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
  • 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: [email protected].
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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