Fine molecular tuning at position 4 of 2H-chromen-2-one derivatives in the search of potent and selective monoamine oxidase B inhibitors

Pisani, Leonardo; Catto, Marco; Nicolotti, Orazio; Grossi, Giancarlo; Braccio, Mario Di; Soto‐Otero, Ramón; Méndez-Álvarez, Estefanı́a; Stefanachi, Angela; Gadaleta, Domenico; Carotti, Angelo

doi:10.1016/j.ejmech.2013.09.034

Cited by 42 publications

(45 citation statements)

References 51 publications

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“…As reported in previous studies, 68 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Inhibition data in Table 4 fulfilled our expectations and docking calculations. As far as the inhibitory activities on hMAO-B are concerned, a consistent increase of activity, from 2.5-fold for compound 2 up to 121-fold for 34, was recorded whereas the activities on hMAO-A remained low or were slightly incremented, from 2.7-fold for compound 11 to 18-fold for It is worth noting that all the coumarin derivatives listed in Table 4 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 2...…”

Section: Inhibitory Activities On Human Enzymessupporting

confidence: 90%

Structure-Based Design and Optimization of Multitarget-Directed 2H-Chromen-2-one Derivatives as Potent Inhibitors of Monoamine Oxidase B and Cholinesterases

et al. 2015

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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.

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Section: Inhibitory Activities On Human Enzymessupporting

confidence: 90%

Structure-Based Design and Optimization of Multitarget-Directed 2H-Chromen-2-one Derivatives as Potent Inhibitors of Monoamine Oxidase B and Cholinesterases

et al. 2015

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“…Depending on the bound substrate/inhibitor, the MAO‐B active site can exhibit a bipartite cavity so that the ligand has to negotiate a smaller entrance room before entering the substrate cavity where FAD is accommodated . The presence of the CF 3 group on the para ‐position of ring B can contribute significant lipophilic nature to the molecule.…”

Section: Resultsmentioning

confidence: 99%

Potent and Selective Monoamine Oxidase‐B Inhibitory Activity: Fluoro‐ vs. Trifluoromethyl‐4‐hydroxylated Chalcone Derivatives

Mathew

Mathew²,

Uçar³

et al. 2016

Chemistry & Biodiversity

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For various neurodegenerative disorders like Alzheimer's and Parkinson's diseases, selective and reversible MAO-B inhibitors have a great therapeutic value. In our previous study, we have shown that a series of methoxylated chalcones with F functional group exhibited high binding affinity toward human monoamine oxidase-B (hMAO-B). In continuation of our earlier study and to extend the understanding of the structure-activity relationships, a series of five new chalcones were studied for their inhibition of hMAO. The results demonstrated that these compounds are reversible and selective hMAO-B inhibitors with a competitive mode of inhibition. The most active compound, (2E)-1-(4-hydroxyphenyl)-3-[4-(trifluoromethyl)phenyl]prop-2-en-1-one, exhibited a Ki value of 0.33 ± 0.01 μm toward hMAO-B with a selectivity index of 26.36. A molecular docking study revealed that the presence of a H-bond network in hydroxylated chalcone with the N(5) atom of FAD is crucial for MAO-B selectivity and potency.

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“…An early oxadiazolone series gave IC50 values in the nM range, inhibiting MAO B by a two-step process, initially competitive, followed by slowly reversible tight binding (Mazouz et al 1993). Other examples include quinolones with IC50 values in the low nM range (Meiring et al 2013), chromenones (best IC50 3.1 nM) (Pisani et al 2013), the N-alkylated indazole-5-carboxamide derivatives (N-(3-chloro-4-fluorophenyl)-1-methyl-1H-indazole-5-carboxamide (IC50 hMAO-B 0.662 nM, >15000-fold selective versus MAO-A) (Tzvetkov et al 2017). This selectivity is desirable.…”

Section: Fig 4 Reversible Inhibitors Of (A) Mao a (With Ki Values) mentioning

confidence: 99%

Kinetics, mechanism, and inhibition of monoamine oxidase

Ramsay

Albreht

2018

J Neural Transm

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Monoamine oxidases (MAOs) catalyse the oxidation of neurotransmitter amines and a wide variety of primary, secondary and tertiary amine xenobiotics, including therapeutic drugs. While inhibition of MAO activity in the periphery removes protection from biogenic amines and so is undesirable, inhibition in the brain gives vital antidepressant and behavioural advantages that make MAO a major pharmaceutical target for inhibitor design. In neurodegenerative diseases, MAO inhibitors can help to maintain neurotransmitter levels, making it a common feature in novel multi-target combinations designed to combat Alzheimer's disease, albeit not yet proven clinically. Vital information for inhibitor design comes from an understanding of the structure, mechanism, and kinetics of the catalyst. This review will summarize the kinetic behaviour of MAO A and B and the kinetic evaluation of reversible inhibitors that transiently decrease catalysis. Kinetic parameters and crystal structures have enabled computational approaches to ligand discovery and validation of hits by docking. Kinetics and a wide variety of substrates and inhibitors along with theoretical modelling have also contributed to proposed schemes for the still debated chemical mechanism of amine oxidation. However, most of the marketed MAO drugs are long-lasting irreversible inactivators. The mechanism of irreversible inhibition by hydrazine, cyclopropylamine, and propargylamine drugs will be discussed. The article finishes with some examples of the propargylamine moiety in multi-target ligand design to combat neurodegeneration.

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Fine molecular tuning at position 4 of 2H-chromen-2-one derivatives in the search of potent and selective monoamine oxidase B inhibitors

Cited by 42 publications

References 51 publications

Structure-Based Design and Optimization of Multitarget-Directed 2H-Chromen-2-one Derivatives as Potent Inhibitors of Monoamine Oxidase B and Cholinesterases

Structure-Based Design and Optimization of Multitarget-Directed 2H-Chromen-2-one Derivatives as Potent Inhibitors of Monoamine Oxidase B and Cholinesterases

Potent and Selective Monoamine Oxidase‐B Inhibitory Activity: Fluoro‐ vs. Trifluoromethyl‐4‐hydroxylated Chalcone Derivatives

Kinetics, mechanism, and inhibition of monoamine oxidase

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