Synthesis and Biochemical Evaluation of Thiochromanone Thiosemicarbazone Analogues as Inhibitors of Cathepsin L

• Published in: ACS medicinal chemistry letters Vol. 3; no. 6; pp. 450 - 453
• Main Authors: Song, Jiangli, Jones, Lindsay M, Kumar, G. D. Kishore, Conner, Elizabeth S, Bayeh, Liela, Chavarria, Gustavo E, Charlton-Sevcik, Amanda K, Chen, Shen-En, Chaplin, David J, Trawick, Mary Lynn, Pinney, Kevin G
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 14-06-2012
• Subjects: Letter; thiochromanone; thiosemicarbazone; inhibitor; cathepsin L; cathepsin B
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/ml200299g

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.