- Pharmacokinetics of hydroxymethylnitrofurazone, a promising new prodrug for chagas' disease treatment
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Hydroxymethylnitrofurazone (NFOH) is a trypanocidal prodrug of nitrofurazone (NF), devoid of mutagenic toxicity. The purpose of this work was to study the chemical conversion of NFOH into NF in sodium acetate buffer (pH 1.2 and 7.4) and in human plasma and to determine preclinical pharmacokinetic parameters in rats. At pH 1.2, the NFOH was totally transformed into NF, the parent drug, after 48 h, while at pH 7.4, after the same period, the hydrolysis rate was 20%. In human plasma, 50% of NFOH was hydrolyzed after 24 h. In the investigation of kinetic disposition, the concentration of drug in serum versus time curve was used to calculate the pharmacokinetic parameters after a single-dose regimen. NFOH showed a time to maximum concentration of drug in serum (Tmax) as 1 h, suggesting faster absorption than NF (4 h). The most important results observed were the volume of distribution (V) of NFOH through the tissues, which showed a rate that is 20-fold higher (337.5 liters/kg of body weight) than that of NF (17.64 liters/kg), and the concentration of NF obtained by in vivo metabolism of NFOH, which was about four times lower (maximum concentration of drug in serum [Cmax]=0.83 μg/ml; area under the concentration-time curve from 0 to 12 h [AUC0-12]=5.683 μg/ml · h) than observed for administered NF (Cmax=2.78 μg/ml; AUC0-12=54.49 μg/ml · h). These findings can explain the superior activity and lower toxicity of the prodrug NFOH in relation to its parent drug and confirm NFOH as a promising anti-Chagas' disease drug candidate. Copyright
- Serafim, Eliana Ometto Pavan,De Albuquerque E Silva, Antonio Tavora,De Haro Moreno, Andreia,De Oliveira Vizioli, Ednir,Ferreira, Elizabeth Igne,Peccinini, Rosangela Goncalves,Ribeiro, Maria Lucia,Chung, Man Chin
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- ESR SPECTRA OF ELECTROCHEMICALLY GENERATED ANION RADICALS OF THE NITROFURAN SERIES
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ESR spectra of anion radicals for 29 derivatives of 5-nitrofuran, elctrochemically generated in situ, have been obtained and studied.Using spectral HFS constants and quantum chemical model parameters (INDO), the structures of ?- and ?-electron systems of 2-nitrofuran and its anion radical have been investigated.Furan ring substituent effects on lone electron distribution have been investigated.On the lone electron level, transmission of substituent effects through the ring has been found to be higher in the case of furan, and lower in the case of thiophene and selenophene, with respect to the benzene ring.Delocalization of the lone electron in various ring-attached substituents has been elucidated.Kinetic studies of radical decay showed a rise in stability with increasing delocalization of the lone electron.
- Gavars, R.,Stradins, J.,Baumane, L.,Baider, L.
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- Nitrofuran drugs beyond redox cycling: Evidence of Nitroreduction-independent cytotoxicity mechanism
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Nitrofurans (5-nitro-2-hydrazonylfuran as pharmacophore) are a group of widely used antimicrobial drugs but also associated to a variety of side effects. The molecular mechanisms that underlie the cytotoxic effects of nitrofuran drugs are not yet clearly understood. One-electron reduction of 5-nitro group by host enzymes and ROS production via redox cycling have been attributed as mechanisms of cell toxicity. However, the current evidence suggests that nitrofuran ROS generation by itself is uncapable to explain the whole toxic effects associated to nitrofuran consumption, proposing a nitro-reduction independent mechanism of toxicity. In the present work, a series of nitrated and non-nitrated derivatives of nitrofuran drugs were synthesized and evaluated in vitro for their cytotoxicity, ROS-producing capacity, effect on GSH-S-transferase and antibacterial activity. Our studies showed that in human cells non-nitrated derivatives were less toxic than parental drugs but, unexpectedly preserved the ability to generate intracellular ROS in similar amounts to nitrofurans despite not entering into a redox cycle mechanism. In addition, some non-nitrated derivatives although being uncapable to generate ROS exhibited the highest cell toxicity among all derivatives. Inhibition of cytosolic glutathione-S-transferase activity by some derivatives was also observed. Finally, only nitrofuran derivatives displayed antibacterial effect. Results suggest that the combined 2-hydrazonylfuran moiety, redox cycling of 5-nitrofuran, and inhibitory effects on antioxidant enzymes, would be finally responsible for the toxic effects of the studied nitrofurans on mammalian cells.
