Indomethacin amides as a novel molecular scaffold for targeting Trypanosoma cruzi sterol 14alpha-demethylase.
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.
Department of Chemistry, School of Medicine, Vanderbilt University, Nashville, Tennessee 37232, USA.
Mary E
ME
Konkle
Tatiana Y
TY
Hargrove
Yuliya Y
YY
Kleshchenko
Jens P
JP
von Kries
Whitney
W
Ridenour
Md Jashim
MJ
Uddin
Richard M
RM
Caprioli
Lawrence J
LJ
Marnett
W David
WD
Nes
Fernando
F
Villalta
Michael R
MR
Waterman
Galina I
GI
Lepesheva
D000577:Amides / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D000977:Antiparasitic Agents / Q000737:chemistry / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D005110:Extracellular Space / Q000187:drug effects / Q000201:enzymology; D007213:Indomethacin / Q000031:analogs & derivatives*; D042541:Intracellular Space / Q000187:drug effects / Q000201:enzymology; D008024:Ligands; D058886:Sterol 14-Demethylase; D013261:Sterols / Q000737:chemistry / Q000378:metabolism; D014349:Trypanosoma cruzi / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*
D000577:Amides; D000977:Antiparasitic Agents; C548418:CYP51A1 protein, human; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D008024:Ligands; D013261:Sterols; D058886:Sterol 14-Demethylase; D007213:Indomethacin