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

• Type: Article in International Scientific Journal
• Date: 2020

Authors

Chavarria, D (Author) Other; Fernandes, C (Author) Other; Silva, V (Author) Other; Silva, C (Author) Other; Gil Martins, E (Author) Other; Soares, P (Author) FCUP; Silva, T (Author) Other; Silva, R (Author) Other; Fernando Remiao (Author) FFUP; Oliveira, PJ (Author) Other; Fernanda Borges (Author) FCUP

Journal

Title: European Journal of Medicinal Chemistry

Vol. 185

ISSN: 0223-5234

Publisher: Elsevier

Indexing

ISI Web of Knowledge - 25 Citations

Scopus - 31 Citations

Other information

Authenticus ID: P-00R-DFD

DOI: 10.1016/j.ejmech.2019.111770

Abstract (EN): 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 alpha-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 mu M, 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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 12