23,417 results match your criteria Bioorg. Med. Chem. Lett.[Journal]


Structure-activity relationship study of antitrypanosomal chalcone derivatives using multivariate analysis.

Bioorg Med Chem Lett 2019 Apr 12. Epub 2019 Apr 12.

Centro de Ciências Naturais e Humanas, Universidade Federal do ABC, Santo André, SP 09210-580, Brazil. Electronic address:

Chagas disease represents one of several neglected diseases with a reduced number of chemotherapeutical drugs including the highly toxic compounds benznidazole and nifurtimox. In this sense, natural products represent an import scaffold for the discovery of new biologically active compounds, in which chalcones are promising representatives due to their antitrypanosomal potential. In this work, a series of 36 chalcone derivatives were synthesized and tested against trypomastigotes of Trypanosoma cruzi. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S0960894X193024
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http://dx.doi.org/10.1016/j.bmcl.2019.04.020DOI Listing
April 2019
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Potent and selective inhibitors of receptor-interacting protein kinase 1 that lack an aromatic back pocket group.

Bioorg Med Chem Lett 2019 Apr 11. Epub 2019 Apr 11.

Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address:

Receptor-interacting protein kinase 1 (RIPK1), a key component of the cellular necroptosis pathway, has gained recognition as an important therapeutic target. Pharmacologic inhibition or genetic inactivation of RIPK1 has shown promise in animal models of disease ranging from acute ischemic conditions, chronic inflammation, and neurodegeneration. We present here a class of RIPK1 inhibitors that is distinguished by a lack of a lipophilic aromatic group present in most literature inhibitors that typically occupies a hydrophobic back pocket of the protein active site. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S0960894X193022
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http://dx.doi.org/10.1016/j.bmcl.2019.04.014DOI Listing
April 2019
1 Read

Discovery of trans-3-(pyridin-3-yl)acrylamide-derived sulfamides as potent nicotinamide phosphoribosyltransferase (NAMPT) inhibitors for the potential treatment of cancer.

Bioorg Med Chem Lett 2019 Apr 8. Epub 2019 Apr 8.

State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China. Electronic address:

Nicotinamide phosphoribosyltransferase (NAMPT) has emerged as a promising target for the discovery of anticancer drugs. Based on NAMPT inhibitor FK866 that has been advanced into phase II trial, we identified a trans-3-(pyridin-3-yl)acrylamide compound 13 incorporating with a biarylsulfanilamide moiety as a new NAMPT inhibitor. Further structure-activity relationship (SAR) exploration led to additional biarylsulfanilamide-derived compounds with high in vitro NAMPT inhibitory potency and antiproliferative activity. Read More

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http://dx.doi.org/10.1016/j.bmcl.2019.04.013DOI Listing

Design, synthesis and biological activity of deuterium-based FFA1 agonists with improved pharmacokinetic profiles.

Bioorg Med Chem Lett 2019 Apr 10. Epub 2019 Apr 10.

School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Key Laboratory of New Drug Discovery and Evaluation of Ordinary Universities of Guangdong Province, Guangdong Pharmaceutical University, Guangzhou 510006, PR China. Electronic address:

The free fatty acid receptor 1 (FFA1) is considered as a promising anti-diabetic target based on its function of glucose-stimulated insulin secretion. The previously reported compound 2 is a highly potent FFA1 agonist, but it might be suffered from poor pharmacokinetic properties because the phenylpropanoic acid is vulnerable to β-oxidation. To identify orally available analogs, we tried to block the route of β-oxidation by incorporating deuterium at phenylpropionic acid moiety. Read More

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http://dx.doi.org/10.1016/j.bmcl.2019.04.019DOI Listing

Cynaropicrin and inhibition of NF-κB activation: A structure activity relationship study.

Bioorg Med Chem Lett 2019 Apr 4. Epub 2019 Apr 4.

Department of Materials and Life Sciences, Faculty of Science and Technology, Sophia University, 7-1 Kioicho, Chiyoda-ku, Tokyo 102-8554, Japan. Electronic address:

Cynaropicrin is a guaianolide sesquiterpene lactone with a 5-7-5 tricyclic skeleton, four exo-olefins, and two hydroxyl groups. This natural product has various biological activities including anti-inflammatory properties and antitrypanosomal activity. It was also found to suppress photoaging of the skin by inhibiting the transcription activity of nuclear factor-kappa B (NF-κB). Read More

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https://linkinghub.elsevier.com/retrieve/pii/S0960894X193021
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http://dx.doi.org/10.1016/j.bmcl.2019.04.004DOI Listing
April 2019
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Microwave-assisted synthesis and in vitro stability of N-benzylamide non-steroidal anti-inflammatory drug conjugates for CNS delivery.

