Synthesis, Molecular Docking and Molecular Dynamic Studies of Thiazolidineones as Acetylcholinesterase and Butyrylcholinesterase Inhibitors

Abstract

Neurodegenerative diseases are chronic, progressive, age-related, and characterized by the loss of function of neurons caused by the accumulation of free radicals and oxidative stress. Although the prevalence of neuro disorders is rising, therapeutic efficacy is still limited due to various variables, including the blood-brain barrier. Hence, to identify molecules targeting different enzymes like acetylcholinesterase, butyrylcholinesterase and peroxiredoxins, a series of thiazolidineone derivatives were designed and synthesized. Schiff base was synthesized and cyclised with thioglycolic acid to yield thiazolidineones (T1-T10). Structural characterization was performed by IR, Mass and 1H NMR spectral studies and then subjected to in silico analysis against acetylcholinesterase (6O4W) and butyrylcholinesterase (1P0P). Compound T-9 (–10.10 kcal/mol) and T-8 (–7.65 kcal/mol) have shown excellent binding with 6O4W and 1P0P, respectively, compared with other derivatives. In addition, the compounds were checked for antioxidant activity by analyzing the interactions with peroxiredoxins (1URM), and compound T-4 was active. According to the physicochemical and ADME properties of Qikprop, synthesized compounds can be considered druglike molecules. In vitro, acetylcholinesterase inhibitory activity reveals compound T-8 as the most potent AChE inhibitor. In vitro, antioxidant activity found that compound T-4 has significant antioxidant activity. The compound T-8, with better docking scores and decisive acetylcholinesterase inhibitory action, was further explored to validate the molecular interactions through molecular dynamics studies. It was observed that compounds with the benzyl sulfonyl group (T-6 to T-10) showed higher AChE inhibitory potency than derivatives with phenyl substituents in place of the benzyl sulfonyl group (T-1 to T-5). Therefore, it is inferred that the sulfonyl group and substituents at the para position are essential for the higher inhibitory activity of compounds. Thus, there is plenty of scope for further study in developing these as promising lead compounds.