- Gallardo-Garrido,Cho,Cortés-Rios,Vasquez,Pessoa-Mahana,Araya-Maturana,Pessoa-Mahana,Faundez
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- A general and convenient synthesis of 4-(tosylmethyl)semicarbazones and their use in amidoalkylation of hydrogen, heteroatom, and carbon nucleophiles
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A general synthesis of previously unknown semicarbazone-based α-amidoalkylating reagents, 4-(tosylmethyl)semicarbazones, has been developed. The synthesis involved three-component condensation of semicarbazones of aliphatic or aromatic aldehydes with the same or other aldehydes and p-toluenesulfinic acid. The scope and limitations of this reaction were investigated. The compounds obtained were demonstrated to be an efficient α-(4-semicarbazono)alkylating agents. They were reacted with H- (sodium borohydride), O- (sodium methylate), S- (sodium phenylthiolate), N- (pyrrolidine, sodium succinimide), P- (trialkyl phosphites), and C-nucleophiles (sodium diethyl malonate) to give the corresponding products of the tosyl group substitution, 4-substituted semicarbazones, including analogues of nitrofurazone. Among the prepared compounds tested in vitro for antibacterial and antifungal activity, three nitrofuryl-containing semicarbazones exhibited high biological activities with minimum inhibitory concentration (MIC) values of 8–32 μg/mL.
- Fesenko, Anastasia A.,Yankov, Alexander N.,Shutalev, Anatoly D.
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- Biological evaluation of arylsemicarbazone derivatives as potential anticancer agents
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Fourteen arylsemicarbazone derivatives were synthesized and evaluated in order to find agents with potential anticancer activity. Cytotoxic screening was performed against K562, HL-60, MOLT-4, HEp-2, NCI-H292, HT-29 and MCF-7 tumor cell lines. Compounds 3c and 4a were active against the tested cancer cell lines, being more cytotoxic for the HL-60 cell line with IC50 values of 13.08 μμM and 11.38 μμM, respectively. Regarding the protein kinase inhibition assay, 3c inhibited seven different kinases and 4a strongly inhibited the CK1δ/ε kinase. The studied kinases are involved in several cellular functions such as proliferation, migration, cell death and cell cycle progression. Additional analysis by flow cytometry revealed that 3c and 4a caused depolarization of the mitochondrial membrane, suggesting apoptosis mediated by the intrinsic pathway. Compound 3c induced arrest in G1 phase of the cell cycle on HL-60 cells, and in the annexin V assay approximately 50% of cells were in apoptosis at the highest concentration tested (26 μμM). Compound 4a inhibited cell cycle by accumulation of abnormal postmitotic cells at G1 phase and induced DNA fragmentation at the highest concentration (22 μμM).
- da Cruz, Anne Cecília Nascimento,Brondani, Dalci José,de Santana, Temístocles I′Talo,da Silva, Lucas Oliveira,Borba, Elizabeth Fernanda da Oliveira,de Faria, Ant?nio Rodolfo,de Albuquerque, Julianna Ferreira Cavalcanti,Piessard, Sylvie,Ximenes, Rafael Matos,Baratte, Blandine,Bach, Stéphane,Ruchaud, Sandrine,Mendon?a Junior, Francisco Jaime Bezerra,Bazin, Marc-Antoine,Rabello, Marcelo Montenegro,Hernandes, Marcelo Zaldini,Marchand, Pascal,da Silva, Teresinha Gon?alves
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- Method for synthesizing furacilin under catalysis of supported catalyst
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The invention discloses a method for synthesizing furacilin under catalysis of a supported catalyst and belongs to the field of chemical synthesis. A 5-nitrofurfural intermediate is synthesized from furfuryl alcohol used as a raw material through steps of esterification, nitration, deprotection, oxidation and the like, and then, 5-nitrofurfural and semicarbazide are subjected to a condensation reaction under the catalytic action of the supported catalyst CuO/CNTs to produce furacilin. The method is simple to operate, the adopted catalyst has the characteristics of being non-toxic, easy to remove and renewable, and the product yield is high.
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- Synthesis, properties, and application of 4-nitrosemicarbazones
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The studies of the condensation of 4-nitrosemicarbazide (4-NSC) with various aldehydes and ketones resulted in the development of an approach to the synthesis of N-nitrosemicarbazones, promising high-energy and biologically active compounds. Subsequent treatment with amines and alkalis led to the synthesis of water-soluble salts of nitrosemicarbazones, as well as the corresponding semicarbazones. The reaction of N,N′-diisopropyl- or N,N′-di-tert-butyl-1,2-ethanediimine with 4-nitrosemicarbazide led to the synthesis of glyoxal bis(nitrosemicarbazone) derivatives. A computer-aided screening using the PASS software showed a probability of high biological activity for the compounds obtained, whereas antiarrhythmic properties of camphor nitrosemicarbazone potassium salt were confirmed in experiments in rats.
