- Design, synthesis and biological evaluation of N-oxide derivatives with potent in vivo antileishmanial activity
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Leishmaniasis is a neglected disease that affects 12 million people living mainly in developing countries. Herein, 24 new N-oxide-containing compounds were synthesized followed by in vitro and in vivo evaluation of their antileishmanial activity. Compound 4f, a furoxan derivative, was particularly remarkable in this regard, with EC50 value of 3.6 μM against L. infantum amastigote forms and CC50 value superior to 500 μM against murine peritoneal macrophages. In vitro studies suggested that 4f may act by a dual effect, by releasing nitric oxide after biotransformation and by inhibiting cysteine protease CPB (IC50: 4.5 μM). In vivo studies using an acute model of infection showed that compound 4f at 7.7 mg/Kg reduced ~90% of parasite burden in the liver and spleen of L. infantum-infected BALB/c mice. Altogether, these outcomes highlight furoxan 4f as a promising compound for further evaluation as an antileishmanial agent.
- da Costa Clementino, Leandro,Fernandes, Guilherme Felipe Santos,Prokopczyk, Igor Muccilo,Laurindo, Wilquer Castro,Toyama, Danyelle,Motta, Bruno Pereira,Baviera, Amanda Martins,Henrique-Silva, Flávio,dos Santos, Jean Leandro,Graminha, Marcia A.S.
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- Synthesis and evaluation of resveratrol derivatives as fetal hemoglobin inducers
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Resveratrol (RVT) derivatives (10a-i) were designed, synthesized, and evaluated for their potential as gamma-globin inducers in treating Sickle Cell Disease (SCD) symptoms. All compounds were able to release NO at different levels ranging from 0 to 26.3percent, while RVT did not demonstrate this effect. In vivo, the antinociceptive effect was characterized using an acetic acid-induced abdominal contortion model. All compounds exhibited different levels of protection, ranging from 5.9 to 37.3percent; the compound 10a was the most potent among the series. At concentrations between 3.13 and 12.5 μM, the derivative 10a resulted in a reduction of 41.1–64.3percent in the TNF-α levels in the supernatants of macrophages that were previously LPS-stimulated. This inhibitory effect was higher than that of RVT used as the control. In addition, the compound 10a and RVT induced double the production of the gamma-globin chains (γG + γA), compared to the vehicle, using CD34+ cells. Compound 10a also did not induce membrane perturbation and it was not mutagenic in the in vivo assay. Thus, compound 10a emerged as a new prototype of the gamma-globin-inducer group with additional analgesic and anti-inflammatory activities and proving to be a useful alternative to treat SCD symptoms.
- Andersen, Olaf Sparre,Barbieri, Karina Pereira,Bosquesi, Priscila Longhin,Carlos, Iracilda Zepone,Chelucci, Rafael Consolin,Costa, Fernando Ferreira,Dos Santos, Jean Leandro,Fernandes, Guilherme Felipe dos Santos,Lanaro, Carolina,Melchior, Aylime Castanho Bolognesi,Pavan, Aline Renata,Rusinova, Radda,de Souza, Cristiane Maria
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- Straightforward Access to the Nitric Oxide Donor Azasydnone Scaffold by Cascade Reactions of Amines
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A novel one-pot cascade method for the assembly of valuable NO-donor azasydnone scaffold has been developed. The construction strategy involves a diazotization/azo coupling/elimination/double rearrangement cascade sequence of readily available amines. The
- Zhilin, Egor S.,Bystrov, Dmitry M.,Ananyev, Ivan V.,Fershtat, Leonid L.,Makhova, Nina N.
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supporting information
p. 14284 - 14289
(2019/11/11)
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- Synthesis of Furoxans (1,2,5-oxadiazole 2-oxides) from Styrenes and Nitrosonium Tetrafluoroborate in Non-Acidic Media and Mechanistic Study
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Diverse furoxans (1,2,5-oxadiazole 2-oxides) were synthesized from the corresponding styrenes using nitrosonium tetrafluoroborate as the nitrosation reagent in pyridine (basic media) or dichloromethane (neutral media). Acid-sensitive functional groups were tolerated under these conditions. The probable reaction mechanism was elucidated. The experimental results support an ionic reaction pathway in contrast to the conventional acidic conditions with a radical mechanism.
