共查询到20条相似文献,搜索用时 0 毫秒
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Daniel S. Wenholz Ming Zeng Cong Ma Marcin Mielczarek Xiao Yang Mohan Bhadbhade David St. C. Black Peter J. Lewis Renate Griffith Naresh Kumar 《Bioorganic & medicinal chemistry letters》2017,27(18):4302-4308
Knoevenagel condensation was employed to generate a set of molecules potentially capable of inhibiting the RNA polymerase-σ70/σA interaction in bacteria. Synthesis was achieved via reactions between a variety of indole-7-carbaldehydes and rhodanine, N-allylrhodanine, barbituric acid or thiobarbituric acid. A library of structurally diverse compounds was examined by enzyme-linked immunosorbent assay (ELISA) to assess the inhibition of the targeted protein–protein interaction. Inhibition of bacterial growth was also evaluated using Bacillus subtilis and Escherichia coli cultures. The structure–activity relationship studies demonstrated the significance of particular structural features of the synthesized molecules for RNA polymerase-σ70/σA interaction inhibition and antibacterial activity. Docking was investigated as an in silico method for the further development of the compounds. 相似文献
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Silver LL 《Current opinion in microbiology》2003,6(5):431-438
Over the past forty years, efforts to discover antibacterials have yielded a wide variety of chemical structures, almost exclusively natural products, which inhibit many steps in cell wall synthesis. Although screening for new cell wall inhibitors has been continuous during that period, there have been few reports of new drugs. With the advent of genomics, high resolution X-ray crystallography and the recognition of the need for new antibiotics to combat resistant organisms, there has been a resurgence in interest in this validated target area. 相似文献
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Germanas JP Wang S Miner A Hao W Ready JM 《Bioorganic & medicinal chemistry letters》2007,17(24):6871-6875
To identify novel inhibitors of tyrosinase, a fluorescent assay was developed which is suitable for high-throughput screening. In the assay, oxidation of the substrate by tyrosinase leads to the release of a fluorescent coumarin. Several small molecules were identified that inhibited mushroom tyrosinase in vitro and human tyrosinase in cell culture. These compounds may represent lead structures for therapies targeted at disorders of hyperpigmentation. 相似文献
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《Microbes and infection / Institut Pasteur》2020,22(6-7):272-277
Hantavirus (HV), a pathogen of animal infectious diseases that poses a threat to humans, has attracted extensive attention. Clinically, HV can cause hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS), between which HFRS is mostly in Eurasia, and HPS is mostly in the Americas. This paper reviews the research progress of small-molecule inhibitors of HV. 相似文献
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Kulanthaivel P Kreuzman AJ Strege MA Belvo MD Smitka TA Clemens M Swartling JR Minton KL Zheng F Angleton EL Mullen D Jungheim LN Klimkowski VJ Nicas TI Thompson RC Peng SB 《The Journal of biological chemistry》2004,279(35):36250-36258
Signal peptidase (SPase) I is responsible for the cleavage of signal peptides of many secreted proteins in bacteria. Because of its unique physiological and biochemical properties, it serves as a potential target for development of novel antibacterial agents. In this study, we report the production, isolation, and structure determination of a family of structurally related novel lipoglycopeptides from a Streptomyces sp. as inhibitors of SPase I. Detailed spectroscopic analyses, including MS and NMR, revealed that these lipoglycopeptides share a common 14-membered cyclic peptide core, an acyclic tripeptide chain, and a deoxy-alpha-mannose sugar, but differ in the degree of oxidation of the N-methylphenylglycine residue and the length and branching of the fatty acyl chain. Biochemical analysis demonstrated that these peptides are potent and competitive inhibitors of SPase I with K(i) 50 to 158 nm. In addition, they showed modest antibacterial activity against a panel of pathogenic Gram-positive and Gram-negative bacteria with minimal inhibitory concentration of 8-64 microm against Streptococcus pneumonniae and 4-8 microm against Escherichia coli. Notably, they mechanistically blocked the protein secretion in whole cells as demonstrated by inhibiting beta-lactamase release from Staphylococcus aureus. Taken together, the present discovery of a family of novel lipoglycopeptides as potent inhibitors of bacterial SPase I may lead to the development of a novel class of broad-spectrum antibiotics. 相似文献
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《Bioorganic & medicinal chemistry letters》2020,30(20):127471
Ubiquitin specific protease-7 (USP7) is considered an attractive target for cancer therapy by promoting degradation of the tumor suppressor p53 and negatively affecting the immune response to tumors. However, the development of selective non-covalent USP7 inhibitors has proven challenging. In this work we report the NMR characterization of a weak binder from SPR screening of an in-house fragment library which reveals that it binds to the allosteric palm site of the catalytic domain. Molecular modeling combined with 1H NMR saturation transfer difference and NOESY experiments enabled structure-based design of additional compounds showing IC50 values in the low-micromolar range with good selectivity over the closest homolog USP47. The most potent analogue represents a promising starting point for the development of novel, selective USP7 inhibitors. 相似文献
