In vitro activity and mode of action of distamycin analogues against African trypanosomes

Franco, J.; Medeiros, Andrea; Benítez, Diego; Perelmuter, Karen; Serra, Gloria; Comini, Marcelo A.; Scarone, Laura

doi:10.1016/j.ejmech.2016.12.002

Cited by 17 publications

(21 citation statements)

References 37 publications

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“…The chemical nature of the disaccharide diselenides suggests that their anti-trypanosomal activity may be a consequence of some interference with the glucose- and/or redox metabolism of the parasite. In order to infer the potential mode of action of the most active compounds, namely 13 and 15 , we first investigated the remaining level of glucose in the culture supernatant of parasites treated for 4 h with 13 , 15 , the antitrypanosomal drug suramine (a compound with multi-target activity; Willson et al., 1993 ), ebselen (an inhibitor of hexokinase 1 and trypanothione reductase from T. brucei ; Joice et al., 2013 ; | Lu et al., 2013 ) and a tri-thiazol that affects the integrity of the parasite lysosome ( Franco et al., 2017 ). All compounds were tested at their corresponding EC 50 or with the vehicle alone (1% v/v DMSO) ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Bloodstream T. b. brucei grown as described above were plated at 5.3–5.8 × 10 6 parasites/mL per well in a 24-well plate and added of 0.54 μM 13 , 1.49 μM 15 , 78 nM suramin, 5 μM ebselen, 0.31 μM tri-thiazol (compound 10b from Franco et al., 2017 ) or 1% v/v DMSO. After 4 h incubation, viable parasites were quantified by light microscopy counting on a Neubauer chamber, then centrifuged at 2000 g for 10 min at room temperature.…”

Section: Methodsmentioning

confidence: 99%

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Diglycosyl diselenides alter redox homeostasis and glucose consumption of infective African trypanosomes

Franco

Sardi

Szilágyi

et al. 2017

International Journal for Parasitology: Drugs and Drug Resistan

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With the aim to develop compounds able to target multiple metabolic pathways and, thus, to lower the chances of drug resistance, we investigated the anti-trypanosomal activity and selectivity of a series of symmetric diglycosyl diselenides and disulfides. Of 18 compounds tested the fully acetylated forms of di-β-D-glucopyranosyl and di-β-D-galactopyranosyl diselenides (13 and 15, respectively) displayed strong growth inhibition against the bloodstream stage of African trypanosomes (EC50 0.54 μM for 13 and 1.49 μM for 15) although with rather low selectivity (SI < 10 assayed with murine macrophages). Nonacetylated versions of the same sugar diselenides proved to be, however, much less efficient or completely inactive to suppress trypanosome growth. Significantly, the galactosyl (15), and to a minor extent the glucosyl (13), derivative inhibited glucose catabolism but not its uptake. Both compounds induced redox unbalance in the pathogen. In vitro NMR analysis indicated that diglycosyl diselenides react with glutathione, under physiological conditions, via formation of selenenylsulfide bonds. Our results suggest that non-specific cellular targets as well as actors of the glucose and the redox metabolism of the parasite may be affected. These molecules are therefore promising leads for the development of novel multitarget antitrypanosomal agents.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Diglycosyl diselenides alter redox homeostasis and glucose consumption of infective African trypanosomes

Franco

Sardi

Szilágyi

et al. 2017

International Journal for Parasitology: Drugs and Drug Resistan

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“…Taking into account these previous results we decided to explore the use of oxyma/EDCI or triphosgene to obtain amides from 2-aminothiazole compounds 5 or 6, Scheme 1. The thiazole and pyrrole carboxylic acids used to obtain 7, 10 and 11, were prepared as was described by our group [41].…”

Section: -Analogues Synthesismentioning

confidence: 99%

“…As part of a research program for the synthesis of potential antimalarials [37][38][39][40][41][42][43][44][45][46][47], in this work, we present the synthesis and biological evaluation against P. falciparum 3 D7 of Ntz, Tiz and 2-aminothiazole analogues, Figure 2. Compounds of A series do not present the nitro substituent in the thiazole ring in order to study the in uence of that group in the antimalarial activity.…”

Section: Introductionmentioning

confidence: 99%

Synthesis And Antiplasmodial Assessment of Nitazoxanide And Analogues As New Antimalarial Candidates

Irabuena

Scarone

Souza

et al. 2021

Preprint

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During the last years, the progression to control malaria disease seems to be slowed and WHO (World Health Organization) reported a modelling analysis with the prediction of the increase in malaria morbidity and mortality in sub-Saharan Africa during the COVID-19 pandemic. A rapid way to the discovery of new drugs could be carried out by performing investigations to identify drugs based on repurposing of “old” drugs. The 5-nitrothiazole drug, Nitazoxanide was shown to be active against intestinal protozoa, human helminths, anaerobic bacteria, viruses, etc. In this work, Nitazoxanide and analogues were prepared using two methodologies and evaluated against P. falciparum 3 D7. A bithiazole analogue, showed attractive inhibitory activity with an EC50 value of 5.9 mM and low propensity to show toxic effect against HepG2 cells at 25 mM.

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“…1) [35], as promising antimalarials with EC 50 values in the low micromolar or submicromolar range, respectively [36]. Considering these results, we decided to explore the "old" and versatile drug Ntz, its metabolite Tiz and bis-heterocycles analogs as part of a research program for the synthesis of potential antimalarials [37][38][39][40][41][42][43][44][45][46][47].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and antiplasmodial assessment of nitazoxanide and analogs as new antimalarial candidates

et al. 2022

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During the last years, the progression to control malaria disease seems to be slowed and WHO (World Health Organization) reported a modeling analysis with the prediction of the increase in malaria morbidity and mortality in sub-Saharan Africa during the COVID-19 pandemic. A rapid way to the discovery of new drugs could be carried out by performing investigations to identify drugs based on repurposing of "old" drugs. The 5-nitrothiazole drug, Nitazoxanide was shown to be active against intestinal protozoa, human helminths, anaerobic bacteria, viruses, etc. In this work, Nitazoxanide and analogs were prepared using two methodologies and evaluated against P. falciparum 3D7. A bithiazole analog, showed attractive inhibitory activity with an EC 50 value of 5.9 μM, low propensity to show toxic effect against HepG2 cells at 25 μM, and no cross-resistance with standard antimalarials.

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In vitro activity and mode of action of distamycin analogues against African trypanosomes

Cited by 17 publications

References 37 publications

Diglycosyl diselenides alter redox homeostasis and glucose consumption of infective African trypanosomes

Diglycosyl diselenides alter redox homeostasis and glucose consumption of infective African trypanosomes

Synthesis And Antiplasmodial Assessment of Nitazoxanide And Analogues As New Antimalarial Candidates

Synthesis and antiplasmodial assessment of nitazoxanide and analogs as new antimalarial candidates

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