Investigation of Thiazolidine-2,4-Dione Derivatives as Acetylcholinesterase Inhibitors: Synthesis, In Vitro Biological Activities and In Silico Studies

Abstract

The inhibition of acetylcholinesterase (AChE), an enzyme responsible for the inactivation and decrease in acetylcholine in the cholinergic pathway, has been considered an attractive target for small-molecule drug discovery in Alzheimer's disease (AD) therapy. In the present study, a series of TZD derivatives were designed, synthesized, and studied for drug likeness, blood–brain barrier (BBB) permeability, and adsorption, distribution, metabolism, excretion, and toxicity (ADMET). Additionally, docking studies of the designed compounds were performed on AChE. Additionally, all the TZD derivatives (CHT1-5) showed an acceptable affinity for AChE inhibition, and the results showed convincing binding modes in the active site of AChE. Among them, 5-(4-methoxybenzylidene) thiazolidine-2,4-dione (CHT1) was identified as the most potent AChE inhibitor (IC₅₀ of 165.93 nM) with the highest antioxidant activity. Following the exposure of PC12 cells to Aβ1-42 (100 μM), a marked reduction in cell survival was observed. Pretreatment of PC12 cells with TZD derivatives had a neuroprotective effect and significantly enhanced cell survival in response to Aβ-induced toxicity. Western blotting analysis revealed that CHT1 (5 and 8 μM) downregulated p-Tau and HSP70 expression levels. The results indicate that CHT1 is a promising and effective AchE-I that could be utilized as a powerful candidate against AD.