title: Inhibitors of Trypanosoma cruzi trypanothione reductase revealed by virtual screening and parallel synthesis.
abstract: In an approach to discover new inhibitors of trypanothione reductase from Trypanosoma cruzi, the causative agent of Chagas' disease, a virtual high-throughput screening was performed. Two structurally new types of inhibitors emerged, the antimicrobial chlorhexidine {1,1'-hexamethylenebis[5-(4-chlorophenyl)biguanide]}, a linear competitive inhibitor (K(i) = 2 +/- 1 microM), and a piperidine derivative acting as mixed inhibitor (K(i) = 6.2 +/- 2 microM and K(i)' = 8.5 +/- 2 microM). Neither compound interferes with human glutathione reductase. Based on chlorhexidine, different series of compounds were synthesized and studied as inhibitors of T. cruzi trypanothione reductase. Most efficient derivatives were three bis(amidines) showing mixed type inhibition with K(i,slope) and K(i,int) values of 2-5 microM and 16-47 microM, respectively. Although these compounds did not exert an improved inhibitory potency compared to chlorhexidine, the change from competitive to mixed-type inhibition is advantageous, since substrate accumulation does not overcome inhibition. Remarkably, all three derivatives carried two copies of an identical 2-methoxy-4-methyl-1-(phenylmethoxy)benzene substituent.
authors: Biochemie-Zentrum, Universität Heidelberg, Im Neuenheimer Feld 504, D-69120 Heidelberg, Germany.
authors: Svea
authors: S
authors: Meiering
authors: Oliver
authors: O
authors: Inhoff
authors: Jan
authors: J
authors: Mies
authors: Adam
authors: A
authors: Vincek
authors: Gabriel
authors: G
authors: Garcia
authors: Bernd
authors: B
authors: Kramer
authors: Matthias
authors: M
authors: Dormeyer
authors: R Luise
authors: RL
authors: Krauth-Siegel
mesh_terms: D000578:Amidines / Q000138:chemical synthesis* / Q000737:chemistry; D000818:Animals; D002710:Chlorhexidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship; D014349:Trypanosoma cruzi / Q000201:enzymology*
chemical_list: D000578:Amidines; D010880:Piperidines; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase; D002710:Chlorhexidine