- Design and synthesis of vandetanib derivatives containing nitroimidazole groups as tyrosine kinase inhibitors in normoxia and hypoxia
-
Sixteen novel epidermal growth factor receptor (EGFR)/vascular endothelial growth factor (VEGF)-2 inhibitors (nitroimidazole-substituted 4-anilinoquinazoline derivatives (16a-p)) were designed and prepared via the introduction of a nitroimidazole group in the piperidine side chain and modification on the aniline moiety of vandetanib. Preliminary biological tests showed that comparing with vandetanib, some target compounds exhibited excellent EGFR inhibitory activities and anti-proliferative over A549/H446 cells in hypoxia. Meanwhile, several of the above compounds demonstrated better bioactivity than vandetanib in VEGF gene expression inhibition. Owing to the excellent IC50 value (1.64 μmol/L), the inhibition ratios of 16f over A549 and H446 cells were 62.01% and 59.86% at the concentration of 0.5 μM in hypoxia, respectively. All of these results indicated that 16f was a potential cancer therapeutic agent in hypoxia and was worthy of further development.
- Wei, Huiqiang,Li, Deguan,Yang, Xiangbo,Shang, Haihua,Fan, Saijun,Li, Yiliang,Song, Dan
-
-
Read Online
- Preparation and biological evaluation of metronidazole derivatives with monoterpenes and eugenol
-
Two series of metronidazole derivatives (ester derivatives and ether derivatives) were prepared reacting metronidazole and its acetic acid oxidized form with menthol, thymol, carvacrol, and eugenol. Both series of compounds were tested in vitro against tw
- Bkhaitan, Majdi M.,Alarjah, Mohammed,Mirza, Agha Zeeshan,Abdalla, Ashraf N.,El-Said, Hamdi M.,Faidah, Hani S.
-
p. 1954 - 1962
(2018/09/06)
-
- A by the MTZ preparation of amine derivatives furan warm and its preparation and in antibacterial drugs in the application of the
-
The invention relates to a furanone aniline derivate prepared from metronidazole, as well as a preparation method and applicable of the furanone aniline derivate in antibacterial drugs. The derivant is named as 4-((3,5-dimethoxy phenyl) amino)-3-(2-methyl-5-nitro-1H-iminazol-1-radical)furan-2(5H)-ketone. The derivant represents a better inhibiting and killing effect on to-be-tested bacteria, the inhibiting activity of bacillus subtilis is close to that of positive control kanamycin, and the inhibiting activity of the staphylococcus epidermidis exceeds that of positive control kanamycin, so that the derivant can be used for preparing anti-infective drugs; the influence due to configuration interconversion is improved by replacing the acrylate part of a lead compound with a furan ketone ring, a metronidazole structure with stronger antimicrobial action is introduced, and on the basis of in-depth study of the structure-function relationship, a novel antibacterial derivate with a higher activity is designed and synthesized, and the preparation method of the derivate is provided.
- -
-
Paragraph 0010; 0021
(2018/06/07)
-
- Anilinoquinazoline compound containing nitroimidazole group and preparation method and application thereof
-
The invention provides a brand new anilinoquinazoline compound of the structure in the formula (I). The anilinoquinazoline compound has a tyrosine kinase inhibiting effect. Real-time fluorogenic quantitative PCR measurement results indicate that the VEGF
- -
-
Paragraph 0084; 0085; 0086; 0087
(2017/08/28)
-
- TREATMENTS FOR GASTROINTESTINAL CONDITIONS
-
Compounds for the treatment of bacterial and parasitic infections which are hybrid compounds of compounds having antibacterial or antiparasitic activity and compounds that decrease the absorption of the hybrid compound from the gastrointestinal tract. The compounds are preferably for use against C. difficile infections and comprise a hybrid molecule of an anti-C. difficile compound such as a nitroimidazole and a tetramic acid derivative.
