Design, synthesis and biological evaluation of new potent 5-nitrofuryl derivatives as anti-Trypanosoma cruzi agents.: Studies of trypanothione binding site of trypanothione reductase as target for rational design

Design, using force-field calculations on the catalytic site of trypanothione reductase from Trypanosoma cruzi, has led to the development of new 5-nitrofuryl derivatives as potential anti-trypanosomal agents. The synthesized compounds were tested in vitro against T cruzi and more than 75% of the prepared derivatives showed higher activity than nifurtimox. Compounds 5 and 11, hexyl 4-(5-nitrofurfurylidene)carbazate and N-hexyl 3-(5-nitrofuryl)propenamide, showed the highest in vitro trypanocidal effect reported to date for members of the nitrofuran family. Partition coefficients and energies for the single-electron reduction of compounds were theoretically determined. These properties could be not the major cause of the activities' differences. The physicochemical environment around E 19, W22, C53 and Y111 residues within the trypanothione binding site of trypanothione reductase resulted a valuable target for the rational design of anti-trypanosomal drugs. (C) 2004 Elsevier SAS. All rights reserved.