Identification of di-substituted ureas that prevent growth of trypanosomes through inhibition of translation initiation

Machado, Fabricio; Franco, Caio Haddad; Neto, Jose Vitorino dos Santos; Teixeira, Karina Luiza Dias; Moraes, Carolina Borsoi; Lopes, Ulisses Gazos; Aktas, Bertal H.; Schenkman, Sérgio

doi:10.1038/s41598-018-23259-9

Cited by 6 publications

(11 citation statements)

References 60 publications

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“…Cells: Monkey kidney epithelial cells LLC-MK2 ( Macaca mulatta ) and VERO ( Cercopithecus aethiops ) were kindly provided by S. Schenkman (Federal University of São Paulo, Brazil) [33] and A. Tanuri (Federal University of Rio de Janeiro, Brazil) [34]. The human cell lines U2OS (osteosarcoma, BCRJ0304) and THP-1 (monocytic leukemia, BCRJ0234) were obtained from the Rio de Janeiro Cell Bank (BCRJ, Brazil), whereas the rat ( Rattus norvegicus ) skeletal myoblast L6 cell line (IFO50364) was obtained from the Japanese Collection of Research Bioresources (JCRB, Japan).…”

Section: Methodsmentioning

confidence: 99%

Drug Discovery for Chagas Disease: Impact of Different Host Cell Lines on Assay Performance and Hit Compound Selection

et al. 2019

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Cell-based screening has become the major compound interrogation strategy in Chagas disease drug discovery. Several different cell lines have been deployed as host cells in screening assays. However, host cell characteristics and host-parasite interactions may play an important role when assessing anti-T. cruzi compound activity, ultimately impacting on hit discovery. To verify this hypothesis, four distinct mammalian cell lines (U2OS, THP-1, Vero and L6) were used as T. cruzi host cells in High Content Screening assays. Rates of infection varied greatly between different host cells. Susceptibility to benznidazole also varied, depending on the host cell and parasite strain. A library of 1,280 compounds was screened against the four different cell lines infected with T. cruzi, resulting in the selection of a total of 82 distinct compounds as hits. From these, only two hits were common to all four cell lines assays (2.4%) and 51 were exclusively selected from a single assay (62.2%). Infected U2OS cells were the most sensitive assay, as 55 compounds in total were identified as hits; infected THP-1 yielded the lowest hit rates, with only 16 hit compounds. Of the selected hits, compound FPL64176 presented selective anti-T. cruzi activity and could serve as a starting point for the discovery of new anti-chagasic drugs.

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Section: Methodsmentioning

confidence: 99%

Drug Discovery for Chagas Disease: Impact of Different Host Cell Lines on Assay Performance and Hit Compound Selection

et al. 2019

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“…Reactions were performed at room temperature for the time required without stirring. The reaction was monitored by 1 H-and 13 C-NMR using a Varian Inova 400 ( 1 H, 400; 13 C, 100 MHz) instrument. General procedure: 20 mg of catechol carbonate was added into an NMR tube containing an excess (10:1 or 5:1) of amine in 0.6 mL of DMSO-d 6 .…”

Section: T H Imentioning

confidence: 99%

“…The chemical structure was confirmed by 1 H-and 13 C-NMR spectroscopy (in deuterated trifluoroacetic acid, TFA-d) together with attenuated total reflectance-Fourier transform infrared spectroscopy (Perkin Elmer ATR-FTIR: 32 scans with 4 cm −1 of resolution over a 450−4000 cm −1 wavelength range). 1 H-NMR analysis has also been used to calculate the molecular weight (see the Supporting Information, Figures S38 and S40).…”

Section: T H Imentioning

confidence: 99%

“…Substituted urea can be exploited in a wide range of applications: as antioxidants in gasoline, agricultural chemicals, − dyes and intermediates, − additives in polymers synthesis, or thanks to their useful biological activities as structural components for drugs, HIV protease inhibitors, heme-regulated inhibitor kinase (HRI), CCK-B receptor, and endothelin antagonists, to name a few. − Moreover, their structures represent the skeleton of polymeric materials such as polyurea (PU) . Although PUs have been known for years in industry for their peculiar properties and high performance, huge efforts have been done in order to find new applications for these compounds.…”

Section: Introductionmentioning

confidence: 99%

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Urea and Polyurea Production: An Innovative Solvent- and Catalyst-Free Approach through Catechol Carbonate

Soccio

Mazzoni

Lucarelli

et al. 2020

ACS Sustainable Chem. Eng.

