Design of novel monoamine oxidase-B inhibitors based on piperine scaffold: Structure-activity-toxicity, drug-likeness and efflux transport studies

Piperine has been associated with neuroprotective effects and monoamine oxidase (MAO) inhibition, thus being an attractive scaffold to develop new antiparkinsonian agents. Accordingly, we prepared a small library of piperine derivatives and screened the inhibitory activities towards human MAO isoforms (hMAO-A and hMAO-B). Structure-activity relationship (SAR) studies pointed out that the combination of α-cyano and benzyl ester groups increased both potency and selectivity towards hMAO-B. Kinetic experiments with compounds 7, 10 and 15 indicated a competitive hMAO-B inhibition mechanism. Compounds 15 and 16, at 10 μM, caused a small but significant decrease in P-gp efflux activity in Caco-2 cells. Compound 15 stands out as the most potent piperine-based hMAO-B inhibitor (IC50 = 47.4 nM), displaying favourable drug-like properties and a broad safety window. Compound 15 is thus a suitable candidate for lead optimization and the development of multitarget-directed ligands. [Display omitted] •A series of piperine derivatives was synthesized, eight of which acted as hMAO-B inhibitors.•α-Cyano and benzyl ester substituents increased both potency and selectivity towards hMAO-B.•Compounds 15 and 16 displayed mild P-gp inhibitory activity in Caco-2 cells.•Compound 15 is highlighted as a potent, selective and competitive hMAO-B inhibitor.•Compound 15 displayed favourable drug-like properties and a safe cytotoxic profile.