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Kinetics of Thiosemicarbazone‐Based Inhibitors of Cathepsin L

Increased cathepsin L activity is linked to invasive and metastatic cancers where it promotes degradation of the extracellular matrix. This major cysteine protease found in cell lysosomes and secreted from tissues, also plays a role in the pathology of degenerative cartilage and neurological disorders, and is reported to be required for SARS coronavirus infection. A small library of thiosemicarbazone derivatives of unsubstituted, bromo‐ and dibromo‐ substituted α‐ and β‐tetralones, chroman‐4‐ones, thiochroman‐4‐ones, benzophenones, and propiophenones were evaluated as inhibitors of cathepsin L. While most of the compounds had IC50 values in the range of 0.4 μM or greater using the fluorogenic substrate, Cbz‐Phe‐Arg‐7‐amino‐4‐methylcoumarin, two of the thiosemicarbazones were very effective inhibitors of cathepsin L: a dibromobenzophenone and a sulfone analog of the bromo substituted thiochroman‐4‐one have IC50 values of 1.5 and 1.0 nM respectively. Both compounds exhibit mixed type inhibition. The sulfone analog fit the Morrison‐Williams equation, which applies to reversible covalent inhibition as well as slow, tight binding. No evidence of cytotoxicity was observed with either inhibitor at a concentration of 20 μM with HEK‐293 cells. The authors thank the Vice‐Provost for Research of Baylor University (MLT) and the Welch Foundation