Hybrid drug strategy is based on the combination of two or more pharmacophores into a new chemical entity to improve the properties of the original compounds or to obtain double action of resulting ...molecule. Hybrid molecules, comprised of some pharmacophore and nitric oxide (NO) donor moiety, constitute one of the more promising approaches for the design of drugs. Furoxans and benzofuroxans are considered NO releasing prodrugs and are of great interest for researchers. In this review we will focus on furoxan and benzofuroxan hybrids described in literature during the last years (from 2005 to 2016).
Since the synthesis of 4,6-dinitrobenzofuroxan in 1899 by Drost, benzofuroxans have attracted particular attention. This peculiar series of compounds exhibit a broad spectrum of biological activity ...including antibacterial, antifungal, antileukemic, acaricide and immunodepressive properties. These works embrace a period of more than 50 years since the pioneering paper of Gosh and Whitehouse and papers in this major field of the heterocyclic chemistry are still published in 2013. The review has been built in two independent parts. The first one is directly dedicated to the structure of substituted benzofuroxans and will show many medicinal applications of these compounds such as nitric oxide-releasing abilities, induction of oxidative stress, potent anti-cancer agents, anti-chagas agent, target for antiamoebic agent, Ca2+ channel blockers or cytotoxic, mutagenic and genotoxic agent… The second part of this review will be in close connection with the use of benzofuroxans as synthetic precursors in the preparation of new biological compounds such as quinoxaline dioxide, benzimidazole and phenazine derivatives. The interaction of substituted benzofuroxans with electron rich heterocycles or carbanions is the key step in the synthesis of these new biological active compounds. These derivatives can be used as cytotoxic drugs, antimycobacterial agent and display anti-malarial, antileishmanial and antituberculosis activity. The nature of the substituent linked to the carbocyclic ring of benzofuroxan is of primary importance to understand the medicinal properties of this family of compounds. For example, when benzofuroxans are substituted by electron-releasing substituents, the chemical reactivity is transferred from the carbocyclic ring to the furoxan ring.
The electrophilic activation of various substrates via double or even triple protonation in superacidic media enables reactions with extremely weak nucleophiles. Despite the significant progress in ...this area, the utility of organophosphorus compounds as superelectrophiles still remains limited. Additionally, the most common superacids require a special care due to their high toxicity, exceptional corrosiveness and moisture sensitivity. Herein, we report the first successful application of the “Brønsted acid assisted Brønsted acid” concept for the superelectrophilic activation of 2-hydroxybenzoe1,2oxaphosphinine 2-oxides (phosphacoumarins). The pivotal role is attributed to the tendency of the phosphoryl moiety to form hydrogen-bonded complexes, which enables the formation of dicationic species and increases the electrophilicity of the phosphacoumarin. This unmasks the reactivity of phosphacoumarins towards non-activated aromatics, while requiring only relatively non-benign trifluoroacetic acid as the reaction medium.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Herein we present the regio- and diastereoselective synthesis of novel pyrrolidine-fused spiro-dihydrophosphacoumarins via intermolecular 3 + 2 cycloaddition reaction. The presented approach is ...complementary to existing ones and provides an easy entry to the otherwise inaccessible derivatives. Additionally, the unprecedented pathway of the reaction of 4-hydroxycoumarin with azomethine ylides is described. The anti-cancer activity of the obtained compounds was tested in vitro, the most potent compound being 2.6-fold more active against the HuTu 80 cell line than the reference 5-fluorouracil, with a selectivity index > 32.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The synthesis of the new 4-fluorobenzodifuroxan has been performed in one step from 2,4,6-trifluoro-1,3-dinitrobenzene implying a safe synthesis. Importantly, due to the 1-oxide/3-oxide ...interconversion, NMR spectra have shown that this compound exists as a mixture of four tautomers. The presence of the fluorine atom allows the determination of the 1H and 13C NMR parameters of the two main isomers. Interestingly, 4-fluorobenzodifuroxan has been partially and totally deoxygenated upon heating with one and two equivalents of triethylphosphite, respectively. Benzodifurazan analog has been obtained in moderate yield and reacts readily with ammonia leading for the first time to 4-aminobenzodifurazan.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Introduction. The formation of new blood vessels is called angiogenesis. As the tumor grows, the oxygen and nutrient requirements of the abnormal cells continuously increase, and new blood vessels ...are formed. These processes are disrupted by angiogenesis inhibitors. Therefore, it is warranted to investigate ways to enhance the capabilities of angiogenesis inhibitors alkaloids, flavonoids, and glycosides.
