Design and Synthesis of Bioisosteres of Acylhydrazones as Stable Inhibitors of the Aspartic Protease Endothiapepsin

摘要

Acylhydrazone-based dynamic combinatorial chemistry (DCC) is apowerful strategy forthe rapid identification of novel hits. Even though acylhydrazones are important structural motifs in medicinal chemistry,their further progression in development may be hampered by major instabilityand potentialtoxicity under physiological conditions. It is therefore of paramount importance to identify stable replacements for acylhydrazone linkers. Herein, we presentthe first reportonthe design and synthesis of stable bioisosteres of acylhydrazone-basedinhibi- tors of the aspartic protease endothiapepsin as afollow-up to aDCC study.The mostsuccessful bioisostere is equipotent, bears an amide linker,and we confirmed its binding mode by X-ray crystallography.Having some validated bioisosteres of acylhydrazones readily available might accelerate hit-to-lead optimization in future acylhydrazone-based DCC projects.