Indomethacin amides as a novel molecular scaffold for targeting trypanosoma cruzi sterol 14α-demethylase

Mary E. Konkle, Tatiana Y. Hargrove, Yuliya Y. Kleshchenko, Jens P. Von Kries, Whitney Ridenour, Md Jashim Uddin, Richard M. Caprioli, Lawrence J. Marnett, W. David Nes, Fernando Villalta, Michael R. Waterman, Galina I. Lepesheva

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Trypanosoma cruzi (TC) causes Chagas disease, which in its chronic stage remains incurable. We have shown recently that specific inhibition of TC sterol 14α-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 indomethacinamides 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.

Original languageEnglish
Pages (from-to)2846-2853
Number of pages8
JournalJournal of Medicinal Chemistry
Issue number9
StatePublished - May 14 2009


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