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Functionalized benzophenone, thiophene, pyridine, and fluorene thiosemicarbazone derivatives as inhibitors of cathepsin L

Authors
Journal
Bioorganic & Medicinal Chemistry Letters
0960-894X
Publisher
Elsevier
Publication Date
Volume
20
Issue
22
Identifiers
DOI: 10.1016/j.bmcl.2010.09.026
Keywords
  • Cathepsin L
  • Inhibitors
  • Cancer Metastasis
Disciplines
  • Chemistry

Abstract

Abstract A series of thiosemicarbazone analogs based on the benzophenone, thiophene, pyridine, and fluorene molecular frameworks has been prepared by chemical synthesis and evaluated as small-molecule inhibitors of the cysteine proteases cathepsin L and cathepsin B. The two most potent inhibitors of cathepsin L in this series (IC 50 <135 nM) are brominated-benzophenone thiosemicarbazone analogs that are further functionalized with a phenolic moiety ( 2 and 6). In addition, a bromo-benzophenone thiosemicarbazone acetyl derivative ( 3) is also strongly inhibitory against cathepsin L (IC 50 = 150.8 nM). Bromine substitution in the thiophene series results in compounds that demonstrate only moderate inhibition of cathepsin L. The two most active analogs in the benzophenone thiosemicarbazone series are highly selective for their inhibition of cathepsin L versus cathepsin B.

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