Bioorg Med Chem Lett 2019 Apr 8. Epub 2019 Apr 8.

Department of Chemistry, Muhlenberg College, 2400 Chew Street, Allentown, PA 18104, United States. Electronic address:

More effective delivery of non-steroidal anti-inflammatory drugs (NSAIDs) to the brain could treat the underlying inflammatory pathology of a range of CNS diseases and conditions. Use of a blood-brain barrier shuttle such as the N-benzylamide moiety, which has been largely unexplored for this purpose, could improve the brain bioavailabilities of NSAIDs. A series of novel N-benzylamide NSAID conjugates was synthesized via a three-step process with a microwave-assisted bimolecular nucleophilic substitution as the final step. Read More

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http://dx.doi.org/10.1016/j.bmcl.2019.04.016DOI Listing

A cross-linking approach to map small molecule-RNA binding sites in cells.

Bioorg Med Chem Lett 2019 Apr 2. Epub 2019 Apr 2.

Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458, USA. Electronic address:

Methods to identify RNAs bound by small molecules in cells are sparse. Herein, an advance to identify the direct RNA targets of small molecules in cells is described. The approach, dubbed Chemical Cross-Linking and Isolation by Pull-down to Map Small Molecule-RNA Binding Sites (Chem-CLIP-Map-Seq), appends a cross-linker and a purification tag onto a small molecule. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S0960894X193021
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http://dx.doi.org/10.1016/j.bmcl.2019.04.001DOI Listing
April 2019
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Singlet oxygen-activatable Paclitaxel prodrugs via intermolecular activation for combined PDT and chemotherapy.

Bioorg Med Chem Lett 2019 Apr 2. Epub 2019 Apr 2.

Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma, Oklahoma City, OK 73117, United States; Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK 73019, United States. Electronic address:

Systemic side effects and high hydrophobicity are major disadvantages of paclitaxel (PTX), one of the most popular anticancer drugs. Here, we present singlet oxygen (SO)-activatable and mitochondria-targeted PTX prodrugs to overcome these problems and boost the cytotoxic effect of photodynamic therapy (PDT). Three PTX prodrugs were prepared by conjugating PTX with various cationic groups. Read More

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http://dx.doi.org/10.1016/j.bmcl.2019.03.053DOI Listing

Synthesis of diphenoxyadamantane alkylamines with pharmacological interest.

Bioorg Med Chem Lett 2019 Apr 6. Epub 2019 Apr 6.

Department of Pathogen Molecular Biology, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1 E7HT, UK.

In this work, the synthesis and the pharmacological evaluation of diphenoxyadamantane alkylamines Ia-f and IIa-f is described. The new diphenoxy-substituted adamantanes share structural features present in trypanocidal and antitubercular agents. 1-Methylpiperazine derivative Ia is the most potent against T. Read More

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http://dx.doi.org/10.1016/j.bmcl.2019.04.010DOI Listing
April 2019
2.420 Impact Factor

Design, synthesis and structure-activity relationship study of aminopyridine derivatives as novel inhibitors of Janus kinase 2.

Bioorg Med Chem Lett 2019 Apr 6. Epub 2019 Apr 6.

Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China. Electronic address:

Janus Kinase 2 (JAK2) is a kind of intracellular non-receptor protein tyrosine kinase and has been certified as an important target for the treatment of myeloproliferative neoplasms and rheumatoid arthritis. However, the low selectivity and potential safety issues restrict the clinical applications of JAK2 inhibitors. Here we found that crizotinib showed good inhibitory activity against JAK2 by enzymatic assays (IC = 27 nM). Read More

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http://dx.doi.org/10.1016/j.bmcl.2019.04.011DOI Listing

Synthesis and evaluation of histamine H receptor ligand based on lactam scaffold as agents for treating neuropathic pain.

Bioorg Med Chem Lett 2019 Apr 8. Epub 2019 Apr 8.

Systems Biology Theme, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China. Electronic address:

The synthesis and H receptor ligand of a new series of lactam derivatives are reported. The new compounds were evaluated in vitro in H and H receptor-binding assays. The structure-activity relationship led us to the promising derivative 2-methyl-7-(3-morpholinopropoxy)-3,4-dihydroisoquinolin-1(2H)-one (11). Read More

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https://linkinghub.elsevier.com/retrieve/pii/S0960894X193022
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http://dx.doi.org/10.1016/j.bmcl.2019.04.015DOI Listing
April 2019
2 Reads

Discovery of a class of highly potent Janus Kinase 1/2 (JAK1/2) inhibitors demonstrating effective cell-based blockade of IL-13 signaling.

Bioorg Med Chem Lett 2019 Apr 4. Epub 2019 Apr 4.

Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.

