Michael Waterman
Faculty Member
Last active: 2/12/2015

Indomethacin amides as a novel molecular scaffold for targeting Trypanosoma cruzi sterol 14alpha-demethylase.

Konkle ME, Hargrove TY, Kleshchenko YY, von Kries JP, Ridenour W, Uddin MJ, Caprioli RM, Marnett LJ, Nes WD, Villalta F, Waterman MR, Lepesheva GI
J Med Chem. 2009 52 (9): 2846-53

PMID: 19354253 · PMCID: PMC2744100 · DOI:10.1021/jm801643b

Trypanosoma cruzi (TC) causes Chagas disease, which in its chronic stage remains incurable. We have shown recently that specific inhibition of TC sterol 14alpha-demethylase (TCCYP51) with imidazole derivatives is effective in killing both extracellular and intracellular human stages of TC. An alternative set of TCCYP51 inhibitors has been identified using optical high throughput screening followed by web-database search for similar structures. The best TCCYP51 inhibitor from this search was found to have structural similarity to a class of cyclooxygenase-2-selective inhibitors, the indomethacin-amides. A number of indomethacin-amides were found to bind to TCCYP51, inhibit its activity in vitro, and produce strong antiparasitic effects in the cultured TC cells. Analysis of TC sterol composition indicated that the mode of action of the compounds is by inhibition of sterol biosynthesis in the parasite.

MeSH Terms (13)

Amides Animals Antiparasitic Agents Cytochrome P-450 Enzyme Inhibitors Drug Evaluation, Preclinical Enzyme Inhibitors Extracellular Space Indomethacin Intracellular Space Ligands Sterol 14-Demethylase Sterols Trypanosoma cruzi

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