- Reactivity of reduced [2Fe-2S] ferredoxins parallels host susceptibility to nitroimidazoles
-
The kinetics of the electron transfer reaction between reduced [2Fe-2S] ferredoxins and select nitroimidazole antimicrobial agents is reported. The ferredoxins from the protozoan Trichomonas vaginalis and the cyanobacterium Anabaena sp. strain 7120 were studied because they are the proximal electron donors to nitroimidazoles in these two organisms with significantly different nitroimidazole susceptibilities. The rates of electron transfer from Anabaena ferredoxin to all nitroimidazoles were 1 to 2 orders of magnitude lower than for T. vaginalis ferredoxin. Quantitative structure-activity analysis of the kinetic data showed that the size of the alkyl substituent on the N-1 position of the imidazole ring strongly influenced the magnitude of the electron transfer rate constant. This implies that the distance between the iron-sulfur cluster and the nitro group of the imidazole is the critical variable in determining the rate of electron transfer. A correlation between the magnitude of the one-electron transfer rate constant with the susceptibility of the host organism to the cytotoxic effects of nitroimidazoles was also discovered. These results demonstrate that reductive activation is the most crucial step in determining the toxicity of nitroimidazoles.
- Vidakovic, Momcilo,Crossnoe, Chetlen R.,Neidre, Christopher,Kim, Kyonghee,Krause, Kurt L.,Germanas, Juris P.
-
-
Read Online
- Green synthesis method of Ronidazole and deuterated derivative thereof
-
The invention belongs to the technical field of chemical synthesis and discloses a green synthesis method of Ronidazole and a deuterated derivative thereof. The method comprises following steps: 4-nitroimidazole and methanol or deuterated methanol are subjected to a nitrogen methylation reaction or a nitrogen deuteration methylation reaction under the action of a catalyst, and 1-methyl-5-nitroimidazole or 1-trideuteromethyl-5-nitroimidazole is produced; the product and paraformaldehyde are subjected to a nucleophilic addition reaction, and 1-methyl-2-hydroxymethyl-5-nitroimidazole or 1-trideuteromethyl-2-hydroxymethyl-5-nitroimidazole is produced; the product of nucleophilic addition and urea are subjected to a heating reaction in the presence of an accelerant, and Ronidazole or the deuterated derivative thereof is produced. The raw materials are almost green reagents and are available and low in cost; conditions are simple, operation is easy, little pollution is produced, byproducts obtained in the three-step reaction are only water and ammonia gas, the post-processing method is simple, the product is easy to purify, and the yield is relatively ideal.
- -
-
Paragraph 0045-0047
(2019/09/17)
-
- Synthesis, crystal structure and antibacterial activity of new highly functionalized ionic compounds based on the imidazole nucleus
-
Several new highly functionalized imidazolium derivatives were synthesized, via appropriate synthetic routes, using imidazole, 1-methylimidazole and 2-phenyl-1-methylimidazole as key intermediates. The antibacterial activity of the prepared compounds was evaluated against: Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa and Salmonella thipymurium using disk-diffusion and MIC methods. Crystal X-ray structures are reported for six compounds.
- Bahnous, Mebarek,Bouraiou, Abdelmalek,Chelghoum, Meryem,Bouacida, Sofiane,Roisnel, Thierry,Smati, Farida,Bentchouala, Chafia,Gros, Philippe C.,Belfaitah, Ali
-
p. 1274 - 1278
(2013/03/14)
-
- Molten-state nitration of substituted imidazoles: New synthetic approaches to the novel melt-cast energetic material, 1-methyl-2,4,5-trinitroimidazole
-
Novel, one-step synthetic routes for the preparation of 1-methyl-2,4,5-trinitroimidazole (MTNI) are described. In addition, a new, molten-state nitration method for the synthesis of 1-methyl-2,4,5- trinitroimidazole is developed. Georg Thieme Verlag Stuttgart - New York.
- Duddu, Raja,Zhang, Mao-Xi,Damavarapu, Reddy,Gelber, Nathaniel
-
experimental part
p. 2859 - 2864
(2011/10/18)
-
- Compounds containing 2-substituted imidazole ring for treatment against human African trypanosomiasis
-
A series of compounds containing 2-substituted imidazoles has been synthesized from imidazole and tested for its biological activity against human African trypanosomiasis (HAT). The 2-substituted 5-nitroimidazoles such as fexinidazole (7a) and 1-[4-(1-methyl-5-nitro-1H-imidazol-2-ylmethoxy)-pyridin-2- yl-piperazine (9e) exhibited potent activity against T. brucei in vitro with low cytotoxicity and good solubility. The presence of the NO2 group at the 5-position of the imidazole ring in 2-substituted imidazoles is the crucial factor to inhibit T. brucei.
