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Shalini, Albertus Viljoen, Laurent Kremer, Vipan Kumar
The success in exploring anti-tubercular potency of nitroimidazole and quinoline, the core moieties of recently approved anti-tubercular drugs instigated us to synthesize a series of alkylated/aminated 2-methyl-5-nitroimidazoles and nitroimidazole-7-chloroquinoline conjugates and to evaluate them for their activities against Mycobacterium tuberculosis as well as for their cytotoxicity towards the J774 murine macrophage cell line. Although the synthesized compounds did not surpass the activity of the standard drug Isoniazid, they have appreciable activities with minimal cytotoxicity...
March 8, 2018: Bioorganic & Medicinal Chemistry Letters
Yi-Lei Fan, Xiao-Hong Jin, Zhong-Ping Huang, Hai-Feng Yu, Zhi-Gang Zeng, Tao Gao, Lian-Shun Feng
Tuberculosis still remains one of the most common, communicable, and leading deadliest diseases known to mankind throughout the world. Drug-resistance in Mycobacterium tuberculosis which threatens to worsen the global tuberculosis epidemic has caused great concern in recent years. To overcome the resistance, the development of new drugs with novel mechanisms of actions is of great importance. Imidazole-containing derivatives endow with various biological properties, and some of them demonstrated excellent anti-tubercular activity...
March 7, 2018: European Journal of Medicinal Chemistry
Gaoli He, Beining Guo, Jing Zhang, Yi Li, Xiaojie Wu, Yaxin Fan, Yuancheng Chen, Guoying Cao, Jicheng Yu
Levornidazole is a novel third-generation nitroimidazoles antibiotic which metabolism and disposition in human are not well known. We have previously developed two methods to quantify levornidazole and its phase I metabolites, Ml (Hydroxylation metabolite), M2 (N-dealkylation metabolite) and M4 (Oxidative dechlorination metabolite), in human plasma and urine. In this study, we developed three novel liquid chromatographic-tandem mass spectrometric (LC-MS/MS) methods and analyzed its phase II metabolites, sulfate conjugate (M6) and glucuronide conjugate (M16), in human plasma and urine, and the parent drug and above-mentioned five metabolites in human feces samples...
February 23, 2018: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
Haiyan Lei, Jianbo Guo, Zhuo Lv, Xiaohong Zhu, Xiaofeng Xue, Liming Wu, Wei Cao
This study reports an analytical method for the determination of nitroimidazole and quinolones in honey using liquid chromatography-tandem mass spectrometry (LC-MS/MS). A modified QuEChERS methodology was used to extract the analytes and determine veterinary drugs in honey by LC-MS/MS. The linear regression was excellent at the concentration levels of 1-100 ng/mL in the solution standard curve and the matrix standard curve. The recovery rates of nitroimidazole and quinolones were 4.4% to 59.1% and 9.8% to 46...
2018: International Journal of Analytical Chemistry
Ryan S Gibbs, Shauna L Murray, Lynn V Watson, Brandy P Nielsen, Ross A Potter, Cory J Murphy
A method using reverse-phase ultra-high-performance liquid chromatography coupled with tandem mass spectrometry is described for eight classes of therapeutants that are used in marine aquaculture products. Validation studies to evaluate recovery, precision, method detection limits, and measurement uncertainty were performed at three levels, using three representative matrices [salmon (fatty fish), tilapia (lean fish), and shrimp (crustaceans)] to assess the method performance for use as a screening or determinative (quantitative and confirmatory) method...
February 27, 2018: Journal of Agricultural and Food Chemistry
Maykel Hernández-Mesa, Carmen Cruces-Blanco, Ana M García-Campaña
A novel multiresidue method is proposed for the determination of 12 5-nitroimidazoles and their metabolites in fish roe samples using UHPLC-MS/MS. A salting-out assisted liquid-liquid extraction procedure was performed prior to sample analysis. The separation of compounds was accomplished using a C18 Zorbax Eclipse Plus column (50 mm × 2.1 mm, 1.8 µm) at 25 °C and a mobile phase consisting of 0.025% (v/v) aqueous formic acid and pure MeOH at a flow rate of 0.5 mL/min. Parameters involved in ionization and fragmentation were also optimized...
June 30, 2018: Food Chemistry
Thaisa Helena Silva Fonseca, Marina Alacoque, Fabrício Marcus Silva Oliveira, Betânia Maria Soares, Henrique Vitor Leite, Marcelo Vidigal Caliari, Maria Aparecida Gomes, Haendel Busatti
The emergence of nitroimidazole resistant isolates has been an aggravating factor in the treatment of trichomoniasis, the most common non-viral sexually transmitted disease in the world. This particularity highlights the importance of new technologies that are safe, effective, and have minor side effects or resistance. Hence, we evaluated the effectiveness of photodynamic therapy on the inactivation of Trichomonas vaginalis in vitro. We used methylene blue as a photosensitizing substance, and a light-emitting diode (LED) for irradiation of metronidazole sensitive and resistant strains...
