- A novel 2-aminobenzimidazole-based compound Jzu 17 exhibits anti-angiogenesis effects by targeting VEGFR-2 signalling
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Background and Purpose: Recent development in drug discovery have shown benzimidazole to be an important pharmacophore,. Benzimidazole derivatives exhibit broad-spectrum pharmacological properties including anti-microbial, anti-diabetic and anti-tumour activity. However, whether benzimidazole derivatives are effective in suppressing angiogenesis and its underlying mechanisms remain incompletely understood. In this study, we aim to characterize the anti-angiogenic mechanisms of a novel 2-aminobenzimidazole-based compound, Jzu 17, in an effort to develop novel angiogenesis inhibitor. Experimental Approach: Effects of Jzu 17 on endothelial cell proliferation, migration, invasion, and activation of signalling molecules induced by VEGF-A, were analysed by immunoblotting, MTT, BrdU, migration, and invasion assays. We performed tube formation assay, aorta ring sprouting assay, matrigel plug assay, and a mouse model of metastasis to evaluate ex vivo and in vivo anti-angiogenic effects of Jzu 17. Key Results: Jzu 17 inhibited VEGF-A-induced cell proliferation, migration, invasion, and endothelial tube formation of HUVECs. Jzu 17 suppressed VEGF-A-induced microvessel sprouting ex vivo and attenuated VEGF-A- or tumour cell-induced neovascularization in vivo. Jzu 17 also reduced B16F10 melanoma lung metastasis. In addition, Jzu 17 inhibited the phosphorylation of VEGFR-2 and its downstream signalling molecules in VEGF-A-stimulated HUVECs. Results from computer modelling further showed that Jzu 17 binds to VEGFR-2 with high affinity. Conclusions and Implications: Jzu 17 may inhibit endothelial remodelling and suppress angiogenesis through targeting VEGF-A-VEGFR-2 signalling. These results also suggest Jzu 17 as a potential lead compound and warrant the clinical development of similar agents in the treatment of cancer and angiogenesis-related diseases.
- Lien, Jin-Cherng,Chung, Chi-Li,Huang, Tur-Fu,Chang, Tsung-Chia,Chen, Kuan-Chung,Gao, Ging-Yan,Hsu, Ming-Jen,Huang, Shiu-Wen
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supporting information
p. 4034 - 4049
(2019/11/02)
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- Synthesis of phenyl 1-benzyl-1H-benzo [d] imidazol-2-ylcarbamates
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1H-Benzo [d] imidazol-2-amine reacts with benzyl halides to give 1-benzyl-1Hbenzo [d] imidazol-2-amines (3a-k). These compounds were treated with phenylchloro formate to yield phenyl 1-benzyl-1H-benzo [d] imidazol-2-ylcarbamates (5a-k). They have been screened for their antibacterial activity.
- Kranthi Kumar,Laxminarayana,Thirupathaiah,Thirumala Chary
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p. 125 - 128
(2019/01/21)
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- Identification of inhibitors of NOD1-induced nuclear factor-κB activation
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NOD1 (nucleotide-binding oligomerization domain 1) protein is a member of the NLR (NACHT and leucine rich repeat domain containing proteins) protein family, which plays a key role in innate immunity as a sensor of specific microbial components derived from bacterial peptidoglycans and induction of inflammatory responses. Mutations in NOD proteins have been associated with various inflammatory diseases that affect NF-κB (nuclear factor κB) activity, a major signaling pathway involved in apoptosis, inflammation, and immune response. A luciferase-based reporter gene assay was utilized in a high-throughput screening program conducted under the NIH-sponsored Molecular Libraries Probe Production Center Network program to identify the active scaffolds. Herein, we report the chemical synthesis, structure-activity relationship studies, downstream counterscreens, secondary assay data, and pharmacological profiling of the 2-aminobenzimidazole lead (compound 1c, ML130) as a potent and selective inhibitor of NOD1-induced NF-κB activation.
