Amaryllidaceae Alkaloids of Norbelladine-Type as Inspiration for Development of Highly Selective Butyrylcholinesterase Inhibitors: Synthesis, Biological Activity Evaluation, and Docking Studies

• Published in: International journal of molecular sciences 2021-08, Vol.22 (15), p.8308
• Main Authors: Mamun, Abdullah Al, Pidaný, Filip, Hulcová, Daniela, Maříková, Jana, Kučera, Tomáš, Schmidt, Monika, Catapano, Maria Carmen, Hrabinová, Martina, Jun, Daniel, Múčková, Lubica, Kuneš, Jiří, Janoušek, Jiří, Andrýs, Rudolf, Nováková, Lucie, Peřinová, Rozálie, Maafi, Negar, Soukup, Ondřej, Korábečný, Jan, Cahlíková, Lucie
• Format: Article
• Language: English
• Subjects: Acetylcholinesterase; Alkaloids; Alzheimer's disease; Amaryllidaceae; amaryllidaceae alkaloid; Binding sites; Biological activity; Blood-brain barrier; butyrylcholinesterase; Central nervous system; Cholinesterase; Cholinesterase inhibitors; Design; docking studies; Enzymes; Glutamic acid receptors; Inhibitors; Memantine; N-Methyl-D-aspartic acid receptors; norbelladine-type; Selectivity
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22158308

Alzheimer’s disease (AD) is a multifactorial neurodegenerative condition of the central nervous system (CNS) that is currently treated by cholinesterase inhibitors and the N-methyl-d-aspartate receptor antagonist, memantine. Emerging evidence strongly supports the relevance of targeting butyrylcholinesterase (BuChE) in the more advanced stages of AD. Within this study, we have generated a pilot series of compounds (1–20) structurally inspired from belladine-type Amaryllidaceae alkaloids, namely carltonine A and B, and evaluated their acetylcholinesterase (AChE) and BuChE inhibition properties. Some of the compounds exhibited intriguing inhibition activity for human BuChE (hBuChE), with a preference for BuChE over AChE. Seven compounds were found to possess a hBuChE inhibition profile, with IC50 values below 1 µM. The most potent one, compound 6, showed nanomolar range activity with an IC50 value of 72 nM and an excellent selectivity pattern over AChE, reaching a selectivity index of almost 1400. Compound 6 was further studied by enzyme kinetics, along with in-silico techniques, to reveal the mode of inhibition. The prediction of CNS availability estimates that all the compounds in this survey can pass through the blood-brain barrier (BBB), as disclosed by the BBB score.