A reversible monoamine oxidase inhibitor, toloxatone: spectrophotometric and molecular orbital studies of the interaction with flavin adenine dinucleotide (FAD)

Moureau, Florence; Wouters, Johan; Vercauteren, Daniel P.; Collin, Sonia; Evrard, G.; Durant, François; Ducrey, F.; Koenig, JJ; Jarreau, F. X.

doi:10.1016/0223-5234(94)90096-5

Cited by 49 publications

(36 citation statements)

References 9 publications

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“…The final conclusion suggests that electron-rich rings systems and higher HOMO levels increased the potency of these derivatives against MAO-A enzyme. The results are in agreement with some studies suggesting the existence of charge-transfer interactions between inhibitors and the FAD cofactor of MAO enzymes [77,99,100]. A previous study carried out in phenylalkylamines also revealed that electronic descriptors had an important contribution in the development of the QSAR model [83].…”

Section: Qsar With 3d Descriptorssupporting

confidence: 80%

“…In previous modeling studies using 2D and 3D QSAR, Kneubuhler et al [76] also related MAO-B inhibitory activity with pyridazines through lipophilic, electronic and steric properties. On the other hand, it has been previously shown that electrostatic interactions and charge-transfer bonding are important parameters in the interaction between inhibitors and the FAD cofactor of the MAO-A [77,78]. The results described by Altomare et al [74] revealed that the majority of the condensed pyridazines were selective towards MAO-B whereas the condensed pyrimidines were more active against MAO-A enzyme.…”

Section: D Qsar Using Multiple Linear Regression (Mlr)supporting

confidence: 47%

“…The compounds showed selectivity towards MAO-A, the most active inhibitor having a potency of IC 50 =40 nM. Although the molecular mechanism by which these molecules present MAO-A activity is not completely understood, a possible hypothesis takes into account charge-transfer interactions with the FAD cofactor [77]. The initial SAR pointed out the importance of -OH substituent at position 1 or 5 rather than -OMe.…”

Section: D Qsar Comfa Modelsmentioning

confidence: 99%

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Predicting Monoamine Oxidase Inhibitory Activity Through Ligand-Based Models

Vilar¹,

Ferino²,

Quezada³

et al. 2013

CTMC

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The evolution of bio-and cheminformatics associated with the development of specialized software and increasing computer power has produced a great interest in theoretical in silico methods applied in drug rational design. These techniques apply the concept that "similar molecules have similar biological properties" that has been exploited in Medicinal Chemistry for years to design new molecules with desirable pharmacological profiles. Ligand-based methods are not dependent on receptor structural data and take into account two and three-dimensional molecular properties to assess similarity of new compounds in regards to the set of molecules with the biological property under study. Depending on the complexity of the calculation, there are different types of ligand-based methods, such as QSAR (Quantitative Structure-Activity Relationship) with 2D and 3D descriptors, CoMFA (Comparative Molecular Field Analysis) or pharmacophoric approaches. This work provides a description of a series of ligand-based models applied in the prediction of the inhibitory activity of monoamine oxidase (MAO) enzymes. The controlled regulation of the enzymes' function through the use of MAO inhibitors is used as a treatment in many psychiatric and neurological disorders, such as depression, anxiety, Alzheimer's and Parkinson's disease. For this reason, multiple scaffolds, such as substituted coumarins, indolylmethylamine or pyridazine derivatives were synthesized and assayed toward MAO-A and MAO-B inhibition. Our intention is to focus on the description of ligand-based models to provide new insights in the relationship between the MAO inhibitory activity and the molecular structure of the different inhibitors, and further study enzyme selectivity and possible mechanisms of action.

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Section: Qsar With 3d Descriptorssupporting

confidence: 80%

Section: D Qsar Using Multiple Linear Regression (Mlr)supporting

confidence: 47%

Section: D Qsar Comfa Modelsmentioning

confidence: 99%

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Predicting Monoamine Oxidase Inhibitory Activity Through Ligand-Based Models

Vilar¹,

Ferino²,

Quezada³

et al. 2013

CTMC

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“…Certain classes of compounds available through these processes, such as N-arylated azoles, [1] N-arylated oxazolidin-2-ones, [2,3] or C-arylated malonic acid derivatives, [4] are industrially important synthetic targets. These motifs are found in a range of pharmaceuticals, agrochemicals, and natural products.…”

Section: Introductionmentioning

confidence: 99%

“…[51] We next attempted to subject oxazolidin-2-one to arylation with iodobenzene. N-Aryloxazolidin-2-ones constitute an important class of therapeutic agents; this is illustrated by the drugs Linezolid (Zyvox) [2] and (R)-Toloxatone (Humoryl), [3] with antibiotic and antidepressant activity, respectively. N-Aryloxazolidin-2-ones are also precursors to vic-arylaminoalcohols, [52] another template in medicinal chemistry.…”

Section: Introductionmentioning

confidence: 99%

Highly Efficient and Mild Copper‐Catalyzed N‐ and C‐Arylations with Aryl Bromides and Iodides

Cristau

Cellier

Spindler³

et al. 2004

Chemistry A European J

576

239

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Mild, efficient, copper-catalyzed N-arylation procedures for nitrogen heterocycles, amides, carbamates, and C-arylation procedures for malonic acid derivatives have been developed that afford high yields of arylated products with excellent selectivity. The N-arylation of imidazole with aryl bromides or iodides was found to be greatly accelerated by inexpensive, air-stable catalyst systems, combining catalytic copper salts or oxides with a set of structurally simple chelating ligands. The reaction was shown to be compatible with a broad range of aryl halides, encompassing sterically hindered, electron-poor, and electron-rich ones, providing the arylated products under particularly mild conditions (50-82 degrees C). The lower limit in ligand and catalyst loading and the scope of Ullmann-type condensations catalyzed by complexes bearing those ligands with respect to the nucleophile class have also been investigated. Chelating Schiff base Chxn-Py-Al (1c) generates a remarkably general copper catalyst for N-arylation of pyrrole, indole, 1,2,4-triazole, amides, and carbamates; and C-arylation of diethyl malonate, ethyl cyanoacetate, and malononitrile with aryl iodides under mild conditions (50-82 degrees C). The new method reported here is the most successful to date with regard to Ullmann-type arylation of some of these nucleophiles.

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Electronic properties of flavins: Implications on the reactivity and absorption properties of flavoproteins

Wouters

Durant

Champagne

et al. 1997

Int. J. Quant. Chem.

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supports the classification of the flavoenzymes into two classes. Moreover, the -U transition has been correctly placed as the lowest energy transition for the neutral oxidized lumiflavin and predicts a blue shift of the low-lying electronic transition upon monoprotonation. Finally, from the analysis of the molecular complex between oxidized Ž . lumiflavin HFl and hydroquinone, we have rationalized the complex formation in ox terms of the complementarity between the molecular electrostatic potentials as well as in terms of the overlap between the frontier orbitals involved in these charge transfer process.

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A reversible monoamine oxidase inhibitor, toloxatone: spectrophotometric and molecular orbital studies of the interaction with flavin adenine dinucleotide (FAD)

Cited by 49 publications

References 9 publications

Predicting Monoamine Oxidase Inhibitory Activity Through Ligand-Based Models

Predicting Monoamine Oxidase Inhibitory Activity Through Ligand-Based Models

Highly Efficient and Mild Copper‐Catalyzed N‐ and C‐Arylations with Aryl Bromides and Iodides

Electronic properties of flavins: Implications on the reactivity and absorption properties of flavoproteins

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