- Matsubara, Ryosuke,Ando, Akihiro,Saeki, Yuta,Eda, Kazuo,Asada, Naoki,Tsutsumi, Tomoaki,Shin, Yong Soon,Hayashi, Masahiko
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p. 1094 - 1105
(2016/07/29)
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- Synthesis and biological activity of furoxan derivatives against Mycobacterium tuberculosis
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Tuberculosis (TB) remains a serious health problem responsible to cause millions of deaths annually. The scenario becomes alarming when it is evaluated that the number of new drugs does not increase proportionally to the emergence of resistance to the current therapy. Furoxan derivatives, known as nitric oxide (NO) donors, have been described to exhibit antitubercular activity. Herein, a novel series of hybrid furoxan derivatives (1,2,5-oxadiazole 2-N-oxide) (compounds 4a-c, 8a-c and 14a-c) were designed, synthesized and evaluated in?vitro against Mycobacterium tuberculosis (MTB) H37Rv (ATCC 27294) and a clinical isolate MDR-TB strain. The furoxan derivatives have exhibited MIC90values ranging from 1.03 to 62?μM (H37Rv) and 7.0–50.0?μM (MDR-TB). For the most active compounds (8c, 14a, 14b and 14c) the selectivity index ranged from 3.78 to 52.74 (MRC-5?cells) and 1.25–34.78 (J774A.1?cells). In addition, it was characterized for those compounds logPo/wvalues between 2.1 and 2.9. All compounds were able to release NO at levels ranging from 0.16 to 44.23%. Among the series, the phenylsulfonyl furoxan derivatives (compounds 14a-c) were the best NO-donor with the lowest MIC90values. The most active compound (14c) was also stable at different pHs (5.0 and 7.4). In conclusion, furoxan derivatives were identified as new promising compounds useful to treat tuberculosis.
- Fernandes, Guilherme Felipe dos Santos,de Souza, Paula Carolina,Marino, Leonardo Biancolino,Chegaev, Konstantin,Guglielmo, Stefano,Lazzarato, Loretta,Fruttero, Roberta,Chung, Man Chin,Pavan, Fernando Rogério,dos Santos, Jean Leandro
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p. 523 - 531
(2016/08/11)
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- Dinitrogen trioxide-mediated domino process for the regioselective construction of 4-nitrofuroxans from acrylic acids
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4-Nitrofuroxans (4-nitro-1,2,5-oxadiazole 2-oxides) were prepared by a dinitrogen trioxide-mediated domino reaction of acrylic acids under the action of NaNO2 excess in AcOH at room temperature. The reaction proceeds completely regioselectively and presents a new, simple, general, and safe method for the preparation of both 3-aryl- and 3-alkyl-4-nitrofuroxans available with difficulty before. A mechanism for the furoxan ring construction through a four-step one-pot protocol is proposed. The synthesized nitrofuroxans have been characterized by multinuclear NMR spectroscopy and X-ray powder diffraction.
- Fershtat, Leonid L.,Struchkova, Marina I.,Goloveshkin, Alexander S.,Bushmarinov, Ivan S.,Makhova, Nina N.
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p. 226 - 237
(2014/07/22)
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- Reactions of furoxanyl and furazanyl diazonium salts with NaNO2 in weakly acidic medium, a new approach to the preparation of nitrofuroxans and nitrofurazans
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A new approach to the preparation of nitrofuroxans and nitrofurazans is suggested based on the diazotization of aminofuroxans and aminofurazans in aqueous organic medium at pH = 4-5 in the presence of excess NaNO2.
