Vitamin B3-Based Biologically Active Compounds as Inhibitors of Human Cholinesterases.

Antonio Zandona,Dajana Gašo-Sokač,Katarina Miš,Valentina Bušić,Gabriela Lihtar,Maja Katalinić,Nikola Maraković,Sergej Pirkmajer

doi:10.3390/ijms21218088

Abstract

We evaluated the potential of nine vitamin B3 scaffold-based derivatives as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors, as a starting point for the development of novel drugs for treating disorders with cholinergic neurotransmission-linked pathology. As the results indicate, all compounds reversibly inhibited both enzymes in the micromolar range pointing to the preference of AChE over BChE for binding the tested derivatives. Molecular docking studies revealed the importance of interactions with AChE active site residues Tyr337 and Tyr124, which dictated most of the observed differences. The most potent inhibitor of both enzymes with Ki of 4 μM for AChE and 8 μM for BChE was the nicotinamide derivative 1-(4′-phenylphenacyl)-3-carbamoylpyridinium bromide. Such a result places it within the range of several currently studied novel cholinesterase inhibitors. Cytotoxicity profiling did not classify this compound as highly toxic, but the induced effects on cells should not be neglected in any future detailed studies and when considering this scaffold for drug development.

Highlights

The therapeutic approach for treating various neurodegenerative disorders and disorders with cholinergic neurotransmission-linked pathology is currently focused mostly on alleviating their symptoms and progression
Our study included the evaluation of a series of vitamin B3-based, nicotinamide derivatives, with the aim to characterise their inhibition potency towards cholinesterases and the overall therapeutic potential to be considered as a new scaffold for novel drug development
It has been shown that the maintaining the right AChE/BChE activity ratio could be of additional help in treatment of ChE-linked neurodegenerative disorders [54]

Summary

Introduction

The therapeutic approach for treating various neurodegenerative disorders and disorders with cholinergic neurotransmission-linked pathology is currently focused mostly on alleviating their symptoms and progression. Considering that there is no adequate treatment or drug that would act on the cause of the AD, the inhibition of human cholinesterases (acetylcholinesterase, AChE, EC 3.1.1.7; and butyrylcholinesterase, BChE, EC 3.1.1.8) emerged as an important therapeutic regime [3,4,5,6,7,8]. This is important especially since a diminished level of ACh in the brain is one of the characteristics of AD, so drugs designed as AChE inhibitors prevent ACh from fast degradation and enable longer-lasting neuro signals [9,10]. The use of nonselective cholinesterase inhibitors may be beneficial to AD patients as well [15,16]

Methods

Findings

Discussion

Conclusion