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

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

  • Eur J Med Chem. 2020 Jan 1;185:111770. doi: 10.1016/j.ejmech.2019.111770.
Daniel Chavarria 1,  Carlos Fernandes 2,  Vera Silva 3,  Catia Silva 2,  Eva Gil-Martins 3,  Pedro Soares 2,  Tiago Silva 1,  Renata Silva 4,  Fernando Remião 4,  Paulo J Oliveira 5,  Fernanda Borges 6
Affiliations

Affiliations

  • 1 CIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal; CNC - Center for Neuroscience and Cell Biology, University of Coimbra, UC Biotech, Biocant Park, Cantanhede, Portugal.
  • 2 CIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal.
  • 3 CIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal; UCIBIO-REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal.
  • 4 UCIBIO-REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal.
  • 5 CNC - Center for Neuroscience and Cell Biology, University of Coimbra, UC Biotech, Biocant Park, Cantanhede, Portugal.
  • 6 CIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal. Electronic address: fborges@fc.up.pt.
PMID: 31711793 DOI: 10.1016/j.ejmech.2019.111770
Abstract

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.

Keywords

Monoamine oxidase; P-gp; Parkinson's disease; Piperine; Structure-activity-toxicity relationship.

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