Details

Autor(en) / Beteiligte

• Toumi, Amani
• Boudriga, Sarra
• Hamden, Khaled
• Daoud, Ismail
• Askri, Moheddine
• Soldera, Armand
• Lohier, Jean-Francois
• Strohmann, Carsten
• Brieger, Lukas
• Knorr, Michael

Titel

Diversity-Oriented Synthesis of Spiropyrrolo­[1,2‑a]­isoquinoline Derivatives via Diastereoselective and Regiodivergent Three-Component 1,3-Dipolar Cycloaddition Reactions: In Vitro and in Vivo Evaluation of the Antidiabetic Activity of Rhodanine Analogues

Ist Teil von

• Journal of organic chemistry, 2021-10, Vol.86 (19), p.13420-13445

Ort / Verlag

American Chemical Society

Erscheinungsjahr

2021

Link zum Volltext

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• An efficient diastereoselective route is developed to get access to novel spiropyrrolo­[1,2-a]­isoquinoline-oxindole skeletons by a one-pot three-component [3 + 2] cycloaddition reaction of (Z)-5-arylidene-1,3-thiazolidine-2,4-diones, isatin derivatives, and 1,2,3,4-tetrahydro­isoquinoline (THIQ). Interestingly, the regioselectivity of the reaction is both temperature- and solvent-dependent, allowing the synthesis of two regioisomeric endo-dispiro­pyrrolo­[2,1-a]­isoquinoline­oxindoles in excellent yield. Unprecedentedly, each isomeric dispiro­pyrrolo­[2,1-a]­isoquinoline­oxindole endured retro-1,3-dipolar cycloaddition/recycloaddition reactions under thermal or catalytic conditions to regenerate the corresponding regioisomeric counterpart. In addition, DFT calculations were performed at the M062X/6-31++g­(d,p) level of theory to unravel the origin of the reversal of regioselectivity and endo-stereoselectivity of the title 1,3-dipolar cycloaddition reactions. Upon treatment of Isatin, THIQ with (Z)-4-arylidene-5-thioxo-thiazolidin-2-ones as dipolarophiles, unusual rhodanine analogues were formed, along with smaller amounts of a dispirooxindole-piperazine. The structure and the relative configuration of these N-heterocycles were unambiguously assigned by spectroscopic techniques and confirmed by four single-crystal structures. In vitro and in vivo studies reveal that the novel rhodanine derivatives exert antidiabetic activity. The binding affinity with the active site of the enzyme α-amylase was studied by molecular docking. Furthermore, the bioavailability assessed through virtual ADME parameters (Absorption, Distribution, Metabolism, Elimination pharmacokinetics) and the excellent fit with the Lipinski and Veber rules predict good drug-likeness properties for a bromo-substituted 2-sulfanylidene-1,3-thiazolidin-4-one.