2. Academic Validation
  3. Highly selective butyrylcholinesterase inhibitors related to Amaryllidaceae alkaloids - Design, synthesis, and biological evaluation

Highly selective butyrylcholinesterase inhibitors related to Amaryllidaceae alkaloids - Design, synthesis, and biological evaluation

  • Eur J Med Chem. 2023 Apr 5;252:115301. doi: 10.1016/j.ejmech.2023.115301.
Filip Pidany 1,  Jana Kroustkova 1,  Abdullah Al Mamun 1,  Daniela Suchankova 1,  Xavier Brazzolotto 2,  Florian Nachon 2,  Fabien Chantegreil 2,  Rafael Dolezal 3,  Lenka Pulkrabkova 4,  Lubica Muckova 4,  Martina Hrabinova 4,  Vladimir Finger 5,  Martin Kufa 5,  Ondrej Soukup 4,  Daniel Jun 6,  Jaroslav Jenco 1,  Jiri Kunes 7,  Lucie Novakova 8,  Jan Korabecny 9,  Lucie Cahlikova 10
Affiliations

Affiliations

  • 1 Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmacy in Hradec Kralove, Charles University, Akademika Heyrovskeho 1203, 500 05, Hradec Kralove, Czech Republic.
  • 2 Institut de Recherche Biomédicale des Armées, Département de Toxicologie et Risques Chimiques, 1 Place Général Valérie André, 91220, Brétigny-sur-Orge, France.
  • 3 Biomedical Research Center, University Hospital Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic.
  • 4 Biomedical Research Center, University Hospital Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic; Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, Trebesska 1575, 500 01, Hradec Kralove, Czech Republic.
  • 5 Biomedical Research Center, University Hospital Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic; Department of Bioorganic and Organic Chemistry, Faculty of Pharmacy Pharmacy in Hradec Kralove, Charles University, Akademika Heyrovskeho 1203, 500 05, Hradec Kralove, Czech Republic.
  • 6 Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, Trebesska 1575, 500 01, Hradec Kralove, Czech Republic.
  • 7 Department of Bioorganic and Organic Chemistry, Faculty of Pharmacy Pharmacy in Hradec Kralove, Charles University, Akademika Heyrovskeho 1203, 500 05, Hradec Kralove, Czech Republic.
  • 8 Department of Analytical Chemistry, Faculty of Pharmacy in Hradec Kralove, Charles University, Akademika Heyrovskeho 1203, 500 05, Hradec Kralove, Czech Republic.
  • 9 Biomedical Research Center, University Hospital Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic; Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, Trebesska 1575, 500 01, Hradec Kralove, Czech Republic. Electronic address: [email protected].
  • 10 Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmacy in Hradec Kralove, Charles University, Akademika Heyrovskeho 1203, 500 05, Hradec Kralove, Czech Republic. Electronic address: [email protected].
PMID: 36996715 DOI: 10.1016/j.ejmech.2023.115301
Abstract

Butyrylcholinesterase (BChE) is one of the most frequently implicated enzymes in the advanced stage of Alzheimer's disease (AD). As part of our endeavors to develop new drug candidates for AD, we have focused on natural template structures, namely the Amaryllidaceae alkaloids carltonine A and B endowed with high BChE selectivity. Herein, we report the design, synthesis, and in vitro evaluation of 57 novel highly selective human BChE (hBChE) inhibitors. Most synthesized compounds showed hBChE inhibition potency ranging from micromolar to low nanomolar scale. Compounds that revealed BChE inhibition below 100 nM were selected for detailed biological investigation. The CNS-targeted profile of the presented compounds was confirmed theoretically by calculating the BBB score algorithm, these data were corroborated by determining the permeability in vitro using PAMPA-assay for the most active derivatives. The study highlighted compounds 87 (hBChE IC50 = 3.8 ± 0.2 nM) and 88 (hBChE IC50 = 5.7 ± 1.5 nM) as the top-ranked BChE inhibitors. Compounds revealed negligible cytotoxicity for the human neuroblastoma (SH-SY5Y) and hepatocellular carcinoma (HepG2) cell lines compared to BChE inhibitory potential. A crystallographic study was performed to inspect the binding mode of compound 87, revealing essential interactions between 87 and hBChE active site. In addition, multidimensional QSAR analyses were applied to determine the relationship between chemical structures and biological activity in a dataset of designed agents. Compound 87 is a promising lead compound with potential implications for treating the late stages of AD.

Keywords

Alzheimer's disease; Amaryllidaceae alkaloids; Butyrylcholinesterase; Cholinesterase inhibitors; Crystallographic study; QSAR.

Figures
Products