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

SARI S., YILMAZ M.

MEDICINAL CHEMISTRY RESEARCH, vol.29, no.10, pp.1804-1818, 2020 (SCI-Expanded) identifier identifier

  • Publication Type: Article / Article
  • Volume: 29 Issue: 10
  • Publication Date: 2020
  • Doi Number: 10.1007/s00044-020-02599-0
  • Journal Name: MEDICINAL CHEMISTRY RESEARCH
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, BIOSIS, CAB Abstracts, Chimica, EMBASE, Veterinary Science Database
  • Page Numbers: pp.1804-1818
  • Keywords: Piperazine, Dihydrofuran, Radical cyclization, Acetylcholinesterase inhibition, FLUORINATED 1,3-DICARBONYL COMPOUNDS, CERIUM(IV) AMMONIUM-NITRATE, MANGANESE(III) ACETATE, RADICAL-CYCLIZATION, STEREOSELECTIVE-SYNTHESIS, QUINOLINONE DERIVATIVES, BIOLOGICAL EVALUATION, ALZHEIMERS-DISEASE, 3-OXOPROPANENITRILES, ALKENES
  • Kocaeli University Affiliated: Yes

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 of3a-hwith 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 of3b(1-methacryloylpiperazine) with4aand4bgave bis-dihydrofurans (5band5d) beside mono-dihydrofurans (5aand5c), the reaction of3b-e,3g,3h, and3ewith 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,H-1 NMR,C-13 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. Compounds5c,5d,5e,5i, and5lshow highest inhibitory activities with IC(50)values of 5.79, 3.89, 5.07, 4.30, and 2.24 mu M, respectively. In addition, molecular docking studies were performed on selected structures5d,5i, and5lto investigate ligand-protein interactions. Binding energies were calculated and compared with standart drug donepezil.