- Khan, Pasha M.,Correa, Ricardo G.,Divlianska, Daniela B.,Peddibhotla, Satyamaheshwar,Sessions, E. Hampton,Magnuson, Gavin,Brown, Brock,Suyama, Eigo,Yuan, Hongbin,Mangravita-Novo, Arianna,Vicchiarelli, Michael,Su, Ying,Vasile, Stefan,Smith, Layton H.,Diaz, Paul W.,Reed, John C.,Roth, Gregory P.
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supporting information; experimental part
p. 780 - 785
(2011/12/02)
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- NOVEL 2-AMINO BENZIMIDAZOLE DERIVATIVES AND THEIR USE AS MODULATORS OF SMALL-CONDUCTANCE CALCIUM-ACTIVATED POTASSIUM CHANNELS
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This invention relates to novel 2-amino benzimidazole derivatives of formula (I1) and (Ib) useful as modulators of small-conductance calcium-activated potassium channels (SK channels) . In other aspects the invention relates to the use of these compounds
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Page/Page column 17; 22
(2008/06/13)
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- Heterocyclic Bis-Cations as Starting Hits for Design of Inhibitors of the Bifunctional Enzyme Histidine-Containing Protein Kinase/Phosphatase from Bacillus subtilis
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The main mechanism of carbon catabolite repression/activation in low-guanine and low-cytosine Gram-positive bacteria seems to involve phosphorylation of HPr (histidine-containing protein) at Ser-46 by the ATP-dependent HPr kinase, which in Bacillus subtilis, Lactobacillus casei, and Staphylococcus xylosus also exhibits phosphatase activity and is thus a bifunctional enzyme (HPrK/P). Since deficiency of HPrK/P in S. xylosus, L. casei, and B. subtilis mutants leads to severe growth defects, inhibitors of the enzyme could form a new family of antibiotic drugs. The aim of the study was to screen an in-house chemical library for identification of hits as inhibitors of HPrK/P in B. subtilis and to further extract additional information of structural features from hit optimization using a radioactive in vitro assay. A symmetrical bis-cationic compound LPS 02-10-L-D09 (2a) with a 12-carbon alkyl linker bridging the two 2-aminobenzimidazole moieties was identified as a non-ATP mimetic compound exhibiting an EC50 value of 10 μM in a kinase assay with HPr as substrate. The substance also inhibited the phosphatase activity of HPrK/P triggered by the addition of inorganic phosphate. Similar results were obtained with 2a and catabolite repression HPr, which, like HPr, can be phosphorylated at Ser-46 by HPrK/P and is involved in catabolite repression. Structure-activity relationship analysis indicated the importance in its structure of a substituted 2-aminobenzimidazole. This typical heterocycle is linked through a C12 alkyl chain to a second scaffold that can bear a cationic or a noncationic moiety but in all cases should present an aromatic ring in its vicinity.
- Ramstr?m, Helena,Bourotte, Maryline,Philippe, Claude,Schmitt, Martine,Haiech, Jacques,Bourguignon, Jean-Jacques
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p. 2264 - 2275
(2007/10/03)
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- Benzimidazole compounds useful as calcium channel blockers
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The present invention discloses compounds of the formula STR1 wherein R'' and R"" independently of each other are hydrogen or alkyl, or R'' and R"" together form a 3 to 6 membered alkylene chain;n is 1 or 2;R 1 is phenyl which may be substituted one or mo
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- Synthesis, Antibacterial, and Antifungal Activities of Some New Benzimidazoles
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1,2-Diaminobenzimidazoles 2 were synthesized by N-amination of 2-aminobenzimidazoles 1 with hydroxylamine-O-sulphonic acid.Substituted 1-alkyl and 1-alkylarylbenzimidazoles 3 were prepared from various benzimidazoles by alkylating with the corresponding a
- Vlaovic, Djordje,Canadanovic-Brunet, Jasna,Balaz, Jelica,Juranic, Ivan,Djokovic, Dejan,Mackenzie, Kenneth
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p. 199 - 206
(2007/10/02)
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