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

Jumde, V. R., Mondal, M., Gierse, R. M., Unver, M. Y., Magari, F., van Lier, R. C. W., Heine, A., Klebe, G. & Hirsch, A. K. H., 6-Nov-2018, In : ChemMedChem. 13, 21, p. 2266-2270 5 p.

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)2266-2270
Number of pages5
JournalChemMedChem
Volume13
Issue number21
Publication statusPublished - 6-Nov-2018

    Keywords

  • acylhydrazones, aspartic proteases, bioisosteres, drug design, dynamic combinatorial chemistry, DYNAMIC COMBINATORIAL CHEMISTRY, RING-CLOSING METATHESIS, CATALYTIC MECHANISM, DICARBA ANALOGS, DRUG DISCOVERY, X-RAY, LIBRARIES, NEUTRON, TOOL, PROTEINASES

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