Structure Report for: 8CGO

Filip Pidany, Jana Kroustkova, Abdullah Al Mamun, Daniela Suchankova, Xavier Brazzolotto, Florian Nachon, Fabien Chantegreil, Rafael Dolezal, Lenka Pulkrabkova, Lubica Muckova, Martina Hrabinova, Vladimir Finger, Martin Kufa, Ondrej Soukup, Daniel Jun, Jaroslav Jenco, Jiri Kunes, Lucie Novakova, Jan Korabecny, Lucie Cahlikova

Title: Highly selective butyrylcholinesterase inhibitors related to Amaryllidaceae alkaloids - Design, synthesis, and biological evaluation
Pidany F, Kroustkova J, Al Mamun A, Suchankova D, Brazzolotto X, Nachon F, Chantegreil F, Dolezal R, Pulkrabkova L and Cahlikova L <10 more author(s)> Pidany F, Kroustkova J, Al Mamun A, Suchankova D, Brazzolotto X, Nachon F, Chantegreil F, Dolezal R, Pulkrabkova L, Muckova L, Hrabinova M, Finger V, Kufa M, Soukup O, Jun D, Jenco J, Kunes J, Novakova L, Korabecny J, Cahlikova L (- 10)
Ref: Eur Journal of Medicinal Chemistry, 252:115301, 2023 : PubMed
Abstract


ESTHER: Pidany_2023_Eur.J.Med.Chem_252_115301
PubMedSearch: Pidany 2023 Eur.J.Med.Chem 252 115301
PubMedID: 36996715
Gene_locus related to this paper: human-BCHE
Inhibitor(s) related to this paper: Compound87

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 IC(50) = 3.8 +/- 0.2 nM) and 88 (hBChE IC(50) = 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.