- Potent galloyl-based selective modulators targeting multidrug resistance associated protein 1 and P-glycoprotein
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The multifactorial nature of chemotherapy failure in controlling cancer is often associated with the occurrence of multidrug resistance (MDR), a phenomenon likely related to the increased expression of members of the ATP binding cassette (ABC) transporter superfamily. In this respect, the most extensively characterized MDR transporters include ABCB1 (also known as MDR1 or P-glycoprotein) and ABCC1 (also known as MRP1) whose inhibition remains a priority to circumvent drug resistance. Herein, we report how the simple galloyl benzamide scaffold can be easily and properly decorated for the preparation of either MRP1 or P-gp highly selective inhibitors. In particular, some gallamides and pyrogallol-1-monomethyl ethers showed remarkable affinity and selectivity toward MRP1. On the other hand, trimethyl ether galloyl anilides, with few exceptions, exhibited moderate to very high and selective P-gp inhibition.
- Pellicani, Raffaella Zoe,Stefanachi, Angela,Niso, Mauro,Carotti, Angelo,Leonetti, Francesco,Nicolotti, Orazio,Perrone, Roberto,Berardi, Francesco,Cellamare, Saverio,Colabufo, Nicola Antonio
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supporting information; experimental part
p. 424 - 436
(2012/03/10)
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- 2-[1H-Benzimidazol-2(3H)-ylidene]-2-(pyrimidin-2-yl)acetamides and 2-[benzothiazol-2(3H)-ylidene]-2-(pyrimidin-2-yl)acetamides as kinase inhibitors
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2-[1H-benzimidazol-2(3H)-ylidene]-2-(pyrimidin-2-yl)acetamides and 2-[benzothiazol-2(3H)-ylidene]-2-(pyrimidin-2-yl)acetamides and their salts are kinase inhibitors, useful in the treatment of cancer.
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Page/Page column 11
(2010/04/25)
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- Novel dual-targeting benzimidazole urea inhibitors of DNA gyrase and topoisomerase IV possessing potent antibacterial activity: Intelligent design and evolution through the judicious use of structure-guided design and stucture-activity relationships
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The discovery of new antibacterial agents with novel mechanisms of action is necessary to overcome the problem of bacterial resistance that affects all currently used classes of antibiotics. Bacterial DNA gyrase and topoisomerase IV are well-characterized clinically validated targets of the fluoroquinolone antibiotics which exert their antibacterial activity through inhibition of the catalytic subunits. Inhibition of these targets through interaction with their ATP sites has been less clinically successful. The discovery and characterization of a new class of low molecular weight, synthetic inhibitors of gyrase and topoisomerase IV that bind to the ATP sites are presented. The benzimidazole ureas are dual targeting inhibitors of both enzymes and possess potent antibacterial activity against a wide spectrum of relevant pathogens responsible for hospital- and community-acquired infections. The discovery and optimization of this novel class of antibacterials by the use of structure-guided design, modeling, and structure-activity relationships are described. Data are presented for enzyme inhibition, antibacterial activity, and in vivo efficacy by oral and intravenous administration in two rodent infection models.
- Charifson, Paul S.,Grillot, Anne-Laure,Grossman, Trudy H.,Parsons, Jonathan D.,Badia, Michael,Bellon, Steve,Deininger, David D.,Drumm, Joseph E.,Gross, Christian H.,LeTiran, Arnaud,Liao, Yusheng,Mani, Nagraj,Nicolau, David P.,Perola, Emanuele,Ronkin, Steven,Shannon, Dean,Swenson, Lora L.,Tang, Qing,Tessier, Pamela R.,Tian, Ski-Kai,Trudeau, Martin,Wang, Tiansheng,Wei, Yunyi,Zhang, Hong,Stamos, Dean
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experimental part
p. 5243 - 5263
(2009/07/01)
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- Syntheses and structure-activity relationships of novel, potent, and selective trans-2-[3-oxospiro[isobenzofuran-1(3H),1′-cyclohexan]-4′-yl]benzimidazole NPY Y5 receptor antagonists
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Syntheses and structure-activity relationships of a novel class of 2-[3-oxospiro[isobenzofuran-1(3H),1′-cyclohexan]-4′-yl]benzimidazole NPY Y5 receptor antagonists are described. Optimization of the lead compound 2a by incorporating substituents into the 5-position or into both the 5- and 6-positions of the benzimidazole core part led to the identification of 5-(5-methyl-1,2,4-oxadiazol-2-yl)benzimidazole (2r: IC50 = 3.3 nM) and 5-(2-methyltetrazol-5-yl)benzimidazole (2u: IC50 = 5.9 nM), both of which are potent, selective, and orally bioavailable Y5 receptor antagonists. Crown Copyright
- Ogino, Yoshio,Ohtake, Norikazu,Nagae, Yoshikazu,Matsuda, Kenji,Ishikawa, Makoto,Moriya, Minoru,Kanesaka, Maki,Mitobe, Yuko,Ito, Junko,Kanno, Tetsuya,Ishihara, Akane,Iwaasa, Hisashi,Ohe, Tomoyuki,Kanatani, Akio,Fukami, Takehiro
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scheme or table
p. 4997 - 5001
(2009/06/30)
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- Gyrase inhibitors and uses thereof
