December 5, 2025Open Access

1-Azinyl-1′-Alkenylferrocenes with Anticholinesterase, Antioxidant, and Antiaggregating Activities as Multifunctional Agents for Potential Treatment of Alzheimer’s Disease

ГМГалина Ф. МахаеваInstitute of Physiologically Active Compounds ЕРЕлена В. РудаковаInstitute of Physiologically Active Compounds NKN. V. KovalevaInstitute of Physiologically Active Compounds

Key Points

Effective cholinesterase inhibition observed with quinoline and bipyridine derivatives, particularly quinoline 7b.
Quinoline 7b demonstrated mixed inhibition with AChE IC50 at 3.32 μM and BChE IC50 at 3.68 μM.
Molecular docking results indicated stable dimer formation and binding to protein surfaces, inhibiting Aβ42 aggregation.
Quinoline derivatives exhibit lower cytotoxicity and significant antioxidant activity, outperforming Trolox in assays.

Abstract

Background/Objectives: This study focused on synthesizing novel alkenyl derivatives of azinylferrocenes and evaluating their potential as Alzheimer’s disease (AD) therapeutics. Methods: 1-Azinyl-1′-acetylferrocenes were obtained by regioselective acetylation of azinylferrocenes, followed by the Wittig reaction or reduction of 1-azinyl-1′-acetylferrocenes and subsequent dehydration of the resulting alcohols. The synthesized compounds underwent the following biological activity testing relevant to AD: inhibition of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and off-target carboxylesterase (CES); antioxidant capacity (ABTS and FRAP assays); inhibition of Aβ42 self-aggregation (thioflavin method); blocking AChE-induced β-amyloid aggregation (propidium displacement); and cytotoxicity in SH-SY5Y and MSC-Neu cells (MTT assay). Results: Quinoline and bipyridine derivatives demonstrated effective cholinesterase inhibition, especially quinoline 7b (AChE IC50 3.32 μM; BChE IC50 3.68 μM), while acridine derivatives were poor inhibitors. Quantum chemical (QC) calculations predicted that acridine derivatives were especially prone to form stable dimers. Molecular docking into protein targets generated by an AlphaFold3 reproduction code showed that these dimers were too bulky to access enzyme active sites, yet they could bind to protein surfaces to inhibit Aβ42 self-aggregation and displace propidium from the AChE peripheral anionic site. All compounds showed high antioxidant activity in ABTS and FRAP assays, with quinoline derivatives being 2–4 times more potent than Trolox. QC calculations supported these findings. Quinoline and bipyridine derivatives also exhibited low cytotoxicity and scant CES inhibition. Conclusions: Overall, the synthesized ferrocenes, particularly the quinoline and bipyridine derivatives, appear promising for further research as multifunctional therapeutic agents targeting AD due to their anticholinesterase, antiaggregating, and antioxidant activities combined with low toxicity.

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