-tyramine as substrate incubated for 20 mins by horse-radish peroxidase/amplex red-based fluorescence method
|
Homo sapiens
|
2.29
nM
|
|
Inhibition of human recombinant MAO-B expressed in baculovirus infected BTI-TN-5B1-4 insect cells assessed as decrease in H2O2 production using p-tyramine as substrate incubated for 20 mins by horse-radish peroxidase/amplex red-based fluorescence method
|
Homo sapiens
|
5.129
nM
|
|
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 MAO-B expressed in baculovirus infected BTI-TN-5B1-4 insect cells using p-tyramine as substrate preincubated for 15 mins and measured after 45 mins by resorufin-based fluorescence assay
|
Homo sapiens
|
5.129
nM
|
|
Journal : Eur J Med Chem
Title : (Pyrrolo-pyridin-5-yl)benzamides: BBB permeable monoamine oxidase B inhibitors with neuroprotective effect on cortical neurons.
Year : 2019
Volume : 162
First Page : 793
Last Page : 809
Authors : Tzvetkov NT, Stammler HG, Hristova S, Atanasov AG, Antonov L.
Abstract : An extensive study was performed to develop a series of (pyrrolo-pyridin-5-yl)benzamides as reversible MAO-B inhibitors. Compounds 14 (NTZ-2020, hMAO-B IC<sub>50</sub> = 1.11 nM, K<sub>i</sub> = 0.56 nM, >9000-fold selective versus MAO-A) and 15 (NTZ-2027, hMAO-B IC<sub>50</sub> = 3.27 nM, K<sub>i</sub> = 1.45 nM, SI > 3058) are identified as the most promising BBB permeable derivatives within the series of (1H-pyrrolo[3,2-b]pyridine-5-yl)benzamides, combining both high potency and selectivity with optimal physicochemical and drug-like properties required for CNS active drugs. Extended photophysical analysis, including single X-ray analysis, quantum-chemical calculations and spectroscopic experiments provided insights into their tautomerism and structural behavioral, which relates to their biologically active form. The reversible MAO-B inhibitor 14 (NTZ-2020) exhibits a neuroprotective effect on cortical neuron survival and induces neurite network outgrowth. These effects are associated with a good BBB penetration of 14 that was confirmed in a triple cell neurovascular unit (NVU) model.
|
Inhibition of human recombinant MAO-B expressed in baculovirus infected BTI-TN-5B1-4 insect cells using p-tyramine as substrate preincubated for 15 mins and measured after 45 mins by Cheng-Prusoff equation analysis
|
Homo sapiens
|
2.29
nM
|
|
Journal : Eur J Med Chem
Title : (Pyrrolo-pyridin-5-yl)benzamides: BBB permeable monoamine oxidase B inhibitors with neuroprotective effect on cortical neurons.
Year : 2019
Volume : 162
First Page : 793
Last Page : 809
Authors : Tzvetkov NT, Stammler HG, Hristova S, Atanasov AG, Antonov L.
Abstract : An extensive study was performed to develop a series of (pyrrolo-pyridin-5-yl)benzamides as reversible MAO-B inhibitors. Compounds 14 (NTZ-2020, hMAO-B IC<sub>50</sub> = 1.11 nM, K<sub>i</sub> = 0.56 nM, >9000-fold selective versus MAO-A) and 15 (NTZ-2027, hMAO-B IC<sub>50</sub> = 3.27 nM, K<sub>i</sub> = 1.45 nM, SI > 3058) are identified as the most promising BBB permeable derivatives within the series of (1H-pyrrolo[3,2-b]pyridine-5-yl)benzamides, combining both high potency and selectivity with optimal physicochemical and drug-like properties required for CNS active drugs. Extended photophysical analysis, including single X-ray analysis, quantum-chemical calculations and spectroscopic experiments provided insights into their tautomerism and structural behavioral, which relates to their biologically active form. The reversible MAO-B inhibitor 14 (NTZ-2020) exhibits a neuroprotective effect on cortical neuron survival and induces neurite network outgrowth. These effects are associated with a good BBB penetration of 14 that was confirmed in a triple cell neurovascular unit (NVU) model.
|
Inhibition of human recombinant MAO-B expressed in insect cells using p-tyramine as substrate preincubated for 30 mins followed by substrate addition measured for 15 mins by resorufin dye-based fluorescence assay
|
Homo sapiens
|
39.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and biological evaluation of novel human monoamine oxidase B inhibitors based on a fragment in an X-ray crystal structure.
