2. Academic Validation
  3. Discovery of novel berberine derivatives with balanced cholinesterase and prolyl oligopeptidase inhibition profile

Discovery of novel berberine derivatives with balanced cholinesterase and prolyl oligopeptidase inhibition profile

  • Eur J Med Chem. 2020 Oct 1:203:112593. doi: 10.1016/j.ejmech.2020.112593.
Katerina Sobolova 1,  Martina Hrabinova 2,  Vendula Hepnarova 1,  Tomas Kucera 1,  Tereza Kobrlova 2,  Marketa Benkova 3,  Jana Janockova 3,  Rafael Dolezal 4,  Lukas Prchal 3,  Ondrej Benek 3,  Eva Mezeiova 3,  Daniel Jun 2,  Ondrej Soukup 5,  Jan Korabecny 6
Affiliations

Affiliations

  • 1 Department of Toxicology and Military Pharmacy, Department of Military Medical Service Organisation and Management, Faculty of Military Health Sciences, University of Defense, Trebesska 1575, 500 05, Hradec Kralove, Czech Republic.
  • 2 Department of Toxicology and Military Pharmacy, Department of Military Medical Service Organisation and Management, Faculty of Military Health Sciences, University of Defense, Trebesska 1575, 500 05, Hradec Kralove, Czech Republic; Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic.
  • 3 Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic.
  • 4 Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic; Department of Chemistry, Faculty of Science, University of Hradec Kralove, Rokitanskeho 62, 500 03, Hradec Kralove, Czech Republic.
  • 5 Department of Toxicology and Military Pharmacy, Department of Military Medical Service Organisation and Management, Faculty of Military Health Sciences, University of Defense, Trebesska 1575, 500 05, Hradec Kralove, Czech Republic; Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic. Electronic address: ondrej.soukup@fnhk.cz.
  • 6 Department of Toxicology and Military Pharmacy, Department of Military Medical Service Organisation and Management, Faculty of Military Health Sciences, University of Defense, Trebesska 1575, 500 05, Hradec Kralove, Czech Republic; Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic. Electronic address: jan.korabecny@fnhk.cz.
PMID: 32688201 DOI: 10.1016/j.ejmech.2020.112593
Abstract

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.

Keywords

Acetylcholinesterase; Alzheimer’s disease; Amyloid beta; Butyrylcholinesterase; In silico; Multi-target directed ligands; Prolyl oligopeptidase; Quantitative structure-activity relationship; Tau protein.

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