February 11, 2018: Photodiagnosis and Photodynamic Therapy
M Van den Kerkhof, D Mabille, E Chatelain, C E Mowbray, S Braillard, S Hendrickx, L Maes, G Caljon
OBJECTIVES: Three new chemical series (bicyclic nitroimidazoles, aminopyrazoles and oxaboroles) were selected by Drugs for Neglected Diseases initiative as potential new drug leads for leishmaniasis. Pharmacodynamics studies included both in vitro and in vivo efficacy, cross-resistance profiling against the current antileishmanial reference drugs and evaluation of their cidal activity potential. METHODS: Efficacy against the reference laboratory strains of Leishmania infantum (MHOM/MA(BE)/67/ITMAP263) and L...
January 31, 2018: International Journal for Parasitology, Drugs and Drug Resistance
Samantha Wellington, Deborah T Hung
After decades of relative inactivity, a large increase in efforts to discover antitubercular therapeutics has brought insights into the biology of Mycobacterium tuberculosis (Mtb) and promising new drugs such as bedaquiline, which inhibits ATP synthase, and the nitroimidazoles delamanid and pretomanid, which inhibit both mycolic acid synthesis and energy production. Despite these advances, the drug discovery pipeline remains underpopulated. The field desperately needs compounds with novel mechanisms of action capable of inhibiting multi- and extensively drug -resistant Mtb (M/XDR-TB) and, potentially, nonreplicating Mtb with the hope of shortening the duration of required therapy...
February 15, 2018: ACS Infectious Diseases
Jian Wang, Daniel Leung, Willis Chow, James Chang, Jon W Wong
This paper presents a multi-class target screening method for the detection of 105 veterinary drug residues from 11 classes in milk using ultra-high performance liquid chromatography electrospray ionization quadrupole Orbitrap mass spectrometry (UHPLC/ESI Q-Orbitrap). The method is based on a non-target approach of full mass scan and multiplexing data-independent acquisition (Full MS/mDIA). The veterinary drugs include endectocides, fluoroquinolones, ionophores, macrolides, nitroimidazole, NSAIDs, β-lactams, penicillins, phenicols, sulfonamides, and tetracyclines...
February 5, 2018: Analytical and Bioanalytical Chemistry
E Salakos, D Korb, C Morin, O Sibony
Trichomonas vaginalis is a very common, sexually transmitted, infection that may sometimes be asymptomatic or cause vaginitis and urethritis. Recently, it has been associated with adverse obstetric outcomes such as preterm delivery, low birth weight and premature rupture of membranes. Trichomonas vaginalis can be vertically transmitted at birth. It has been found in pharynx and low respiratory tract of neonates with respiratory disease. It has also been involved in some cases of intellectual disability. The recommended treatment is a 2g metronidazole oral single dose, even for asymptomatic patients...
January 29, 2018: Journal of Gynecology Obstetrics and Human Reproduction
Shujing Liu, Michael T Tetzlaff, Tao Wang, Xiang Chen, Ruifeng Yang, Suresh M Kumar, Adina Vultur, Pengxiang Li, James S Martin, Meenhard Herlyn, Ravi Amaravadi, Bin Li, Xiaowei Xu
Angiogenesis is a critical step during tumor progression. Anti-angiogenic therapy has only provided modest benefits in delaying tumor progression despite its early promise in cancer treatment. It has been postulated that anti-angiogenic therapy may promote the emergence of a more aggressive cancer cell phenotype by generating increased tumor hypoxia-a well-recognized promoter of tumor progression. TH-302 is a 2-nitroimidazole triggered hypoxia-activated prodrug (HAP) which has been shown to selectively target the hypoxic tumor compartment and reduce tumor volume...
December 29, 2017: Oncotarget
Hua He, Rongying Zhu, Wei Sun, Kaimin Cai, Yongbing Chen, Lichen Yin
The precise and selective delivery of chemodrugs into tumors represents a critical requirement for anti-cancer therapy. Intelligent delivery systems that are responsive to a single internal or external stimulus often lack sufficient cancer selectivity, which compromises the drug efficacy and induces undesired side effects. To overcome this dilemma, we herein report a cancer-targeting vehicle which allows highly cancer-selective drug release in response to cascaded external (light) and internal (hypoxia) dual triggers...
January 24, 2018: Nanoscale
Paul Nyirjesy, Jane R Schwebke
Secnidazole is a next-generation 5-nitroimidazole approved for more than three decades in Europe, Asia, South America and Africa and recently in the USA as a single-dose (2 g) treatment of bacterial vaginosis (BV). Secnidazole is characterized by potent in vitro antimicrobial activity against BV-associated pathogens, as well as prolonged terminal elimination half-life and systemic exposure. These characteristics form the basis of effective and safe treatment of BV with a 2-g single-dose secnidazole regimen, which was recently confirmed in double-blind, placebo-controlled clinical trials conducted in the USA...
