Design, Synthesis, and Biological Activities of Pyrrolylethanoneamine Derivatives, a Novel Class of Monoamine Oxidases Inhibitors

Santo, Roberto Di; Costi, Roberta; Roux, Alessandra; Artico, M.; Befani, Olivia; Meninno, Tiziana; Agostinelli, Enzo; Palmegiani, Paola; Turini, Paola; Cirilli, Roberto; Ferretti, Rosella; Gallinella, Bruno; Torre, Francesco La

doi:10.1021/jm050172c

Cited by 35 publications

(26 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…7, structure 17). A database was collected from previous publications along with pK i values [61,[152][153][154] and divided in raining (67 molecules) and test set (15 compounds). The necessary steps to develop the pharmacophore models, including the conformation analysis, alignment and pharmacophoric hypothesis generation, were carried out with the help of Phase module [150].…”

Section: D Pharmacophoric Modelsmentioning

confidence: 99%

Predicting Monoamine Oxidase Inhibitory Activity Through Ligand-Based Models

Vilar¹,

Ferino²,

Quezada³

et al. 2013

CTMC

View full text Add to dashboard Cite

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.

show abstract

Section: D Pharmacophoric Modelsmentioning

confidence: 99%

Predicting Monoamine Oxidase Inhibitory Activity Through Ligand-Based Models

Vilar¹,

Ferino²,

Quezada³

et al. 2013

CTMC

View full text Add to dashboard Cite

show abstract

“…Together these suggest that inhibiting the action of MAO-B can not only reduce the degradation of dopamine and reuptake, improving the concentration of dopamine in the brain, but also lower levels of H 2 O 2 , and MPP + to enhance neuroprotective properties. [6][7][8][9][10][11][12] Recently, xanthine and its derivatives were reported to produce little or no inhibition of MAO-B. In the last decade, when introducing phenyl at position-8, 8-phenyl xanthine exhibited MAO-B inhibition activity in vitro with a inhibition constant (K i ) value of 86.2 μM.…”

Section: Design Synthesis and Inhibitory Activities Of 8-(substitutementioning

confidence: 99%

Design, Synthesis and Inhibitory Activities of 8-(Substituted styrol-formamido)phenyl-xanthine Derivatives on Monoamine Oxidase B

Nian

Qin

et al. 2012

CHEMICAL & PHARMACEUTICAL BULLETIN

View full text Add to dashboard Cite

The design and synthesis of two series of 8-(substituted styrol-formamido)phenyl-xanthine derivatives are described. Their in vitro monoamine oxidase B (MAO-B) inhibition were tested and the effect of substituents on the N-7, phenyl and the substituted positions are discussed. It was observed that compound 9b displayed significant MAO-B inhibition activity and selectivity, fluorine substitution plays a key role in the selectivity of MAO-B inhibition, and the styrol-formamido group at position-3′ may enhance the activity and selectivity of 8-phenyl-xanthine analogues. These results suggest that such compounds may be utilized for the development of new candidate MAO-B inhibitors for treatment of Parkinson's disease.Key words xanthine derivative; monoamine oxidase B inhibition activity; substituent effect Parkinson's disease (PD) is a neurodegenerative disorder characterized pathologically by a marked loss of dopaminergic nigrostriatal neurons and clinically by disabling movement disorders.1) Currently, the therapy of PD is largely focused on dopamine replacement strategies with the dopamine precursor levodopa and dopamine agonist drugs. Although these strategies are highly effective in controlling the disease at the early stages, drug-related complications are associated with long-term treatment. The inadequacies of dopamine replacement therapy have prompted the research of alternative drug targets. 2-5)Monoamine oxidase (MAO) is an integral protein of the outer mitochondrial membrane, and exist in two forms, namely, monoamine oxidase A (MAO-A) and MAO-B. MAO-A preferentially deaminates aromatic monoamines such as the neurotransmitters serotonin (5-HT), noradrenaline (NA), andadrenaline (A); MAO-B is one of the most important key enzymes in metabolic pathways in vivo and plays mainly three roles: firstly, MAO-B decomposes dopamine into 3,4-dihydroxyphenyl acetic acid and homovanillic acid, meanwhile producing the neurotoxic H 2 O 2 . Secondly, MAO-B inactivates p-phenylethylamine which has the ability to stimulate secrection and reuptake function of dopamine. Thirdly, in the precence of MAO-B, catalyzed oxidation of 1-methyl-4-phenyl-1,2,3,6-terahydropyridine (MPTP) to intermediate 1-methyl-4-phenyl-2,3-dihydropyridin-1-ium (MPDP + ) and then to 1-methyl-4-phenylpyridin-1-ium (MPP + )with neurotoxicity occurs. Together these suggest that inhibiting the action of MAO-B can not only reduce the degradation of dopamine and reuptake, improving the concentration of dopamine in the brain, but also lower levels of H 2 O 2 , and MPP + to enhance neuroprotective properties. [6][7][8][9][10][11][12] Recently, xanthine and its derivatives were reported to produce little or no inhibition of MAO-B. In the last decade, when introducing phenyl at position-8, 8-phenyl xanthine exhibited MAO-B inhibition activity in vitro with a inhibition constant (K i ) value of 86.2 μM.2) Petzer et al. found a series of 8-styryl xanthine analogues exhibiting more powerful inhibition of MAO-B than 8-phenyl xanthine analogues (CSC K i =100 nM; KW6...