Disruption of interleukin-13 (IL-13) signaling with large molecule antibody therapies has shown promise in diseases of allergic inflammation. Given that IL-13 recruits several members of the Janus Kinase family (JAK1, JAK2, and TYK2) to its receptor complex, JAK inhibition may offer an alternate small molecule approach to disrupting IL-13 signaling. Herein we demonstrate that JAK1 is likely the isoform most important to IL-13 signaling. Read More

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http://dx.doi.org/10.1016/j.bmcl.2019.04.008DOI Listing

Enzymatic activation of indolequinone-substituted 5-fluorodeoxyuridine prodrugs in hypoxic cells.

Bioorg Med Chem Lett 2019 Apr 4. Epub 2019 Apr 4.

Department of Chemistry and Biological Science, College of Science and Engineering, Aoyama Gakuin University, 5-10-1 Fuchinobe, Chuo-ku, Sagamihara 252-5258, Japan.

Among the various enzymes, reductases that catalyze one-electron reduction are involved in the selective activation of functional compounds or materials in hypoxia, which is one of the well-known pathophysiological characteristics of solid tumors. Enzymatic one-electron reduction has been recognized as a useful reaction that can be applied in the design of tumor hypoxia-targeting drugs. In this report, we characterized the enzymatic reaction of 5-fluorodeoxyuridine (FdUrd) prodrug bearing an indolequinone unit (IQ-FdUrd), which is a substrate of reductases. Read More

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http://dx.doi.org/10.1016/j.bmcl.2019.04.003DOI Listing
April 2019
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Discovery of nitropyridyl-based dichloropropene ethers as insecticides.

Bioorg Med Chem Lett 2018 Dec 24. Epub 2018 Dec 24.

National Engineering Research Center for Agrochemicals, Hunan Research Institute of Chemical Industry, Changsha 410007, People's Republic of China. Electronic address:

A series of nitropyridyl-based dichloropropene ethers were prepared and evaluated for their insecticidal activities against main lepidopteran pests such as M. separate, P. xylostella and P. Read More

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http://dx.doi.org/10.1016/j.bmcl.2018.12.055DOI Listing
December 2018

Four N-(E)-cinnamoyl (cinnamamide) derivatives of aminoalkanols with promising anticonvulsant and analgesic activity.

Bioorg Med Chem Lett 2019 Apr 4. Epub 2019 Apr 4.

Department of Bioorganic Chemistry, Chair of Organic Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland.

Epilepsy and neuropathic pain are frequent neurological disorders with pathomechanism based on abnormal neuronal discharges. Secondary tissue impairment observed after traumatic brain injury is also connected with neuronal dysfunction. Those three neurological disorders are ineffectively treated with currently available pharmacotherapy options so great effort is made in searching for new effective drugs. Read More

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http://dx.doi.org/10.1016/j.bmcl.2019.04.006DOI Listing

Discovery of 1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-ones based novel, potent and PI3Kδ selective inhibitors.

Bioorg Med Chem Lett 2019 Apr 4. Epub 2019 Apr 4.

Department of Medicinal Chemistry, Zydus Research Centre, Sarkhej-Bavla, N.H. 8A Moraiya, Ahmedabad 382210, India.

PI3Kδ is implicated in various inflammatory and autoimmune diseases. For the effective treatment of chronic immunological disorders such as rheumatoid arthritis, it is essential to develop isoform selective PI3Kδ inhibitors. Structure guided optimization of an imidazo-quinolinones based pan-PI3K/m-TOR inhibitor (Dactolisib) led to the discovery of a potent and orally bioavailable PI3Kδ isoform selective inhibitor (10h), with an improved efficacy in the animal models. Read More

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http://dx.doi.org/10.1016/j.bmcl.2019.04.007DOI Listing
April 2019
2.420 Impact Factor

Structure-guided design of antibacterials that allosterically inhibit DNA gyrase.

Bioorg Med Chem Lett 2019 Mar 22. Epub 2019 Mar 22.

GlaxoSmithKline, Collegeville, PA 19426, USA. Electronic address:

A series of DNA gyrase inhibitors were designed based on the X-ray structure of a parent thiophene scaffold with the objective to improve biochemical and whole-cell antibacterial activity, while reducing cardiac ion channel activity. The binding mode and overall design hypothesis of one series was confirmed with a co-crystal structure with DNA gyrase. Although some analogs retained both biochemical activity and whole-cell antibacterial activity, we were unable to significantly improve the activity of the series and analogs retained activity against the cardiac ion channels, therefore we stopped optimization efforts. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S0960894X193016
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http://dx.doi.org/10.1016/j.bmcl.2019.03.029DOI Listing
March 2019
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Discovery of an EGFR tyrosine kinase inhibitor from Ilex latifolia in breast cancer therapy.

