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Bioorganic & Medicinal Chemistry Letters

Nagaraju Marepu, Sunandamma Yeturu, Manojit Pal
The 1,2,3-triazole ring fused with pyridine/pyrimidine was explored as new template for the identification of potential antimicrobial agents. The regioselective synthesis of these pre-designed N-heteroarenes was achieved via exploring the application of Buchwald's strategy (i.e. C-N bond formation/reduction/diazotization/cyclization sequence) to the N-heteroarene system. Two of them showed promising antibacterial (comparable to streptomycin) and several showed potent antifungal (comparable to mancozeb) activities...
September 17, 2018: Bioorganic & Medicinal Chemistry Letters
Hui Qiu, Lesley Liu-Bujalski, Richard D Caldwell, Ariele Viacava Follis, Anna Gardberg, Andreas Goutopoulos, Roland Grenningloh, Jared Head, Theresa Johnson, Christopher C V Jones, Reinaldo Jones, Igor Mochalkin, Federica Morandi, Constantin Neagu, Justin Potnick, Brian Sherer
Bruton's tyrosine kinase (Btk) is a member of the Tec kinase family that is expressed in cells of hematopoietic lineage (e.g. B cells, macrophages, monocytes, and mast cells). Small molecule covalent irreversible Btk inhibitors targeting Cys481 within the ATP-binding pocket have been applied in the treatment of B-cell malignancies. Starting from a fragment, we discovered a novel series of potent covalent irreversible Btk inhibitors that bear N-linked groups occupying the solvent accessible pocket (SAP) of the active site of the Btk kinase domain...
September 15, 2018: Bioorganic & Medicinal Chemistry Letters
Olga Minenkova, Loredana Vesci, Rita De Santis, Daniela Santapaola, Raffaella Cincinelli, Loana Musso, Sabrina Dallavalle, Giuseppe Giannini
Oxidized form of avidin, named AvidinOX, provides stable fixation of biotinylated molecules in tissues thus representing a breakthrough in topical treatment of cancer. AvidinOX proved to be a stable receptor for radiolabeled biotin, biotinylated antibodies and cells. In order to expand applicability of the AvidinOX-based delivery platform, in the present study we investigated the possibility to hold biotinylated chemotherapeutics in AvidinOX-treated sites. A novel biotinylated gimatecan-derived camptothecin, coded ST8161AA1, was injected at suboptimal doses into human tumors xenografted in mice alone or pre-complexed to AvidinOX...
September 15, 2018: Bioorganic & Medicinal Chemistry Letters
Shaoyi Sun, Jianmin Fu
The importance of methyl groups in modulating biological activity, selectivity, solubility, metabolism and pharmacokinetic/pharmacodynamic properties of biologically active molecules is highlighted. The information compiled from selected beneficial cases, focuses mostly on marketed drugs and clinical candidates, and indicates that the methylation strategy has been successful in drug design.
September 14, 2018: Bioorganic & Medicinal Chemistry Letters
Chiara M A Gangemi, Roberta Puglisi, Andrea Pappalardo, Giuseppe Trusso Sfrazzetto
Host-guest interactions studied in supramolecular chemistry have been inspired by interactions between enzymes and substrates. Furthermore, most of the interactions involved in the cells are based on non-covalent bonds between two or more molecules. The common aspects between supramolecular chemistry and medicine have led to the development of a "new" area called "supramolecular medicine", in which non-covalent interactions and self-assembly processes are applied within several medical fields...
September 13, 2018: Bioorganic & Medicinal Chemistry Letters
Anne Loesche, Jana Wiemann, Zayan Al Halabi, Julia Karasch, Wolfgang Sippl, René Csuk
A small library of (E) α,β-unsaturated fatty acids was prepared, and 20 different saturated and mono-unsaturated fatty acids differing in chain length were subjected to Ellman's assays to determine their ability to act as inhibitors for AChE or BChE. While the compounds were only very weak inhibitors of BChE, seven molecules were inhibitors of AChE holding IC50  = 4.3-12.8 M with three of them as significant inhibitors of this enzyme. The results have shown trans 2-mono-unsaturated fatty acids are better inhibitors for AChE than their saturated analogs...
September 11, 2018: Bioorganic & Medicinal Chemistry Letters
Yinhui Qin, Shengsheng Qiang, Shengli Ji, Zhiyang Liu, Chaoyu Hu, Shutao Ma
A novel series of 3-O-arylalkylcarbamoyl-3-O-descladinosyl-9-O-(2-chlorobenzyl)oxime clarithromycin derivatives, were designed, synthesized and evaluated for their in vitro antibacterial activity. These derivatives were found to have strong activity against susceptible and resistant bacteria strains. Among them, compounds 7a and 7q showed the most potent activity (0.125 µg/mL) against erythromycin-resistant S. pneumoniae expressing the mefA gene. Moreover, compounds 7f, 7i, 7p and 7z displayed remarkably improved activity (4 µg/mL) against penicillin-resistant S...
