Evaluating 5-nitrothiazoles as trypanocidal agents

OA Monitor ExerciseOA Monitor ExerciseThe growth inhibitory properties of a 5-nitrothiazole series was evaluated against Trypanosoma brucei. A subset of related compounds displayed the greatest potency towards the parasite while exhibiting little cytotoxic effect on mammalian cells, with this anti-parasitic activity being dependent on expression of a type I nitroreductase by the trypanosome. We conclude that the 5-nitrothiazole class of nitroheterocycle may represent new leads in the treatment of human African trypanosomiasis.BAV acknowledges financial support by FONDECYT Postdoctorado 313036

3-Nitrotriazole-based piperazides as potent antitrypanosomal agents

publisher: Elsevier articletitle: 3-Nitrotriazole-based piperazides as potent antitrypanosomal agents journaltitle: European Journal of Medicinal Chemistry articlelink: http://dx.doi.org/10.1016/j.ejmech.2015.08.042 content_type: article copyright: Copyright © 2015 Elsevier Masson SAS. All rights reserved.publisher: Elsevier articletitle: 3-Nitrotriazole-based piperazides as potent antitrypanosomal agents journaltitle: European Journal of Medicinal Chemistry articlelink: http://dx.doi.org/10.1016/j.ejmech.2015.08.042 content_type: article copyright: Copyright © 2015 Elsevier Masson SAS. All rights reserved.publisher: Elsevier articletitle: 3-Nitrotriazole-based piperazides as potent antitrypanosomal agents journaltitle: European Journal of Medicinal Chemistry articlelink: http://dx.doi.org/10.1016/j.ejmech.2015.08.042 content_type: article copyright: Copyright © 2015 Elsevier Masson SAS. All rights reserved.publisher: Elsevier articletitle: 3-Nitrotriazole-based piperazides as potent antitrypanosomal agents journaltitle: European Journal of Medicinal Chemistry articlelink: http://dx.doi.org/10.1016/j.ejmech.2015.08.042 content_type: article copyright: Copyright © 2015 Elsevier Masson SAS. All rights reserved

Challenges in Chagas Disease Drug Development.

The protozoan parasite Trypanosoma cruzi causes Chagas disease, an important public health problem throughout Latin America. Current therapeutic options are characterised by limited efficacy, long treatment regimens and frequent toxic side-effects. Advances in this area have been compromised by gaps in our knowledge of disease pathogenesis, parasite biology and drug activity. Nevertheless, several factors have come together to create a more optimistic scenario. Drug-based research has become more systematic, with increased collaborations between the academic and commercial sectors, often within the framework of not-for-profit consortia. High-throughput screening of compound libraries is being widely applied, and new technical advances are helping to streamline the drug development pipeline. In addition, drug repurposing and optimisation of current treatment regimens, informed by laboratory research, are providing a basis for new clinical trials. Here, we will provide an overview of the current status of Chagas disease drug development, highlight those areas where progress can be expected, and describe how fundamental research is helping to underpin the process

Functional characterisation of the methionine sulfoxide reductase repertoire in Trypanosoma brucei

We thank Guy Hanke (QMUL) for their critical review of this manuscript. We acknowledge the members of the T. brucei genome (http://tritrypdb.org/tritrypdb/) and TrypTag (http://tryptag.org) projects for sequence and localisation data, respectively. A component of this work was supported by grants from ANPCyT (PICT-2015-1149; PICT-2014-2103). SAG, and DGA are investigator career members from CONICET. AK was a recipient of a Queen Mary University of London PhD studentshi

Evaluating 5-nitrofurans as trypanocidal agents

The nitroheterocycle nifurtimox, as part of a nifurtimox-eflornithine combination therapy, represents one of a limited number of treatments targeting Trypanosoma brucei, the causative agent of human African trypanosomiasis. The mode of action of this prodrug involves an initial activation reaction catalysed by a type I nitroreductase (NTR), an enzyme found predominantly in prokaryotes, leading to the formation of a cytotoxic unsaturated open chain nitrile metabolite. Here, we evaluate the trypanocidal activity of a library of other 5-nitrofurans against bloodstream form T. brucei as a preliminary step in the identification of additional nitroaromatic compounds that could potentially partner eflornithine. Biochemical screening against purified enzyme revealed that all 5-nitrofurans were effective substrates for TbNTR with the preferred compounds having apparent kcat/KM values approximately 50-fold greater than nifurtimox. For several compounds, in vitro reduction by this nitroreductase yielded products characterized by mass spectroscopy as either unsaturated or saturated open chain nitriles. When tested against bloodstream form T. brucei, many of the derivatives displayed significant growth inhibitory properties with the most potent compounds generating IC50 values around 200 nM. The anti-parasitic activity of the most potent agents was demonstrated to be NTR dependent as parasites having reduced levels of the enzyme displayed resistance to the compounds while parasites over expressing TbNTR showed hypersensitivity. We conclude that other members of the 5-nitrofurans class of nitroheterocycles have potential to treat human African trypanosomiasis perhaps as an alternative partner prodrug to nifurtimox in the next generation of eflornithine-based combinational therapies

Discovery of potent nitrotriazole-based antitrypanosomal agents: In vitro and in vivo evaluation

publisher: Elsevier articletitle: Discovery of potent nitrotriazole-based antitrypanosomal agents: In vitro and in vivo evaluation journaltitle: Bioorganic & Medicinal Chemistry articlelink: http://dx.doi.org/10.1016/j.bmc.2015.08.014 content_type: article copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.publisher: Elsevier articletitle: Discovery of potent nitrotriazole-based antitrypanosomal agents: In vitro and in vivo evaluation journaltitle: Bioorganic & Medicinal Chemistry articlelink: http://dx.doi.org/10.1016/j.bmc.2015.08.014 content_type: article copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.publisher: Elsevier articletitle: Discovery of potent nitrotriazole-based antitrypanosomal agents: In vitro and in vivo evaluation journaltitle: Bioorganic & Medicinal Chemistry articlelink: http://dx.doi.org/10.1016/j.bmc.2015.08.014 content_type: article copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.publisher: Elsevier articletitle: Discovery of potent nitrotriazole-based antitrypanosomal agents: In vitro and in vivo evaluation journaltitle: Bioorganic & Medicinal Chemistry articlelink: http://dx.doi.org/10.1016/j.bmc.2015.08.014 content_type: article copyright: Copyright © 2015 Elsevier Ltd. All rights reserved