Synthesis of coumarins as subtype-selective inhibitors of monoamine oxidase

Rendenbach-Müller, B.; Schlecker, Rainer; Traut, M; Weifenbach, H

doi:10.1016/s0960-894x(01)80328-0

Cited by 38 publications

(26 citation statements)

References 2 publications

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“…Ether derivatives demonstrate MAO-B selectivity, and sulfonic ester derivatives demonstrate MAO-A selectivity [113,311]. A QSAR study of coumarin derivatives acting on MAO B was done, revealing the importance of lipophilic interactions in modulating the inhibition and excluding any dependence on electronic properties [113].…”

Section: Enzyme Inhibitionmentioning

confidence: 99%

Simple Coumarins and Analogues in Medicinal Chemistry: Occurrence, Synthesis and Biological Activity

Borges¹,

Roleira²,

Milhazes³

et al. 2005

CMC

890

458

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Coumarins, also known as benzopyrones, are present in remarkable amounts in plants, although their presence has also been detected in microorganisms and animal sources. The structural diversity found in this family of compounds led to the division into different categories, from simple coumarins to many other kinds of policyclic coumarins, such as furocoumarins and pyranocoumarins. Simple coumarins and analogues are a large class of compounds that have attracted their interest for a long time due to their biological activities: they have shown to be useful as antitumoural, anti-HIV agents and as CNS-active compounds. Furthermore, they have been reported to have multiple biological activities (anticoagulant, anti-inflammatory), although all these properties have not been evaluated systematically. In addition, their enzyme inhibition properties, antimicrobial and antioxidant activities are other foremost topics of this field of research. The present work is to survey the information published or abstracted from 1990 till 2003, which is mainly related to the occurrence, synthesis and biological importance of simple coumarins and some analogues, such as biscoumarins and triscoumarins. Data are also highlighted, concerning the development of new synthetic strategies that could help in drug design and in the work on SAR or QSAR.

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Section: Enzyme Inhibitionmentioning

confidence: 99%

Simple Coumarins and Analogues in Medicinal Chemistry: Occurrence, Synthesis and Biological Activity

Borges¹,

Roleira²,

Milhazes³

et al. 2005

CMC

890

458

View full text Add to dashboard Cite

show abstract

“…As a part of our ongoing research in this field, [40][41][42][43][44][45][46][47] herein we report the design, synthesis, and biochemical evaluation of a new series of coumarins that maintained the potent and selective MAO-B inhibition found for this class of compounds [48][49][50] but that exhibited more appropriate physicochemical and pharmacokinetic properties for clinical applications as novel therapeutics of neurological disorders. In fact, most of the potent and selective MAO-B coumarin inhibitors studied so far have generally displayed too high lipophilicity and poor aqueous solubility, and this might strongly limit their investigations even at the level of experimental preclinical profiling.…”

Section: Introductionmentioning

confidence: 99%

Discovery of a Novel Class of Potent Coumarin Monoamine Oxidase B Inhibitors: Development and Biopharmacological Profiling of 7-[(3-Chlorobenzyl)oxy]-4-[(methylamino)methyl]-2H-chromen-2-one Methanesulfonate (NW-1772) as a Highly Potent, Selective, Reversible, and Orally Active Monoamine Oxidase B Inhibitor

et al. 2009

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In an effort to discover novel selective monoamine oxidase (MAO) B inhibitors with favorable physicochemical and pharmacokinetic profiles, 7-[(m-halogeno)benzyloxy]coumarins bearing properly selected polar substituents at position 4 were designed, synthesized, and evaluated as MAO inhibitors. Several compounds with MAO-B inhibitory activity in the nanomolar range and excellent MAO-B selectivity (selectivity index SI > 400) were identified. Structure-affinity relationships and docking simulations provided valuable insights into the enzyme-inhibitor binding interactions at position 4, which has been poorly explored. Furthermore, computational and experimental studies led to the identification and biopharmacological characterization of 7-[(3-chlorobenzyl)oxy]-4-[(methylamino)methyl]-2H-chromen-2-one methanesulfonate 22b (NW-1772) as an in vitro and in vivo potent and selective MAO-B inhibitor, with rapid blood-brain barrier penetration, short-acting and reversible inhibitory activity, slight inhibition of selected cytochrome P450s, and low in vitro toxicity. On the basis of this preliminary preclinical profile, inhibitor 22b might be viewed as a promising clinical candidate for the treatment of neurodegenerative diseases.

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“…Indeed, depending on the nature and substitution pattern, they have shown a variety of pharmacological activities such as antithrombotic (including anticoagulant and antiplatelet), anti-inflammatory, antihypertension, anti-arrhythmic, antioxidant, antimicrobial, anti-HIV, and antitumor effects [32] [33]. Over the last decade, coumarin derivatives have been identified as inhibitors of medicinally important enzymes such as aromatase [34] [35], acetylcholinesterase (AChE) [36 ± 38], and MAO [39] [40].…”

mentioning

confidence: 99%

Lipophilicity Plays a Major Role in Modulating the Inhibition of Monoamine Oxidase B by 7‐Substituted Coumarins

Carotti

Altomare

Catto

et al. 2006

Chemistry & Biodiversity

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A series of coumarin derivatives (1-22), bearing at the 7-position ether, ketone, ester, carbamate, or amide functions of varying size and lipophilicity, were synthesized and investigated for their in vitro monoamine oxidase-A and -B (MAO-A and -B) inhibitory activities. Most of the compounds acted preferentially as MAO-B inhibitors, with IC(50) values in the micromolar to low-nanomolar range. A structure-activity-relationship (SAR) study highlighted lipophilicity as an important property modulating the MAO-B inhibition potency of 7-substituted coumarins, as shown by a linear correlation (n=20, r(2)=0.72) between pIC(50) and calculated log P values. The stability of ester-containing coumarin derivatives in rat plasma provided information on factors that either favor (lipophilicity) or decrease (steric hindrance) esterase-catalyzed hydrolysis. Two compounds (14 and 22) were selected to investigate how lipophilicity and enzymatic stability may affect in vivo MAO activities, as assayed ex vivo in rat. The most-potent and -selective MAO-B inhibitor 22 (=7-[(3,4-difluorobenzyl)oxy]-3,4-dimethyl-1-benzopyran-2(2H)-one) within the examined series significantly inhibited (>60%) ex vivo rat-liver and striatal MAO-B activities 1 h after intraperitoneal administration of high doses (100 and 300 mumol kg(-1)), revealing its ability to cross the blood-brain barrier. At the same doses, liver and striatum MAO-A was less inhibited in vivo, somehow reflecting MAO-B selectivity, as assessed in vitro. In contrast, the metabolically less stable derivative 14, bearing an isopropyl ester in the lateral chain, had a weak effect on hepatic MAO-B activity in vivo, and none on striatal MAO-B, but, surprisingly, displayed inhibitory effects on MAO-A in both peripheral and brain tissues.

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Synthesis of coumarins as subtype-selective inhibitors of monoamine oxidase

Cited by 38 publications

References 2 publications

Simple Coumarins and Analogues in Medicinal Chemistry: Occurrence, Synthesis and Biological Activity

Simple Coumarins and Analogues in Medicinal Chemistry: Occurrence, Synthesis and Biological Activity

Lipophilicity Plays a Major Role in Modulating the Inhibition of Monoamine Oxidase B by 7‐Substituted Coumarins

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