Targeting metabolic pathways in microbial pathogens: oxidative stress and anti-folate drug resistance in trypanosomatids

Hunter, W.N.; Alphey, M.S.; Bond, Charles S.; Schüttelkopf, Alexander W.

doi:10.1042/bst0310607

Cited by 12 publications

(11 citation statements)

References 15 publications

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“…34,35 Taking this in account, we have given importance to iron superoxide dismutase (Fe-SOD), a trypanosomatid exclusive enzyme that is absent in other eukaryotic cells. 36,37 Alternatively, trypanosomatids have a shared redox system in which trypanothione and glutathione team up to protect the parasite from reactive oxygen species (ROS). Trypanothione [bis(glutathionyl) spermidine] is synthesized from spermidine, the major polyamine in these parasites.…”

Section: Inhibition Of the T Cruzi Fe-sod Enzymementioning

confidence: 99%

In Vitro and in Vivo Anti-Trypanosoma cruzi Activity of New Arylamine Mannich Base-Type Derivatives

et al. 2016

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ABSTRACT. Chagas disease is a neglected tropical disease with 6-7 million people infected worldwide and there is no effective treatment. Therefore, there is an urgent need to continue researching in order to discover novel therapeutic alternatives. We present a series of arylaminoketone derivatives as means of identifying new drugs to treat Chagas disease in the acute phase with greater activity, less toxicity and with a larger spectrum of action than that corresponding to the reference drug benznidazole. Indexes of high selectivity found in vitro formed the basis for later in vivo assays in BALB/c mice. Murine model results show that compounds 3, 4, 7 and 10 induced a remarkable decrease in parasitemia levels in acute phase and the parasitemia reactivation following immunosuppression, and curative rates were higher than with benznidazole. These high anti-parasitic activities encourage us to propose these compounds as promising molecules for developing an easy to synthesize anti-Chagas agent.

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Section: Inhibition Of the T Cruzi Fe-sod Enzymementioning

confidence: 99%

In Vitro and in Vivo Anti-Trypanosoma cruzi Activity of New Arylamine Mannich Base-Type Derivatives

et al. 2016

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“…Enzymes are one of the most studied therapeutic targets, and the Fe‐SOD is a trypanosomatid exclusive enzyme and absent in other eukaryotic cells . It presents biochemical and structural differences with respect to its human homologue Cu/Zn‐SOD enzyme.…”

Section: Resultsmentioning

confidence: 99%

“…Nonspecific nucleic acid degradation is af eature intimately connected to cell necrosis, [38] accordingly,D NA and RNA levels were determined ( Figure 10 Enzymes are one of the most studied therapeutic targets, and the Fe-SOD is at rypanosomatid exclusive enzyme and absent in other eukaryotic cells. [39,40] It presents biochemical and structural differencesw ith respectt oi ts human homologue Cu/Zn-SOD enzyme. The crucial role performed by this enzyme is the elimination of reactiveo xygen species( ROS), allowing trypanosomatidst op rotect themselves from the damage produced by oxidative stress.…”

Section: Studies Of the Action Mechanismmentioning

confidence: 99%

Synthesis and Biological in vitro and in vivo Evaluation of 2‐(5‐Nitroindazol‐1‐yl)ethylamines and Related Compounds as Potential Therapeutic Alternatives for Chagas Disease

et al. 2018

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Chagas disease, a neglected tropical disease caused by infection with the protozoan parasite Trypanosoma cruzi, is a potentially life-threatening illness that affects 5-8 million people in Latin America, and more than 10 million people worldwide. It is characterized by an acute phase, which is partly resolved by the immune system, but then develops as a chronic disease without an effective treatment. There is an urgent need for new antiprotozoal agents, as the current standard therapeutic options based on benznidazole and nifurtimox are characterized by limited efficacy, toxicity, and frequent failures in treatment. In vitro and in vivo assays were used to identify some new low-cost 5-nitroindazoles as a potential antichagasic therapeutic alternative. Compound 16 (3-benzyloxy-5-nitro-1-vinyl-1H-indazole) showed improved efficiency and lower toxicity than benznidazole in both in vitro and in vivo experiments, and its trypanocidal activity seems to be related to its effect at the mitochondrial level. Therefore, compound 16 is a promising candidate for the development of a new anti-Chagas agent, and further preclinical evaluation should be considered.

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“…To tackle these targets efficiently with up‐to‐date drug discovery methods, a diverse screening library is needed 6. 12 The three dimensional structures for some targets have been determined allowing virtual screening as a complementary approach to high volume biochemical screening 21. In addition, there are also potential parasite targets that are homologues of well‐known drug targets, such as parasite protein kinases 22.…”

Section: Introductionmentioning

confidence: 99%

Lessons Learnt from Assembling Screening Libraries for Drug Discovery for Neglected Diseases

et al. 2008

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To enable the establishment of a drug discovery operation for neglected diseases, out of 2.3 million commercially available compounds 222 552 compounds were selected for an in silico library, 57 438 for a diverse general screening library, and 1 697 compounds for a focused kinase set. Compiling these libraries required a robust strategy for compound selection. Rules for unwanted groups were defined and selection criteria to enrich for lead-like compounds which facilitate straightforward structure–activity relationship exploration were established. Further, a literature and patent review was undertaken to extract key recognition elements of kinase inhibitors (“core fragments”) to assemble a focused library for hit discovery for kinases. Computational and experimental characterisation of the general screening library revealed that the selected compounds 1) span a broad range of lead-like space, 2) show a high degree of structural integrity and purity, and 3) demonstrate appropriate solubility for the purposes of biochemical screening. The implications of this study for compound selection, especially in an academic environment with limited resources, are considered.

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Targeting metabolic pathways in microbial pathogens: oxidative stress and anti-folate drug resistance in trypanosomatids

Cited by 12 publications

References 15 publications

In Vitro and in Vivo Anti-Trypanosoma cruzi Activity of New Arylamine Mannich Base-Type Derivatives

In Vitro and in Vivo Anti-Trypanosoma cruzi Activity of New Arylamine Mannich Base-Type Derivatives

Synthesis and Biological in vitro and in vivo Evaluation of 2‐(5‐Nitroindazol‐1‐yl)ethylamines and Related Compounds as Potential Therapeutic Alternatives for Chagas Disease

Lessons Learnt from Assembling Screening Libraries for Drug Discovery for Neglected Diseases

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