Bioorg Med Chem Lett 2019 Apr 4. Epub 2019 Apr 4.

Anhui Provincial Engineering Research Center for Polysaccharide Drugs, Wannan Medical College, Wuhu, Anhui 241002, China. Electronic address:

Deficient signaling of the EGFR and other receptor tyrosine kinases in humans is associated with diseases such as cancer. Some EGFR tyrosine kinase inhibitors have become a new class of targeted therapeutic agents in the last years. We found that 27-O-p-(E)-coumaroyl ursolic acid (27-CAUA) had a strong activity of apoptosis according to preparation by screening for a series of Ilex latifolia products. Read More

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http://dx.doi.org/10.1016/j.bmcl.2019.04.009DOI Listing
April 2019
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Design, synthesis, and biological evaluation of novel 2'-deoxy-2'-fluoro-2'-C-methyl 8-azanebularine derivatives as potent anti-HBV agents.

Bioorg Med Chem Lett 2019 Apr 4. Epub 2019 Apr 4.

College of Chemistry and Molecular Engineering, Zhengzhou University, Henan 450001, PR China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Zhengzhou 450001, PR China. Electronic address:

Hepatitis B virus (HBV) is a global health problem requiring more efficient and better tolerated anti-HBV agent. In this paper, a series of novel 2'-deoxy-2'-fluoro-2'-C-methyl-β-d-arabinofuranosyl 8-azanebularine analogues (1 and 2a) and N-substituted 8-azaadenosine derivatives (2b-g) were designed, synthesized and screened for in vitro anti-HBV activity. Two concise and practical synthetic routes were developed toward the structural motif construction of 2'-deoxy-2'-fluoro-2'-C-methyl-β-d-arabinofuranosyl 8-azainosine from the ribonolactone 3 under mild conditions. Read More

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http://dx.doi.org/10.1016/j.bmcl.2019.04.005DOI Listing

Synthesis and biological evaluation of solithromycin analogs against multidrug resistant pathogens.

Bioorg Med Chem Lett 2019 Mar 26. Epub 2019 Mar 26.

Department of Chemistry, Temple University, Philadelphia, PA 19122, United States. Electronic address:

Novel antibacterial drugs that treat multidrug resistant pathogens are in high demand. We have synthesized analogs of solithromycin using Cu(I)-mediated click chemistry. Evaluation of the analogs using Minimum Inhibitory Concentration (MIC) assays against resistant Staphylococcus aureus, Escherichia coli, and multidrug resistant pathogens Enterococcus faecium and Acinetobacter baumannii showed they possess potencies similar to those of solithromycin, thus demonstrating their potential as future therapeutics to combat the existential threat of multidrug resistant pathogens. Read More

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http://dx.doi.org/10.1016/j.bmcl.2019.03.038DOI Listing

Cu-mediated synthesis of differentially substituted diazepines as AChE inhibitors; validation through molecular docking and Lipinski's filter to develop novel anti-neurodegenerative drugs.

Bioorg Med Chem Lett 2019 Apr 3. Epub 2019 Apr 3.

Department of Chemistry, B. S. Abdur Rahman Crescent University, Vandalur, Chennai 600 048, India.

A highly efficient Cu-mediated route for the synthesis of fused [1,2,3]triazolo[1,4]diazepines has been developed by azidation-cyclization of 2-bromo-N-propargylamines in a one-pot fashion. The key highlight of the present work is that the 2-bromo-N-propargylamines are prepared through the A-reaction of cyclic amines such as isoquinoline and decarboxylative coupling of proline and pipecolinic acid with 2-bromo benzaldehyde and alkyne. As preliminary, these compounds were analyzed for their most probable bioactivity using various in silico tools. Read More

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http://dx.doi.org/10.1016/j.bmcl.2019.04.002DOI Listing
April 2019
1 Read
2.420 Impact Factor

Development of the binding molecules for the RNA higher-order structures based on the guanine-recognition by the G-clamp.

Bioorg Med Chem Lett 2019 Apr 1. Epub 2019 Apr 1.

Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai-shi, Miyagi 980-8577, Japan. Electronic address:

RNA higher-order structures play an important role for control of the gene expression, and the small molecules binding to these structures have potential to act as interfering agents in the RNA-mediated-pathway. In this study, we synthesized new RNA binding molecules based on the G-clamp structure and evaluated their binding properties using the model RNA. The monomeric G-clamp ligand exhibited a fluorescence quenching with RNA-binding. Read More

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http://dx.doi.org/10.1016/j.bmcl.2019.03.052DOI Listing

Design, synthesis, evaluation and molecular modeling study of 4-N-phenylaminoquinolines for Alzheimer disease treatment.

