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

Brand, Stephen; Ko, Eun Jung; Viayna, Elisabet; Thompson, Stephen; Spinks, Daniel; Thomas, Michael G.; Sandberg, Lars; Francisco, Amanda Fortes; Jayawardhana, Shiromani; Smith, Victoria; Jansen, Chimed; Rycker, Manu De; Thomas, John; MacLean, Lorna; Osuna‐Cabello, Maria; Riley, Jennifer; Scullion, Paul; Stojanovski, Laste; Simeons, Frederick R. C.; Epemolu, Ola; Shishikura, Yoko; Crouch, Sabrinia; Bakshi, Tania; Nixon, C. J.; Reid, Iain H.; Hill, Anthony; Underwood, Tim; Hindley, Seán; Robinson, Sharon A.; Kelly, John M.; Fiandor, José M.; Wyatt, Paul G.; Marco, María; Miles, Timothy J.; Read, Kevin D.; Gilbert, Ian H.

doi:10.1021/acs.jmedchem.7b00463

Cited by 38 publications

(31 citation statements)

References 65 publications

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“…This bioluminescence imaging system has now been incorporated into several Chagas disease drug development programmes [ 34 , 52 , 106 ]. It can be used to monitor drug efficacy against both acute and chronic infections ( Figure 2 A,B, Figure 3 B) [ 34 , 67 ], enables several different dosing regimens to be assessed in parallel, allows tissue-specific differences in drug sensitivity to be investigated, and can be adapted to study the correlation between drug activity and disease pathology [ 53 ].…”

Section: Highly Sensitive In Vivo Bioluminescence Imaging and Its mentioning

confidence: 99%

Challenges in Chagas Disease Drug Development

et al. 2020

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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.

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Section: Highly Sensitive In Vivo Bioluminescence Imaging and Its mentioning

confidence: 99%

Challenges in Chagas Disease Drug Development

et al. 2020

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“…5-Amino-1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carbonitrile ( 1aj ): Prepared following the procedure of Brand et al [35] in 77% yield following recrystallization from ethanol as a red solid. 1 H-NMR (400 MHz, DMSO- d 6 ) δ 7.51 (m, 1H), 7.26 (s, 2H), 7.21–7.10 (m, 2H), 5.40 (d, J = 1.1 Hz, 2H).…”

Section: Methodsmentioning

confidence: 99%

Flow Hydrodediazoniation of Aromatic Heterocycles

2019

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Continuous flow processing was applied for the rapid replacement of an aromatic amino group with a hydride. The approach was applied to a range of aromatic heterocycles, confirming the wide scope and substituent-tolerance of the processes. Flow equipment was utilized and the process optimised to overcome the problematically-unstable intermediates that have restricted yields in previous studies relying on batch procedures. Various common organic solvents were investigated as potential hydride sources. The approach has allowed key structures, such as amino-pyrazoles and aminopyridines, to be deaminated in good yield using a purely organic-soluble system.

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“…Posaconazole was purchased from Sequoia Research Products. All other compounds were synthesised in house as previously published [12][13][14][15][16][17].…”

Section: Reagentsmentioning

confidence: 99%

Live-imaging rate-of-kill compound profiling for Chagas disease drug discovery with a new automated high-content assay

et al. 2021

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Chagas disease, caused by the protozoan intracellular parasite Trypanosoma cruzi, is a highly neglected tropical disease, causing significant morbidity and mortality in central and south America. Current treatments are inadequate, and recent clinical trials of drugs inhibiting CYP51 have failed, exposing a lack of understanding of how to translate laboratory findings to the clinic. Following these failures many new model systems have been developed, both in vitro and in vivo, that provide improved understanding of the causes for clinical trial failures. Amongst these are in vitro rate-of-kill (RoK) assays that reveal how fast compounds kill intracellular parasites. Such assays have shown clear distinctions between the compounds that failed in clinical trials and the standard of care. However, the published RoK assays have some key drawbacks, including low time-resolution and inability to track the same cell population over time. Here, we present a new, live-imaging RoK assay for intracellular T. cruzi that overcomes these issues. We show that the assay is highly reproducible and report high time-resolution RoK data for key clinical compounds as well as new chemical entities. The data generated by this assay allow fast acting compounds to be prioritised for progression, the fate of individual parasites to be tracked, shifts of mode-of-action within series to be monitored, better PKPD modelling and selection of suitable partners for combination therapy.

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

Cited by 38 publications

References 65 publications

Challenges in Chagas Disease Drug Development

Challenges in Chagas Disease Drug Development

Flow Hydrodediazoniation of Aromatic Heterocycles

Live-imaging rate-of-kill compound profiling for Chagas disease drug discovery with a new automated high-content assay

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