- -
-
Page/Page column 23
(2015/10/05)
-
- COMPOUNDS AND METHODS FOR SELECTIVE IMAGING AND/OR ABLATION
-
The invention relates generally to compounds and methods for imaging and/or selective ablation of nitroreductase-expressing cells and/or biological agents. More particularly, although not exclusively, the invention provides compounds that are selectively metabolised by bacterial nitroreductases and are substantially insensitive to metabolism under oxic or hypoxic conditions by human nitroreductase enzymes.
- -
-
Page/Page column 54; 55
(2014/01/18)
-
- Synthesis of new compounds derived from metronidazole and amino acids and their esters as antiparasitic agents
-
A number of new compounds derived from metronidazole and amino acids and their esters have been synthesized through a reaction between 2-(2-methyl-5-nitro-1H-imidazol-1-yl)acetic acid and a number of amino acid esters in the presence of N,N'carbonyldiimidazole (CDI). Hydrolysis of the esters derivatives with sodium hydroxide (4%) followed by acidification with hydrochloric acid (3 M) afforded the corresponding acids. The newly synthesized compounds were characterized by elemental analysis and by spectroscopic techniques such as 1H-NMR, 13C-NMR, and mass spectrometry. Some of the prepared compounds exhibited lethal activity against pathogenic protozoan parasites. Springer Science+Business Media, LLC 2011.
- Al-Masri, Ahmed T.,Saadeh, Haythem A.,Mosleh, Ibrahim M.,Mubarak, Mohammad S.
-
p. 1700 - 1707
(2012/11/13)
-
- Metronidazole acid acyl sulfonamide: A novel class of anticancer agents and potential EGFR tyrosine kinase inhibitors
-
A series of novel metronidazole derivatives were recently reported as potent anticancer agents targeting EGFR and HER-2 by our group [Qian, Y.; Zhang, H. J.; Zhang, H.; Xu, C.; Zhao, J.; Zhu, H. L. Bioorg. Med. Chem. 2010, 18, 4991]. Based on the previous
- Luo, Yin,Li, Yao,Qiu, Ke-Ming,Lu, Xiang,Fu, Jie,Zhu, Hai-Liang
-
experimental part
p. 6069 - 6076
(2011/11/06)
-
- Synthesis of nitroimidazole derived oxazolidinones as antibacterial agents
-
A series of N-alkylated derivatives of nitroimidazolyl oxazolidinones 6a-i with various substituent at N-1 position of the nitroimidazole were synthesized and their in-vitro antibacterial activities were evaluated against several Gram-positive and Gram-ne
- Varshney, Vandana,Mishra, Nripendra N.,Shukla, Praveen K.,Sahu, Devi P.
-
scheme or table
p. 661 - 666
(2010/04/04)
-
- Convenient syntheses of 5-[(2-Methyl-5-nitro-1H-imidazol-1-yl)methyl]-1,3, 4-oxadiazole-2(3H)thione and N-substituted 2-amino-5-[(2-methyl-5-nitro-1H- imidazol-1-yl)methyl]-1,3,4-thiadiazoles
-
(Chemical Equation Presented) Oxidation of metronidazole (4) with sodium dichromate yielded the corresponding 2-(2-methyl-5-nitro-1H-imidazol-1-yl)acetic acid (5) which was esterified with 1-butanol to give butyl 2-(2-methyl-5-nitro- 1H-imidazol-1-yl)acetate (8). Reaction of the latter with hydrazine hydrate gave 2-(2-methyl-5-nitro-1H-imidazol-1-yl)acetohydrazide (9). Compound 5-[(2-methyl-5-nitro-1H-imidazol-1-yl)methyl]-1,3,4-oxadiazole-2(3H)-thione (10) could be obtained through the reaction of compound 9 with carbon disulfide in basic medium. Subsequent alkylation of compound 10 afforded alkyl 2-(5-[(2-methyl-5-nitro-1H-imidazol-1-yl)methyl]-1,3,4-oxadiazol-2-ylthio) acetate (11) in good yield. Reaction of hydrazide 9 with substituted isothiocynate yielded 1-[2-(2-methyl-5-nitro-1H-imidazol-1-yl)acetyl]-4-aryl(or ethyl)thiosemicarbazide (12) which was cyclized in acidic media to N-substituted 2-amino-5-[(2-methyl-5-nitro-1H-imidazol-1-yl)methyl]-1,3,4-thiadiazole (13).