- Samant, Bhupesh S.,Sukhthankar, Mugdha G.
-
supporting information; experimental part
p. 1015 - 1018
(2011/03/21)
-
- [(NHC)(NHCewg)RuCl2(CHPh)] complexes with modified NHCewg ligands for efficient ring-closing metathesis leading to tetrasubstituted olefins
-
Imidazolium salts (NHCewg-HCl) with electronically variable substituents in the 4,5-position (H,H or C1,C1 or H,NO2 or CN 5CN) and sterically variable substituents in the 1,3-position (Me,Me or Et,Et or iPr,iPr or Me,iPr) were synthesized and converted into the respective [AgI(NHC)ewg] complexes. The reactions of [(NHC)RuCl 2(CHPh)(Py)2] with the [AgI(NHQw8)] complexes provide the respective [(NHC)(NHCewg)RuCl2(CHPh)] complexes in excellent yields. The catalytic activity of such complexes in ring-closing metathesis (RCM) reactions leading to tetrasubstituted olefins was studied. To obtain quantitative substrate conversion, catalyst loadings of 0.2-0.5 mol% at 80°C in toluene are sufficient. The complex with the best catalytic activity in such RCM reactions and the fastest initiation rate has an NHCewg group with l,3-Me,iPr and 4,5-Cl,Cl substituents and can be synthesized in 95 % isolated yield from the ruthenium precursor. To learn which one of the two NHC ligands acts as the leaving group in olefin metathesis reactions two complexes, [(FL-NHC)-(NHCcwg)RuCl2(CHPh)] and [(FLNHCewg)(NHC)RuCl2(CHPh)], with a dansyl fluorophore (FL)-tagged electron-rich NHC ligand (FL-NHC) and an electron-deficient NHC ligand (FLNHCewg) were prepared. The fluorescence of the dansyl fluorophore is quenched as long as it is in close vicinity to ruthenium, but increases strongly upon dissociation of the respective fluorophore-tagged ligand. In this manner, it was shown for ring-opening metathesis ploymerization (ROMP) reactions at room temperature that the NHCewg ligand normally acts as the leaving group, whereas the other NHC ligand remains ligated to ruthenium.
- Sashuk, Volodymyr,Peeck, Lars H.,Plenio, Herbert
-
experimental part
p. 3983 - 3993
(2010/07/04)
-
- Strategies toward the design of energetic ionic liquids: Nitro- and nitrile-substituted N,N′-dialkylimidazolium salts
-
Twelve novel 1,3-dialkylimidazolium salts containing strongly electron-withdrawing nitro- and cyano-functionalities directly appended to the cationic heterocyclic rings have been synthesized; the influences of the substituents on both formation and thermal properties of the resultant ionic liquids have been determined by DSC, TGA, and single crystal X-ray diffraction, showing that an electron-withdrawing nitro-substituent can be successfully appended and has a similar influence on the melting behaviour as that of corresponding methyl group substitution. Synthesis of di-, or trinitro-substituted 1,3-dialkylimidazolium cations was unsuccessful due to the resistance of dinitro-substituted imidazoles to undergo either N-alkylation or protonation, while 1-alkyl-4,5-dicyanoimidazoles were successfully alkylated to obtain 1,3-dialkyl-4,5-dicyanoimidazolium salts. Five crystal structures (one of each cation type) show that, in the solid state, the NO2-group has little significant effect, beyond the steric contribution, on the crystal packing. the Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2006.
- Katritzky, Alan R.,Yang, Hongfang,Zhang, Dazhi,Kirichenko, Kostyantyn,Smiglak, Marcin,Holbrey, John D.,Reichert, W. Matthew,Rogers, Robin D.
-
p. 349 - 358
(2007/10/03)
-
- Synthesis and biological activity of nitro heterocycles analogous to megazol, a trypanocidal lead
-
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
-
p. 427 - 440
(2007/10/03)
-
- Oxidative Alkylation of Azoles: V. Synthesis of 1-Chloro-4-nitroimidazole and Its Reaction with Methyl Iodide
-
Chlorination of 4-nitroimidazole in alkaline medium gave 1-chloro-4-nitroimidazole. The reaction of the latter with methyl iodide results in liberation of iodine and formation of 4-nitroimidazole, isomeric 1-methyl-4-nitro- and 1-methyl-5-nitroimidazoles, and 1,3-dimethyl-4-nitroimidazolium triiodide.
