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

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• 作者：Jiangli Song ; Lindsay M. Jones ; G. D. Kishore Kumar ; Elizabeth S. Conner ; Liela Bayeh ; Gustavo E. Chavarria ; Amanda K. Charlton-Sevcik ; Shen-En Chen ; David J. Chaplin ; Mary Lynn Trawick ; Kevin G. Pinney
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2012
• 出版时间：June 14, 2012
• 年：2012
• 卷：3
• 期：6
• 页码：450-453
• 全文大小：223K
• 年卷期：v.3,no.6(June 14, 2012)
• ISSN：1948-5875

文摘

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鈥揳ctivity relationship known for small molecule, nonpeptidic inhibitors of cathepsin L.

Keywords:

thiochromanone; thiosemicarbazone; cathepsin L; cathepsin B; inhibitor