Analysis of novel low nanomolar thiosemicarbazone inhibitors of cruzain

Chagas’ disease, caused by the protozoan Trypanosoma cruzi, affects millions of people in Latin America where it is a major cause of heart disease. Currently, there is no satisfactory treatment for the chronic stage of the disease and there is an urgent need for new therapeutic agents. Cruzipain, a potent Trypanosoma cruzi protease, and a member of the papain family of cysteine proteases, is a validated molecular target for the parasite. An analysis of a small library of thiosemicarbazones revealed that the 3,3′‐dibromobenzophenone thiosemicarbazone was an excellent enzyme inhibitor (Siles, R. et al., Bioorg. Med. Chem. Lett., 2006 ,16:4405–4409). Testing of a second generation of substituted monobromo‐benzophenone thiosemicarbazones against cruzain, a recombinant form of the target protease, revealed a number of compounds that were more effective than the dibromobenzophenone thiosemicarbazone lead compound. A group of these thiosemicarbazone derivatives demonstrated low nanomolar IC 50 values against cruzain using a fluorometric microplate assay. This study was supported in part by funds from the Baylor University Undergraduate Research and Scholarly Achievement Small Grant Program and the Vice Provost for Research (M.L.T.) and by a Welch Foundation Grant, AA1278 (K.G.P.)