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Discovery of antibiotics of a novel mode of action is highly required in the fierce battlefield with multi-drug resistant bacterial infections. Previously we have validated the protein-protein interaction between bacterial NusB and NusE proteins as an unprecedented antimicrobial target and reported the identification of a first-in-class inhibitor of bacterial ribosomal RNA synthesis with antimicrobial activities. In this paper, derivatives of the hit compound were rationally designed based on the pharmacophore model for chemical synthesis, followed by biological evaluations. Some of the derivatives demonstrated the improved antimicrobial activity with the minimum inhibitory concentration (MIC) at 1–2 μg/mL against clinically significant bacterial pathogens. Time-kill kinetics, confocal microscope, ATP production, cytotoxicity, hemolytic property and cell permeability using Caco-2 cells of a representative compound were also measured. This series of compounds were named “nusbiarylins” based on their target protein NusB and the biaryl structure and were expected to be further developed towards novel antimicrobial drug candidates in the near future. 相似文献
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Discovery of selective small-molecule CD80 inhibitors 总被引:1,自引:0,他引:1
Uvebrant K da Graça Thrige D Rosén A Akesson M Berg H Walse B Björk P 《Journal of biomolecular screening》2007,12(4):464-472
Protein-protein interactions are widely found in biological systems controlling diverse cellular events. Because these interactions are implicated in many diseases such as autoimmunity and cancer, regulation of protein-protein interactions provides ideal targets for drug intervention. The CD80-CD28 costimulatory pathway plays a critical role in regulation of the immune response and thus constitutes an attractive target for therapeutic manipulation of autoimmune diseases. The objective of this study is to identify small compounds disrupting these pivotal protein-protein interactions. Compounds that specifically blocked binding of CD80 to CD28 were identified using a strategy involving a cell-based scintillation proximity assay as the initial step. Secondary screening (e.g., by analyzing the direct binding of these compounds to the target immobilized on a biosensor surface) revealed that these compounds are highly selective CD80 binders. Screening of structurally related derivatives led to the identification of the chemical features required for inhibition of the CD80-CD28 interaction. In addition, the optimization process led to a 10-fold increase in binding affinity of the CD80 inhibitors. Using this approach, the authors identify low-molecular-weight compounds that specifically and with high potency inhibit the interaction between CD80 and CD28. These compounds serve as promising starting points for further development of CD80 inhibitors as potential immunomodulatory drugs. 相似文献
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Weihe Zhang Yi Liu Xiaozhuo Chen Stephen C. Bergmeier 《Bioorganic & medicinal chemistry letters》2010,20(7):2191-2194
Cancer cells commonly show increased levels of glucose uptake and dependence. A potential strategy for the treatment of cancer may be the inhibition of basal glucose transport. We report here the synthesis of a small library of polyphenolic esters that inhibit basal glucose transport in H1299 lung and other cancer cells. These basal glucose transport inhibitors also inhibit cancer cell growth in H1299 cells, and these two activities appear to be correlated. 相似文献
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Jun-ichi Kuroyanagi Kazuo Kanai Yuuichi Sugimoto Tetsunori Fujisawa Chikanori Morita Takashi Suzuki Katsuhiro Kawakami Makoto Takemura 《Bioorganic & medicinal chemistry》2010,18(16):5845-5854
Preparations and in vitro antifungal activities of triazolopyridines, imidazopyridines, and a pyrazolopyridine were reported. Among those scaffolds, triazolopyridine was found to be the specific inhibitor of the synthesis of β-1,6-glucan, an essential component of the fungal cell wall, and to show potent antifungal activities against several Candida species. 相似文献
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Lefoix M Coudert G Routier S Pfeiffer B Caignard DH Hickman J Pierré A Golsteyn RM Léonce S Bossard C Mérour JY 《Bioorganic & medicinal chemistry》2008,16(9):5303-5321
We describe here an efficient synthesis of new 5-azaindolocarbazoles designed for cytotoxic and Chk1 inhibiting properties. The synthesis of ‘symmetrical’ and ‘dissymmetrical’ structures is discussed. Concerning the dissymmetrical 5-azaindolocarbazoles derivatives, with both an indole moiety and a 5-azaindole moiety, the synthesis was achieved using two very efficient key steps. The first one is a Stille reaction with a 3-trimethylstannyl-5-azaindole derivative and the second one a photochemical step leading to the proposed polycyclic structure. Various pharmacomodulations were performed to investigate the structure–activity relationships (SAR). Several substituents such as OBn, OH, and methylenedioxy groups were successfully introduced on the indole moiety of the 5-azaindolocarbazole. Compounds with or without substituents on the nitrogen atom of the maleimide were prepared, as well as derivatives with glucopyranosyl substituent on the nitrogen atom of the indole moiety. The cytotoxicity of these new compounds was evaluated on two cell lines (L1210, HT29). Several compounds showed cytotoxicity in the sub-micromolar range. Among the most cytototoxic was the 1,3-dioxolo[4,5-b]-6-(2-dimethylaminoethyl)-1H-pyrido[3′,4′:4,5]pyrrolo[3,2-i]pyrrolo[3,4-g]carbazole-5,7(6H,12H)-dione (35, IC50 = 195 nM on L1210). The compounds were also investigated for their Chk1 inhibiting activity. Compounds without any substitution on the maleimide moiety were the most potent. This is the case of compounds 45–47 with IC50 of, respectively, 72, 27, and 14 nM toward Chk1. Compound 46, which exhibits moderate cytotoxicity, appears to be a good candidate for development in a multi-drug anticancer therapy. 相似文献