- Design, synthesis, in vitro inhibition and toxicological evaluation of human carbonic anhydrases I, II and IX inhibitors in 5-nitroimidazole series
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With the aim to obtain novel compounds possessing both strong affinity against human carbonic anhydrases and low toxicity, we synthesised novel thiourea and sulphonamide derivatives 3, 4 and 10, and studied their in vitro inhibitory properties against human CA I, CA II and CA IX. We also evaluated the toxicity of these compounds using zebrafish larvae. Among the three compounds, derivative 4 showed efficient inhibition against hCA II (KI = 58.6 nM). Compound 10 showed moderate inhibition against hCA II (KI = 199.2 nM) and hCA IX (KI = 147.3 nM), whereas it inhibited hCA I less weakly at micromolar concentrations (KI = 6428.4 nM). All other inhibition constants for these compounds were in the submicromolar range. The toxicity evaluation studies showed no adverse effects on the zebrafish larvae. Our study suggests that these compounds are suitable for further preclinical characterisation as potential inhibitors of hCA I, II and IX.
- Aspatwar, Ashok,Parvathaneni, Nanda Kumar,Barker, Harlan,Anduran, Emilie,Supuran, Claudiu T.,Dubois, Ludwig,Lambin, Philippe,Parkkila, Seppo,Winum, Jean-Yves
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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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- A rifamycin - nitro imidazole coupled molecular preparation method of (by machine translation)
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The invention discloses a rifamycin - nitro imidazole coupling molecule of the preparation method. Preparation method of this invention to MTZ as raw materials, by changing the synthetic route, overcomes the reaction conditions must be controlled to the defect under the low temperature condition, and has improved the yield of target product. (by machine translation)
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Paragraph 0027-0029
(2017/09/12)
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- Metronidazole-triazole conjugates: Activity against Clostridium difficile and parasites
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Abstract Metronidazole has been used clinically for over 50 years as an antiparasitic and broad-spectrum antibacterial agent effective against anaerobic bacteria. However resistance to metronidazole in parasites and bacteria has been reported, and improved second-generation metronidazole analogues are needed. The copper catalysed Huigsen azide-alkyne 1,3-dipolar cycloaddition offers a way to efficiently assemble new libraries of metronidazole analogues. Several new metronidazole-triazole conjugates (Mtz-triazoles) have been identified with excellent broad spectrum antimicrobial and antiparasitic activity targeting Clostridium difficile, Entamoeba histolytica and Giardia lamblia. Cross resistance to metronidazole was observed against stable metronidazole resistant C. difficile and G. lamblia strains. However for the most potent Mtz-triazoles, the activity remained in a therapeutically relevant window.
- Jarrad, Angie M.,Karoli, Tomislav,Debnath, Anjan,Tay, Chin Yen,Huang, Johnny X.,Kaeslin, Geraldine,Elliott, Alysha G.,Miyamoto, Yukiko,Ramu, Soumya,Kavanagh, Angela M.,Zuegg, Johannes,Eckmann, Lars,Blaskovich, Mark A.T.,Cooper, Matthew A.
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supporting information
p. 96 - 102
(2015/07/01)
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- EXPANDED THERAPEUTIC POTENTIAL IN NITROHETEROARYL ANTIMICROBIALS
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Disclosed herein are antimicrobial compounds compositions, pharmaceutical compositions, the use and preparation thereof. Some embodiments relate to imidazole, thiazole, and furan derivatives and their use as therapeutic agents.
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Paragraph 0296
(2015/01/07)
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- NITROIMIDAZOLE COMPOUNDS AND THEIR USE IN CANCER THERAPY
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The invention provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof, formula (I) wherein m, n, X, Y and Z are as defined herein. Also provided are pharmaceutical compositions containing compounds of Formula (I), and methods of treating cancer and/or improving the response of tumors to radiotherapy by administering a compound of Formula (I) to a warm-blooded animal.
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Paragraph 42
(2014/03/25)
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- Novel nitroimidazole alkylsulfonamides as hypoxic cell radiosensitisers
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A novel class of nitroimidazole alkylsulfonamides have been prepared and evaluated as hypoxia-selective cytotoxins and radiosensitisers. The sulfonamide side chain markedly influences the physicochemical properties of the analogues: lowering aqueous solubility and raising the electron affinity of the nitroimidazole group. The addition of hydroxyl or basic amine groups increased aqueous solubility, with charged amine groups contributing to increased electron affinity. The analogues covered the range of electron affinity for effective radiosensitisation with one-electron reduction potentials ranging from -503 to -342 mV. Cytotoxicity under normoxia or anoxia against a panel of human tumour cell lines was determined using a proliferation assay. 2-Nitroimidazole sulfonamides displayed significant hypoxia-selective cytotoxicity (6 to 64-fold), while 4- and 5-nitroimidazole analogues did not display hypoxia-selective cytotoxicity. All analogues sensitised anoxic HCT-116 human colorectal cells to radiation at non-toxic concentrations. 2-Nitroimidazole analogues provided modest sensitisation due to the relatively low concentrations used while several 5-nitroimidazole analogues provided equivalent sensitisation to misonidazole and etanidazole at similar molar concentrations.
- Bonnet, Muriel,Hong, Cho Rong,Gu, Yongchuan,Anderson, Robert F.,Wilson, William R.,Pruijn, Frederik B.,Wang, Jingli,Hicks, Kevin O.,Hay, Michael P.
