Rational design of nitrofuran derivatives: Synthesis and valuation as inhibitors of Trypanosoma cruzi trypanothione reductase

Arias, Diego Gustavo; Herrera, Fernando E.; Garay, A. Sergio; Rodrígues, Daniel E.; Forastieri, Pamela Soledad; Luna, Liliana E.; Bürgi, Milagros; Prieto, Claudio; Iglesias, Alberto A.; Cravero, Raquel M.; Guerrero, Sandra

doi:10.1016/j.ejmech.2016.10.055

Cited by 30 publications

(21 citation statements)

References 46 publications

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“…However, there is a relative lack of information about the enzymes responsible for these reactions in parasites. Another point of view is that in trypanosomatids and Leishmania spp., a possible mode of ArNO 2 action is the inhibition of the antioxidant flavoenzyme trypanothione reductase (TR) [11][12][13][14][15][16]. In this case, nitroaromatics also undergo TR-catalyzed redox cycling.…”

Section: Introductionmentioning

confidence: 99%

Antiplasmodial Activity of Nitroaromatic Compounds: Correlation with Their Reduction Potential and Inhibitory Action on Plasmodium falciparum Glutathione Reductase

et al. 2019

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With the aim to clarify the mechanism(s) of action of nitroaromatic compounds against the malaria parasite Plasmodium falciparum, we examined the single-electron reduction by P. falciparum ferredoxin:NADP+ oxidoreductase (PfFNR) of a series of nitrofurans and nitrobenzenes (n = 23), and their ability to inhibit P. falciparum glutathione reductase (PfGR). The reactivity of nitroaromatics in PfFNR-catalyzed reactions increased with their single-electron reduction midpoint potential (E17). Nitroaromatic compounds acted as non- or uncompetitive inhibitors towards PfGR with respect to NADPH and glutathione substrates. Using multiparameter regression analysis, we found that the in vitro activity of these compounds against P. falciparum strain FcB1 increased with their E17 values, octanol/water distribution coefficients at pH 7.0 (log D), and their activity as PfGR inhibitors. Our data demonstrate that both factors, the ease of reductive activation and the inhibition of PfGR, are important in the antiplasmodial in vitro activity of nitroaromatics. To the best of our knowledge, this is the first quantitative demonstration of this kind of relationship. No correlation between antiplasmodial activity and ability to inhibit human erythrocyte GR was detected in tested nitroaromatics. Our data suggest that the efficacy of prooxidant antiparasitic agents may be achieved through their combined action, namely inhibition of antioxidant NADPH:disulfide reductases, and the rapid reduction by single-electron transferring dehydrogenases-electrontransferases.

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Section: Introductionmentioning

confidence: 99%

Antiplasmodial Activity of Nitroaromatic Compounds: Correlation with Their Reduction Potential and Inhibitory Action on Plasmodium falciparum Glutathione Reductase

et al. 2019

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“…To the best of our knowledge, this is the first demonstration of the semiquantitative relationship between the antitrypanosomal in vitro activity of a series of homologous compounds, and their efficacy as TR inhibitors. Interestingly, this type of parallelism has not been observed in the recent studies of hybrids of indole and 1,3-thiazole [24,25], and amides of 5-nitrofuran-2-carbonic acid [9]. In our opinion, this may be attributed to the presence of a great variety of functional groups in the investigated compounds, and/or to the differences in their lipophilicity.…”

Section: Discussionmentioning

confidence: 64%

“…Another potentially more important factor is their 2/4-electron reduction by NADH-dependent oxygen-insensitive nitroreductase(s), which yields hydroxylamines and their secondary products that alkylate DNA [1,6,7]. In addition, nitroheterocycles, in particular nitrofurans, inhibit enzyme trypanothione reductase (TR) [4,8,9], which is essential for parasite virulency and survival [10]. TR regenerates reduced glutathione-spermidine conjugate, trypanothione (T(SH) 2 ), at the expense of NADPH.…”

Section: Introductionmentioning

confidence: 99%

5-Vinylquinoline-substituted nitrofurans as inhibitors of trypanothione reductase and antitrypanosomal agents

Benítez¹,

Comini²,

Anusevičius³

et al. 2020

chemija

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Trypanothione reductase (TR) and trypanothione synthase (TS) are critical for the maintenance of thiol-redox homeostasis and antioxidant protection in trypanosomal parasites, which cause African sleeping sickness and Chagas disease. Both enzymes are absent in mammals. Thus, the design of efficient and specific TR and TS inhibitors represents one of the pathways for a development of new antitrypanosomal drugs. 5-Vinylquinoline-substituted nitrofurans (n = 7), studied in this work, acted as un- or noncompetitive to trypanothione inhibitors of Trypanosoma congolense TR. Their inhibition constants (Ki) varied from 2.3 µM to 150 µM. We for the first time observed a parallelism between their antitrypanosomal in vitro activity and their efficacy as TR inhibitors. The inhibition of TS appears not to be a significant factor of trypanocidal activity of examined compounds.

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“…This was the case for propyl/isopropyl quinoxaline-7-carboxylate 1,4-di-N-oxide-based compounds, active against T. cruzi, which were found to target TrypR by using docking simulations and enzymatic validation (Chaćon-Vargas et al 2017). Arias et al (2017) synthesized a set of nitrofuran derivatives, which demonstrated uncompetitive inhibition of TrypR in subsequent experiments. Docking studies indicated that the inhibitors may in fact be capable of binding to the enzymesubstrate complex, thus explaining the observed behavior.…”

Section: Trypanothione Metabolismmentioning

confidence: 99%

Hits and Lead Discovery in the Identification of New Drugs against the Trypanosomatidic Infections

Calogeropoulou¹,

Magoulas²,

Pöhner³

et al. 2019

Medicinal Chemistry of Neglected and Tropical Diseases

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The Neglected Tropical Diseases (NTDs) are a group of 17 pathologies, recognized by the World Health Organization (WHO), which are endemic in 149 countries of tropical and subtropical areas of the globe, and affect more than one billion people overall (Feasey et al. 2010). The pathologies are all caused by microparasites or macroparasites. Among the diseases provoked by microparasites, three are caused by kinetoplastidae, a group of flagellated protozoa transmitted by insect vectors: Chagas disease, Human African Trypanosomiasis and leishmaniasis. The focus of the present chapter is on the identification of new drugs for the treatment of trypanosomatidic infections such as Chagas disease, caused by Trypanosoma cruzi, and Human African Trypanosomiasis, caused by Trypanosoma brucei (Filardy et al. 2018).

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Rational design of nitrofuran derivatives: Synthesis and valuation as inhibitors of Trypanosoma cruzi trypanothione reductase

Cited by 30 publications

References 46 publications

Antiplasmodial Activity of Nitroaromatic Compounds: Correlation with Their Reduction Potential and Inhibitory Action on Plasmodium falciparum Glutathione Reductase

Antiplasmodial Activity of Nitroaromatic Compounds: Correlation with Their Reduction Potential and Inhibitory Action on Plasmodium falciparum Glutathione Reductase

5-Vinylquinoline-substituted nitrofurans as inhibitors of trypanothione reductase and antitrypanosomal agents

Hits and Lead Discovery in the Identification of New Drugs against the Trypanosomatidic Infections

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