show abstract

“…The aim of the present study was to design MAO-A inhibitors while taking into consideration various factors responsible for selectivity against the A isoform, 9) namely i) the presence of electron-rich aromatic moieties (e.g. Bazinaprine 10) ), ii) the presence of hydrazido functionality (e.g. Iproniazid 11) ), iii) the presence of an ethoxycarbonyl methylene group side chain of an aromatic system (e.g.…”

Section: Notesmentioning

confidence: 99%

Synthesis of Some Pyridazinylacetic Acid Derivatives as a Novel Class of Monoamine Oxidase-A Inhibitors

Khattab

Bekhit

El‐Faham

et al. 2008

CHEMICAL & PHARMACEUTICAL BULLETIN

View full text Add to dashboard Cite

NotesMonoamic oxidase (MAO) (EC 1.4.3.4) is an integral flavin-containing enzyme of the outer mitochondrial membrane which is responsible for regulation and metabolism of major monoamine neurotransmitters such as serotonin (5-OH tryptamine), noradrenaline and dopamine. It is also involved in the biodegradation of exogenic amines such as benzylamine, tyramine, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTT), 1-methyl-4-phenyl pyridium (MPP ϩ ), and a Parkinsonian-producing neurotoxin.2) It is found in two different isoforms designated as MAO-A and MAO-B which are encoded by two different genes 3) and distinguished by different substrate specificities and sensitivities to the selective inhibitors. 4)The new generation of MAO inhibitors is characterized by their relative specificities for the MAO subtypes and in some cases by the reversibility of their actions. In spite of considerable progress in our understanding of the interactions of the two enzyme forms with their preferred substrates and inhibitors, no general rules are yet available for the rational design of potent and selective inhibitors of MAO. This is partly due to the fact that the mechanism of interaction of several new drugs with MAOs has not been fully characterized. Therefore, the discovery of several selective MAO inhibitors has relied on serendipity. Preferential MAO-A inhibitors have been recognized as therapeutically useful antidepressants 5) , while MAO-B inhibitors have been found to be beneficial in the treatment of Parkinson's disease and Alzheimer's disease. 6,7)Recently, we have demonstrated a series of 3-benzyl-2-substituted quinoxalines as selective MAO-A inhibitors bearing substituted amino or hydrazino functionalities at position 2 (e.g. 2-morpholinoethylamino, 2-hydroxyethylamino, hydrazino, etc).8) The rational design of these compounds was based on a hybrid structure of known inhibitors. The aim of the present study was to design MAO-A inhibitors while taking into consideration various factors responsible for selectivity against the A isoform, 9) namely i) the presence of electron-rich aromatic moieties (e.g. Bazinaprine 10) ), ii) the presence of hydrazido functionality (e.g. Iproniazid 11) ), iii) the presence of an ethoxycarbonyl methylene group side chain of an aromatic system (e.g. Eugenol analog 12) ); exchanging the ester group with an amido group was also considered, and iv) the benzyl group was retained in the new model compounds in Fig. 1.The new substituted pyridazine-1-yl acetic acid derivatives (2, 3, 5) were designed as selective monoamine oxidase-A inhibitors. The synthesis and biological evaluation of these compounds were described. As a preliminary result of the biological investigation, compound 5d showed the highest MAO-A selectivity and could be the lead compound for designing more potent and selective MAO-A inhibitors.First, the 4-benzyl-2H-pyridazin-3-one derivatives 1 were prepared. The reaction of the 4-benzyl-2H-pyridazin-3-one derivatives 1 with bromo ethyl acetate in dimethyl formamide in the presence...

show abstract

Design, Synthesis, and Biological Activities of Pyrrolylethanoneamine Derivatives, a Novel Class of Monoamine Oxidases Inhibitors

Cited by 35 publications

References 26 publications

Predicting Monoamine Oxidase Inhibitory Activity Through Ligand-Based Models

Predicting Monoamine Oxidase Inhibitory Activity Through Ligand-Based Models

Design, Synthesis and Inhibitory Activities of 8-(Substituted styrol-formamido)phenyl-xanthine Derivatives on Monoamine Oxidase B

Synthesis of Some Pyridazinylacetic Acid Derivatives as a Novel Class of Monoamine Oxidase-A Inhibitors

Contact Info

Product

Resources

About