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

• Tipo: Artigo em Revista Científica Internacional
• Data: 2020

Autores

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

Revista

Título: European Journal of Medicinal Chemistry

Vol. 185

ISSN: 0223-5234

Editora: Elsevier

Indexação

ISI Web of Knowledge - 25 Citações

Scopus - 31 Citações

Outras Informações

ID Authenticus: 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.

Idioma: Inglês

Tipo (Avaliação Docente): Científica

Nº de páginas: 12