Discovery of novel berberine derivatives with balanced cholinesterase and prolyl oligopeptidase inhibition profile
Language English Country France Media print-electronic
Document type Journal Article
PubMed
32688201
DOI
10.1016/j.ejmech.2020.112593
PII: S0223-5234(20)30565-1
Knihovny.cz E-resources
- Keywords
- Acetylcholinesterase, Alzheimer’s disease, Amyloid beta, Butyrylcholinesterase, In silico, Multi-target directed ligands, Prolyl oligopeptidase, Quantitative structure-activity relationship, Tau protein,
- MeSH
- Berberine chemistry metabolism pharmacology MeSH
- Cholinesterase Inhibitors chemistry metabolism pharmacology MeSH
- Cholinesterases metabolism MeSH
- Blood-Brain Barrier metabolism MeSH
- Humans MeSH
- Cell Line, Tumor MeSH
- Prolyl Oligopeptidases antagonists & inhibitors MeSH
- Drug Design * MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Berberine MeSH
- Cholinesterase Inhibitors MeSH
- Cholinesterases MeSH
- Prolyl Oligopeptidases MeSH
Berberine, a naturally occurring compound, possesses an interesting multipotent pharmacological profile potentially applicable for Alzheimer's disease (AD) treatment. In this study, a series of novel 22 berberine derivatives was developed and tested in vitro. Berberine core was substituted at position 9-O of its aromatic ring region. All the hybrids under the study revealed multi-targeted profile inhibiting prolyl oligopeptidase, acetylcholinesterase and butyrylcholinesterase highlighting 4a, 4g, 4j, 4l and 4s possessing balanced activities in the micromolar range. The top-ranked candidates in terms of the most pronounced potency against POP, AChE and BChE can be classified as 4d, 4u and 4v, bearing 4-methylbenzyl, (naphthalen-2-yl)methylene and 1-phenoxyethyl moieties, respectively. In vitro data were corroborated by detailed kinetic analysis of the selected lead molecules. 4d, 4u and 4v were also inspected for their potential to inhibit aggregation of two abberant proteins in AD, namely amyloid beta and tau, indicating their potential disease-modifying properties. To explain the results of our study, we carried out docking simulation to the active sites of the respective enzyme with the best berberine derivatives, along with QSAR study. We also investigated compounds' potential permeability through blood-brain barrier by applying parallel artificial membrane permeation assay and addressed their cytotoxicity profile.
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