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The present invention relates to compounds that inhibit bacterial gyrase and/or Topo IV and pharmaceutically acceptable compositions comprising said compounds. These compounds, and compositions thereof, are useful in treating bacterial infection. Accordin
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- Gyrase inhibitors and uses thereof
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The present invention relates to methods of treating, preventing, or lessening the severity of resistant bacterial infections in mammals, utilizing compounds of formula I or formula VII or pharmaceutically salts thereof. The present invention also relates
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- Gyrase inhibitors and uses thereof
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The present invention relates to compounds which inhibit bacterial gyrase and/or Topo IV and pharmaceutically acceptable compositions comprising said compounds. These compounds, and compositions thereof, are useful in treating bacterial infection. Accordi
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- Gyrase inhibitors and uses thereof
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The present invention relates to compounds of the formula I: or a pharmaceutically acceptable derivative or prodrug thereof. The compounds are useful as inhibitors of bacterial gyrase activity. The present invention also relates to methods for treating ba
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- Trisbenzimidazoles useful as topoisomerase I inhibitors
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The present invention provides anti-neoplastic topoisomerase I inhibitors of the formula: STR1 wherein Ar is (C6 -C12)aryl or (5- to 12-membered) heteroaryl comprising 1-3 N, S or non-peroxide O, wherein N is unsubstituted or is substituted with (C1 -C4)alkyl; X is H, CN, CHO, OH, acetyl, CF3, O(C1 -C4)alkyl, NO2, NH2, halogen or halo-(C1 -C4)alkyl; each Y is individually H, (C1 -C4)alkyl or aralkyl; Y' is H or (C1 -C4)alkyl; n is 0 or 1; and each Z is individually H, (C1 -C4)alkyl, halogen or halo(C1 -C4)alkyl; or a pharmaceutically acceptable salt therein.
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- Terbenzimidazoles useful as antifungal agents
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The present invention provides a method of treatment of fungal infection with an antifungal topoisomerase I inhibitor of the formula: STR1 wherein Ar is (C6 -C12)aryl, a (5- to 12-membered) heteroaryl comprising 1-3 N, S or non-peroxide O, wherein N is unsubstituted or is substituted with H, (C1 -C4)alkyl or benzyl; or benzo; X is H, CN, CHO, OH, acetyl, CF3, O(C1 -C4)alkyl, NO2, NH2, halogen or halo-(C1 -C4)alkyl; each Y is individually H, (C1 -C4)alkyl or aralkyl; Y' is H or (C1 -C4)alkyl; n is 0 or 1; and each Z is individually H, (C1 -C4)alkyl, halogen or halo(C1 -C4)alkyl; or a pharmaceutically acceptable salt thereof.
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- Synthesis and evaluation of terbenzimidazoles as topoisomerase I inhibitors
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The synthesis and pharmacological activity of a series of terbenzimidazoles are described. The ability of these derivatives to induce DNA cleavage in the presence of topoisomerase I was evaluated in vitro. These analogs were also assayed for their cytotoxicity in RPMI 8402 cells and the camptothecin-resistant CPT-K5 cells. In addition the potential for these compounds to serve as substrates for MDR1 was also determined. Several terbenzimidazoles exhibited similar cytotoxicity against variants of human tumor cells that either overexpress MDR1 or are camptothecin-resistant.
- Sun,Gatto,Yu,Liu,Liu,LaVoie
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p. 3638 - 3644
(2007/10/03)
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- 6-(1H-imidazol-1-yl)-7-nitro-2,3 (1H,4H)-quinoxalinedione hydrochloride (YM90K) and related compounds: Structure-activity relationships for the AMPA- type non-NMDA receptor
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A novel series of quinoxalinediones possessing imidazolyl and related heteroaromatic substituents was synthesized and evaluated for their activity to inhibit [3H]AMPA binding from rat whole brain. From the structure- activity relationships, it was found that the 1H-imidazol-1-yl moiety could function as a bioisostere for the cyano and nitro groups, and that 6-(1H- imidazol-yl)-7-nitro-2,3(1H,4H)-quinoxalinedione (11) showed the most potent activity for the AMPA receptor. Compound 11 was evaluated for selectivity versus other excitatory amino acid receptors, and its action against AMPA at its receptor in the rat striatum was characterized. These data showed that compound 11 was a selective antagonist for the AMPA receptor with a K(i) value of 0.084 μM, being approximately equipotent with 2,3-dihydro-6-nitro- 7-sulfamoylbenzo(f)quinoxaline (3) (NBQX; K(i) = 0.060 μM). Compound 11 was also found to give protection against sound-induced seizure on DBA/2 mice at the minimum effective dose of 3 mg/kg ip (3; 10 mg/kg ip).
- Ohmori,Sakamoto,Kubota,Shimizu-Sasamata,Okada,Kawasaki,Hidaka,Togami,Furuya,Murase
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p. 467 - 475
(2007/10/02)
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