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

SUBMITTER: Konkle ME 

PROVIDER: S-EPMC2744100 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

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

Konkle Mary E ME   Hargrove Tatiana Y TY   Kleshchenko Yuliya Y YY   von Kries Jens P JP   Ridenour Whitney W   Uddin Md Jashim MJ   Caprioli Richard M RM   Marnett Lawrence J LJ   Nes W David WD   Villalta Fernando F   Waterman Michael R MR   Lepesheva Galina I GI  

Journal of medicinal chemistry 20090501 9

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 foun  ...[more]

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