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2-Nitroimidazole

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Haibin Gong – One of the best experts on this subject based on the ideXlab platform.

  • design synthesis and antimicrobial activities of nitroimidazole derivatives containing 1 3 4 oxadiazole scaffold as fabh inhibitors
    Bioorganic & Medicinal Chemistry, 2012
    Co-Authors: Yao Li, Yang Hu, Shuai Zhang, Haibin Gong

    Abstract:

    Abstract Nitroimidazoles and their derivatives have drawn continuing interest over the years because of their varied biological activities, recently found application in drug development for antimicrobial chemotherapeutics and antiangiogenic hypoxic cell radiosensitizers. In order to search for novel antibacterial agents, we designed and synthesized a series of secnidazole analogs based on oxadiazole scaffold ( 4 – 21 ). Among these compounds, 4 and 7 – 21 were reported for the first time. These compounds were tested for antibacterial activities against Escherichia coli , Pseudomonas aeruginosa , Bacillus subtilis and Staphylococcus aureus . This new nitroimidazole derivatives class demonstrated strong antibacterial activities. Escherichia coli β-ketoacyl-acyl carrier protein synthase III (FabH) inhibitory assay and docking simulation indicated that the compounds 2-(2-methoxyphenyl)-5-((2-methyl-5-nitro-1 H -imidazol-1-yl)methyl)-1,3,4-oxadiazole ( 11 ) with MIC of 1.56–3.13 μg/mL against the tested bacterial strains and 2-((2-methyl-5-nitro-1 H -imidazol-1-yl)methyl)-5-(2-methylbenzyl)-1,3,4-oxadiazole ( 12 ) with MIC of 1.56–6.25 μg/mL were most potent inhibitors of Escherichia coli FabH.

Andrew M Rauth – One of the best experts on this subject based on the ideXlab platform.

  • bru59 21 a second generation 99mtc labeled 2 nitroimidazole for imaging hypoxia in tumors
    The Journal of Nuclear Medicine, 2000
    Co-Authors: T Melo, J Duncan, James R Ballinger, Andrew M Rauth

    Abstract:

    UNLABELLED: Hypoxia in tumors is believed to be an important cause of local failure of radiotherapy in certain types of cancer. BRU59-21 (BMS194796) is a second-generation 99mTc-labeled 2-Nitroimidazole that has been shown to offer improved characteristics for imaging myocardial ischemia. It has now been evaluated in models of tumor hypoxia. METHODS: Accumulation of BRU59-21 was compared with that of BMS181321 in Chinese hamster ovary cells incubated under aerobic or hypoxic conditions. The effects of competition with unlabeled nitroimidazoles and oxygen were studied. Biodistribution studies were performed in mice bearing transplanted KHT-C tumors in the leg. RESULTS: Within 5 min, BRU59-21 partitioned into aerobic cells in vitro at a level 10 times higher than external medium with no further increase over time. In hypoxic cells this initial partitioning was followed by selective accumulation to levels 5 times higher than in aerobic cells by 4 h. Low levels of oxygen (approximately 40 ppm) inhibited the maximal accumulation rate by 50%. Unlabeled misonidazole, a 2-Nitroimidazole, inhibited accumulation of radioactivity, whereas tinidazole, a 5-nitroimidazole, enhanced accumulation; similar effects had been reported with BMS181321. Biodistribution studies in mice showed rapid clearance of radioactivity from the blood, resulting in enhanced tumor-to-blood ratios compared with BMS181321. Increasing the hypoxic fraction in the tumor by injection of nitro-L-arginine resulted in increased retention of tracer in the tumor without affecting other tissues. CONCLUSION: These results suggest that BRU59-21 warrants further investigation as an agent for imaging tumor hypoxia in the clinic.

  • A novel amine-dioxime chelator for technetium-99m: synthesis and evaluation of 2-Nitroimidazole-containing analogues as markers for hypoxic cells.
    Bioconjugate chemistry, 2000
    Co-Authors: James R Ballinger, Andrew M Rauth, Douglas N. Abrams, Mervyn W. Billinghurst

    Abstract:

    A novel amine−dioxime chelator for 99mTc has been developed. It offers the advantages of ease of synthesis and flexibility in alteration of lipophilicity. Labeling by stannous reduction of pertechnetate takes place rapidly and efficiently at room temperature and is stable for 24 h. The 99mTc:ligand ratio is believed to be 1:2. Seven different alkyl moieties were used to achieve a range of lipophilicities. Three series of compounds were prepared:  2-Nitroimidazoles as potential hypoxia-targeting agents, 4-nitroimidazoles as a less easily reduced isomer, and untargeted anilines. In an in vitro model of cellular hypoxia, the 2-Nitroimidazole compounds all showed selective accumulation whereas 4-nitroimidazoles showed variable selectivity and aniline showed no selectivity. These experiments demonstrate the potential utility of the 2-Nitroimidazole derivatives of the amine−dioxime class of chelator as hypoxia-targeting agents.

