edoc

Synthesis, inhibition potency, binding mode, and antiprotozoal activities of fluorescent inhibitors of trypanothione reductase based on mepacrine-conjugated diaryl sulfide scaffolds

Eberle, C. and Burkhard, J. A. and Stump, B. and Kaiser, M. and Brun, R. and Krauth-Siegel R. L., and Diederich, F.. (2009) Synthesis, inhibition potency, binding mode, and antiprotozoal activities of fluorescent inhibitors of trypanothione reductase based on mepacrine-conjugated diaryl sulfide scaffolds. ChemMedChem : chemistry enabling drug discovery, Vol. 4, H. 12. S. 2034-2044.

Full text not available from this repository.

Official URL: http://edoc.unibas.ch/dok/A5843347

Downloads: Statistics Overview

Abstract

Trypanothione reductase (TR) is a flavoenzyme unique to trypanosomatid parasites and a target for lead discovery programs. Various inhibitor scaffolds have emerged in the past, exhibiting moderate affinity for the parasite enzyme. Herein we show that the combination of two structural motifs of known TR inhibitors - diaryl sulfides and mepacrine - enables the simultaneous addressing of two hydrophobic patches in the active site. The binding efficacy of these conjugates is enhanced over that of the respective parent inhibitors. They show K(ic) values for the parasite enzyme down to 0.9+/-0.1 microm and exhibit high selectivity for TR over human glutathione reductase (GR). Despite their considerable molecular mass and in some cases permanent positive charges, in vitro studies revealed IC(50) values in the low micromolar to sub-micromolar range against Trypanosoma brucei rhodesiense and Trypanosoma cruzi, as well as the malaria parasite Plasmodium falciparum, which lack trypanothione metabolism. The inhibitors exhibit strong fluorescence due to their aminoacridine moiety. This feature allows visualization of the drugs in the parasite where high accumulation was observed by fluorescence microscopy even after short exposure times
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Brun, Reto and Kaiser, Marcel
Item Type:Article, refereed
Bibsysno:Link to catalogue
Publisher:Wiley-VCH
ISSN:1860-7179
Note:Publication type according to Uni Basel Research Database: Journal article
Related URLs:
Identification Number:
Last Modified:14 Sep 2012 07:17
Deposited On:14 Sep 2012 06:41

Repository Staff Only: item control page