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

AbstractA 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 theirin vitromonoamine oxidase‐A and ‐B (MAO‐A and ‐B) inhibitory activities. Most of the compounds acted preferentially as MAO‐B inhibitors, withIC50values 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,r2=0.72) between pIC50and calculated logPvalues. 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 (14and22) were selected to investigate how lipophilicity and enzymatic stability may affectin vivoMAO activities, as assayedex vivoin rat. The most‐potent and ‐selective MAO‐B inhibitor22(=7‐[(3,4‐difluorobenzyl)oxy]‐3,4‐dimethyl‐1‐benzopyran‐2(2H)‐one) within the examined series significantly inhibited (>60%)ex vivorat‐liver and striatal MAO‐B activities 1 h after intraperitoneal administration of high doses (100 and 300 μmol kg−1), revealing its ability to cross the blood–brain barrier. At the same doses, liver and striatum MAO‐A was less inhibitedin vivo, somehow reflecting MAO‐B selectivity, as assessedin vitro.In contrast, the metabolically less stable derivative14, bearing an isopropyl ester in the lateral chain, had a weak effect on hepatic MAO‐B activityin vivo, and none on striatal MAO‐B, but, surprisingly, displayed inhibitory effects on MAO‐A in both peripheral and brain tissues.