Nonpeptidic Tetrafluorophenoxymethyl Ketone Cruzain Inhibitors as Promising New Leads for Chagas Disease Chemotherapy

作者：Brak Katrien; Kerr Iain D; Barrett Kimberly T; Fuchi Nobuhiro; Debnath Moumita; Ang Kenny; Engel Juan C; McKerrow James H; Doyle Patricia S^*; Brinen Linda S; Ellman Jonathan A

来源：Journal of Medicinal Chemistry, 2010, 53(4): 1763-1773.

DOI：10.1021/jm901633v

A century after discovering that file Trypanosoma cruzi parasite is the etiological agent of Chagas disease, treatment is still plagued by limited efficacy, toxicity, and the emergence of drug, resistance. The development of inhibitors of the major T. cruzi cysteine protease, cruzain, has been demonstrated to be a promising drug discovery avenue for this neglected disease. Here we establish that a nonpeptidic tetrafluorophenoxymethyl ketone cruzain inhibitor Substantially ameliorates symptoms of acute Chagas disease in a mouse model With no apparent toxicity. A high-resolution Crystal Structure confirmed the mode of inhibition and revealed key binding interactions of this novel inhibitor class. Subsequent structure-guided optimization then resulted in inhibitor analogues With improvements in potency despite minimal or no additions in molecular weight. Evaluation Of file analogues in cell Culture showed enhanced activity. These results suggest that nonpeptidic tetrafluorophenoxymethyl ketone cruzain inhibitors have the Potential to fulfill file Urgent need for improved Chagas disease chemotherapy.

• 出版日期2010-2-25