- Synthesis and evaluation of a new 99mTc(I)-tricarbonyl complex bearing the 5-nitroimidazol-1-yl moiety as potential hypoxia imaging agent
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The objective of this work was to develop a novel 99mTc complex bearing the 5-nitroimidazol-1-yl moiety with recognised selectivity towards hypoxic tissue, as a potential radiopharmaceutical for imaging tumour hypoxia.The new metronidazole derivative (2-amine-3-[2-(2-methyl-5-nitro-1H- imidazol-1-yl)ethylthio]propanoic acid) (L) containing adequate groups to coordinate technetium through the formation of a Tc(I)-tricarbonyl complex was synthesised with adequate yield (33%) and characterised by spectroscopy. Labelling was performed by substitution of three labile water molecules of the technetium tricarbonyl precursor, fac-[99mTc(CO)3(H 2O)3]+ with the ligand. A radiochemical purity higher than 90% was achieved and remained unchanged for more than 4 h. The complex has a high stability in plasma, a moderate plasma protein binding and a moderate hydrophilicity.In vitro cell uptake studies showed a ratio between the activity taken up by cells in hypoxia/normoxia of 1.6 ± 0.4 (p 0.5).Biodistribution in normal mice showed rapid depuration and low uptake in all organs and tissues except liver. Biodistribution in mice bearing induced tumours showed a low tumour uptake, but tumour/muscle ratio was favourable thanks to depuration. Comparison with biological results of other metronidazole derivatives clearly shows that modifications of the chelator are very important and contribute to improve the biological behaviour.
- Giglio,Dematteis,Fernandez,Cerecetto,Rey
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- Synthesis and leishmanicidal evaluation of sulfanyl- and sulfonyl-tethered functionalized benzoate derivatives featuring a nitroimidazole moiety
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A series of new nitroimidazole-containing derivatives was synthesized by coupling of 2-[2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethylthio]ethanol with diversely substituted benzoic acids. Upon treatment with m-CPBA, 12 of these sulfanyl compounds were further oxidized to their sulfonyl analogs. All the 26 synthetic compounds were examined for in vitro activity against Leishmania (V.) braziliensis and Leishmania (L.) mexicana, and some of them displayed an efficient antileishmanial activity. Among the compounds tested, the catecholic derivative 2-{[2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl]sulfanyl}ethyl 3,4-dihydroxybenzoate (9a, LC50 = 13 and 11 μM) and the pyrogallolic derivative 2-{[2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl]sulfanyl}ethyl 3,4,5-trihydroxybenzoate (9b, LC50 = 4 and 1 μM) were the most active ones against the two Leishmania strains.
- Charris, Jaime,Deffieux, Denis,Domínguez, José,Fernández, Alexis,Gutiérrez, Joyce,Peixoto, Philippe A.,Pouységu, Laurent,Quideau, Stéphane,Rodríguez, Miguel,Rodríguez, Noris,Rojas, Luis
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- DUAL ACTION CARBONIC ANHYDRASE INHIBITORS
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The present invention is directed to novel carbonic anhydrase IX inhibitors comprising a nitroimidazole moiety substituted with a heterocycle or phosphinate and having sulfonamide, sulfamate or sulfamide groups. The present invention is also related to the use of these novel carbonic anhydrase IX inhibitors in cancer treatment, especially radiotherapy and chemotherapy and the use in treatment of infections.
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Page/Page column 79
(2015/03/13)
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- Potentiating metronidazole scaffold against resistant Trichomonas: Design, synthesis, biology and 3D-QSAR analysis
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Metronidazole (MTZ), the FDA-approved drug against Trichomonas vaginalis (TV), is being challenged seriously by drug resistance, while its inertness to sperm makes it ineffective as a vaginal contraceptive. Thirteen piperidine dithiocarbamate hybrids of 2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethane (8-20) were designed to potentiate the MTZ framework against drug resistance and sperm. New compounds were 1.2-12.1 times more effective against MTZ-susceptible and -resistant strains of TV. All of the compounds exhibited high safety toward cervical (HeLa) cells and Lactobacillus. Thirty-eight compounds were scrutinized by CoMFA and CoMSIA techniques of 3D quantitative structure-activity relationship. Good predictive rpred2 values for CoMFA and CoMSIA models reflected the robustness of the predictive ability. This was validated by designing five new analogues (46-50), which were potently microbicidal (3-10 and 10-20 times against MTZ-susceptible and -resistant TV, respectively) and spermicidal. This in vitro study may have significant clinical relevance, which could become evident in due course.
- Kumar, Lalit,Jain, Ashish,Lal, Nand,Sarswat, Amit,Jangir, Santosh,Kumar, Lokesh,Singh, Vishal,Shah, Priyanka,Jain, Swatantra K.,Maikhuri, Jagdamba P.,Siddiqi, Mohammad I.,Gupta, Gopal,Sharma, Vishnu L.
