Synthesis, characterization, acetylcholinesterase inhibition, and molecular docking studies of new piperazine substituted dihydrofuran compounds

Abstract

Novel unsaturated piperazine and homopiperazine derivatives (3a–h) were synthesized in medium to good yields by acylation reactions of piperazine and homopiperazine with methacrylic anhydride (2a) and benzoyl chloride (2b). Piperazine containing dihydrofuran compounds (5a–l) were obtained from radical addition and cyclizations of 3a–h with 1,3-dicarbonyl compounds such as dimedone (4a), ethyl acetoacetate (4b) and acetylacetone (4c) mediated by Mn(OAc)3 for the first time. While the reaction of 3b (1-methacryloylpiperazine) with 4a and 4b gave bis-dihydrofurans (5b and 5d) beside mono-dihydrofurans (5a and 5c), the reaction of 3b–e, 3g, 3h, and 3e with 1,3-dicarbonyl compounds gave mono dihydrofuran compounds (5f–l) in medium to high yields. Structures of all novel compounds were determined by melting point analysis, 1H NMR, 13C NMR, HRMS, and FTIR methods. All piperazine containing dihydrofuran compounds were evaluated for their inhibitory activities toward acetylcholinesterase (AChE) by Ellman method and IC50 values were presented. Compounds 5c, 5d, 5e, 5i, and 5l show highest inhibitory activities with IC50 values of 5.79, 3.89, 5.07, 4.30, and 2.24 µM, respectively. In addition, molecular docking studies were performed on selected structures 5d, 5i, and 5l to investigate ligand–protein interactions. Binding energies were calculated and compared with standart drug donepezil.