Two series of iododiflunisal and diflunisal analogues have been obtained by using a two step sequential reaction solution-phase parallel synthesis. The synthesis combined an aqueous Suzuki-Miyaura cross-coupling and a mild electrophilic aromatic iodination step using a new polymer-supported iodonium version of Barluenga's reagent. From a selected set of 77 noniodinated and 77 iodinated diflunisal analogues, a subset of good transthyretin amyloid inhibitors has been obtained with improved turbidimetry inhibition constants, high binding affinity to transthyretin, and good selectivity for TTR compared to other thyroxine binding proteins.
Keywords: 5-aryl salicylic acid core libraries; Barluenga’s reagent; TTR amyloidosis inhibitors; aqueous Suzuki-Miyaura reaction; iododiflunisal analogues library; polymer-supported iodonium reagent; solution-phase parallel synthesis; transthyretinkinetic stabilizers.