Investigation of 2-substituted-5-methylsulfonylbenzoxazole derivatives as potential cholinesterase inhibitors: Synthesis, in vitro, and computational studies

In this study, a new series of 2-substituted-5-methylsulfonylbenzoxazole derivatives (C1-C16) were successfully synthesized. The structures of the compounds were confirmed by FT-IR, ¹H NMR, ¹³C NMR, and mass spectroscopy, and the results for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzyme inhibitory activity were reported as IC₅₀ and Ki values. The compounds' Ki values against AChE ranged from 7.55 ± 2.88 to 87.39 ± 11.67 nM, and their Ki values against BChE ranged from 3.23 ± 0.64 to 107.86 ± 13.38 nM. Accordingly, all compounds except C1, C2, C11, and C12 were found to be more effective than donepezil against AChE, and all compounds except C1, C5, and C12 were found to be more effective than donepezil against BChE. Molecular docking studies were performed for all compounds against the AChE and BChE Enzymes. Conventional hydrogen bonds and π interactions (π-π stacked, π-π T-shaped, π-alkyl, π-sigma, π-cation) were observed in the interactions of the compounds with the target Enzymes. Molecular dynamics (MD) simulation of complexes formed by compounds with the highest inhibition activity on the two Enzymes affirmed formation of stable complexes. Additionally, the molecular electrostatic potential (MEP) map of all compounds and the extent to which the HOMO-LUMO energy gaps affect the reactivity, stability, and inhibitor profiles of these compounds were investigated using density functional theory (DFT) studies, a computational analysis method. The study proves that 2-substituted-5-methylsulfonylbenzoxazole derivatives exhibit potent and selective cholinesterase inhibition.

ADMET; Benzoxazole; Cholinesterase; DFT; MD simulation; Molecular docking.