Integrated Dataset of Screening Hits against Multiple Neglected Disease Pathogens

Nwaka, Solomon; Besson, Dominique; Ramirez, Bernadette; Maes, Louis; Matheeussen, An; Bickle, Q. D.; Mansour, Nuha R.; Yousif, Fouad; Townson, Simon; Gokool, Suzanne; Cho-Ngwa, Fidelis; Samje, Moses; Misra‐Bhattacharya, Shailja; Murthy, P. K.; Fakorede, Foluke; Paris, Jean‐Marc; Yeates, Clive; Ridley, Robert G.; Voorhis, Wesley C. Van; Geary, Timothy G.

doi:10.1371/journal.pntd.0001412

Cited by 50 publications

(43 citation statements)

References 39 publications

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“…Extracellular form (epimastigote) is the most commonly used owing to its easy culture in laboratory, but tests obtained on intracellular amastigotes (responsible for the chronic phase of CD) and blood trypomastigotes are more indicative due to these form of the parasite is the developed form in vertebrate hosts 23 . According to some authors, for deeming a compound as potential antichagasic agent, it has to meet certain criteria 24 . In the first place, the IC 50 value has to be around 10 µM and the in second place the SI has to be 50 times higher than that of the reference drug.…”

Section: Resultsmentioning

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: Resultsmentioning

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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“…The initial aim of the Malaria Box was to catalyze research into malaria and the discovery of new antimalarial clinical candidates. However, the utility of the Malaria Box goes beyond the malaria field since these biologically active, cell permeable compounds are highly likely to be active against other parasitic or neglected diseases [30],[31]. The overlap between the biologies of the basic apicocomplexan parasites suggests that hits from malaria screens would be useful against leishmaniasis and trypanosomiasis, and even on helminth targets [30].…”

Section: Discussionmentioning

confidence: 99%

The Open Access Malaria Box: A Drug Discovery Catalyst for Neglected Diseases

et al. 2013

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Historically, one of the key problems in neglected disease drug discovery has been identifying new and interesting chemotypes. Phenotypic screening of the malaria parasite, Plasmodium falciparum has yielded almost 30,000 submicromolar hits in recent years. To make this collection more accessible, a collection of 400 chemotypes has been assembled, termed the Malaria Box. Half of these compounds were selected based on their drug-like properties and the others as molecular probes. These can now be requested as a pharmacological test set by malaria biologists, but importantly by groups working on related parasites, as part of a program to make both data and compounds readily available. In this paper, the analysis and selection methodology and characteristics of the compounds are described.

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“…All series which were not cidal, or which had been the subject of previously reported studies, were subsequently excluded. 25−31 The screening cascade is shown in Figure 1. 22 …”

Section: Hit Discoverymentioning

confidence: 99%

Discovery and Optimization of 5-Amino-1,2,3-triazole-4-carboxamide Series against Trypanosoma cruzi

Brand

Viayna

et al. 2017

J. Med. Chem.

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Chagas’ disease, caused by the protozoan parasite Trypanosoma cruzi, is the most common cause of cardiac-related deaths in endemic regions of Latin America. There is an urgent need for new safer treatments because current standard therapeutic options, benznidazole and nifurtimox, have significant side effects and are only effective in the acute phase of the infection with limited efficacy in the chronic phase. Phenotypic high content screening against the intracellular parasite in infected VERO cells was used to identify a novel hit series of 5-amino-1,2,3-triazole-4-carboxamides (ATC). Optimization of the ATC series gave improvements in potency, aqueous solubility, and metabolic stability, which combined to give significant improvements in oral exposure. Mitigation of a potential Ames and hERG liability ultimately led to two promising compounds, one of which demonstrated significant suppression of parasite burden in a mouse model of Chagas’ disease.

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Integrated Dataset of Screening Hits against Multiple Neglected Disease Pathogens

Cited by 50 publications

References 39 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

The Open Access Malaria Box: A Drug Discovery Catalyst for Neglected Diseases

Discovery and Optimization of 5-Amino-1,2,3-triazole-4-carboxamide Series against Trypanosoma cruzi

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