Year : 2019
Volume : 29
Issue : 8
First Page : 1012
Last Page : 1018
Authors : Cheng K, Li S, Lv X, Tian Y, Kong H, Huang X, Duan Y, Han J, Xie Z, Liao C.
Abstract : Herein we report our efforts of developing reversible selective hMAO-B inhibitors based on isatin, a fragment in an X-ray crystal structure. Five different scaffolds were designed and many compounds were synthesized. Among them, compound A3 demonstrated very high potency and isoform selectivity against hMAO-B, 11 and 13 times more potent (IC<sub>50</sub> = 3 nM) and 23.64 and 6.8 times more selective than the marked drugs, selegiline and safinamide. However, the endeavors to modify the polar 3-one group of isatin, that is in a hydrophobic environment in the binding site of hMAO-B, to small nonpolar hydrophobic groups did not bring about improved hMAO-B inhibitors, which may challenge our understanding of molecular interactions and molecular recognition in biological systems.
|
Inhibition of human microsomal MAO-B expressed in recombinant baculovirus infected insect BTI-TN-5B1-4 cells assessed as reduction in H2O2 production using p-tyramine as substrate after 15 mins by fluorescence assay
|
Homo sapiens
|
23.07
nM
|
|
Inhibition of human microsomal MAO-B expressed in recombinant baculovirus infected insect BTI-TN-5B1-4 cells assessed as reduction in H2O2 production using p-tyramine as substrate after 15 mins by fluorescence assay
|
Homo sapiens
|
22.91
nM
|
|
Journal : J Med Chem
Title : Discovery of New Chemical Entities for Old Targets: Insights on the Lead Optimization of Chromone-Based Monoamine Oxidase B (MAO-B) Inhibitors.
Year : 2016
Volume : 59
Issue : 12
First Page : 5879
Last Page : 5893
Authors : Reis J, Cagide F, Chavarria D, Silva T, Fernandes C, Gaspar A, Uriarte E, Remião F, Alcaro S, Ortuso F, Borges F.
Abstract : The discovery of new chemical entities endowed with potent, selective, and reversible monoamine oxidase B inhibitory activity is a clinically relevant subject. Therefore, a small library of chromone derivatives was synthesized and screened toward human monoamine oxidase isoforms (hMAO-A and hMAO-B). The structure-activity relationships studies strengthen the importance of the amide spacer and the direct linkage of carbonyl group to the γ-pyrone ring, along with the presence of meta and para substituents in the exocyclic ring. The most potent MAO-B inhibitors were N-(3'-chlorophenyl)-4-oxo-4H-chromene-3-carboxamide (20) (IC50 = 403 pM) and N-(3',4'-dimethylphenyl)-4-oxo-4H-chromene-3-carboxamide (27) (IC50 = 669 pM), acting as competitive and noncompetitive reversible inhibitors, respectively. Computational docking studies provided insights into enzyme-inhibitor interactions and a rationale for the observed selectivity and potency. Compound 27 stands out due to its favorable toxicological profile and physicochemical properties, which pointed toward blood-brain barrier permeability, thus being a valid candidate for subsequent animal studies.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
12.51
%
|
|
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
|
0.16
%
|
|
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
|
0.16
%
|
|
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 human recombinant MAO-B at 1 mM using tyramine as substrate preincubated with enzyme for 30 mins followed by incubation with substrate for 30 mins by Amplex Red reagent based fluorometric method relative to control
|
Homo sapiens
|
97.38
%
|
|
Journal : RSC Med Chem