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scheme or table
p. 83 - 87
(2012/04/23)
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- Synthesis and biological characterisation of novel dithiocarbamate containing 5-nitroimidazole 99mTc-complexes as potential agents for targeting hypoxia
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With the aim to develop new potential 99mTc-radiopharmaceuticals for imaging hypoxia based on the formation of Tc-nitrido complexes, two novel dithiocarbamate containing metronidazole derivatives (L1 and L2) have been prepared and characterised. The synthesis of L1 and L2 was achieved in excellent yield and high purity. Labelling with 99mTc was successfully performed using a low ligand concentration (approximately 2-3 mg) and the desired products were obtained with high radiochemical purity (>90%). Lipophilicity, plasma protein binding, and biodistribution in normal- and tumour-bearing-CD1 mice studies were performed to asses the potentiality for nuclear medicine oncology. According to the physicochemical and biological behaviour both in healthy animals and in animals bearing solid tumours complex dtcTc1 could be considered as a starting point for the development of new radiopharmaceuticals for imaging hypoxia.
- Giglio, Javier,Fernández, Soledad,Rey, Ana,Cerecetto, Hugo
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scheme or table
p. 394 - 397
(2011/02/26)
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- The syntheses and crystal structures of metronidazole-derived compounds
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Metronidazole (MET-OH), widely used as an antibacterial agent, is found to have some side effects on human bodies. Due to these disadvantages, people have been looking for its modification compounds for substituents. In this article, four MET-OH derivatives were designed, prepared, and structurally characterized by single crystal X-ray diffraction. These compounds are MET-OTs (1), MET-Br (2), MET-Cl (3), and MET-I (4). X-ray structure analyses revealed that, 1 crystallized in the monoclinic system with space group P2 1 /c, with a = 16.1178, b = 7.5473, c = 13.4161 A, V = 1520.3 A3, β = 111.3210o and Z = 4. 2 crystallized in the monoclinic system with space group P2 1 /c, with a = 12.079, b = 11.089, c = 6.380 A, V = 847.1 A3, β = 97.57o and Z = 4. 3 crystallized in the monoclinic system with space group P2 1 /c, with a = 12.098, b = 11.007, c = 6.295 A, V = 830.3 A3, β = 97.886o and Z = 4. 4 crystallized in the triclinic system with space group P1, with a = 6.192, b = 7.740, c = 10.001 A, V = 457.9 A3, α = 89.073, β = 86.903, γ = 73.097 o and Z = 2. In this article, metronidazole-derived compounds were prepared and structurally characterized by single crystal X-ray diffraction [Figure not available: see fulltext.]
- Li, Huan-Qiu,Xiao, Zhu-Ping,Fang, Rui-Qin,Zhu, Hai-Liang
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p. 461 - 466
(2008/09/21)
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- Hypoxia-Selective Antitumor Agents. 10. Bis(nitroimidazoles) and Related Bis(nitroheterocycles): Development of Derivatives with Higher Rates of Metabolic Activation under Hypoxia and Improved Aqueous Solubility
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A series of analogues of the prviously described compound N--4-(2-nitroimidazol-1H-yl)butanamide (4), a novel hypoxic cell cytotoxin and radiosensitizer, have been prepared and evaluated for hypoxia-selective cytot
- Hay, Michael P.,Lee, Ho H.,Wilson, William R.,Roberts, Peter B.,Denny, William A.
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p. 1928 - 1941
(2007/10/02)
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- Chemotherapeutically active nitro compounds, 4, 5-nitroimidazoles (part I)
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More than 135 new 2-methyl-5-nitroimidazoles substituted in 1-position and 1-methyl-5-nitroimidazoles substituted in 2-position were investigated for their activity against various protozoan species, in particular Entamoeba histolytica in the golden hamster, Trichomonas fetus, Trypanosoma brucei and T. cruzi in the NMRI mouse. Among the nitroimidazoles substituted in the 1-position only two preparations exhibited a similar effect as metronidazole against T. fetus. In the class of the nitroimidazoles substituted in the 2-position 16 compounds were as effective as metronidazole, 19 showed an effect superior to metronidazole, 1 was as good as tinidazole and 2 exhibited an activity superior to tinidazole against T. fetus. Only few compounds displayed any amoebicidal activity. Of the mono and bis-hydrazones of 1-methyl-5-nitroimidazole-2-aldehyde substituted in the 2-position 3 compounds had an amoebicidal effect 2 to 8 times stronger than that of metronidazole. Only few representatives of the 1-methyl-5-nitroimidazoles substituted in the 2-position produced a useful trypanocidal effect when given in relatively high doses. The structure-activity relationship of 5-nitroimidazole derivatives has been discussed.
- Winkelmann,Raether,Gebert,Sinharay
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p. 2251 - 2263
(2007/10/05)
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