CHINIFUR, A SELECTIVE INHIBITOR AND SUBVERSIVE SUBSTRATE FOR TRYPANOSOMA-CONGOLENSE TRYPANOTHIONE REDUCTASE

Nitrofurans with aromatic and heterocyclic substituents inhibit Trypan osoma congolense trypanothione reductase (TR) and yeast glutathione re ductase (GR), acting as uncompetitive inhibitors vs. NADPH and noncomp etitive or uncompetitive inhibitors vs. disulfide substrate. Many of t hese compounds inhibited trypanothione reductase more efficiently than glutathione reductase. Chinifur (2-(5'-nitro(furo-2'-yl)-ethene-1-yl) -4(N, ino)-1-methyl-but-1-yl-arninocarbonyl-4-quinoline) was the most selective inhibitor of, and free radical-generating substrate for, try panothione reductase (K-i = 4.5 mu m, TN = 3 s(-1), TN/K-m = 3.2 x 10( 4) M(-1) s(-1)), only weakly inhibiting glutathione reductase (K-i = 1 00 mu m). These findings point to the importance of hydrophobic intera ctions in the design of redox active heteroaromatic compounds acting a s selective inhibitors of, and ''subversive substrates'' for, trypanot hione reductase. (C) 1994 Academic Press, Inc.