Synthesis of Tacrine/Amiridine Conjugates with Aminomethylidene Derivatives of Trifluoroacetoacetic Ester and their Biological Potential for the Therapy of Alzheimer's Disease.

Abstract

To assess the influence of the nature of the anticholinesterase pharmacophore on the properties of potential multitarget Alzheimer's disease (AD) agents, new conjugates of tacrine (3a, b) and amiridine (5a, b) with ethyl-2-aminomethylidene-4,4,4-trifluoro-3-oxobutanoate linked by an alkylene spacer with n = 4,6 were synthesized. All conjugates are effective cholinesterase inhibitors with predominant inhibition of butyrylcholinesterase (BChE). The inhibitory activity of tacrine conjugates 3a, b toward acetylcholinesterase (AChE) and BChE increases with spacer elongation: IC₅₀ AChE up to 0.185 µM, IC₅₀ BChE up to 0.0806 µM. Amiridine conjugates 5a, b are less active as AChE inhibitors and their anti-AChE activity (IC₅₀ up to 3.09 µM) remains virtually unchanged with spacer elongation, while anti-BChE activity increases significantly (n = 6, IC₅₀ = 0.063 µM), which leads to increased selectivity toward BChE (up to 56). The effects are consistent with the results of kinetic studies and molecular docking of 3b and 5b. Both types of conjugates displace propidium from the AChE peripheral anionic site at the level of and above that of donepezil, and are capable of blocking self-aggregation of β-amyloid (up to 49.5%). The compounds demonstrate very weak antioxidant activity (tacrine conjugates) or its absence (amiridine). Thus, new conjugates are potential multitarget anti-AD agents with high selectivity toward BChE for amiridine derivative 5b.