- Veretennikov,Pevzner
-
p. 1764 - 1766
(2007/10/03)
-
- Michael adducts in regioselective synthesis of N-substituted azoles
-
Michael adducts of azoles (4-phenyl-, 4-methyl- and 4-nitroimidazole, 4-methylbenzimidazole, 1,2,4-triazole and theophylline) are shown to be valuable substrates for obtaining the N-substituted derivatives of the parent heterocycles by a quaternization-Hofmann elimination sequence. The effectiveness of the procedure is dependent on the regiochemical outcome of the first, N-protective step, i.e. the Michael addition. By choosing the appropriate Michael acceptor, alkylating agent and deprotection conditions, the thermodynamically less stable regioisomers of N-substituted azoles have been obtained in high yields.
- Horvath
-
p. 1183 - 1189
(2007/10/02)
-
- Process for preparing 1-alkyl-5-nitroimidazoles
-
Process for preparing 1-alkyl-5-nitroimidazoles of formula: STR1 which comprises reacting an alkyl sulphate with an imidazole derivative of general formula: STR2 in an organic solvent, and then hydrolyzing or alcoholyzing the product obtained. In the formulae (I) and (II), R denotes hydrogen, unsubstituted or substituted alkyl, aryl or cycloalkyl. In the formula (I), R1 denotes alkyl. In the formula (II), X denotes a group which can be removed by hydrolysis or alcoholysis.
- -
-
-
- Radical-nucleophilic Substitution (SRN1) Reactions. Part 5. Anions of Nitroimidazoles in SRN1 and Oxidative Addition Reactions
-
The anions of 2- and 4(5)-nitroimidazole, and 2-methyl-4(5)-nitroimidazole, have been shown to undergo SRN1 reactions with a range of halogeno-nitroalkanes (which include p-nitrobenzyl chloride, 2-bromo- and 2-chloro-2-nitropropane, 2,2-dinitropropane, 5-bromo-5-nitro-1,3-dioxane, and 2-(bromo- and chloromethyl)-1-methyl-5-nitroimidazole to yield the corresponding N(1)-(nitroalkyl) derivatives.The anions of 2-methyl-4(5)-nitro- and 4(5)-nitro-imidazole, but not the anion of 2-nitroimidazole, underwent oxidative addition to the anion of 2-nitropropane (using potassium ferricyanide and sodium persulphate as oxidants) to yield the corresponding N(1)-(1-methyl-1-nitroethyl) derivatives.The anions of 2-methyl-4-nitro- and 4-nitro-imidazole have also been shown to act as nucleofuges in the SRN1 reactions between their 1-(1-methyl-1-nitroethyl)-derivatives and anions (which include Me2CNO2- and PhSO2-).Steric constrains, kinetic control, and the nature of the intermediate radical anions in the above reactions are discussed.
- Adebayo, Adelaide T. O. M.,Bowman, W. Russell,Salt, W. G.
-
p. 2819 - 2828
(2007/10/02)
-
- Reactions with Dimethyl Carbonate, 2. - N-Methylation of Imidazole and Derivatives
-
The use of dimethyl carbonate as methylating agent for imidazole derivatives is demonstrated by selected examples.The comparison of the toxicological values of dimethyl carbonate and dimethyl sulfate should inspire to replace the highly toxic dimethyl sulfate by dimethyl carbonate.
- Lissel, Manfred
-
-
- A NEW SIMPLE PROCEDURE FOR ALKYLATION OF NITROGEN HETEROCYCLES USING DIALKYL OXALATES AND ALKOXIDES.
-
A variety of nitrogen heterocycles are N-alkylated in high yields with dialkyl oxalates and potassium alkoxides in refluxing dimethylformamide.
- Bergman, Jan,Sand, Peter
-
p. 1957 - 1960
(2007/10/02)
-
- Production of 1-alkyl-5-nitroimidazoles
-
1-Alkyl-5-nitroimidazoles are prepared by reacting a 5-nitroimidazole with an alkylating agent in the presence of an aliphatic carboxylic acid. The products are intermediates for the production of dyes, textiles auxiliaries and insecticides.
- -
-
-
- Isoxazole substituted nitroimidazoles
-
Novel substituted nitroimidazoles are provided, for example, 2-(4,5-substituted-isoxazol-3-yl)-1-substituted-5-nitroimidazole; 2-(4,5-disubstituted-Δ2 -isoxazolin-3-yl)-1-substituted-5-nitroimidazole; or 2-(4,5-disubstituted-2-loweralkyl-isoxazolidin-3-yl)-1-substituted-5-nitroimidazole. These compounds have antibacterial and antiprotozoal activity, especially against human and animal trypanosomiasis and trichomoniasis.
- -
-
-