Title : Novel 1,3,4-thiadiazole compounds as potential MAO-A inhibitors - design, synthesis, biological evaluation and molecular modelling
Year : 2020
Volume : 11
Issue : 9
First Page : 1063
Last Page : 1074
Authors : Saglik, Begum Nurpelin, Kaya Cavusoglu, Betul, Acar Cevik, Ulviye, Osmaniye, Derya, Levent, Serkan, Ozkay, Yusuf, Kaplancikli, Zafer Asim
Abstract : Monoamine oxidases (MAOs) are important drug targets for the management of neurological disorders. Herein, a series of new 1,3,4-thiadiazole derivatives bearing various alkyl/arylamine moieties as MAO inhibitors were designed and synthesized. All of the compounds were more selective against hMAO-A than hMAO-B. The half maximal inhibitory concentration (IC50) values of most of the compounds were lower than that of the common drug moclobemide (IC50 = 4.664 microM) and compound 6b was proven to be the most active compound (IC50 = 0.060 microM). Moreover, it was seen that compound 6b showed a similar inhibition profile to that of clorgyline (IC50 = 0.048 microM). The inhibition profile was found to be reversible and competitive for compound 6b with MAO-A selectivity. Molecular modelling studies aided in the understanding of the interaction modes between compound 6b and MAO-A. Furthermore, this compound was predicted to have a good pharmacokinetic profile and high BBB penetration. Therefore, such compounds are of interest towards developing new MAO inhibitors.
|
Inhibition of human recombinant MAO-B at 100 uM using tyramine as substrate preincubated with enzyme for 30 mins followed by incubation with substrate for 30 mins by Amplex Red reagent based fluorometric method relative to control
|
Homo sapiens
|
94.45
%
|
|
Journal : RSC Med Chem
Title : Novel 1,3,4-thiadiazole compounds as potential MAO-A inhibitors - design, synthesis, biological evaluation and molecular modelling
Year : 2020
Volume : 11
Issue : 9
First Page : 1063
Last Page : 1074
Authors : Saglik, Begum Nurpelin, Kaya Cavusoglu, Betul, Acar Cevik, Ulviye, Osmaniye, Derya, Levent, Serkan, Ozkay, Yusuf, Kaplancikli, Zafer Asim
Abstract : Monoamine oxidases (MAOs) are important drug targets for the management of neurological disorders. Herein, a series of new 1,3,4-thiadiazole derivatives bearing various alkyl/arylamine moieties as MAO inhibitors were designed and synthesized. All of the compounds were more selective against hMAO-A than hMAO-B. The half maximal inhibitory concentration (IC50) values of most of the compounds were lower than that of the common drug moclobemide (IC50 = 4.664 microM) and compound 6b was proven to be the most active compound (IC50 = 0.060 microM). Moreover, it was seen that compound 6b showed a similar inhibition profile to that of clorgyline (IC50 = 0.048 microM). The inhibition profile was found to be reversible and competitive for compound 6b with MAO-A selectivity. Molecular modelling studies aided in the understanding of the interaction modes between compound 6b and MAO-A. Furthermore, this compound was predicted to have a good pharmacokinetic profile and high BBB penetration. Therefore, such compounds are of interest towards developing new MAO inhibitors.
|
Inhibition of recombinant human MAO-B expressed in Sf9 cells using benzylamine as substrate preincubated for 15 mins followed by substrate addition for 60 mins by Luminex assay
|
Homo sapiens
|
249.0
nM
|
|
Journal : J Med Chem
Title : Computational Fragment-Based Design Facilitates Discovery of Potent and Selective Monoamine Oxidase-B (MAO-B) Inhibitor.
