New spiropyrrolothiazole derivatives bearing an oxazolone moiety as potential antidiabetic agent: Design, synthesis, crystal structure, Hirshfeld surface analysis, ADME and molecular docking studies (2022)

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[1] : Département de Chimie, Faculté des Sciences de Monastir
[2] : Bioressources : Biologie Intégrative & Valorisation «BIOLIVAL » - Institut Supérieur de Biotechnologie de Monastir - LR14ES06
[3] : Institut UTINAM (UMR 6213) (Université de Franche-Comté)
[4] : Observatoire des Sciences de l'Univers - Terre, Homme, Environnement, Temps, Astronomie (UAR 3245) (Université de Franche-Comté)
[5] : Technische Universität Dortmund
[6] : Department of Chemistry, College of Science and Humanities in Al-Kharj, Prince Sattam bin Abdulaziz University
[7] : Department of Biology, College of Sciences, University of Hail
[8] : Department of Chemistry, College of Science and Arts, Qassim University
[9] : Department of Chemistry, Faculty of Sciences of Sfax
Description :
In a sustained search for novel and effective antihyperglycemics, a new series of fifteen isomeric oxazolone-fused dispiropyrrolothiazoles resulting from one-pot three component reaction between L-4-thiazolidine carboxylic acid, arylidene-oxazolones and isatin (or acenaphthenequinone) has been synthesized. Four crystal structure determinations further corroborate the proposed stereochemistry and composition of these spirocompounds. The Hirshfeld surface analysis was carried out to quantify the intermolecular interactions involved in the crystalline environment. Results showed the main contribution of H···H and C···H/ H···C contacts for the crystal structures 4b, 5c, 6a and 6e as well as those of O···H/ H···O contacts followed by the S···H/ H···S contacts. Furthermore, the hypoglycemic potency of these heterocycles has been evaluated against both α-amylase from human saliva (HAA) and α-glucosidase from Saccharomyces cerevisiae (SCAG). Among the spiropyrrolothiazole derivatives, the high significantly were 4b (IC50 (HAA) = 1.76 ± 0.14 μM; IC50 (SCAG) = 4.81 ± 0.24 μM) and 5d (IC50 (HAA) = 2.88 ± 0.19 μM; IC50 (SCAG) = 7.78 ± 0.37 μM), while in dispiropyrrolothiazole analogues, those of 6f (IC50 (HAA) = 2.18 ± 0.17 μM), 6e (IC50 (HAA) = 2.28 ± 0.18 μM) and 6c (IC50 (HAA) = 2.49 ± 0.20 μM) and 6e (IC50 (SCAG) = 6.41 ± 0.25 μM), 6f (IC50 (SCAG) = 6.93 ± 0.34 μM) and 6c (IC50 (SCAG) = 7.11 ± 0.31 μM) were found to be the most active, respectively as compared to the standard drug, acarbose (IC50 (HAA) = 1.28 ± 0.13 μM; IC50 (SCAG) = 2.80 ± 0.20 μM). Structural activity relationships (SARs) and molecular dockings of the most active inhibitors into the binding sites of HAA (1B2Y) and SCAG (3W37) were also established. Furthermore, pharmacokinetic studies indicate that the heterocycles exhibit acceptable predictive ADME properties and good drug ability. Overall, our results indicate that these derivatives could be a promising template to design potent dual HAA and SCAG inhib.
Disciplines :
chemistry, organic (chemistry), crystallography (chemistry), mathematical & computational biology (fundamental biology), microbiology (fundamental biology)

General metadata

Data acquisition date : from 2017 to 2020
Data acquisition methods :
Update periodicity : no update
Language : English (eng)
Formats : application/pdf, application/vnd.openxmlformats-officedocument.wordprocessingml.document, chemical/x-cif
Audience : University: master, Research
Publications :
  • New spiropyrrolothiazole derivatives bearing an oxazolone moiety as potential antidiabetic agent: Design, synthesis, crystal structure, Hirshfeld surface analysis, ADME and molecular docking studies (doi:10.1016/j.molstruc.2022.132398)
Publisher : Elsevier
Record created 20 May 2022 by Michael Knorr.
Local identifier: FR-18008901306731-2022-05-20-02.

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