Bioorg Med Chem Lett 2019 Mar 30. Epub 2019 Mar 30.

Department of Pharmacy Engineering, Tianjin University of Technology, Tianjin 300384, PR China. Electronic address:

Dual binding site acetylcholinesterase (AChE) inhibitors and butyrylcholinesterase (BChE) inhibitors have recently emerged as two classes of new anti-Alzheimer agents to positively modify the disease's course. In this work, a new series of 4-N-phenylaminoquinolines was synthesized and evaluated for their abilities to inhibit AChE and BChE. Compound 11b showed significant inhibitory activities on AChE and BChE with IC values of 0. Read More

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http://dx.doi.org/10.1016/j.bmcl.2019.03.050DOI Listing
March 2019
2 Reads

Nucleoside protein arginine methyltransferase 5 (PRMT5) inhibitors.

Bioorg Med Chem Lett 2019 Mar 27. Epub 2019 Mar 27.

Prelude Therapeutics, 200 Powder Mill Road, Wilmington, DE 19803, United States.

Protein Arginine Methyltransferase 5 (PRMT5) is known to symmetrically dimethylate numerous cytosolic and nuclear proteins that are involved in a variety of cellular processes. Recent findings have revealed its potential as a cancer therapeutic target. PRMT5 selective inhibitors, GSK3326595, a substrate competitive inhibitor, and JNJ64619178, a SAM (S-adenosyl-l-methionine) mimetic/competitive inhibitor, have entered clinic trials for multiple cancer types. Read More

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http://dx.doi.org/10.1016/j.bmcl.2019.03.042DOI Listing

Synthesis, fungicidal activity and SAR of 3,4-dichloroisothiazole-based cycloalkylsulfonamides.

Bioorg Med Chem Lett 2019 Mar 29. Epub 2019 Mar 29.

Department of Pesticide Science, Plant Protection College, Shenyang Agricultural University, Shenyang 110866, Liaoning, China. Electronic address:

To develop more valuable and effective fungicide candidates, a novel series of 3,4-dichloroisothioxazole-based cycloalkylsulfonamides were synthesized and their structures were identified by H NMR, C NMR, MS and elemental analysis. Compound 3k was further confirmed by X-ray single crystal diffraction. The in vitro bioassay results demonstrated that the target compounds showed significant fungicidal activity on mycelial growth and spore germination of Botrytis cinerea. Read More

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http://dx.doi.org/10.1016/j.bmcl.2019.03.047DOI Listing
March 2019
1 Read

Discovery of niclosamide and its O-alkylamino-tethered derivatives as potent antibacterial agents against carbapenemase-producing and/or colistin resistant Enterobacteriaceae isolates.

Bioorg Med Chem Lett 2019 Mar 23. Epub 2019 Mar 23.

Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555, United States. Electronic address:

Carbapenemase-producing Enterobacteriaceae (CPE) represents the most worrisome evolution of the antibiotic resistance crisis, which is almost resistant to most of available antibiotics. This situation is getting even worse particularly due to the recent emergence of colistin resistance. Herein, niclosamide, an FDA-approved traditional drug, and its novel O-alkylamino-tethered derivatives were discovered as new and potent antibacterial agents against carbapenemase-producing and/or colistin resistant Enterobacteriaceae isolates. Read More

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http://dx.doi.org/10.1016/j.bmcl.2019.03.032DOI Listing
March 2019
2 Reads

Modulation of mitochondrial dysfunction for treatment of disease.

Bioorg Med Chem Lett 2019 Mar 29. Epub 2019 Mar 29.

Mitobridge Inc, an Astellas Company, 1030 Massachusetts Ave, Cambridge, MA 02138, USA. Electronic address:

Mitochondrial dysfunction is a causative and/or exacerbating feature of many pathologies. We discuss below approaches to modulate mitochondrial dysfunction that involve (1) increasing their energetic efficiency by targeting gene expression regulators such as PPAR or AMPK, (2) using antioxidant compounds to reduce the toxic reactive oxygen species mitochondria produce under stress, or (3) modulating aspects on the innate mitochondrial quality control system. The latter comprise linked processes of biogenesis, dynamic morphological changes, and elimination of defective mitochondria by mitophagy. Read More

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http://dx.doi.org/10.1016/j.bmcl.2019.03.041DOI Listing

Peptide-based covalent inhibitors of MALT1 paracaspase.

Bioorg Med Chem Lett 2019 Mar 29. Epub 2019 Mar 29.

Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, 360 Longwood Ave, Boston, MA 02115, USA. Electronic address:

Potent and selective substrate-based covalent inhibitors of MALT1 protease were developed from the tetrapeptide tool compound Z-VRPR-fmk. To improve cell permeability, we replaced one arginine residue. We further optimized a series of tripeptides and identified compounds that were potent in both a GloSensor reporter assay measuring cellular MALT1 protease activity, and an OCI-Ly3 cell proliferation assay. Read More

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http://dx.doi.org/10.1016/j.bmcl.2019.03.046DOI Listing
March 2019
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Design, synthesis, and biological evaluation of novel pyrrolo[1,2-a]pyrazine derivatives.

Bioorg Med Chem Lett 2019 Mar 28. Epub 2019 Mar 28.

College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Republic of Korea. Electronic address:

A pyrrolo[1,2-a]pyrazine-based chemical territory was expanded via construction of new chemical library with distinctive substitution patterns, which was made possible by regiodivergent electrophilic acylation followed by aldol condensation. Biological screening of the compounds in this class revealed that the viability of human lymphoma U937 cells was strongly inhibited by 6b with a methoxy group at the o-position of the aromatic ring, but not by compounds 6t-w bearing a halogen at the o-position. Furthermore, 6x having a 2,4-dimethoxyphenyl group inhibited the survival of U937 cells more potently than 6b. Read More

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http://dx.doi.org/10.1016/j.bmcl.2019.03.044DOI Listing
March 2019
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Peptides conjugated to 2-alkoxy-8-oxo-adenine as potential synthetic vaccines triggering TLR7.

Bioorg Med Chem Lett 2019 Mar 30. Epub 2019 Mar 30.

Leiden Institute of Chemistry and The Institute for Chemical Immunology, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands. Electronic address:

Covalent linking of immunogenic oligopeptides with synthetic Toll-like receptor ligands is a useful approach to develop self-adjuvanting vaccines. In particular, small-molecule based agonists of Toll-like receptor 7 (TLR7) that are derived from 8-oxo-adenine core are potentially promising because these chemically robust TLR7 ligands can be connected to peptide T-cell epitopes via straightforward solid-phase peptide synthesis. In this contribution we present the synthesis of a Boc-protected 9-benzyl-2-alkoxy-8-oxo-adenine building block and its application in the online solid phase synthesis of three peptide conjugates that differ in the position of the TLR7 ligand within the peptide. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S0960894X193020
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http://dx.doi.org/10.1016/j.bmcl.2019.03.048DOI Listing
March 2019
2 Reads

Synthesis of α-methylstilbenes using an aqueous Wittig methodology and application toward the development of potent human aromatase inhibitors.

Bioorg Med Chem Lett 2019 Mar 26. Epub 2019 Mar 26.

Department of Chemistry and Chemical Biology, McMaster University, 1280 Main Street West, Hamilton, Ont. L8S 4M1, Canada. Electronic address:

The development of aqueous Wittig methodology for the synthesis of α-methylstilbenes using tripropylphosphine-derived phosphonium salts is described. The Wittig olefination reaction was high yielding and allowed isolation of stilbenes by simple filtration and washing with water. The novel phosphonium salts employed were accessed via a highly efficient, regioselective addition of hydrogen bromide to styrenes. Read More

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http://dx.doi.org/10.1016/j.bmcl.2019.03.033DOI Listing

Ultra-potent vinblastine analogues improve on-target activity of the parent microtubulin-targeting compound.

Bioorg Med Chem Lett 2019 Mar 26. Epub 2019 Mar 26.

Department of Chemistry and Skaggs Institute of Chemical Biology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address:

In recent efforts, several C20' urea vinblastine analogues were discovered that displayed remarkable potency against vinblastine-sensitive tumor cell lines (IC 50-75 pM), being roughly 100-fold more potent than vinblastine, and that exhibited decreased susceptibility to Pgp efflux-derived resistance in a vinblastine-resistant cell line. Their extraordinary activity indicate that it is not likely or even possible that their cellular functional activity is derived from stoichiometric occupancy of the intracellular tubulin binding sites. Rather, their potency indicates sub-stoichiometric or even catalytic occupancy of candidate binding sites may be sufficient to disrupt tubulin dynamics or microtubule assembly during mitosis. Read More

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http://dx.doi.org/10.1016/j.bmcl.2019.03.036DOI Listing

Accelerating the discovery of DGAT1 inhibitors through the application of parallel medicinal chemistry (PMC).

Bioorg Med Chem Lett 2019 Mar 27. Epub 2019 Mar 27.

Discovery and Preclinical Sciences, Merck & Co. Inc, 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States.

The parallel medicinal chemistry (PMC) was effectively applied to accelerate the optimization of diacylglycerol O-acyltransferase I (DGAT-1) inhibitors. Through a highly collaborative and iterative library design, synthesis and testing, a benzimidazole lead was rapidly and systematically advanced to a highly potent, selective and bioavailable DGAT1 inhibitor with the potential for further development. Read More

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http://dx.doi.org/10.1016/j.bmcl.2019.03.039DOI Listing
March 2019
2 Reads
2.420 Impact Factor

Structural requirements of cholenamide derivatives as the LXR ligands.