Year : 2020
Volume : 63
Issue : 23
First Page : 15021
Last Page : 15036
Authors : Jin CF,Wang ZZ,Chen KZ,Xu TF,Hao GF
Abstract : Parkinson's disease (PD) is one of the most common age-related neurodegenerative diseases. Inhibition of monoamine oxidase-B (MAO-B), which is mainly found in the glial cells of the brain, may lead to an elevated level of dopamine (DA) in patients. MAO-B inhibitors have been used extensively for patients with PD. However, the discovery of the selective MAO-B inhibitor is still a challenge. In this study, a computational strategy was designed for the rapid discovery of selective MAO-B inhibitors. A series of (S)-2-(benzylamino)propanamide derivatives were designed. In vitro biological evaluations revealed that (S)-1-(4-((3-fluorobenzyl)oxy)benzyl)azetidine-2-carboxamide (C3) was more potent and selective than safinamide, a promising drug for regulating MAO-B. Further studies revealed that the selectivity mechanism of C3 was due to the steric clash caused by the residue difference of Phe208 (MAO-A) and Ile199 (MAO-B). Animal studies showed that compound C3 could inhibit cerebral MAO-B activity and alleviate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neuronal loss.
|
Inhibition of recombinant human MAO-B expressed in baculovirus infected BTI cells using p-tyramine as substrate by fluorometric assay
|
Homo sapiens
|
8.0
nM
|
|
Journal : Eur J Med Chem
Title : Rational design of new multitarget histamine H receptor ligands as potential candidates for treatment of Alzheimer's disease.
Year : 2020
Volume : 207
First Page : 112743
Last Page : 112743
Authors : Łażewska D,Bajda M,Kaleta M,Zaręba P,Doroz-Płonka A,Siwek A,Alachkar A,Mogilski S,Saad A,Kuder K,Olejarz-Maciej A,Godyń J,Stary D,Sudoł S,Więcek M,Latacz G,Walczak M,Handzlik J,Sadek B,Malawska B,Kieć-Kononowicz K
Abstract : Design and development of multitarget-directed ligands (MTDLs) has become a very important approach in the search of new therapies for Alzheimer's disease (AD). In our present research, a number of xanthone derivatives were first designed using a pharmacophore model for histamine H receptor (HR) antagonists/inverse agonists, and virtual docking was then performed for the enzyme acetylcholinesterase. Next, 23 compounds were synthesised and evaluated in vitro for human HR (hHR) affinity and inhibitory activity on cholinesterases. Most of the target compounds showed hHR affinities in nanomolar range and exhibited cholinesterase inhibitory activity with IC values in submicromolar range. Furthermore, the inhibitory effects of monoamine oxidases (MAO) A and B were investigated. The results showed low micromolar and selective human MAO B (hMAO B) inhibition. Two azepane derivatives, namely 23 (2-(5-(azepan-1-yl)pentyloxy)-9H-xanthen-9-one) and 25 (2-(5-(azepan-1-yl)pentyloxy)-7-chloro-9H-xanthen-9-one), were especially very promising and showed high affinity for hHR (K = 170 nM and 100 nM respectively) and high inhibitory activity for acetylcholinesterase (IC = 180 nM and 136 nM respectively). Moreover, these compounds showed moderate inhibitory activity for butyrylcholinesterase (IC = 880 nM and 394 nM respectively) and hMAO B (IC = 775 nM and 897 nM respectively). Furthermore, molecular docking studies were performed for hHR, human cholinesterases and hMAO B to describe the mode of interactions with these biological targets. Next, the two most promising compounds 23 and 25 were selected for in vivo studies. The results showed significant memory-enhancing effect of compound 23 in dizocilpine-induced amnesia in rats in two tests: step-through inhibitory avoidance paradigm (SIAP) and transfer latency paradigm time (TLPT). In addition, favourable analgesic effects of compound 23 were observed in neuropathic pain models. Therefore, compound 23 is a particularly promising structure for further design of new MTDLs for AD.
|
Inhibition of recombinant human MAO-B expressed in baculovirus infected BTI insect cells using p-tyramine as substrate preincubated for 30 mins followed by substrate addition and measured after 1 hr by fluorimetric analysis
|
Homo sapiens
|
7.0
nM
|
|
Journal : Eur J Med Chem
Title : A dual-acting 5-HT receptor inverse agonist/MAO-B inhibitor displays glioprotective and pro-cognitive properties.
