Development of New Benzo[b]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. 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 IC₅₀ of 13.2 µM, shows similar interactions with RAGE as the reference molecule Azeliragon (13.0 µM).