Design and Synthesis of Bioisosteres of Acylhydrazones as Stable Inhibitors of the Aspartic Protease Endothiapepsin.
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Authors
Jumde, Varsha RMondal, Milon
Gierse, Robin M
Unver, M Yagiz
Magari, Francesca
van Lier, Roos C W
Heine, Andreas
Klebe, Gerhard
Hirsch, Anna K H
Issue Date
2018-11-06
Metadata
Show full item recordAbstract
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.Citation
ChemMedChem. 2018 Nov 6;13(21):2266-2270. doi: 10.1002/cmdc.201800446. Epub 2018 Oct 9.Affiliation
HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.Publisher
ElsevierJournal
ChemMedChemPubMed ID
30178575Type
ArticleLanguage
enISSN
1860-7187ae974a485f413a2113503eed53cd6c53
10.1002/cmdc.201800446
Scopus Count
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- Creative Commons
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