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

Abstract

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.

Recent Progress on Biological Activity of Amaryllidaceae and Further Isoquinoline Alkaloids in Connection with Alzheimer’s Disease

“…The structure of the best AChE/BuChE inhibitor within this study ( 1 ) is displayed in Figure 3 , together with belladine-type AAs. The latest study published by Al Mamun et al [ 80 ] reported synthesis of compounds with the same fundamental unit, but the developed compounds possessed different substitution patterns within the A-ring ( Figure 3 ). Seven compounds of the twenty synthesized possessed a strong and selective h BuChE inhibition profile, with IC 50 values below 1 μM [ 80 ].…”

“…The latest study published by Al Mamun et al [ 80 ] reported synthesis of compounds with the same fundamental unit, but the developed compounds possessed different substitution patterns within the A-ring ( Figure 3 ). Seven compounds of the twenty synthesized possessed a strong and selective h BuChE inhibition profile, with IC 50 values below 1 μM [ 80 ]. The most potent one showed nanomolar range activity with an IC 50 value of 72 nM and an excellent selectivity pattern over AChE, reaching almost 1400 ( Figure 3 ).…”

“…The prediction of CNS availability estimates that all synthesized compounds within the survey can pass through the blood–brain barrier (BBB), as disclosed by the BBB score. These synthetic compounds, inspired by the norbelladine structural type of AAs, display an interesting structure scaffold for further development of selective h BuChE inhibitors [ 80 ].…”

“…The prediction of CNS availability estimates that all synthesized compounds within the survey can pass through the blood-brain barrier (BBB), as disclosed by the BBB score. These synthetic compounds, inspired by the norbelladine structural type of AAs, display an interesting structure scaffold for further development of selective hBuChE inhibitors [80]. A phytochemical study of bulbs of Lycoris longituba yielded thirteen AAs that have been screened for their neuroprotective, and electric eel AChE (EeAChE) inhibition activity [70].…”

Chemical Synthesis and Biological Activities of Amaryllidaceae Alkaloid Norbelladine Derivatives and Precursors

“…One study demonstrated that norbelladine itself has slight in vitro anti-inflammatory and anti-oxidant properties [ 25 ]. In another study, synthetically designed complex alkaloid derivatives of carltonin A and B of the norbelladine-type were shown to exhibit anti-butyrylcholinesterase (BuChE) and -prolyl oligopeptidase (POP) properties, both of which are considered interesting targets for AD [ 26 , 27 , 28 ]. However, the pharmaceutical properties of norbelladine-type alkaloids in relation to AD, viral infections, and cytotoxicity remain largely unknown.…”