Design and Synthesis of Bioisosteres of Acylhydrazones as Stable Inhibitors of the Aspartic Protease Endothiapepsin.
Cast your vote
You can rate an item by clicking the amount of stars they wish to award to this item.
When enough users have cast their vote on this item, the average rating will also be shown.
Your vote was cast
Thank you for your feedback
Thank you for your feedback
AuthorsJumde, Varsha R
Gierse, Robin M
Unver, M Yagiz
van Lier, Roos C W
Hirsch, Anna K H
MetadataShow full item record
AbstractAcylhydrazone-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.
CitationChemMedChem. 2018 Nov 6;13(21):2266-2270. doi: 10.1002/cmdc.201800446. Epub 2018 Oct 9.
AffiliationHIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.
The following license files are associated with this item:
- Creative Commons
Except where otherwise noted, this item's license is described as Attribution-NonCommercial-ShareAlike 4.0 International
- Fragment Linking and Optimization of Inhibitors of the Aspartic Protease Endothiapepsin: Fragment-Based Drug Design Facilitated by Dynamic Combinatorial Chemistry.
- Authors: Mondal M, Radeva N, Fanlo-Virgós H, Otto S, Klebe G, Hirsch AK
- Issue date: 2016 Aug 1
- Structure-Based Optimization of Inhibitors of the Aspartic Protease Endothiapepsin.
- Authors: Hartman AM, Mondal M, Radeva N, Klebe G, Hirsch AK
- Issue date: 2015 Aug 14
- Structure-based design of inhibitors of the aspartic protease endothiapepsin by exploiting dynamic combinatorial chemistry.
- Authors: Mondal M, Radeva N, Köster H, Park A, Potamitis C, Zervou M, Klebe G, Hirsch AK
- Issue date: 2014 Mar 17
- The structure of endothiapepsin complexed with a Phe-Tyr reduced-bond inhibitor at 1.35 Å resolution.
- Authors: Guo J, Cooper JB, Wood SP
- Issue date: 2014 Jan
- Fragment-Based Drug Design Facilitated by Protein-Templated Click Chemistry: Fragment Linking and Optimization of Inhibitors of the Aspartic Protease Endothiapepsin.
- Authors: Mondal M, Unver MY, Pal A, Bakker M, Berrier SP, Hirsch AK
- Issue date: 2016 Oct 10