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

Abstract

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.

Structural Insights into Monoamine Oxidase Inhibitory Potency and Selectivity of 7-Substituted Coumarins from Ligand- and Target-Based Approaches

“…In conclusion, the present study confirmed and reinforced the validity of the interaction models proposed by our group on MAO-B inhibitors 19,20 and deepened our understanding of the structural requirements for high MAO affinity and selectivity. The easy synthetic accessibility and potentially low toxicity of coumarins make them "privileged scaffolds" for preparing new inhibitors with improved in vitro affinity.…”

“…On the basis of previous 19,20 and herein reported results, the major structural determinants of rMAO affinity and B/A selectivity were established for this biologically important and easily accessible class of natural compounds. 41 We demonstrated that rMAO affinity and selectivity can be efficiently modulated by appropriate modifications of length, size, and chemical nature of the substituents at position 7 and by introducing methyl groups in positions 3 and 4.…”

“…Our previous investigations 19, 20 Table 1), other previously reported 7-substituted coumarins, with no, one, or two methyl groups in position 3 or 4 were considered for a more complete analysis.…”

Evaluation of multifunctional synthetic tetralone derivatives for treatment of Alzheimer's disease

“…The MAO‐B inhibitory activities of this series of tetralone derivatives can help to analyze the structure–activity relationship. The hydroxyl group introduction at R 5 position of tetralone ring system resulted in a decrease in efficacy against MAO‐B isoforms, whereas some substitutions including Br/Cl and OCH 3 on various positions of main backbone, marginally enhanced the MAO‐B inhibitory activity in some compounds in comparison with the unsubstituted homolog and this finding is also supported by previous reports . The MAO‐B activity can increase up to threefold in frontal, parietal, and temporal cortex of AD patients in comparison with healthy individuals, resulting in higher levels of oxidative free radicals and H 2 O 2 , which are known to be involved in the development of oxidative stress .…”

8‐Substituted 3‐Arylcoumarins as Potent and Selective MAO‐B Inhibitors: Synthesis, Pharmacological Evaluation, and Docking Studies

“…This is related to the recent discovery that the increase in MAO-B activity is associated with gliosis, which can result in high levels of hydrogen peroxide and oxidative free radicals. [29] Substitution patterns at the 3-and 7-positions have been thoroughly studied. The increment of dopamine metabolism, as well as the described oxidative stress, may play a role in the etiology of ND.…”