In vitro and in silico correlation of benzoxazole-based thiazolidinone hybrids derivatives: A promising acetylcholinesterase and butyrylcholinesterase inhibitors

Abstract

Benzoxazole-based thiazolidinone hybrids derivatives (1–19) were afforded and further subjected to in vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition studies for the first time. All these analogues were found to display good inhibition against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE)enzymes with IC50 values 4.20 ± 1.10 µM to 43.20 ± 4.50 µM (against AChE) and 3.80 ± 1.20 µM to 34.50 ± 3.30 µM (against BuChE) as compared to standard donepezil having IC50 values of 21.86 ± 0.40 µM (against AChE) and 32.47 ± 2.30 µM (against BuChE) respectively. Specifically, compound 16, characterized by a 3,4-dichloro substitution on ring B and 2–OH and 4-CF3 substitutions on ring C, along with compound 13, having 2,4-diCl on ring B and 2-OH and 4-CF3 on ring C, were identified as the most potent inhibitors of the targeted AChE and BuChE enzymes, even manifolds more potent than standard donepezil drug. The structures of all synthesized analogues were verified through the utilization of multiple spectroscopic techniques, including HREI-MS and NMR (1H NMR and 13C NMR). The structure-activity relationship (SAR) demonstrated that analogs bearing electron withdrawing groups such as –CF3, –Cl and -NO2 groups displayed superior AChE and BuChE activities. In the molecular docking analysis of the most potent analogs, a favorable protein-ligand interaction (PLI) profile was observed with the respective targets (AChE and BuChE). These interactions encompassed crucial bonding types such as hydrogen bonding, π-π interactions, π-π stacking, and hydrophobic interactions.