Year : 2020
Volume : 208
First Page : 112765
Last Page : 112765
Authors : Canale V,Grychowska K,Kurczab R,Ryng M,Keeri AR,Satała G,Olejarz-Maciej A,Koczurkiewicz P,Drop M,Blicharz K,Piska K,Pękala E,Janiszewska P,Krawczyk M,Walczak M,Chaumont-Dubel S,Bojarski AJ,Marin P,Popik P,Zajdel P
Abstract : The complex etiology of Alzheimer's disease has initiated a quest for multi-target ligands to address the multifactorial causes of this neurodegenerative disorder. In this context, we designed dual-acting 5-HT receptor (5-HTR) antagonists/MAO-B inhibitors using pharmacophore hybridization strategy. Our approach involved linking priviliged scaffolds of 5-HTR with aryloxy fragments derived from reversible and irreversible MAO-B inhibitors. The study identified compound 48 that acts as an inverse agonist of 5-HTR at G signaling and an irreversible MAO-B inhibitor. Compound 48 showed moderate metabolic stability in rat microsomal assay, artificial membrane permeability, no hepatotoxicity, and it was well distributed to the brain. Additionally, 48 showed glioprotective properties in a model of cultured astrocytes using 6-OHDA as the cytotoxic agent. Finally, compound 48 (MED = 1 mg/kg, p.o.) fully reversed memory deficits in the NOR task induced by scopolamine in rats. A better understanding of effects exerted by dual-acting 5-HTR/MAO-B modulators may impact the future development of neurodegenerative-directed treatment strategies.
|
Inhibition of recombinant human MAO-B expressed in baculovirus infected BTI insect cells at 1 uM using p-tyramine as substrate preincubated for 30 mins followed by substrate addition and measured after 1 hr by fluorimetric analysis relative to control
|
Homo sapiens
|
100.0
%
|
|
Journal : Eur J Med Chem
Title : A dual-acting 5-HT receptor inverse agonist/MAO-B inhibitor displays glioprotective and pro-cognitive properties.
Year : 2020
Volume : 208
First Page : 112765
Last Page : 112765
Authors : Canale V,Grychowska K,Kurczab R,Ryng M,Keeri AR,Satała G,Olejarz-Maciej A,Koczurkiewicz P,Drop M,Blicharz K,Piska K,Pękala E,Janiszewska P,Krawczyk M,Walczak M,Chaumont-Dubel S,Bojarski AJ,Marin P,Popik P,Zajdel P
Abstract : The complex etiology of Alzheimer's disease has initiated a quest for multi-target ligands to address the multifactorial causes of this neurodegenerative disorder. In this context, we designed dual-acting 5-HT receptor (5-HTR) antagonists/MAO-B inhibitors using pharmacophore hybridization strategy. Our approach involved linking priviliged scaffolds of 5-HTR with aryloxy fragments derived from reversible and irreversible MAO-B inhibitors. The study identified compound 48 that acts as an inverse agonist of 5-HTR at G signaling and an irreversible MAO-B inhibitor. Compound 48 showed moderate metabolic stability in rat microsomal assay, artificial membrane permeability, no hepatotoxicity, and it was well distributed to the brain. Additionally, 48 showed glioprotective properties in a model of cultured astrocytes using 6-OHDA as the cytotoxic agent. Finally, compound 48 (MED = 1 mg/kg, p.o.) fully reversed memory deficits in the NOR task induced by scopolamine in rats. A better understanding of effects exerted by dual-acting 5-HTR/MAO-B modulators may impact the future development of neurodegenerative-directed treatment strategies.
|
Inhibition of recombinant human MAO-B expressed in baculovirus infected BTI-TN-5B1-4 insect cells using p-tyramine as substrate preincubated for 15 mins followed by substrate addition and measured over 20 mins by horse-radish peroxidase/Amplex Red coupled fluorimetric analysis
|
Homo sapiens
|
29.0
nM
|
|
Journal : Eur J Med Chem
Title : Pyrimido[1,2-b]indazole derivatives: Selective inhibitors of human monoamine oxidase B with neuroprotective activity.
