Chinifur, a selective inhibitor and "subversive substrate" for Trypanosoma congolense trypanothione reductase.
Nitrofurans with aromatic and heterocyclic substituents inhibit Trypanosoma congolense trypanothione reductase (TR) and yeast glutathione reductase (GR), acting as uncompetitive inhibitors vs. NADPH and noncompetitive or uncompetitive inhibitors vs. disulfide substrate. Many of these compounds inhibited trypanothione reductase more efficiently than glutathione reductase. Chinifur (2-[5'-nitro(furo-2'-yl)-ethene-1-yl]-4(N,N-diethylamino)-1-methyl-but-1 -yl - aminocarbonyl-4-quinoline) was the most selective inhibitor of, and free radical-generating substrate for, trypanothione reductase (Ki = 4.5 microns, TN = 3 s-1, TN/Km = 3.2 x 10(4) M-1 s-1), only weakly inhibiting glutathione reductase (Ki = 100 microns). These findings point to the importance of hydrophobic interactions in the design of redox active heteroaromatic compounds acting as selective inhibitors of, and "subversive substrates" for, trypanothione reductase.
Cenas
N
N
Institute of Biochemistry, Lithuanian Academy of Sciences, Mokslininku.
Bironaite
D
D
Dickancaite
E
E
Anusevicius
Z
Z
Sarlauskas
J
J
Blanchard
J S
JS
D000818:Animals; D005980:Glutathione Reductase / Q000037:antagonists & inhibitors; D007700:Kinetics; D015394:Molecular Structure; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors*; D009581:Nitrofurans / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D012441:Saccharomyces cerevisiae / Q000201:enzymology; D013329:Structure-Activity Relationship; D014348:Trypanosoma congolense / Q000201:enzymology*
D009581:Nitrofurans; D011804:Quinolines; C089986:chinifur; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase; D005980:Glutathione Reductase