SAR and 3D-QSAR Studies on Thiadiazolidinone Derivatives:  Exploration of Structural Requirements for Glycogen Synthase Kinase 3 Inhibitors

  1. Martinez, Ana 14
  2. Alonso, Mercedes 14
  3. Castro, Ana 14
  4. Dorronsoro, Isabel 14
  5. Gelpí, J. Luis 3
  6. Luque, F. Javier 3
  7. Pérez, Concepción 1
  8. Moreno, Francisco J. 2
  1. 1 Instituto de Química Médica
    info

    Instituto de Química Médica

    Madrid, España

    ROR https://ror.org/02vznxv75

  2. 2 Centro de Biología Molecular Severo Ochoa
    info

    Centro de Biología Molecular Severo Ochoa

    Madrid, España

    ROR https://ror.org/03v9e8t09

  3. 3 Universitat de Barcelona
    info

    Universitat de Barcelona

    Barcelona, España

    ROR https://ror.org/021018s57

  4. 4 NeuroPharma, SA
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Revista:
Journal of Medicinal Chemistry

ISSN: 0022-2623,  1520-4804

Año de publicación: 2005

Volumen: 48

Número: 23

Páginas: 7103-7112

Tipo: Artículo

DOI: 10.1021/JM040895G GOOGLE SCHOLAR lock_openAcceso abierto editor

Otras publicaciones en: Journal of Medicinal Chemistry

Resumen

The 2,4-disubstituted thiadiazolidinones (TDZD) are described as the first ATP-noncompetitive GSK-3 inhibitors. Following an SAR study about TDZD, different structural modifications in the heterocyclic ring aimed to test the influence of each heteroatom on the biological study are here reported here. Various compounds such as hydantoins, dithiazolidindiones, rhodanines, maleimides, and triazoles were synthesized and screened as GSK-3 inhibitors. After an extensive SAR study among these different heterocyclic families, TDZDs have been revealed as a privileged scaffold for the selective inhibition of GSK-3. A CoMFA analysis was also performed highlighting the molecular electrostatic field interaction in the interaction of TDZDs with GSK-3. Moreover, first mapping studies indicate two binding modes which in turn might imply relevant differences in the mechanism that underly the inhibitory activity of TDZDs.

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