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 (2021)

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Data collector : Stéphanie Boullanger [7] [8], Albert Marcual [9]
[1] : Département de Chimie, Faculté des Sciences de Monastir
[2] : Bioressources : Biologie Intégrative & Valorisation «BIOLIVAL » - Institut Supérieur de Biotechnologie de Monastir - LR14ES06
[3] : Université de Biskra - Mohamed Khider
[4] : Départment de Chimie - Université de Sherbrooke
[5] : Laboratoire de Chimie Moléculaire et Thio-organique - UMR6507
[6] : Technische Universität Dortmund
[7] : Institut UTINAM (UMR 6213) (Université de Franche-Comté)
[8] : Observatoire des Sciences de l'Univers - Terre, Homme, Environnement, Temps, Astronomie (UAR 3245) (Université de Franche-Comté)
[9] : Laboratoire COBRA - Chimie Organique et Bioorganique : Réactivité et Analyse - UMR6014
Description :
An efficient diastereoselective route is developed to get access to novel spiropyrrolo[1,2-a]isoquinoline-oxindole skeletons by a one-potthree-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.
Disciplines :

General metadata

Data acquisition date : from 2018 to 2021
Data acquisition methods :
Language : English (eng)
Formats : application/pdf, chemical/x-cif
Audience : University: master, Research
Publications :
  • 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 (doi:10.1021/acs.joc.1c01544)
Project and funders :
Record created 30 Sep 2021 by Michael Knorr.
Local identifier: FR-18008901306731-2021-09-30-03.

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Université de Bourgogne, Université de Franche-Comté, UTBM, AgroSup Dijon, ENSMM, BSB, Arts des Metiers