- Finogenov,Ovchinnikov,Kulikov,Makhova
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p. 472 - 475
(2013/06/05)
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- Nitrosation of salts of 1-hydroxyimino-2,2-dinitro-1-R-ethanes, a novel method for the preparation of isomeric 3(4)-nitro-4(3)-R-furoxans
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A novel general method for the synthesis of isomeric 3(4)-nitro-4(3)-R- furoxans is developed. 3-Nitro isomers were obtained by reaction of hydroximoyl chlorides with dinitromethane sodium salt followed by conversion of the resulting 1-substituted 1-hydroxyimino-2,2-dinitroethanes into dipotassium (or disodium salts) and their subsequent nitrosation with NaNO2 in AcOH or with N2O4. Thermal isomerization of 3-nitro isomers afforded 4-nitro isomers were prepared in high yields.
- Ovchinnikov,Finogenov,Epishina,Kulikov,Strelenko,Makhova
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experimental part
p. 2137 - 2146
(2011/01/09)
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- Regiospecific and Regioselective Synthesis of Isomeric Nitrofuroxanes from Unsaturated Compounds
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Reaction of substituted unsaturated compounds with NaNO2 in acidic medium is studied and the reaction is shown to be a general method for preparation of isomeric nitrofuroxanes: β-nitrostyrenes and α-substituted acrylic acids form the corresponding 4-nitrofuroxanes (regiospecifically and regioselectively, respectively). The product of the reaction with phenylacetylene is 3-nitro-4-phenylfuroxan. Nitration of the aromatic ring in the synthesized 3-aryl-4-nitrofuroxanes is performed and the influence of the 4-nitro-furoxanyl fragment on the orientation of the NO2 groups in this reaction is revealed.
- Makhova,Dubonos,Blinnikov,Ovchinnikov,Khmel'nitskii
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p. 1140 - 1148
(2007/10/03)
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- Utilization of Wieland furoxan synthesis for preparation of 4-aryl-1,2,5-oxadiazole-3-yl carbamate derivatives having potent anti-HIV activity
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The classical Wieland furoxan synthesis was reinvestigated and this procedure was applied to the preparation of 4-aryl-1,2,5-oxadiazole-3-yl N,N-dialkylcarbamate derivatives, which were found to exhibit potent anti-HIV-1 activity.
- Takayama, Hiromitsu,Shirakawa, Seiichiro,Kitajima, Mariko,Aimi, Norio,Yamaguchi, Kentaro,Hanasaki, Yasuaki,Ide, Teruhiko,Katsuura, Kimio,Fujiwara, Masatoshi,Ijichi, Katsushi,Konno, Kenji,Sigeta, Shiro,Yokota, Tomoyuki,Baba, Masanori
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p. 1993 - 1996
(2007/10/03)
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- SULFYLIMINOFUROXANS: SYNTHESIS, STRUCTURE, AND OXIDATION TO NITRO AND NITROSO DERIVATIVES
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We have synthesized sulfylimines of the furoxan series.It was shown that by oxidation of 4-dimethylsulfyliminofuroxans both nitro and nitroso derivatives, the first examples of nitrosofuroxans, can be prepared.With x-ray structural analysis the main struc
- Rakitin, O. A.,Vlasova, O. G.,Chertanova, L. F.,Khmel'nitskii, L. I.
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p. 1474 - 1478
(2007/10/02)
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- REACTIONS OF NITRILE OXIDES WITH NITROGEN OXIDES. 1. REACTIONS WITH NITROGEN TETROXIDE
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We have studied the reaction of nitrile oxides with nitrogen tetroxide.It was shown that the reaction is selective: acetonitrile oxide yields ethylnitrolic acid, α-oximinophenylacetonitrile oxide gives a mixture of isomers of phenylnitrofuroxan, and aromatic nitrile oxides give aryltrinitromethanes.
- Rakitin, O. A.,Ogurtsov, V. A.,Godovikova, T. I.,Khmel'nitskii, L. I.
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p. 1469 - 1471
(2007/10/02)
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- Antimicrobial properties of some furazan and furoxan derivatives
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Nitro and phenylsulfonyl derivatives of furazan and furoxan ring systems have been synthesized and tested in vitro for their antimicrobial properties. The nitro derivatives and the 4-phenyl-3-phenyl sulphonylfuroxan showed antibacterial, antifungal and antiprotozoal activity.
- Calvino,Mortarini,Gasco,et al.
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p. 485 - 487
(2007/10/02)
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