Barbiturate–sulfonate hybrids as potent cholinesterase inhibitors: design, synthesis and molecular modeling studies

Aim: Design and synthesis of a series of 5-benzylidene(thio)barbiturates 3a–r. Methodology: Evaluation of the inhibitory activity of the new chemical entities on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) using Donepezil as the standard reference. Results & Conclusion: Compound 3r emerged as the most potent AChE inhibitor (IC₅₀ = 9.12 μM), while compound 3q exhibited the highest inhibitory activity against BChE (IC₅₀ = 19.43 μM). Toxicological bioassays confirmed the absence of cytotoxicity for the most potent compounds at the tested doses. Molecular docking analysis demonstrated that the tested derivatives effectively bind to the active sites of both enzymes. Overall, this study sheds light on the potential of barbiturate–sulfonate conjugates as promising drug candidates.