Synthesis and Molecular Modeling Studies on Novel C2 Alkylated Benzoazonine Scaffold and Corresponding 2-Pyrazoline Derivatives as Acetylcholinestrase Enzyme Inhibitors

Abstract

A rapid and efficient methodology was performed for the synthesis of α,β-unsaturated ketones 2a–k containing benzoazonine core through Claisen-Schmidt reaction of the benzoazonine-2,7-dione 1 and various aldehydes in acidic medium. The obtained exocyclic α,β-unsaturated ketones were subjected to an irradiating microwave gave unexpected asymmetric spiro pyran compound 3 via a self-Diels–Alder reaction. The initially formed exocyclic α,β-unsaturated ketones underwent cyclocondesation with phenylhydrazine to afford 2-pyrazoline derivatives 4. The structure of the synthesized scaffolds was characterized using ¹H-NMR, APT and 2DNMR spectra. A molecular modeling study using Molecular Operating Environment was performed to investigate their binding modes to the Acetylcholinestrase enzyme active site. Docking results demonstrated that the newly synthesized compounds recognized the active sites of Acetylcholinestrase and form different types of bonding interactions with key active site amino acid residues.

Graphical Abstract

Keywords:

• Acetylcholinestrase
• benzoazonine
• modeling
• α,β-unsaturated ketones
• 2-pyrazoline

Acknowledgment

Mohamed Hammouda wants to acknowledge Ghent University, Dr. Jurgen Caroen, Jan L. Goeman, Prof. Elsayed M. Afsah.

Additional information

Funding

Funding was provided by Erasmus mundus (Welcome project) and Egyptian Ministry of Higher Education.