September 10, 2018: Bioorganic & Medicinal Chemistry Letters
James T Fletcher, Jill M Sobczyk, Sarah C Gwazdacz, Aaron J Blanck
A series of 1,3,4-trisubstituted-1,2,3-triazolium bromide salts were prepared by efficient two-step sequences of azide-alkyne cycloaddition and benzylic substitution. The antimicrobial activity of each triazolium salt and correlating triazole precursor was evaluated using a minimum inhibitory concentration (MIC) assay. MIC activities as low as 1 µM against Gram-positive bacteria, 8 µM against Gram-negative bacteria and 4 µM against fungi were observed for salt analogs, while neutral triazoles were inactive...
September 10, 2018: Bioorganic & Medicinal Chemistry Letters
Tanya Sahyoun, Caroline Gaucher, Yi Zhou, Naïm Ouaini, Raphaël Schneider, Axelle Arrault
Four compounds bearing amidoxime functions were synthetized: (1) 2a,b bearing an aromatic amidoxime function, (2) 2c bearing an aliphatic amidoxime function, and (3) 2d bearing aromatic and aliphatic amidoximes functions. The ability of these compounds to release NO was evaluated in vitro using the oxidative metabolism of cytochrome P450 from rat liver microsomes. Results obtained demonstrate that all amidoximes were able to release NO with a highest amount of NO produced by the 2a aromatic amidoxime. Moreover, all amidoximes exhibit cytocompatibility with human aorta smooth muscle cells...
September 8, 2018: Bioorganic & Medicinal Chemistry Letters
Takeshi Fukuda, Takashi Ishiyama, Takahiro Katagiri, Kenjiro Ueda, Sumie Muramatsu, Masami Hashimoto, Anri Aki, Daichi Baba, Kengo Watanabe, Naoki Tanaka
Hepcidin has emerged as the central regulatory molecule in systemic iron homeostasis. The inhibition of hepcidin may be a favorable strategy for the treatment of anemia of chronic disease. Here, we have reported the design, synthesis, and structure-activity relationships (SAR) of a series of 4-aminopyrimidine compounds as inhibitors of hepcidin production. The optimization study of 1 led to the design of a potent and bioavailable inhibitor of hepcidin production, 34 (DS42450411), which showed serum hepcidin-lowering effects in a mouse model of interleukin-6-induced acute inflammation...
September 8, 2018: Bioorganic & Medicinal Chemistry Letters
Jian-Kang Jiang, Xiuli Huang, Khalida Shamim, Paresma R Patel, Arthur Lee, Amy Q Wang, Kimloan Nguyen, Gregory Tawa, Gregory D Cuny, Paul B Yu, Wei Zheng, Xin Xu, Philip Sanderson, Wenwei Huang
The pyrazolo[1,5-a]pyrimidine LDN-193189 is a potent inhibitor of activin receptor-like kinase 2 (ALK2) but is nonselective for highly homologous ALK3 and shows only modest kinome selectivity. Herein, we describe the discovery of a novel series of potent and selective ALK2 inhibitors by replacing the quinolinyl with a 4-(sulfamoyl)naphthyl, yielding ALK2 inhibitors that exhibit not only excellent discrimination versus ALK3 but also high kinome selectivity. In addition, the optimized compound 23 demonstrates good ADME and in vivo pharmacokinetic properties...
September 6, 2018: Bioorganic & Medicinal Chemistry Letters
Satoru Tamura, Kunichika Yoshihira, Tomikazu Kawano, Nobutoshi Murakami
We found out 2',3'-dihydroxypuberulin from South American medicinal plant, V. thapsus L., as a candidate of an anti-allergic lead which inhibits the expression of high-affinity receptor of IgE (FcεRI) on the surface of mast cells. Furthermore, the analysis of structure-activity relationship by using synthesized 2',3'-dihydroxypuberulin analogs revealed that both hydroxy groups in the side chain and both of methyl moieties on phenolic hydroxy groups were crucial for potent activity, but absolute configuration of C-3' position wasn't...
September 6, 2018: Bioorganic & Medicinal Chemistry Letters
Wenlong Kong, Yinhe Bao, Qianjun Ma, Hui Xu
In continuation of our program aimed at the development of new natural product-based pesticides, a series of novel pyrazolomatrine derivatives were prepared by structural modifications of matrine, isolated as a quinolizidine alkaloid from the roots of Sophora flave. Their structures were confirmed by 1 H NMR, HRMS, etc. Moreover, the steric structures of three compounds were determined by single-crystal X-ray diffraction. Among all derivatives, 19-(naphthyl-2-oyl)pyrazolomatrine (5y) showed 3.13-fold more potent acaricidal activity than its precusor matrine against Tetranychus cinnabarinus; 19-(4-methylbenzoyl)pyrazolomatrine (5j) and 19-(3,5-dimethylbenzoyl)pyrazolomatrine (5k) displayed the promising aphicidal activity against Aphis citricola van der...
