Dibenzo[b,f]azocin-6(5H)-ones and Benzo[b]pyrido[2,3-f]azocin-5(6H)-ones: Useful Scaffolds for Development of Protein-Protein Interaction Inhibitors †.

Modulation of protein-protein interactions (PPIs) by small molecules is a vital strategy in drug discovery. Nevertheless, due to the inherent nature of PPI interfaces, practical implementation of this approach remains a high-hanging fruit in medicinal chemistry. In this report, we develop a new line of PEX14-PEX5 PPI inhibitors by homologation of a previously developed dibenzo[b,e]azepin-6(6H)-one scaffold. The challenging chemistry of 8-membered ring formation led to the development of novel PEX14 inhibitors featuring a 6+8+6 tricyclic system. The obtained analogs were tested for their capability of disrupting the PEX5-TbPEX14 PPI, as well as for in vitro activity against the T. brucei protist. Overall, the developed scaffold not only represents an interesting alternative for prospective trypanocidal TbPEX14 ligands but may also be useful in the design of inhibitors of other PPIs mediated by a similar topology of hydrophobic binding pockets.