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p. 2123 - 2132
(2014/04/17)
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- DIAGNOSTIC AGENT FOR INFECTIOUS DISEASES
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A diagnostic agent for infectious diseases which is capable of distinguishing among different kinds of bacterial species and which allows simple and non-invasive measurement and/or imaging in a short period of time is provided; and a screening method for a therapeutic agent for infectious diseases caused by microorganisms are provided. A diagnostic agent for infectious diseases caused by nitroimidazole susceptible microorganisms, containing an imidazole derivative or a fused imidazole derivative having at least one nitro group on an imidazole ring, or a labeled form thereof as an active ingredient is provided.
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- Imidazole derivatives as possible microbicides with dual protection
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Twenty seven derivatives (2-28) of 2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethanol were synthesized and evaluated for anti-trichomonas, spermicidal and antifungal activities. Twenty six compounds were active against Trichomonas vaginalis at MIC ranging from 1-42 μM and seven compounds (9,18,19,22,24,26,28) immobilized 100% human spermatozoa at 1% concentration (w/v). Twenty three compounds (2,3,5,8-26,28) exhibited antifungal activity at 25-50 μg/mL concentration. Seven compounds (9,18,19,22,24,26,28) showed significant anti-trichomonas and spermicidal activities and also exhibited mild antifungal activity. All the compounds were highly safe towards human cervical cell line (HeLa) as shown by the cell-viability assay of HeLa cells at 200 μg/mL concentration, whereas nonoxynol-9 (N-9, the marketed spermicidal microbicide) was highly cytotoxic. Therefore, it may be concluded that introduction of the pharmacophore responsible for spermicidal activity into a proven anti-trichomonas structure may lead to a potent dual function microbicide better and safer than N-9.
- Kumar, Lalit,Sarswat, Amit,Lal, Nand,Sharma, Vishnu L.,Jain, Ashish,Kumar, Rajeev,Verma, Vikas,Maikhuri, Jagdamba P.,Kumar, Awanit,Shukla, Praveen K.,Gupta, Gopal
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experimental part
p. 817 - 824
(2010/04/06)
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- Synthesis, molecular modeling, and biological evaluation of cinnamic acid metronidazole ester derivatives as novel anticancer agents
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A series of novel cinnamic acid metronidazole ester derivatives have been designed and synthesized, and their biological activities were also evaluated as potential EGFR and HER-2 kinase inhibitors. Compound 3h showed the most potent biological activity (IC50 = 0.62 μM for EGFR and IC50 = 2.15 μM for HER-2). Docking simulation was performed to position compound 3h into the EGFR active site to determine the probable binding model. Antiproliferative assay results demonstrated that some of these compounds possessed good antiproliferative activity against MCF-7. Compound 3h with potent inhibitory activity in tumor growth inhibition may be a potential anticancer agent.
- Qian, Yong,Zhang, Hong-Jia,Zhang, Hao,Xu, Chen,Zhao, Jing,Zhu, Hai-Liang
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experimental part
p. 4991 - 4996
(2010/09/05)
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- Epoxysuccinamide derivative or salt thereof
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PCT No. PCT/JP98/01778 Sec. 371 Date Dec. 17, 1998 Sec. 102(e) Date Dec. 17, 1998 PCT Filed Apr. 17, 1998 PCT Pub. No. WO98/47887 PCT Pub. Date Oct. 29, 1998The invention relates an epoxysuccinamide derivative represented by a formula (I): wherein R1 represents a hydrogen atom, an alkyl or aminoalkyl group, R2 represents an aminoalkyl group which May be substituted, an aryl group which may be substituted, a heterocyclic group which may be substituted, an aralkyl group which may be substituted, or an alkyl group substituted by a heterocyclic ring which may be substituted, or R1 and R2 may form a nitrogen-containing heterocyclic ring, which may be substituted, together with the adjacent nitrogen atoms, and R3 and R4 are the same or different from each other and independently represent a hydrogen atom, or an alkyl or aralkyl group, or a salt thereof, a preparation process thereof, and a medicine comprising such a derivative or salt as an active ingredient. This compound has a specific inhibitory activity for cathepsin L and family enzymes thereof, and is useful as an agent for preventing and treating metabolic osteopathy such as osteoporosis and hypercalcemia.
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- Hypoxia-selective antitumor agents. 8. Bis(nitroimidazolyl)alkanecarboxamides: A new class of hypoxia-selective cytotoxins and hypoxic cell radiosensitisers
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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
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p. 381 - 391
(2007/10/02)
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- Synthesis of Steroidal Nitroimidazoles as Site-Selective Radiosensitizers
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The synthesis of a series of nitroimidazole derivatives of estradiol and hexestrol, as potential site-selective radiosensitizers for estrogen receptor-rich tumours, is described.Nitroimidazole moeities are attached directly via a C-N linkage onto the C-16 position or via a 1-4 atom spacer chain at the C-17α position of estradiol.Nitroimidazoles are also coupled on the C-1' position of the side chain of substituted hexestrol and norhexestrol, using bromo intermediates whereas C-3 ether-linked products are prepared using a nitroimidazole methanesulfonate.In vitro evaluation for receptor binding properties indicates that these conjugates exhibit considerably diminished affinity for the estrogen receptor.
- Ali, Hasrat,Quellet, Rene,DaSilva, Jean N.,Lier, Johan E. van
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p. 612 - 634
(2007/10/02)
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