Synthesis, α‐Glucosidase Inhibitory Activity, and Molecular Docking Studies of Tri(benzo)‐5‐azacrownophanes with a γ‐Piperidone Moiety

• Published in: ChemistrySelect (Weinheim) 2023-07, Vol.8 (25), p.n/a
• Main Authors: Nhung, Dao T., Tram, Nguyen N., Tam, Pham T. T., Alekseeva, Kseniia A., Khrustalev, Victor N., Hoang, Dang T., Duan, Le. T., Anh, Le. T.
• Format: Article
• Language: English
• Subjects: Antidiabetic drugs; Crown compounds; Glucosidase; Molecular docking; Multicomponent reactions
• ISSN: 2365-6549; 2365-6549
• DOI: 10.1002/slct.202300860

Multicomponent reactions (MCR) are power tools in modern organic synthesis. These reactions have many advantages over single component reactions, including saving time and chemicals. Moreover, compounds with complicated structures can be synthesized based on simple substrates and one‐step reactions, without the tedious work of separating intermediate compounds. Taking full advantage of this tool, over the past 10 years we have synthesized novel crown compounds with the successful introduction of different bioactive moieties into molecules. As part of our ongoing research, this study reports on the synthesis of a new type of crown ether based on a three component reaction of an aldehyde, a ketone, and ammonium acetate in dry solvent, at specific temperature. The structure of the new compounds was identified using physical‐chemical methods of analysis including IR, 1H & 13C NMR, HRMS and single‐X ray diffraction. The effects of the newly synthesized azacrown ethers on the enzyme α‐glucosidase were then explored and they were shown to be potential candidates in the search for new antidiabetic drugs. Among five tested compounds, two compounds are active again the enzyme α‐glucosidase and expressed IC50 values of 407.17±9.01 μM and 345.90±6.75 μM. Molecular docking studies were also performed to investigate the binding mode of the synthetic compounds to α‐glucosidase. Finally, ADMET parameters were assessed to investigate the relationship between structure and biological activities. The new type of crown ethers was well prepared based on three component reaction of dialdehyde, a methylene active ketone and ammonium acetate. Synthesized compounds were fully characterized by IR, NMR, HRMS and single Xray diffraction. In addition, their α‐glucosidase inhibitory activities were firstly evaluated in vitro as well as studied by docking method and showed the potential candidates in the search of new antidiabetic drugs.