Inhibitors of Trypanosoma cruzi trypanothione reductase revealed by virtual screening and parallel synthesis.
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.
Meiering
Svea
S
Biochemie-Zentrum, Universität Heidelberg, Im Neuenheimer Feld 504, D-69120 Heidelberg, Germany.
Inhoff
Oliver
O
Mies
Jan
J
Vincek
Adam
A
Garcia
Gabriel
G
Kramer
Bernd
B
Dormeyer
Matthias
M
Krauth-Siegel
R Luise
RL
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*
D000578:Amidines; D010880:Piperidines; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase; D002710:Chlorhexidine