- Mirzaei, Javad,Amini, Mohsen,Pirelahi, Hooshang,Shafiee, Abbas
-
p. 921 - 925
(2008/09/21)
-
- A comparative study of precision cut liver slices, hepatocytes, and liver microsomes from the Wistar rat using metronidazole as a model substance
-
1. Metronidazole is metabolized by rat liver in vitro models to form a hydroxy metabolite, an acetic acid metabolite, a glucuronic acid conjugate, and a sulphate conjugate; 2. Four different in vitro systems for investigation of drug metabolism based on liver preparations from the male Wistar rat have been investigated. 3. An incubation system where liver slices are Incubated in 12-well culture plates was evaluated with respect to metabolism of metronidazole. Optimal viability was observed for a time period of up to 24 h. The Michaelis-Menten parameters for the metabolism of metronidazole in liver slices were calculated and the intrinsic clearance values compared with the values determined in hepatocytes incubated in suspension,It was found that the intrinsic clearance with respect to formation of oxidative metabolites, the hydroxy metabolite, and the acetic acid metabolite correlated, whereas the intrinsic clearance with respect to formation of the glucuronic acid conjugate was lower in slices compared with hepatocytes. 4. The metabolism of metronidazole in liver slices, in hepatocytes in primary monolayer culture, in hepatocytes incubated in suspension, and in liver microsomes was compared. All the incubations were performed under identical incubation conditions including the same incubation medium. The trend observed was that the initial metabolic rates of the production of the hydroxy metabolite, the glucuronic acid metabolite, and the acetic acid metabolite of metronidazole were higher in microsomes than in the other liver preparations. The metabolic rates in hepatocytes in primary culture and in suspension with respect to the oxidative metabolites were higher than in liver slices. The metabolic turnover observed in liver slices was predicted to correlate with in vivo data earlier obtained for rat.
- Sidelmann,Cornett,Tjornelund,Hansen
-
p. 709 - 722
(2007/10/03)
-
- Hypoxia-selective antitumor agents. 8. Bis(nitroimidazolyl)alkanecarboxamides: A new class of hypoxia-selective cytotoxins and hypoxic cell radiosensitisers
-
A series of novel bis(nitroimidazolyl)alkanecarboxamides has been prepared and evaluated for hypoxia-selective cytotoxicity and hypoxic cell radiosensitisation in vitro and in vivo. The compounds were prepared by direct coupling of preformed side chain acid and amine components, using diethyl phosphorocyanidate at room temperature. Although designed to be bis- bioreductive prodrugs of DNA cross-linking agents, none of the compounds showed evidence of DNA cross-linking activity, being equally potent against cell lines deficient and proficient in repair of cross-links. However, one of these compounds, N-[2-(2-methyl-5-nitro-1H-imidazolyl)ethyl]-4-(2-nitro-1H- imidazolyl)butanamide (10; SN 24699), showed high hypoxic selectivity as a cytotoxin (rising to 200-fold after exposure to the drug for several hours) in the repair-proficient Chinese hamster cell line AA8. This selectivity was greater than observed for the alkylating 2-nitroimidazole (4; RB 6145) (40- fold) or simple mononitroimidazoles (5-25-fold). Investigation of structure- activity relationships for hypoxic selectivity of bis(nitroimidzoles) was restricted by their low aqueous solubility, but a certain minimum separation of the two nitroimidazole units (by more than five atoms) appears desirable. All the compounds radiosensitized hypoxic cells in vitro but were little more potent as radiosensitizers than the corresponding monomeric nitroimidazoles. Compound 10 caused additional cell killing in the KHT tumor when multiple drug doses were administered in combination with a single dose of radiation. It is not yet clear whether this activity reflects hypoxic cell radiosensitization or cytotoxicity toward hypoxic cells, but this new class of bis-bioreductive agent clearly warrants further investigation.
- Hay,Wilson,Moselen,Palmer,Denny
-
p. 381 - 391
(2007/10/02)
-
