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

• Published in: Medicinal chemistry research Vol. 29; no. 10; pp. 1804 - 1818
• Main Authors: Sari, Sait, Yilmaz, Mehmet
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.10.2020; Springer Nature B.V
• Subjects: Acetylacetone; Acetylcholinesterase; Acylation; Biochemistry; Biomedical and Life Sciences; Biomedicine; Bioorganic Chemistry; Carbonyl compounds; Chemical synthesis; Donepezil; Inorganic Chemistry; Medicinal Chemistry; Melting points; Molecular docking; NMR; Nuclear magnetic resonance; Original Research; Pharmacology/Toxicology; Piperazine; Protein interaction; Dihydrofuran; Radical cyclization; Acetylcholinesterase inhibition; Piperazine
• ISSN: 1054-2523; 1554-8120
• DOI: 10.1007/s00044-020-02599-0

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, 1 H NMR, 13 C NMR, HRMS, and FTIR methods. All piperazine containing dihydrofuran compounds were evaluated for their inhibitory activities toward acetylcholinesterase (AChE) by Ellman method and IC 50 values were presented. Compounds 5c , 5d , 5e , 5i , and 5l show highest inhibitory activities with IC 50 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.