Beilstein J. Org. Chem.2013,9, 15–25, doi:10.3762/bjoc.9.3
)-1-(benzenesulfonyl)-5-phenylpent-1-en-3-yl]amino]-3-(4-methylphenyl)-1-oxopropan-2-yl]pyridine-4-carboxamide (4), which is trypanocidal at ten-fold lower concentrations than for 1. We now find that the trypanocidal activity of 4 derives primarily from the inhibition of T. cruzi 14-α-demethylase
of this new class of inhibitors.
Keywords: activity-based probes; Chagas’ disease; cruzain; CYP51; 14-α-demethylase; hybrid drugs; Trypanosoma cruzi; Introduction
The kinetoplastid protozoan Trypanosoma cruzi is the causative agent of Chagas’ disease, a leading cause of heart failure in endemic
investigated are cruzain [7][8][9][10], the major cysteine protease active in the parasite, and T. cruzi CYP51 (TcCYP51), a 14-α-demethylase enzyme of the cytochrome P450 family required for ergosterol biosynthesis [11][12][13][14]. TcCYP51 is analogous to the fungal enzyme targeted by the azole class of
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Graphical Abstract
Figure 1:
Chemical structures of vinylsulfone-based cruzain inhibitors 1–4, known TcCYP51 inhibitor 5, dihydr...