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

doi:10.1021/jm801643b

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

Chemistry and Biochemistry

Research output: Contribution to journal › Article › peer-review

42 Scopus citations

Abstract

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 language	English
Pages (from-to)	2846-2853
Number of pages	8
Journal	Journal of Medicinal Chemistry
Volume	52
Issue number	9
DOIs	https://doi.org/10.1021/jm801643b
State	Published - May 14 2009

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Konkle, M. E., Hargrove, T. Y., Kleshchenko, Y. Y., Von Kries, J. P., Ridenour, W., Uddin, M. J., Caprioli, R. M., Marnett, L. J., Nes, W. D., Villalta, F., Waterman, M. R., & Lepesheva, G. I. (2009). Indomethacin amides as a novel molecular scaffold for targeting trypanosoma cruzi sterol 14α-demethylase. Journal of Medicinal Chemistry, 52(9), 2846-2853. https://doi.org/10.1021/jm801643b

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

abstract = "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.",

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

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doi = "10.1021/jm801643b",

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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 2009, 'Indomethacin amides as a novel molecular scaffold for targeting trypanosoma cruzi sterol 14α-demethylase', Journal of Medicinal Chemistry, vol. 52, no. 9, pp. 2846-2853. https://doi.org/10.1021/jm801643b

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T1 - Indomethacin amides as a novel molecular scaffold for targeting trypanosoma cruzi sterol 14α-demethylase

AU - Konkle, Mary E.

AU - Hargrove, Tatiana Y.

AU - Kleshchenko, Yuliya Y.

AU - Von Kries, Jens P.

AU - Ridenour, Whitney

AU - Uddin, Md Jashim

AU - Caprioli, Richard M.

AU - Marnett, Lawrence J.

AU - Nes, W. David

AU - Villalta, Fernando

AU - Waterman, Michael R.

AU - Lepesheva, Galina I.

PY - 2009/5/14

Y1 - 2009/5/14

N2 - 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.

AB - 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.

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

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