Synthesis and Evaluation of Arylamides with Hydrophobic Side Chains for Insulin Aggregation Inhibition

Insulin, a peptide hormone, forms fibrils under aberrant physiological conditions leading to a reduction in its biological activity. To ameliorate insulin aggregation, we have synthesized a small library of oligopyridylamide foldamers decorated with different combination of hydrophobic side chains. Screening of these compounds for insulin aggregation inhibition using a Thioflavin‐T assay resulted in the identification of a few hit molecules. The best hit molecule, BPAD2 inhibited insulin aggregation with an IC50 value of 0.9 μM. Mechanistic analyses suggested that BPAD2 inhibited secondary nucleation and elongation processes during aggregation. The hit molecules worked in a mechanistically distinct manner, thereby underlining the importance of structure‐activity relationship studies in obtaining a molecular understanding of protein aggregation. A structure‐activity relationship study in a family of arylamides towards inhibition of insulin aggregation is reported. Among the three best hit molecules identified through primary screening, BPAD2 was the most effective with an IC50 value of 0.9 μM. The hit molecules worked in a mechanistically distinct manner, thereby underlining the importance of structure‐activity relationship studies in obtaining a molecular understanding of protein aggregation.