Design and Synthesis of Bioisosteres of Acylhydrazones as Stable Inhibitors of the Aspartic Protease Endothiapepsin. (9th October 2018)

• Record Type: Journal Article
• Authors: Jumde, Varsha R.; Mondal, Milon; Gierse, Robin M.; Unver, M. Yagiz; Magari, Francesca; van Lier, Roos C. W.; Heine, Andreas; Klebe, Gerhard; Hirsch, Anna K. H.
• Is Part Of: ChemMedChem. Volume 13:Number 21(2018)
• Page Start: 2266
• Page End: 2270
• Publication Date: 2018-10-09
• Subjects: acylhydrazones -- aspartic proteases -- bioisosteres -- drug design -- dynamic combinatorial chemistry; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201800446
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: Acylhydrazone‐based dynamic combinatorial chemistry (DCC) is a powerful strategy for the 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 instability and potential toxicity under physiological conditions. It is therefore of paramount importance to identify stable replacements for acylhydrazone linkers. Herein, we present the first report on the design and synthesis of stable bioisosteres of acylhydrazone‐based inhibitors of the aspartic protease endothiapepsin as a follow‐up to a DCC study. The most successful 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. Abstract : Acylhydrazone‐based dynamic combinatorial chemistry (DCC) can be used for the rapid identification of novel hits. To identify replacements of the unstable acylhydrazones, we performed a computer‐guided search for bioisosteres on a previously found hit that inhibits the aspartic protease endothiapepsin. A peptidic linker emerged as an equipotent bioisostere, and its predicted binding mode was verified by determination of the crystal structure with the bound bioisostere. This readily available bioisosteric linker might accelerate future lead development from hits found using acylhydrazone‐based DCC.