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Development of New Benzo[b]Thiophene-2-Carboxamide Derivatives as Advanced Glycation End-Products Receptor (RAGE)

Lisa Bonin1,2,3, Matthieu Hedouin2, Christophe Furman3

  • 1Junia, Health and Environment, Laboratory of Sustainable Chemistry and Health, F-59000, Lille, France.

Chemmedchem
|November 30, 2025
PubMed

Insights

Researchers developed novel benzo[b]thiophene-2-carboxamide derivatives targeting the receptor for advanced glycation end-products (RAGE). These compounds show potential for combating inflammaging and related diseases, with one analog demonstrating comparable RAGE interaction to Azeliragon.

Area of Science:

  • Medicinal Chemistry
  • Aging Research
  • Molecular Biology

Background:

  • Receptor for advanced glycation end-products (RAGE) activation drives chronic inflammation (inflammaging), linked to aging and diseases like Alzheimer's and diabetes.
  • RAGE is a significant therapeutic target for healthy aging interventions.
  • Benzo[b]thiophene-2-carboxamide derivatives are explored as potential RAGE ligands.

Purpose of the Study:

  • To develop a novel synthetic strategy for benzo[b]thiophene-2-carboxamide analogs.
  • To identify new RAGE ligands for therapeutic applications in aging and age-related diseases.
  • To investigate the structure-activity relationship of synthesized compounds.

Main Methods:

  • Synthesis of benzo[b]thiophene-2-carboxamide analogs via Ullmann-Goldberg coupling of 5-arylidene-2,4-thiazolidinedione intermediates.
  • Characterization using Liquid Chromatography-Mass Spectrometry (LCMS), Nuclear Magnetic Resonance (NMR), and X-ray crystallography.
  • Computational studies including Density Functional Theory (DFT) for mechanistic insights.
  • In vitro assessment of RAGE ligand activity (IC50 determination).

Main Results:

  • An efficient synthetic route to benzo[b]thiophene-2-carboxamide analogs was established.
  • The reaction mechanism was elucidated through spectroscopic and computational analyses.
  • Molecule 3t' demonstrated potent RAGE binding affinity (IC50 = 13.2 µM), comparable to the reference drug Azeliragon (IC50 = 13.0 µM).

Conclusions:

  • The developed synthetic methodology provides access to novel RAGE-targeting benzo[b]thiophene-2-carboxamide derivatives.
  • Compound 3t' represents a promising lead candidate for further development against RAGE-mediated pathologies.
  • This work contributes to the therapeutic strategies for managing inflammaging and associated diseases.
Keywords:
5‐arylidene‐2,4‐thiazolidinedioneadvanced glycation end-product receptorantagonistbenzo[b]thiophene‐2‐carboxamidecopper

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