Bioorg Med Chem Lett 2019 Mar 30. Epub 2019 Mar 30.

Department of Applied Life Sciences, Niigata University of Pharmacy and Applied Life Sciences, 265-1 Higashijima, Akiha-ku, Niigata 956-8603, Japan. Electronic address:

A study of the structural requirements of cholic acid derivatives as liver X receptor (LXR) ligands was performed. A model of cholenamide derivative 1 complexed with LXR showed that the C24 carbonyl oxygen forms a hydrogen bond with His435 located close to Trp457. The N,N-dimethyl group is located in a hydrophobic pocket. Read More

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http://dx.doi.org/10.1016/j.bmcl.2019.03.051DOI Listing

Benzothiophene derivatives as phosphodiesterase 10A (PDE10A) inhibitors: Hit-to-lead studies.

Bioorg Med Chem Lett 2019 Mar 19. Epub 2019 Mar 19.

Asubio Pharma Co., Ltd., 6-4-3 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.

A novel series of benzothiophene derivatives was discovered as phosphodiesterase 10A (PDE10A) inhibitors. Structure-activity relationship studies on high-throughput screening hit compound 1 led to the identification of 7-acetyl-3-methyl-N-(quinolin-2-yl)-1-benzothiophene-2-carboxamide (16), with potent inhibitory activity (PDE10A IC = 7.6 nM) and selectivity (>1300-fold selectivity over the other tested phosphodiesterases). Read More

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http://dx.doi.org/10.1016/j.bmcl.2019.03.021DOI Listing
March 2019
2.420 Impact Factor

A survey of core replacements in indole-based HIV-1 attachment inhibitors.

Bioorg Med Chem Lett 2019 Mar 28. Epub 2019 Mar 28.

Department of Discovery Chemistry and Molecular Technologies, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.

Indole- and azaindole-based glyoxylyl amide derivatives have been described as HIV-1 attachment inhibitors (AIs) that act by blocking the interaction between the viral gp120 coat protein and the human host cell CD4 receptor. As part of an effort to more deeply understand the role of the indole/azaindole heterocycle in the expression of antiviral activity, a survey of potential replacements was conducted using parallel synthesis methodology. The design and optimization was guided by a simple 2-dimensional overlay based on an overall planar topography between the indole/azaindole and C-7 substituents that had been deduced from structure-activity studies leading to the discovery of temsavir (3). Read More

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http://dx.doi.org/10.1016/j.bmcl.2019.03.018DOI Listing
March 2019
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Synthesis, antibacterial and cytotoxic evaluation of flavipucine and its derivatives.

Bioorg Med Chem Lett 2019 Mar 26. Epub 2019 Mar 26.

Department of Applied Biological Science, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan. Electronic address:

The antibacterial and cytotoxic activity of seven racemic lactams and both enantiomers of flavipucine were evaluated. Of the compounds tested in this study, flavipucine and phenylflavipucine displayed bactericidal activity against Bacillus subtilis. These results indicate that the pyridione epoxide moiety is a pharmacophore for antibacterial activity against B. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S0960894X193017
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http://dx.doi.org/10.1016/j.bmcl.2019.03.034DOI Listing
March 2019
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Anticancer platinum(II) complexes bearing N-heterocycle rings.

Bioorg Med Chem Lett 2019 Mar 29. Epub 2019 Mar 29.

Department of Pharmaceutical Sciences, University of Milan, Via Golgi 19, 20133 Milan, Italy. Electronic address:

Starting from the pioneering discovery of picoplatin and phenanthriplatin, many efforts were realized by different research groups in the synthesis of different platinum(II) complexes, bearing a N-heterocycle moiety active as anticancer agents in different types of solid tumors. This review deals in particular with both the bifunctional and monofunctional platinum drugs, not only in dichloride platinum(II) complexes, but also in recent advances in modern platinum structures, i.e. Read More

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http://dx.doi.org/10.1016/j.bmcl.2019.03.045DOI Listing
March 2019
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The synthesis of 4,6-diaryl-2-pyridones and their bioactivation in CYP1 expressing breast cancer cells.

Bioorg Med Chem Lett 2019 Mar 22. Epub 2019 Mar 22.