January 12, 2018: Future Microbiology
Peter Wardman
Nitroimidazoles have been extensively explored as hypoxic cell radiosensitizers but have had limited clinical success, with efficacy restricted by toxicity. However, they have proven clinically useful as probes for tumour hypoxia. Both applications, and probably much of the dose-limiting toxicities, reflect the dominant chemical property of electron affinity or ease of reduction, associated with the nitro substituent in an aromatic structure. This single dominant property affords unusual, indeed extraordinary flexibility in drug or probe design, suggesting further development is possible in spite of earlier limitations, in particular building on the benefit of hindsight and an appreciation of errors made in earlier studies...
January 5, 2018: British Journal of Radiology
Andrew M Thompson, Muriel Bonnet, Ho H Lee, Scott G Franzblau, Baojie Wan, George S Wong, Christopher B Cooper, William A Denny
A published study of structural features associated with the aerobic and anaerobic activities of 4- and 5-nitroimidazoles had found that the 3-nitro isomer of pretomanid, 8, displayed interesting potencies, including against nitroreductase mutant Mycobacterium tuberculosis. However, recent nuclear magnetic resonance analyses of two trace byproducts, isolated from early process optimization studies toward a large-scale synthesis of pretomanid, raised structural assignment queries, particularly for 8, stimulating further investigation...
December 14, 2017: ACS Medicinal Chemistry Letters
Wenting Zhang, Wei Fan, Zhengyuan Zhou, Jered Garrison
Tumor hypoxia has been widely explored over the years as a diagnostic and therapeutic marker. Herein, we synthesized an alkyne functionalized version of evofosfamide, a hypoxia-selective prodrug. The purpose of this effort was to investigate if this novel 2-nitroimidazole phosphoramide nitrogen mustard (2-NIPAM) retained hypoxia selectivity and could be utilized in radiopharmaceutical development to significantly increase retention of conjugated agents in hypoxic cells. 2-NIPAM demonstrated good hypoxia selectivity with a 62- and 225-fold increase in cytotoxicity toward PC-3 and DU145 human prostate cancer cell lines, respectively, under hypoxic conditions...
December 14, 2017: ACS Medicinal Chemistry Letters
Paulo Sérgio Gonçalves Nunes, Zhengxing Zhang, Hsiou-Ting Kuo, Chengcheng Zhang, Julie Rousseau, Etienne Rousseau, Joseph Lau, Daniel Kwon, Ivone Carvalho, François Bénard, Kuo-Shyan Lin
2-Nitroimidazole-based hypoxia imaging tracers such as 18 F-FMISO are normally imaged at late time points (several hours post-injection) due to their slow clearance from background tissues. Here we investigated if a hydrophilic zwitterion-based ammoniomethyl-trifluoroborate derivative of 2-nitroimidazole, 18 F-AmBF3 -Bu-2NI, could have the potential to image tumor hypoxia at earlier time points. AmBF3 -Bu-2NI was prepared in four steps. 18 F labeling was conducted via 18 F-19 F isotope exchange reaction, and 18 F-AmBF3 -Bu-2NI was obtained in 14...
December 16, 2017: Journal of Labelled Compounds & Radiopharmaceuticals
Nicola Thorley, Jonathan Ross
OBJECTIVES: Trichomoniasis, caused by Trichomonas vaginalis (TV), is the most common curable sexually transmitted infection worldwide. Current guidance in the UK is to treat TV with a nitroimidazole antibiotic. The high prevalence of TV, high rate of antibiotic resistance and limited tolerability to nitroimidazoles suggest that alternative treatment regimens are needed. Intravaginal boric acid (BA) has been used safely for the treatment of candida vulvovaginitis and bacterial vaginosis, and in vitro studies suggest BA is active against TV...
December 9, 2017: Sexually Transmitted Infections
Aurélien Voissiere, Valérie Weber, Yvain Gerard, Françoise Rédini, Florian Raes, Jean-Michel Chezal, Françoise Degoul, Caroline Peyrode, Elisabeth Miot-Noirault
Due to its abundant chondrogenic matrix and hypoxic tissue, chondrosarcoma is chemo- and radio-resistant. Our group has developed a proteoglycan targeting strategy by using a quaternary ammonium (QA) function as a carrier of DNA alkylating agents to chondrosarcoma environment. Here, we assessed the relevance of this strategy applied to hypoxia-activated prodrugs, by conjugating a QA to 2-nitroimidazole phosphoramidate. This derivative, named as 8-QA , was evaluated respectively to its non-QA equivalent and to a QA-conjugated but non-hypoxia activated...
November 10, 2017: Oncotarget
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