Synthesis and biochemical evaluation of thiochromanone thiosemicarbazone analogues as inhibitors of cathepsin L

Song, J. et al. (2012) Synthesis and biochemical evaluation of thiochromanone thiosemicarbazone analogues as inhibitors of cathepsin L. ACS Medicinal Chemistry Letters, 3(6), pp. 450-453. (doi: 10.1021/ml200299g)

Abstract

A series of 36 thiosemicarbazone analogues containing the thiochromanone molecular scaffold functionalized primarily at the C-6 position were prepared by chemical synthesis and evaluated as inhibitors of cathepsins L and B. The most promising inhibitors from this group are selective for cathepsin L and demonstrate IC₅₀ values in the low nanomolar range. In nearly all cases, the thiochromanone sulfide analogues show superior inhibition of cathepsin L as compared to their corresponding thiochromanone sulfone derivatives. Without exception, the compounds evaluated were inactive (IC₅₀ > 10000 nM) against cathepsin B. The most potent inhibitor (IC₅₀ = 46 nM) of cathepsin L proved to be the 6,7-difluoro analogue 4. This small library of compounds significantly expands the structure–activity relationship known for small molecule, nonpeptidic inhibitors of cathepsin L.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Gaddale Devanna, Dr Kishore Kumar
• Authors: Song, J., Jones, L.M., Kumar, G.D.K., Conner, E.S., Bayeh, L., Chavarria, G.E., Charlton-Sevcik, A.K., Chen, S.E., Chaplin, D.J., Trawick, M.L., and Pinney, K.G.
• College/School: College of Science and Engineering > School of Chemistry
• Journal Name: ACS Medicinal Chemistry Letters
• Publisher: American Chemical Society
• ISSN: 1948-5875