Development of piperic acid-based monoamine oxidase inhibitors: Synthesis, structural characterization and biological evaluation

Abstract

A series of piperic acid esters and amides were synthesized using a two-step strategy. Mass spectrometry and unidimensional (1H NMR, 13C NMR, DEPT) and bidimensional (COSY, HSQC, HMBC) NMR methodologies were used to study the molecular structure of the final compounds, resulting in the assignment of all detected signals.Preliminary biological data of piperine and the derivatives thereof showed that piperic acid 2 and amides 3 and 4 did not display significant inhibitory activity at 10 μM against both hMAO-A and hMAO-B. In contrast, the esters 5 and 6 displayed relevant hMAO inhibitory activities, with IC50 values for hMAO-B lower than piperine and within the nanomolar range (compound 1: IC50 = 1.05 μM; compound 6: IC50 = 169 nM; compound 5: IC50 = 156 nM). Moreover, X-ray crystallographic analyses showed relevant differences between amides 3 and 4 and esters 5 and 6 constituting a valuable information to understand the ligand-target interactions.Additional studies are warranted for a systematic lead optimization process that can lead in the future to a more potent and selective hMAO-B inhibitor based on piperine scaffold.