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

Farina, Roberta; Pisani, Leonardo; Catto, Marco; Nicolotti, Orazio; Gadaleta, Domenico; Denora, Nunzio; Soto‐Otero, Ramón; Méndez-Álvarez, Estefanı́a; Passos, Carolina S.; Muncipinto, Giovanni; Altomare, Cosimo; Nurisso, Alessandra; Carrupt, Pierre‐Alain; Carotti, Angelo

doi:10.1021/acs.jmedchem.5b00599

Cited by 92 publications

(99 citation statements)

References 83 publications

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“…M30D is metabolized to M30 by acetylcholinesterase ensuring that the chelating activity is released only in the nervous tissue and thus decreasing toxicity in the periphery (Zheng et al, 2010). Similar aims to design inhibition of both cholinesterases and monoamine oxidases into one compound resulted in PF1901N (Bolea et al, 2014) or in aminocoumarins (Farina et al, 2015) both of which also show neuroprotective effects.…”

Section: Multi-target Drugsmentioning

confidence: 99%

Molecular aspects of monoamine oxidase B

Ramsay

2016

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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Graphical abstract Highlights• MAO B activity depends on both amine and oxygen concentrations KeywordsMonoamine oxidase B; kinetics; drug design; neurotransmitter levels; platelet AbbreviationsAlzheimer's Disease, AD; Parkinson's Disease, PD; dopamine transporter, DAT; serotonin transporter, SERT; noradrenaline transporter, NET; the vesicular transporter, VMAT; Gprotein coupled receptor, GPCR; induced pluripotent stem cells, iPSC; serotonin reuptake inhibitor, SSRI; brain-derived neurotrophic factor, BDNF; multi-target designed ligands, MTDL; IC 50 , the concentration of compound required to inhibit a specified assay by 50%; K i , a kinetically measured inhibitor dissociation constant. Word count -approx 5490 (excluding references). Abstract 196 words.3

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Section: Multi-target Drugsmentioning

confidence: 99%

Molecular aspects of monoamine oxidase B

Ramsay

2016

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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“…Recent approaches in the development of drug leads for Alzheimer's disease have been multi-target-directed. 25,26) This is the first report to identify p-coumaric acid phenethyl ester derivatives as potent and selective MAO-B inhibitors and multi-target-directed drug leads.…”

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confidence: 97%

Synthesis of Amide and Ester Derivatives of Cinnamic Acid and Its Analogs: Evaluation of Their Free Radical Scavenging and Monoamine Oxidase and Cholinesterase Inhibitory Activities

Takao

Toda

Saito

et al. 2017

CHEMICAL & PHARMACEUTICAL BULLETIN

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A series of cinnamic acid derivatives, amides (1-12) and esters (13-22), were synthesized, and structureactivity relationships for antioxidant activity, and monoamine oxidases (MAO) A and B, acetylcholinesterase, and butyrylcholinesterase (BChE) inhibitory activities were analyzed. Among the synthesized compounds, compounds 1-10, 12-18, and rosmarinic acid (23), which contained catechol, o-methoxyphenol or 5-hydroxyindole moieties, showed potent 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging activity. Compounds 9-11, 15, 17-22 showed potent and selective MAO-B inhibitory activity. Compound 20 was the most potent inhibitor of MAO-B. Compounds 18 and 21 showed moderate BChE inhibitory activity. In addition, compound 18 showed potent antioxidant activity and MAO-B inhibitory activity. In a comparison of the cinnamic acid amides and esters, the amides exhibited more potent DPPH free radical scavenging activity, while the esters showed stronger inhibitory activities against MAO-B and BChE. These results suggested that cinnamic acid derivatives such as compound 18, p-coumaric acid 3,4-dihydroxyphenethyl ester, and compound 20, p-coumaric acid phenethyl ester, may serve as lead compounds for the development of novel MAO-B inhibitors and candidate lead compounds for the prevention or treatment of Alzheimer's disease.Key words cinnamic acid amide; cinnamic acid ester; monoamine oxidase; cholinesterase; antioxidant; Alzheimer's disease Plant secondary metabolites are important sources of bioactive constituents that promote health. Natural products have long played a significant role in the development of new therapeutic leads. For example, phenolic compounds have been shown to prevent oxidative stress, a condition known to cause cell injury and death and to exacerbate the development of several age-related chronic pathologies like cancer, and neurodegenerative diseases such as Alzheimer's and Parkinson's diseases.

