Medicinal Chemistry Research

, Volume 26, Issue 10, pp 2420–2431 | Cite as

Novel synthesis of isoindoline/isoindoline-1,3-dione derivatives under solventless conditions and evaluation with the human D2 receptor

  • Erik Andrade-Jorge
  • José R. Bahena-Herrera
  • Jesus Garcia-Gamez
  • Itzia I. Padilla-Martínez
  • José G. Trujillo-Ferrara
Original Research

Abstract

Isoindolines are the focus of much research because of being an important family of compounds present in a wide array of bioactive molecules. Although many different pathways of synthesis have been described, they do not follow green chemistry principles. The aim of this contribution was to develop a green synthesis technique for isoindolines/dioxoisoindolines. These compounds derived from analogs of important biogenic amines were tested in silico (on the human dopamine receptor D2) to predict their affinities and some pharmacokinetic parameters. One of them, YaI-01, was evaluated in vivo in a Parkinsonism mouse model. Seven molecules, including three isoindolines and four dioxoisoindolines, were synthesized using simple heating and relatively quick solventless reactions. They were then purified with a methodology as green as possible. Since no published crystal structure exists for dopamine receptor D2, it was necessary to generate and validate a homology model for molecular docking studies of the seven molecules synthesized presently. Docking was performed to assess affinity in terms of binding energy (∆G). Apart from pharmacokinetic parameters, Lipinski’s rule of five and some properties of toxicity from QSAR models were evaluated. Whereas no risk was found for the isoindolines, there was evidence of three kinds of toxicity for the isoindoline-1,3-dione compounds. Overall, the in silico analysis suggests that the three isoindolines herein tested have the best properties as ligands of the dopamine receptor D2, interacting with the main amino acid residues at its allosteric binding site. YaI-01 (254 µmol/kg) reverted Parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

Keywords

Solventless reactions Dopamine receptor Pharmacokinetic parameters 2,3-dihydro-1H-isoindoles N-substituted phthalimide Docking 

Notes

Acknowledgements

This work was supported by SIP of Instituto Politécnico Nacional, and CONACyT-México.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

44_2017_1942_MOESM1_ESM.docx (3.9 mb)
Supplementary Material

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Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  1. 1.Departamento de Bioquímica y Sección de GraduadosEscuela Superior de Medicina del Instituto Politécnico NacionalMexico CityMexico
  2. 2.Laboratorio de Investigación en Química, Departamento de Ciencias BásicasUnidad Profesional Interdisciplinaria de Biotecnología del Instituto Politécnico NacionalMexico CityMexico

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