September 6, 2018: Bioorganic & Medicinal Chemistry Letters
Da-You Ma, Long-Long Wang, Qin Lai, Kun-Jian Peng, Xuan Li, Zeng-Xia Li, Li-Jun Liu, Zhi-Yong Luo, Su-You Liu
In order to enhance the mitochondria-targeting ability of spinosad. A series of quartenary ammonium spinosyn derivatives was designed and synthesized. Some of the derivatives displayed greatly enhanced antiproliferative ability towards tested human cancer cell lines. The structure activity relationship study indicated that lipophilicity has a great influence on the antiproliferative effects of these derivatives. The most active compound 11d exhibited remarkably enhanced OXPHS inhibition and apoptosis inducing ability than spinosyn A...
September 5, 2018: Bioorganic & Medicinal Chemistry Letters
Jorge E Gómez-Galeno, Cecilia Hurtado, Jiongjia Cheng, Ceren Yardimci, Mark Mercola, John R Cashman
The Notch signaling pathway is involved in cell proliferation and differentiation, and has been recognized as an active pathway in regenerating tissue and cancerous cells. Notch signaling inhibition is considered a viable approach to the treatment of a variety of conditions including colorectal cancer, pancreatic cancer, breast cancer and metastatic melanoma. The discovery that the b-annulated dihydropyridine FLI-06 (1) is an inhibitor of the Notch pathway with an EC50 ≈ 2.5 μM prompted us to screen a library of related analogs...
September 5, 2018: Bioorganic & Medicinal Chemistry Letters
Imadul Islam, Shendong Yuan, Christopher W West, Marc Adler, Ulrich Bothe, Judi Bryant, Zheng Chang, Kieu Chu, Kumar Emayan, Giovanna Gualtieri, Elena Ho, David Light, Cornell Mallari, John Morser, Gary Phillips, Caralee Schaefer, Drew Sukovich, Marc Whitlow, Deborah Chen, Brad O Buckman
We report here the design and synthesis of a novel series of benzylamines that are potent and selective inhibitors of uPA with promising oral availability in rat. Further evaluation of one representative (ZK824859) of the new structural class showed that this compound lowered clinical scores when dosed in either acute or chronic mouse EAE models, suggesting that uPA inhibitors of this type could be useful for the treatment of multiple sclerosis.
September 5, 2018: Bioorganic & Medicinal Chemistry Letters
Guangcheng Wang, Zhiyun Peng, Shanshan Peng, Jie Qiu, Yongjun Li, Yanyu Lan
A series of (E)-N-Aryl-2-oxo-2-(3,4,5-trimethoxyphenyl)acetohydrazonoyl cyanides have been synthesized and evaluated for their anticancer activity in human hepatocellular liver carcinoma HepG2 and breast adenocarcinoma MCF-7 cell lines. Among all the tested compounds, compound 3a, 3e and 3n displayed more activity than lead compound with IC50 value of 0.26-0.61 μM. Meanwhile, these compounds (3a, 3e and 3n) showed potent antiproliferative activity against a panel of cancer cells and the HCT-8/T multidrug resistant cell line with IC50 values in the range of 0...
September 5, 2018: Bioorganic & Medicinal Chemistry Letters
Tom Willemse, Emilie Eiselt, Karlijn Hollanders, Wim Schepens, Herman W T van Vlijmen, Nga N Chung, Véronique Blais, Brian Holleran, Jean-Michel Longpré, Peter W Schiller, Bert U W Maes, Philippe Sarret, Louis Gendron, Steven Ballet
No abstract text is available yet for this article.
September 5, 2018: Bioorganic & Medicinal Chemistry Letters
Namki Cho, Ana Lisa Valenciano, Yongle Du, Jason Clement, Maria B Cassera, Michael Goetz, David G I Kingston
Bioassay-guided fractionation of an extract of Carpha glomerata (Cyperaceae) led to the isolation of seven compounds. Compounds 1 (carphorin A), 3 (carphorin C), 4 (carphorin D), and 5 (carphabene) are new compounds, and compound 2 (8-(3″-hydroxyisoamyl)-naringenin) was isolated for the first time as a natural product. All structures were elucidated based on analyses of their HR-ESIMS and 1D and 2D NMR data. Compounds 1, 2, and 6, which have prenyl or hydroxyprenyl side chains, exhibited antiplasmodial activities with IC50 values of 5...
September 4, 2018: Bioorganic & Medicinal Chemistry Letters
Ting Xu, Xiaoguang Wang, Qian Zhang, Jiangping Fan, Liu Liu, Mingzhu Liu, Haojie Zhang, Jing Li, Yong Guo
In continuation of our research aimed at discovery and development of new pesticidal agents, a series of new 8-hydroxyquinaldine derivatives containing a N-phenylpyrazole moiety were prepared and their structures were characterized by 1 H NMR, IR, ESI-MS and mp. Meanwhile, an efficient way of using iodine-mediated oxidative cyclization for one pot synthesis of these 8-hydroxyquinaldine derivatives containing a N-phenylpyrazole moiety was developed. The bioassay showed that compounds 8g and 9f exhibited potent pesticidal activities against both Mythimna separata Walker and Plutella xylostella Linnaeus...
September 1, 2018: Bioorganic & Medicinal Chemistry Letters
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