- Glukhacheva,Il’yasov,Sakovich,Tolstikova,Bryzgalov,Pleshkova
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p. 550 - 560
(2017/03/08)
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- Synthesis and biological activity of nitro heterocycles analogous to megazol, a trypanocidal lead
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As part of our efforts to develop new compounds aimed at the therapy of parasitic infections, we synthesized and assayed analogues of a lead compound megazol, 5-(1-methyl-5-nitro-1H-2-imidazolyl)-1,3,4-thiadiazol-2-amine, CAS no. 19622-55-0), in vitro. We first developed a new route for the synthesis of megazol. Subsequently several structural changes were introduced, including substitutions on the two rings of the basic nucleus, replacement of the thiadiazole by an oxadiazole, replacement of the nitroimidazole part by a nitrofurane or a nitrothiophene, and substitutions on the exocyclic nitrogen atom for evaluation of an improved import by the glucose or the purine transporters. Assays of the series of compounds on the protozoan parasites Trypanosoma brucei, Trypanosoma cruzi, and Leishmania donovani, as either extracellular cells or infected macrophages, indicated that megazol was more active than the derivatives. Megazol was then evaluated on primates infected with Trypanosoma brucei gambiense, including late-stage central nervous system infections in combination with suramin. Full recovery was observed in five monkeys in the study with no relapse of parasitemia within a 2 year follow-up. Because there is a lack of efficacious treatments for sleeping sickness in Africa and Chagas disease in South America, megazol is proposed as a potential alternative. The mutagenicity of this compound is at present being reevaluated, and metabolism is also under investigation prior to possible further developments.
- Chauvière, Gérard,Bouteille, Bernard,Enanga, Bertin,De Albuquerque, Cristina,Croft, Simon L.,Dumas, Michel,Périé, Jacques
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p. 427 - 440
(2007/10/03)
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- Trypanosoma cruzi: Effect and mode of action of nitroimidazole and nitrofuran derivatives
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With the aim of determining the actual target(s) of nitro-group bearing compounds considered as possible leads for the development of drugs against Chagas' disease, we studied in parallel nitrofurans and nitroimidazoles. We investigated nine representative compounds for the following properties: efficacy on different Trypanosoma cruzi strains, redox cyclers, inhibition of respiration, production of corresponding nitroso derivatives and intracellular thiol scavengers. Our results indicate that nifurtimox and related compounds act as redox cyclers, whereas the most active in the series, the 5-nitroimidazole megazol essentially acts as thiol scavenger particularly for trypanothione, the cofactor for trypanothione reductase, an essential enzyme in the detoxification process.
- Maya, Juan Diego,Bollo, Soledad,Nunez-Vergara, Luis J.,Squella, Juan A.,Repetto, Yolanda,Morello, Antonio,Perie, Jacques,Chauviere, Gerard
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p. 999 - 1006
(2007/10/03)
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- Process for formulating a synthetic drug for use in animal feed, and resulting formulation
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A method of formulating a synthetic drug for use in animal feed, for the purpose of reducing carry-over of the synthetic drug to subsequent lots of animal feed in the feed mill.
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- The Reaction of Aniline with 5-Nitro-2-furaldehyde. A Model for Non-Enzymic Browning Reactions
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The condensation between 5-nitro-2-furaldehyde and aniline, a model for food browning reactions, yields the corresponding Schiff base, 5-nitro-2-furfurylideneaniline, cleanly.The corresponding reaction with 2-furaldehyde itself yields, in contrast, a mixture of products.Since the equilibrium constant for formation of the Schiff base from 5-nitro-2-furaldehyde and aniline, 177 dm3mol-1, is not large enough to drive the reaction to completion at moderate concentrations of aniline, phenylhydrazine was employed to trap the Schiff base as it was formed: that is, the reaction with aniline was studied by examining aniline-catalysed phenylhydrazone formation.
- Rio, Maria D. del,Ojeda, Olga D. de,Urquia, M.,Scarabino, Carlos,Yunes, Rosendo A.
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p. 519 - 525
(2007/10/02)
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- Method of therapeutically treating warm blooded animals and compositions therefor
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Tissue in warm blooded animals which is damaged and/or infected is treated by administering a therapeutically effective amount of a composition containing a novel catalyst and water soluble catalyst treated lignite. The treatment is also effective in relieving stress and/or shock. In a further variant, warm blooded animals having damaged and/or infected tissue are treated with a composition containing therapeutically effective amounts of at least one antibiotic, the novel catalyst, and the catalyst treated lignite. Novel compositions are provided which contain therapeutic amounts of at least one antibiotic, the catalyst, and the catalyst treated lignite. The novel catalyst and the catalyst treated lignite are prepared by processes described in detail hereinafter.
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