Year : 2021
Volume : 209
First Page : 112911
Last Page : 112911
Authors : Jismy B,El Qami A,Pišlar A,Frlan R,Kos J,Gobec S,Knez D,Abarbri M
Abstract : Structurally diverse heterotricyclic compounds are recognized as monoamine oxidase (MAO) inhibitors and thus represent an appealing scaffold in development and optimization of novel MAO inhibitors. Herein we explored the chemical space of pyrimido[1,2-b]indazoles as MAO inhibitors by preparing a small library of (hetero)aryl derivatives. An efficient synthetic strategy was developed starting from commercially available 1H-indazol-3-amines, which were converted to various 3-bromoheterotricyclic derivatives and further functionalized via Suzuki-Miyaura coupling reaction. Derivatives 4a-t selectively inhibited human MAO-B isoform in a reversible and competitive manner as confirmed by kinetic experiments and docking studies. Selected derivatives were not cytotoxic to neuroblastoma SH-SY5Y cells. Moreover, analogue 4i protected human neuroblastoma SH-SY5Y cells against 6-hydroxydopamine-induced cell death, which confirms the applicability of the pyrimido[1,2-b]indazoles as potential antiparkinsonian agents.
|
Inhibition of recombinant human MAO-B expressed in baculovirus infected BTI-TN- 5B1-4 insect cells using kynuramine as substrate preincubated for 10 mins in presence of substrate followed by enzyme addition and measured every minute for 30 mins by spectrophotometry analysis
|
Homo sapiens
|
25.3
nM
|
|
|
Inhibition of recombinant human MAO-A expressed in baculovirus infected BTI-TN- 5B1-4 insect cells at 10 uM using kynuramine as substrate preincubated for 10 mins in presence of substrate followed by enzyme addition and measured every minute for 30 mins by spectrophotometry analysis relative to control
|
Homo sapiens
|
30.5
%
|
|
|
Inhibition of human MAO-B
|
Homo sapiens
|
98.0
nM
|
|
|
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
|
63.0
nM
|
|
|
Inhibition of recombinant human MAOA using kynuramine as substrate at 10 uM measured for 30 mins by fluorescence spectrophotometric assay relative to control
|
Homo sapiens
|
13.0
%
|
|
|
Inhibition of recombinant MAO-A (unknown origin) assessed as reduction in 4-hydroxyquinoline level using kynuramine as a substrate at 1 uM incubated for 20 mins by discontinuous fluorimetric assay relative to control
|
Homo sapiens
|
-1.6
%
|
|
|
Inhibition of recombinant MAO-B (unknown origin) assessed as reduction in 4-hydroxyquinoline level using kynuramine as a substrate at 1 uM incubated for 20 mins by discontinuous fluorimetric assay relative to control
|
Homo sapiens
|
97.0
%
|
|
|
Inhibition of recombinant human MAO-B expressed in Sf9 cells preincubated for 15 min followed by addition of benzylamine and measured after 60 min by Luminex assay
|
Homo sapiens
|
163.0
nM
|
|
|
Inhibition of human recombinant MAO-B expressed in supersomes assessed as inhibition of 4-hydroxyquinoline formation using kynuramine as substrate by spectrofluorimetric analysis
|
Homo sapiens
|
18.0
nM
|
|
|
Inhibition of human recombinant MAO-A expressed in supersomes assessed as inhibition of 4-hydroxyquinoline formation using kynuramine as substrate at 10 uM by spectrofluorimetric analysis
|
Homo sapiens
|
20.0
%
|
|
