Three-Component Access to Functionalized Spiropyrrolidine Heterocyclic Scaffolds and Their Cholinesterase Inhibitory Activity

Sarra Boudriga (1) , Saoussen Haddad (1) , Vikneswaran Murugaiyah (2) , Moheddine Askri (1) , Michael Knorr (3) , Carsten Strohmann (4) , Christopher Golz (4)

1 CHPNR - Laboratoire de Chimie Hétérocyclique, Produits Naturels et Réactivité [Monastir]
2 USM - Universiti Sains Malaysia
3 UTINAM - Univers, Transport, Interfaces, Nanostructures, Atmosphère et environnement, Molécules (UMR 6213)
4 TU - Technische Universität Dortmund [Dortmund]

A novel one-pot [3+2]-cycloaddition reaction of (E)-3-arylidene-1-phenyl-succinimides, cyclic 1,2-diketones (isatin, 5-chloro-isatin and acenaphtenequinone), and diverse α-aminoacids such as 2-phenylglycine or sarcosine is reported. The reaction provides succinimide-substituted dispiropyrrolidine derivatives with high regio-and diastereoselectivities under mild reaction conditions. The stereochemistry of these N-heterocycles has been confirmed by four X-ray diffraction studies. Several synthetized compounds show higher inhibition on acetylcholinesterase (AChE) than butyrylcholinesterase (BChE). Of the 17 synthesized compounds tested, five exhibit good AChE inhibition with IC 50 of 11.42 to 22.21 µM. A molecular docking study has also been undertaken for compound 4n possessing the most potent AChE inhibitory activity, disclosing its binding to the peripheral anionic site of AChE enzymes.

Mots clés: [3+2]-cycloaddition reaction; azomethine ylides; succinimide; dispiropyrrolidine derivatives

Domaines: Chimie organique; Chimie thérapeutique

Sarra Boudriga, Saoussen Haddad, Vikneswaran Murugaiyah, Moheddine Askri, Michael Knorr, et al.. Three-Component Access to Functionalized Spiropyrrolidine Heterocyclic Scaffolds and Their Cholinesterase Inhibitory Activity. Molecules, 2020, 25 (8), pp.1963. ⟨10.3390/molecules25081963⟩. ⟨hal-02552728⟩