  • Targeting Hypoxia in Tumors Using 2-Nitroimidazoles with Peptidic Chelators for Technetium-99m: Effect of Lipophilicity
    Bioconjugate chemistry, 2000
    Co-Authors: Xiuguo Zhang, Andrew M Rauth, James R Ballinger, And Alfred Pollak, John R. Thornback

    Abstract:

    Tumor hypoxia is an important prognostic factor for response to therapy. Radiolabeled 2-Nitroimidazoles have been used for imaging hypoxia, and the octanol/water partition coefficient (P) of these compounds appears to play a crucial role in their suitability for imaging. A series of 11 2-Nitroimidazoles coupled to peptidic chelators for (99m)Tc with divergent P was developed and evaluated in an in vitro system. Two classes of N(3)S chelators were used: dialkyl-Gly-Ser-Cys-linker-2-Nitroimidazole (Class I) and dialkyl-Gly-Lys(2-Nitroimidazole)-Cys (Class II). The chelators were prepared by automated solid-phase peptide synthesis. Xanthine oxidase was able to reduce the 2-nitroimidiazole moiety on the ligands, but the rate of reduction varied 5-fold among the different chelators. The chelators were labeled by transchelation from [(99m)Tc]gluconate at temperatures between 22 and 100 degrees C. The reaction mixtures were analyzed by HPLC and their P values determined. The accumulation of each complex in suspension cultures of Chinese hamster ovary cells incubated under aerobic or extremely hypoxic conditions was determined. Radiochemical yields ranged from 5 to 80% for the 11 compounds. HPLC showed that some of the compounds formed two complexes with (99m)Tc, possibly syn and anti conformations with respect to the Tc=O bond. In general, the Class I chelators labeled more readily than the class II chelators. The P values of the (99m)Tc complexes varied from 0.0002 to 5 and were generally in accordance with predictions based on structure. There were also differences in P as a function of pH; the free acids had a lower P at pH 7.4 than at pH 2.0 due to ionization, whereas the amides did not show this effect. Accumulation levels in aerobic cells were related to P but varied over a narrow range. Four of the 11 compounds showed selective accumulation in hypoxic cells. The peptidic class of 2-Nitroimidazoles, with flexible design and convenient solid-phase synthesis, deserves further study as agents for imaging hypoxia in tumors.

Cynthia S. Dowd – One of the best experts on this subject based on the ideXlab platform.

  • Structure−Activity Relationships of Antitubercular Nitroimidazoles. 1. Structural Features Associated with Aerobic and Anaerobic Activities of 4- and 5-Nitroimidazoles
    Journal of Medicinal Chemistry, 2009
    Co-Authors: Liang Zhang, Ujjini H. Manjunatha, Ramandeep Singh, Sejal J. Patel, Jan Jiricek, Thomas H Keller, Helena I. Boshoff, Clifton E. Barry, Cynthia S. Dowd

    Abstract:

    The 4-nitroimidazole PA-824 is active against aerobic and anaerobic Mycobacterium tuberculosis (Mtb) while 5-nitroimidazoles like metronidazole are active against only anaerobic Mtb. We have synthesized analogues of both 4- and 5-nitroimidazoles and explored their antitubercular activities. The nitro group is required for both activities in all compounds. The key determinants of aerobic activity in the 4-nitroimidazoles include the bicyclic oxazine, the lipophilic tail, and the 2-position oxygen. For the 5-nitroimidazoles, neither the corresponding bicyclic analogue nor addition of a lipophilic tail conveyed aerobic activity. Incorporation of a 2-position oxygen atom into a rigid 5-nitroimidazooxazine provided the first 5-nitroimidazole with aerobic activity. Across both series, anaerobic and aerobic activities were not correlated and Mtb mutants lacking the deazaflavin-dependent nitroreductase (Ddn) retained anaerobic sensitivity to some compounds. Aerobic activity appears to be correlated with efficienc…

  • structure activity relationships of antitubercular nitroimidazoles 1 structural features associated with aerobic and anaerobic activities of 4 and 5 nitroimidazoles
    Journal of Medicinal Chemistry, 2009
    Co-Authors: Pilho Kim, Liang Zhang, Ujjini H. Manjunatha, Ramandeep Singh, Jan Jiricek, Thomas H Keller, Helena I. Boshoff, Clifton E. Barry, Sejal Patel, Cynthia S. Dowd

    Abstract:

    The 4-nitroimidazole PA-824 is active against aerobic and anaerobic Mycobacterium tuberculosis (Mtb) while 5-nitroimidazoles like metronidazole are active against only anaerobic Mtb. We have synthesized analogues of both 4- and 5-nitroimidazoles and explored their antitubercular activities. The nitro group is required for both activities in all compounds. The key determinants of aerobic activity in the 4-nitroimidazoles include the bicyclic oxazine, the lipophilic tail, and the 2-position oxygen. For the 5-nitroimidazoles, neither the corresponding bicyclic analogue nor addition of a lipophilic tail conveyed aerobic activity. Incorporation of a 2-position oxygen atom into a rigid 5-nitroimidazooxazine provided the first 5-nitroimidazole with aerobic activity. Across both series, anaerobic and aerobic activities were not correlated and Mtb mutants lacking the deazaflavin-dependent nitroreductase (Ddn) retained anaerobic sensitivity to some compounds. Aerobic activity appears to be correlated with efficiency as a substrate for Ddn, suggesting a means of structure-based optimization of improved nitroimidazoles.