Synthesis and Molecular Docking of New Bis-Thiazolidinone-Based Chalcone Analogs as Effective Inhibitors of Acetylcholinesterase and Butyrylcholinesterase

Abstract

This work reports the convenient strategy for the synthesis of bis-thiazolidinone based chalcone analogs (1-20) from readily available thiosemicarbazide hydrochloride, ammonium thiocyanate and benzaldehyde. All the newly afforded bis-thiazolidinone based chalcone analogs (1-20) were screened in vitro for their acetylcholinesterase and butyrylcholinesterase inhibition profile. It was noteworthy, that all the synthetic analogs (except analogs 10, 12 and 14, which are found to be inactive) showed moderate to good inhibitory potentials on screening against acetylcholinesterase having range of inhibitory with IC₅₀ values from 0.070±0.050 to 7.60±0.10 μM, and similarly for butyrylcholinesterase with range IC₅₀ values from 0.10±0.050 μM to 10.70±0.20 μM, respectively as compared to standard Donepezil inhibitor (IC₅₀ =2.16±0.12 μM), (IC₅₀ =4.5±0.11 μM).Among the series, the analogs with hydroxy group showed superior inhibitory potentials against acetylcholinesterase and butyrylcholinesterase enzymes. Therefore, analog 20 (IC₅₀ =0.070±0.050 μM), (IC₅₀ =0.10±0.050 μM) bearing trihydroxy substitutions on ortho-, meta- and para-position of both rings A and B was found to be the most active inhibitor of acetylcholinesterase and butyrylcholinesterase enzymes among the current synthesized series (1-23). Analog 19 (IC₅₀ =0.15±0.050 μM), (IC₅₀ =0.20±0.050 μM) bearing dihydroxy substitutions on ortho- and meta-position of both ring A and ring B was identified as the second most potent inhibitor against both these enzymes. Interestingly, the compound (16) (IC₅₀ =1.50±0.10 μM against AChE) has a better selectivity index (2.60) than standard Donepezil drug (2.083) for AChE over BuChE. The different types of spectroscopic techniques such as HR-EI-MS, ¹ H- and ¹³ C- NMR were used to confirm the structure of all the newly synthetics analogs. To find structure-activity relationship, molecular docking studies were carried out to understand the binding mode of active inhibitors with active site of enzymes and results supported the experimental data.

Keywords: acetylcholinesterase; bis-thiazolidinone-based; butyrylcholinesterase; chalcone; molecular docking; structure-activity relationship; synthesis.