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“…During biological assessment, it became apparent that this compound has neuroprotective properties, by inhibiting Aβ42 and Aβ40 self-aggregation into plaques, and by protecting against depletion of antioxidative enzymes (Bolea et al, 2013). Therefore ASS234 has been patented (PCT/ES070186; WO2011/113988 A1) as a promising compound for the treatment of AD.Many other ChE/MAO targeted MTDL have been designed in the last 5 years, either propargyl-based (Youdim, 2013; Bautista-Aguilera et al, 2014b; Samadi et al, 2015; Weinreb et al, 2015) or coumarins derivatives (Pisani et al, 2011; Patil et al, 2013; Farina et al, 2015; Xie et al, 2015). The challenge will be to add further neuroprotective properties to progress to a disease-modifying drug.…”

Section: Neurotransmitter Degrading Enzymesmentioning

confidence: 99%

Key Targets for Multi-Target Ligands Designed to Combat Neurodegeneration

et al. 2016

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HIGHLIGHTS Compounds that interact with multiple targets but minimally with the cytochrome P450 system (CYP) address the many factors leading to neurodegeneration.Acetyl- and Butyryl-cholineEsterases (AChE, BChE) and Monoamine Oxidases A/B (MAO A, MAO B) are targets for Multi-Target Designed Ligands (MTDL).ASS234 is an irreversible inhibitor of MAO A >MAO B and has micromolar potency against the cholinesterases.ASS234 is a poor CYP substrate in human liver, yielding the depropargylated metabolite.SMe1EC2, a stobadine derivative, showed high radical scavenging property, in vitro and in vivo giving protection in head trauma and diabetic damage of endothelium.Control of mitochondrial function and morphology by manipulating fission and fusion is emerging as a target area for therapeutic strategies to decrease the pathological outcome of neurodegenerative diseases.Growing evidence supports the view that neurodegenerative diseases have multiple and common mechanisms in their aetiologies. These multifactorial aspects have changed the broadly common assumption that selective drugs are superior to “dirty drugs” for use in therapy. This drives the research in studies of novel compounds that might have multiple action mechanisms. In neurodegeneration, loss of neuronal signaling is a major cause of the symptoms, so preservation of neurotransmitters by inhibiting the breakdown enzymes is a first approach. Acetylcholinesterase (AChE) inhibitors are the drugs preferentially used in AD and that one of these, rivastigmine, is licensed also for PD. Several studies have shown that monoamine oxidase (MAO) B, located mainly in glial cells, increases with age and is elevated in Alzheimer (AD) and Parkinson's Disease's (PD). Deprenyl, a MAO B inhibitor, significantly delays the initiation of levodopa treatment in PD patients. These indications underline that AChE and MAO are considered a necessary part of multi-target designed ligands (MTDL). However, both of these targets are simply symptomatic treatment so if new drugs are to prevent degeneration rather than compensate for loss of neurotransmitters, then oxidative stress and mitochondrial events must also be targeted. MAO inhibitors can protect neurons from apoptosis by mechanisms unrelated to enzyme inhibition. Understanding the involvement of MAO and other proteins in the induction and regulation of the apoptosis in mitochondria will aid progress toward strategies to prevent the loss of neurons. In general, the oxidative stress observed both in PD and AD indicate that antioxidant properties are a desirable part of MTDL molecules. After two or more properties are incorporated into one molecule, the passage from a lead compound to a therapeutic tool is strictly linked to its pharmacokinetic and toxicity. In this context the interaction of any new molecules with cytochrome P450 and other xenobiotic metabolic processes is a crucial point. The present review covers the biochemistry of enzymes targeted in the design of drugs against neurodegeneration and the cytochrome P450-dependent met...

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

Cited by 92 publications

References 83 publications

Molecular aspects of monoamine oxidase B

Molecular aspects of monoamine oxidase B

Synthesis of Amide and Ester Derivatives of Cinnamic Acid and Its Analogs: Evaluation of Their Free Radical Scavenging and Monoamine Oxidase and Cholinesterase Inhibitory Activities

Key Targets for Multi-Target Ligands Designed to Combat Neurodegeneration

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