Synthesis, antidiabetic activity and molecular docking study of rhodanine-substitued spirooxindole pyrrolidine derivatives as novel α-amylase inhibitors (2020)

[1] : Département de Chimie, Faculté des Sciences de Monastir
[2] : Bioressources : Biologie Intégrative & Valorisation «BIOLIVAL » - Institut Supérieur de Biotechnologie de Monastir - LR14ES06
[3] : Mohammed VI Polytechnic University
[4] : Institut UTINAM (UMR 6213) (Université de Franche-Comté)
[5] : Observatoire des Sciences de l'Univers - Terre, Homme, Environnement, Temps, Astronomie (UAR 3245) (Université de Franche-Comté)
[6] : Technische Universität Dortmund
Description :
In a sustained search for novel α-amylase inhibitors for the treatment of type 2 diabetes mellitus (T2DM), we report herein the synthesis of a series of nineteen novel rhodanine-fused spiro[pyrrolidine-2,3′-oxindoles]. They were obtained by one-pot three component [3 + 2] cycloaddition of stabilized azomethine ylides, generated in situ by condensation of glycine methyl ester and the cyclic ketones 1H-indole-2,3-dione (isatin), with (Z)-5-arylidine-2-thioxothiazolidin-4-ones. The highlight of this protocol is the efficient high-yield construction of structurally diverse rhodanine-fused spiro[pyrrolidine-2,3′-oxindoles] scaffolds, including four contiguous stereocenters, along with excellent regio- and diastereoselectivities. The stereochemistry of all compounds was confirmed by NMR and corroborated by an X-ray diffraction study performed on one derivative. All cycloadducts were evaluated in vitro for their α-amylase inhibitory activity and showed good α-amylase inhibition with IC50 values ranging between 1.49 ± 0.10 and 3.06 ± 0.17 µM, with respect to the control drug acarbose (IC50 = 1.56 µM). Structural activity relationships (SARs) were also established for all synthesized compounds and the binding interactions of the most active spiropyrrolidine derivatives were modelled by means of molecular in silico docking studies. The most potent compounds 5 g, 5 k, 5 s and 5 l were further screened in vivo for their hypoglycemic activity in alloxan-induced diabetic rats, showing a reduction of the blood glucose level. Therefore, these spiropyrrolidine derivatives may be considered as promising candidates for the development of new classes of antidiabetic drugs.
Disciplines :
chemistry, organic (chemistry), crystallography (chemistry), materials science, characterization & testing (chemistry), mathematical & computational biology (fundamental biology), microbiology (fundamental biology)

General metadata

Data acquisition date : from 2017 to 2020
Data acquisition methods :
  • Experimental data :
    X-ray diffraction
    Organic synthesis
    Biological tests
    In-vitro and In-vivo tests
    DFT (Density Functional Theory) calculations
    NMR spectroscopy
Update periodicity : no update
Language : English (eng)
Formats : application/msword, application/pdf, chemical/x-cif
Audience : University: master, Research
Publications :
  • Synthesis, antidiabetic activity and molecular docking study of rhodanine-substitued spirooxindole pyrrolidine derivatives as novel α-amylase inhibitors (doi:10.1016/j.bioorg.2020.104507)
  • Antimicrobial Activity and In Silico Molecular Docking Studies of Pentacyclic Spiro[oxindole-2,3′-pyrrolidines] Tethered with Succinimide Scaffolds (doi:10.3390/app12010360)
Publisher : Elsevier
Project and funders :
Record created 13 May 2022 by Michael Knorr.
Local identifier: FR-18008901306731-2022-05-13.


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