Design and synthesis of thiophenone and furanthione butenolide bioisosteres with inhibitory activity towards acetylcholinesterase

• A library of butenolide bioisosteres was synthetized. • Synthetic strategies were based on bioisosteric exchange of oxygen for Sulfur. • Nucleophilic alkylation resulted in differential binding with acetylcholinesterase. • A new C5 disubstituted furan-2(5H)-thione was identified as a promising inhibitor. • Toxicity, dynamics and quantum states were determined. A library of butenolide bioisosteres with sulfur incorporated in the molecule was synthetized and used for the structure-activity relationship studies associated with their inhibitory activity towards the AChE enzyme. Modifications through bioisosteric exchange of oxygen for sulfur either in position one of the butenolide ring (thiophenones) or on C2 (furanthiones) and further modification of the backbone via nucleophilic alkylation resulted in differential binding with the AChE enzyme. In general, the furanthiones were more efficient at binding AChE while some of the thiophenones were predicted to be toxic. Compound 11a , a C5 disubstituted furan-2(5H)-thione containing both the methyl and the isopropyl groups at C5 displayed the most encouraging inhibitory activity towards AChE. Molecular dynamics simulations in terms of the RMSD and RMSF trajectories and intermolecular bond analysis revealed considerable stability of the complex. Reactivity of 11a was further validated by quantum chemical calculations using DFT.