( E )-3-Heteroarylidenechroman-4-ones as potent and selective monoamine oxidase-B inhibitors

Desideri, N.; Monaco, Luca Proietti; Fioravanti, Rossella; Biava, Mariangela; Yáñez, Matilde; Alcaro, Stefano; Ortuso, Francesco

doi:10.1016/j.ejmech.2016.03.081

Cited by 32 publications

(22 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The inhibitors of MAO B (Fig. 4b) (Mazouz et al 1993;Binda et al 2007;Binda et al 2012;Desideri et al 2016;Borroni et al 2017;Tzvetkov et al 2017) have a typical linear shape reminiscent of the diphenylbutene molecule in the first crystal structure of MAO B (Binda et al 2002).…”

Section: Reversible Inhibitorsmentioning

confidence: 99%

Kinetics, mechanism, and inhibition of monoamine oxidase

Ramsay

Albreht

2018

J Neural Transm

View full text Add to dashboard Cite

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.

show abstract

Section: Reversible Inhibitorsmentioning

confidence: 99%

Kinetics, mechanism, and inhibition of monoamine oxidase

Ramsay

Albreht

2018

J Neural Transm

View full text Add to dashboard Cite

show abstract

“…Desideri et al investigated a series of ( E )‐3‐heteroarylidenechroman‐4‐ones ( 45a‐r ) for their ability to inhibit hMAO‐B (Figure ). All the compounds were found to be selective hMAO‐BIs showing IC 50 values in nanomolar to micromolar range.…”

Section: Discovery and Development Of Mao‐b Inhibitors (2015‐2018)mentioning

confidence: 99%

“…( E )‐3‐Heteroarylidenechroman‐4‐ones ( 45a ‐ r ) . hMAO, human monoamine oxidase; IC 50 , half maximal inhibitory concentration…”

Section: Discovery and Development Of Mao‐b Inhibitors (2015‐2018)mentioning

confidence: 99%

Monoamine oxidase‐B inhibitors as potential neurotherapeutic agents: An overview and update

Tripathi

Ayyannan

2019

Medicinal Research Reviews

View full text Add to dashboard Cite

Monoamine oxidase (MAO) inhibitors have made significant contributions and remain an indispensable approach of molecular and mechanistic diversity for the discovery of antineurodegenerative drugs. However, their usage has been hampered by nonselective and/or irreversible action which resulted in drawbacks like liver toxicity, cheese effect, and so forth. Hence, the search for selective MAO inhibitors (MAOIs) has become a substantial focus in current drug discovery. This review summarizes our current understanding on MAO‐A/MAO‐B including their structure, catalytic mechanism, and biological functions with emphases on the role of MAO‐B as a potential therapeutic target for the development of medications treating neurodegenerative disorders. It also highlights the recent developments in the discovery of potential MAO‐B inhibitors (MAO‐BIs) belonging to diverse chemical scaffolds, arising from intensive chemical‐mechanistic and computational studies documented during past 3 years (2015‐2018), with emphases on their potency and selectivity. Importantly, readers will gain knowledge of various newly established MAO‐BI scaffolds and their development potentials. The comprehensive information provided herein will hopefully accelerate ideas for designing novel selective MAO‐BIs with superior activity profiles and critical discussions will inflict more caution in the decision‐making process in the MAOIs discovery.

show abstract

“…MAO-A and MAO-B are distinguished by the main differences, which contain details of the relevant active regions that explain their differences in substrate and inhibitor specificity [ 4 ]. Serotonin is a common MAO-A substratum, whereas 2-phenylethylamine and benzylamine are similar MAO-B substrates [ 5 , 6 ]. By knowing these structural differences, the rationalized drug design of isoform selective MAO inhibitors has been paved.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, In Vitro and In Silico Studies of New Thiazolylhydrazine-Piperazine Derivatives as Selective MAO-A Inhibitors

et al. 2020

View full text Add to dashboard Cite

Monoamine oxidase (MAO) isoenzymes are very important drug targets among neurological disorders. Herein, novel series of thiazolylhydrazine-piperazine derivatives were designed, synthesized and evaluated for their MAO-A and -B inhibitory activity. The structures of the synthesized compounds were assigned using different spectroscopic techniques such as 1H-NMR, 13C-NMR and HRMS. Moreover, the prediction of ADME (Absorption, Distribution, Metabolism, Elimination) parameters for all of the compounds were performed using in silico method. According to the enzyme inhibition results, the synthesized compounds showed the selectivity against MAO-A enzyme inhibition. Compounds 3c, 3d and 3e displayed significant MAO-A inhibition potencies. Among them, compound 3e was found to be the most effective derivative with an IC50 value of 0.057 ± 0.002 µM. Moreover, it was seen that this compound has a more potent inhibition profile than the reference inhibitors moclobemide (IC50 = 6.061 ± 0.262 µM) and clorgiline (IC50 = 0.062 ± 0.002 µM). In addition, the enzyme kinetics were performed for compound 3e and it was determined that this compound had a competitive and reversible inhibition type. Molecular modeling studies aided in the understanding of the interaction modes between this compound and MAO-A. It was found that compound 3e had significant and important binding property.

show abstract

( E )-3-Heteroarylidenechroman-4-ones as potent and selective monoamine oxidase-B inhibitors

Cited by 32 publications

References 26 publications

Kinetics, mechanism, and inhibition of monoamine oxidase

Kinetics, mechanism, and inhibition of monoamine oxidase

Monoamine oxidase‐B inhibitors as potential neurotherapeutic agents: An overview and update

Design, Synthesis, In Vitro and In Silico Studies of New Thiazolylhydrazine-Piperazine Derivatives as Selective MAO-A Inhibitors

Contact Info

Product

Resources

About