Trypanothione is a low molecular weight antioxidant that is unique to the members of the order of Kinetoplastida and that has been proposed to play the correspondent role of human glutathione in maintaining an intracellular reducing environment against oxidative stress in parasites. Trypanothione reductase (TR) is the enzyme responsible for maintaining the required levels of reduced-state of trypanothione by catalyzing the NADPH-dependent reduction of its substrate trypanothione disulfide, in the same way as the homolog human glutathione reductase (GR) enzyme processes glutathione disulfide. TR represents a validated molecular target in the search for new antiparasitic drug candidates [1]. Actually, despite high percentage of sequence identity with GR, the active sites of TR and GR bear remarkably different physicochemical features that can be exploited for designing of selective inhibitors. In this context, a new series of quinazoline-based derivatives was designed, docked, synthesized, and tested against Trypanosoma cruzi TR. The quinazoline fragment was chosen as this heterocyclic ring is found in a broad variety of biologically active compounds that hit different pharmaceutical targets. Therefore, it meets the requirements of a privileged structure that is, ‘a single molecular framework able to provide ligands for diverse receptors’ [2]. A series of seven new compounds (1-7) was synthesized, and their biological activity tested using recombinant T. cruzi TR.

Structure-based design and synthesis of inhibitors of the trypanothione reductase enzyme from Trypanosoma cruzi.

CAVALLI, ANDREA;BOLOGNESI, MARIA LAURA
2008

Abstract

Trypanothione is a low molecular weight antioxidant that is unique to the members of the order of Kinetoplastida and that has been proposed to play the correspondent role of human glutathione in maintaining an intracellular reducing environment against oxidative stress in parasites. Trypanothione reductase (TR) is the enzyme responsible for maintaining the required levels of reduced-state of trypanothione by catalyzing the NADPH-dependent reduction of its substrate trypanothione disulfide, in the same way as the homolog human glutathione reductase (GR) enzyme processes glutathione disulfide. TR represents a validated molecular target in the search for new antiparasitic drug candidates [1]. Actually, despite high percentage of sequence identity with GR, the active sites of TR and GR bear remarkably different physicochemical features that can be exploited for designing of selective inhibitors. In this context, a new series of quinazoline-based derivatives was designed, docked, synthesized, and tested against Trypanosoma cruzi TR. The quinazoline fragment was chosen as this heterocyclic ring is found in a broad variety of biologically active compounds that hit different pharmaceutical targets. Therefore, it meets the requirements of a privileged structure that is, ‘a single molecular framework able to provide ligands for diverse receptors’ [2]. A series of seven new compounds (1-7) was synthesized, and their biological activity tested using recombinant T. cruzi TR.
2008
XIX National Meeting on Medicinal Chemistry, Book of Abstracts
180
180
A. Cavalli; M. L. Bolognesi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/69221
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