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The peculiar reactivity of catechol carbonate (CC) with amines and polyamines in both solvent-and catalyst-free conditions is herein described. In all the tests performed at room temperature, CC conversion reached 100% in a few seconds leading to the selective formation of the corresponding 2hydroxyphenylcarbamate. This compound is further rapidly converted to the disubstituted urea by the consecutive nucleophilic attack of another amine. Noteworthy, the application of this approach can be successfully extended to the one-pot bioaminebased synthesis of polyurea as herein proposed for the first time in the literature. The reaction is of general purpose for primary amines, and catechol can be easily recovered by sublimation as pure crystals ready to be recycled for the synthesis of new CC. An exception is related to the reactivity of secondary amine, which leads to the selective formation of substituted phenolic carbamates (e.g., 2-hydroxyphenyl diethylcarbamate), suitable as intermediates in medicinal chemistry.

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“…The utilisation of host cells relevant to in vivo models or sites of human infection may help facilitate translation in T. cruzi drug discovery. Host cells commonly used in T. cruzi compound sensitivity assays include U2OS (human osteosarcoma cell line) [ 13 , 16 , 17 ], VERO (African green monkey kidney cells) [ 11 , 13 , 18 , 19 ], and L6 (rat myoblast) [ 13 , 17 , 20 , 21 , 22 ]. As U2OS is a cancer cell line, up or down regulation of protein expression is likely when compared to its to non-cancerous counterpart [ 23 ], which may affect the growth/metabolism of intracellular parasites and hence compound activity.…”

Section: Introductionmentioning

confidence: 99%

Impact of Laboratory-Adapted Intracellular Trypanosoma cruzi Strains on the Activity Profiles of Compounds with Anti-T. cruzi Activity

2023

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Chagas disease is caused by infection with the protozoan parasite, Trypanosoma cruzi. The disease causes ~12,000 deaths annually and is one of the world’s 20 neglected tropical diseases, as defined by the World Health Organisation. The drug discovery pipeline for Chagas disease currently has few new clinical candidates, with high attrition rates an ongoing issue. To determine if the Trypanosoma cruzi strain utilised to assess in vitro compound activity impacts activity, a comparison of laboratory-adapted T. cruzi strains from differing geographical locations was undertaken for a selection of compounds with anti-T. cruzi activity. To minimise the possible effect of differences in experimental methodology, the same host cell and multiplicity of infection were utilised. To determine whether the compound exposure time influenced results, activity was determined following exposure for 48 and 72 h of incubation. To ascertain whether replication rates affected outcomes, comparative rates of replication of the T. cruzi strains were investigated, using the nucleoside analogue, 5-ethynyl-2′-deoxyuridine. Minimal differences in the in vitro activity of compounds between strains were observed following 48 h incubation, whereas significant differences were observed following 72 h incubation, in particular for the cytochrome P450 inhibitors tested and the cell cycle inhibitor, camptothecin. Thus, the use of panels of laboratory adapted strains in vitro may be dependent on the speed of action that is prioritised. For the identification of fast-acting compounds, an initial shorter duration assay using a single strain may be used. A longer incubation to identify compound activity may alternatively require profiling of compounds against multiple T. cruzi strains.

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Identification of di-substituted ureas that prevent growth of trypanosomes through inhibition of translation initiation

Cited by 6 publications

References 60 publications

Drug Discovery for Chagas Disease: Impact of Different Host Cell Lines on Assay Performance and Hit Compound Selection

Drug Discovery for Chagas Disease: Impact of Different Host Cell Lines on Assay Performance and Hit Compound Selection

Urea and Polyurea Production: An Innovative Solvent- and Catalyst-Free Approach through Catechol Carbonate

Impact of Laboratory-Adapted Intracellular Trypanosoma cruzi Strains on the Activity Profiles of Compounds with Anti-T. cruzi Activity

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