Development of New Benzo[ <i>b</i> ]Thiophene‐2‐Carboxamide Derivatives as Advanced Glycation End‐Products Receptor (RAGE) Antagonists

The activation of the receptor for advanced glycation end‐products (RAGE) induces a chronic, low‐noise inflammation responsible for the aging process, known as inflammaging(definition). Associated with numerous pathologies such as Alzheimer's, insulin‐resistant diabetes, cardiovascular diseases, and certain cancers, RAGE has become an interesting therapeutic target in the context of aging well. To this end, we identified new benzo[ b ]thiophene‐2‐carboxamide derivatives as potential RAGE ligands. Herein, we developed an alternative approach to easily synthesize benzo[ b ]thiophene‐2‐carboxamide analogs from 5‐arylidene‐2,4‐thiazolidinedione intermediates based on the Ullmann–Goldberg coupling conditions. In light of LCMS, NMR, X‐ray, and DFT studies, a mechanism for this reaction was proposed. This novel strategy enabled us to synthesize analogs whose best molecule 3t′ , with an IC 50 of 13.2 µM, shows similar interactions with RAGE as the reference molecule Azeliragon (13.0 µM).