In silico design of novel 2H-chromen-2-one derivatives as potent and selective MAO-B inhibitors

Pisani, Leonardo; Farina, Roberta; Nicolotti, Orazio; Gadaleta, Domenico; Soto‐Otero, Ramón; Catto, Marco; Braccio, Mario Di; Méndez-Álvarez, Estefanı́a; Carotti, Angelo

doi:10.1016/j.ejmech.2014.10.029

Cited by 61 publications

(35 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the additional series of more rigid hybrids, to improve AChE inhibitory potency of 7benzyloxycoumarins 44 we approached a "designing in" strategy 29,39,42 by adding in a suitable position of the coumarin ring a protonatable basic moiety that might bind CAS through π-cation interactions ( Figure 2). Taking into account that, as recently reported, 68,69 the steric hindrance of substituents placed at position 4 of the coumarin ring exerts a negative impact on MAO affinity, the basic head was anchored to the 7-benzyloxy substituent. This rational hybrid design was supported by prospective docking studies based on X-ray crystal structures of the two target enzymes.…”

Section: Introductionmentioning

confidence: 97%

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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionmentioning

confidence: 97%

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

Self Cite

View full text Add to dashboard Cite

show abstract

“…Motivated by a financial interest in MAO inhibitors, but also the academic challenge of designing high potency and isoform-specific inhibitors, the discovery of new MAO inhibitors is pursued by a number of research groups [25][26][27][28][29]. A limited number of studies have reported that the quinone class of compounds, specifically 1,4-naphthoquinones and 1,4-benzoquinone, possess MAO inhibition properties.…”

Section: Introductionmentioning

confidence: 99%

The evaluation of 1,4-benzoquinones as inhibitors of human monoamine oxidase

Mostert

Petzer

2017

European Journal of Medicinal Chemistry

View full text Add to dashboard Cite

“…Pisani et al synthesized novel 7‐ meta‐ chlorobenzyloxy‐2 H ‐chromen‐2‐one derivatives ( 33a ‐ i ) and evaluated them for rMAO‐B inhibition activity (Figure ). Several inhibitors showed MAO‐B inhibitory potencies in the low nanomolar range ( 33a , 33b , 33c , 33f , 33g , and 33h ).…”

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

confidence: 99%

“… 7 ‐ meta‐ Chlorobenzyloxy‐2 H ‐chromen‐2‐one derivatives ( 33a ‐ i ) . hMAO, human monoamine oxidase; IC 50 , half maximal inhibitory concentration; SI, selectivity index…”

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

In silico design of novel 2H-chromen-2-one derivatives as potent and selective MAO-B inhibitors

Cited by 61 publications

References 35 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

The evaluation of 1,4-benzoquinones as inhibitors of human monoamine oxidase

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

Contact Info

Product

Resources

About