Synthesis of 2,5‐Diaryl‐Substituted Thiophenes as Helical Mimetics: Towards the Modulation of Islet Amyloid Polypeptide (IAPP) Amyloid Fibril Formation and Cytotoxicity

A range of 2,5-diarylated thiophenes were synthesised as small molecule mimetics of the α-helix to modulate the amyloidogenesis and cytotoxic effect of islet amyloid polypeptide (IAPP). 3-Substituted thiophene-2-carboxylic acids were used as key intermediates and functionalised by palladium decarboxylative cross-coupling and direct C-H activation successively with overall yields ranging from 23 to 95 %. The effect of the ligands on IAPP amyloid fibril formation was evaluated with the thioflavin T (ThT) fluorescence-based assay. Furthermore, the capacity of these compounds to inhibit the cytotoxic effect of IAPP was assessed using β-pancreatic cells.