Aim. To justify the extension of clinical use of alkaloids, flavonoids and glycosides (Conium maculatum and Hydrastis canadensis, Thuja occidentalis), being a part of the complex medical product Mastopol, taking into account the obtained data on the angiogenic balance in the nodular form of benign mammary dysplasia (BMD).
Materials and methods. The study included 69 volunteers divided into two groups: Group 1 included 27 patients with medical history of surgery for nodular BMD who received antiproliferative preoperative therapy with Mastopol for 12 weeks. Group 2 (comparison group), n=42, also included patients with medical history of surgery for nodular BMD but without preoperative therapy with the herbal medicine Mastopol. We studied angiogenesis markers (VEGF-A vascular endothelial growth factor and pVEGF-1) and immunohistochemical marker CD34 (cluster of differentiation CD).
Results. We found a significantly higher (p0.001) rate of CD34 detection on medium and small caliber vessels in the comparison group, i.e., in the patients who were not treated preoperatively with alkaloids, flavonoids, and glycosides (Mastopol), while blood supply to the nodules by the medium and small vessels was 1.4 and 1.8 times lower in the Group 1, respectively. Analysis of VEGF expression shows an increase of angiogenic promoters VEGF-A and pVEGF-1 in serum before treatment with biologically active herbal components of Mastopol in both groups. There were no statistically significant differences in vascular markers. However, a statistically significant decrease in VEGF-A and pVEGF-1 (p0.001) was noted in Group 1 after Mastopol therapy. Note the presence of a moderate direct correlation (rs=0.49) of CD34 expression with VEGF-A expression in Group 1 and rs=0.41 in Group 2, which indicated a direct relationship between angiogenesis and proangiogenic factors.
Conclusion. In addition to the proven antiproliferative, anti-inflammatory, cytokine stabilizing, analgesic, and anti-edema properties of Mastopol, the study also showed the antiangiogenic effect of the herbal drug components. Considering the decreased vascular growth in fibroadenomas during Mastopol treatment, the indications for its use in patients with fibroadenomas before the surgery can be extended. Specific immunological test to measure VEGF can be proposed as a noninvasive screening method to evaluate the effectiveness of conservative treatment in general clinical practice.
It was found that quaternary ammonium salts of benzofuroxan based on
o
-,
m
-, and
p
-dibromoxylenes are formed as a mixture of two tautomers. Only one bromomethyl group participates in the ...quaternization of benzofuroxan with different dibromoxylenes. Bacteriostatic activity of the most active mixture of tautomers was two and four times higher than the reference drug, chloramphenicol, with respect to
Staphylococcus aureus
209p and
Bacillus cereus
8035, correspondingly. Hemolysis of these compounds does not exceed 1%, i.e., such compounds are not toxic.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
(Di)chloro(di)nitrobenzofuroxans form substitution products involving carbon atoms with phenolates in isopropyl alcohol medium. In the case of 4,6-dinitro-5,7-dichlorobenzofuroxan, besides ...replacement of one chlorine atom and the formation of C-bonded product, we observed the hydrolysis of the second chlorine and replacement of it by hydroxyl group. Products of reaction of 4,6-dichloro-5-nitrobenzofuroxan with phenolates display excellent antimicrobial activity and have dual action, both against bacteria and fungi.
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BFBNIB, DOBA, GIS, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
A method was developed for the synthesis of 2-(pyrrolidin-1-yl)pyrimidines and 2-(4,4-diarylbutyl)aminopyrimidines by reactions of (hetero)aromatic C-nucleophiles with
N
...-(4,4-diethoxybutyl)pyrimidin-2-amine in the presence of trifluoroacetic acid. The structures of the obtained products were confirmed by methods of IR spectroscopy,
1
H and
13
C NMR spectroscopy, and X-ray structural analysis.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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Novel hybrid compounds containing both benzofuroxan and 1H-imidazol-2(3H)-one moieties were synthesized by an SNAr reaction between 7-chloro-4,6-dinitrobenzofuroxan and ...imidazol-2-ones, with the only C4 regioisomer having been formed. Cytotoxic effects of parent and obtained compounds were estimated on human cancer and normal cells, while two of imidazolones showed higher cytotoxicity in relation to the M-HeLa cancer line compared to the hybrid products. In relation to the normal liver cell line Chang, the tested compounds were found to be non-toxic and can be promising for further development of anticancer agents.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