Leicester School of Pharmacy, Faculty of Health and Life Sciences, De Montfort University, The Gateway, Leicester LE1 9BH, UK. Electronic address:

As part of a programme to develop anticancer prodrugs which are activated by cytochrome P450 (CYP)1B1, a library of 4,6-diaryl-2-pyridones was synthesised in yields of 6-60% from the corresponding chalcones. A number of these derivatives showed promising antiproliferative activities in human breast cancer cell lines which express CYP1B1 and CYP1A1, while showing little toxicity towards a non-tumour breast cell line with no CYP expression. Metabolism studies provided evidence supporting the involvement of CYP1 enzymes in the bioactivation of these compounds. Read More

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http://dx.doi.org/10.1016/j.bmcl.2019.03.030DOI Listing
March 2019
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Selective degradation of CDK6 by a palbociclib based PROTAC.

Bioorg Med Chem Lett 2019 Mar 26. Epub 2019 Mar 26.

Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68022, USA; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska 68022, USA; Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, Nebraska 68022, USA. Electronic address:

Development of selective kinase inhibitors that target the ATP binding site continues to be a challenge largely due to similar binding pockets. Palbociclib is a cyclin-dependent kinase inhibitor that targets the ATP binding site of CDK4 and CDK6 with similar potency. The enzymatic function associated with the kinase can be effectively probed using kinase inhibitors however the kinase-independent functions cannot. Read More

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http://dx.doi.org/10.1016/j.bmcl.2019.03.035DOI Listing
March 2019
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Synthesis and characterization of polyaniline-drug conjugates as effective antituberculosis agents.

Bioorg Med Chem Lett 2019 Mar 27. Epub 2019 Mar 27.

Department of Chemistry, Mohanlal Sukhadia University, Udaipur (Raj.), India. Electronic address:

Polyaniline (PANI) and its drug composites with some drugs like Neomycin (NM), Trimethoprim (TMP) and Streptomycin (ST) have been prepared by oxidative polymerization of aniline using hydrochloric acid (HA) and ammonium persulfate (APS) as a dopant and as an oxidant, respectively. The structures of PANI and PANI-drug composites were elucidated by FTIR and NMR spectroscopy, which confirmed the presence of benzenoid and quinoid rings in the synthesized compound. Molecular weight and thermal stability were determined by gel permeation chromatography (GPC) and thermogarvimetric analysis, respectively. Read More

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http://dx.doi.org/10.1016/j.bmcl.2019.03.040DOI Listing

Design, synthesis, and evaluation of α-galactopyranosylceramide mimics promoting Th2 cytokines production.

Bioorg Med Chem Lett 2019 Mar 27. Epub 2019 Mar 27.

National Engineering Research Center for Carbohydrate Synthesis, Jiangxi Normal University, Nanchang 330022, Jiangxi, China; School of Chemical Sciences, University of Chinese Academy of Sciences, Beijing 100049, China; State Key Laboratory of Environmental Chemistry and Eco-toxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China. Electronic address:

The binding properties of CD1d/glycolipid/TCR, glycolipid/TCR interactions in particular, have been investigated using docking computation. Accordingly, efficient modification on C-6' of galactose head was recommended in this report to favor the production of Th2 cytokines. The designed glycolipids have been successfully prepared taking advantages of inverse glycosylation procedure, and their abilities to stimulate mouse iNKT cells in vivo have been tested. Read More

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http://dx.doi.org/10.1016/j.bmcl.2019.03.043DOI Listing
March 2019
2.420 Impact Factor

Novel allosteric covalent inhibitors of bifunctional Cryptosporidium hominis TS-DHFR from parasitic protozoa identified by virtual screening.

Bioorg Med Chem Lett 2019 Mar 20. Epub 2019 Mar 20.

Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA; Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA. Electronic address:

Protozoans of the genus Cryptosporidium are the causative agent of the gastrointestinal disease, cryptosporidiosis, which can be fatal in immunocompromised individuals. Cryptosporidium hominis (C. hominis) bifunctional thymidylate synthase-dihydrofolate reductase (TS-DHFR) is an essential enzyme in the folate biosynthesis pathway and a molecular target for inhibitor design. Read More

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http://dx.doi.org/10.1016/j.bmcl.2019.03.022DOI Listing

Structural hybridization of pyrrolidine-based T-type calcium channel inhibitors and exploration of their analgesic effects in a neuropathic pain model.

Bioorg Med Chem Lett 2019 May 21;29(10):1168-1172. Epub 2019 Mar 21.

Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, 5, Hwarang-ro 14-gil, Seongbuk-gu, Seoul 02792, Republic of Korea; Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, 5, Hwarang-ro 14-gil, Seongbuk-gu, Seoul 02792, Republic of Korea. Electronic address:

Highly effective and safe drugs for the treatment of neuropathic pain are urgently required and it was shown that blocking T-type calcium channels can be a promising strategy for drug development for neuropathic pain. We have developed pyrrolidine-based T-type calcium channel inhibitors by structural hybridization and subsequent assessment of in vitro activities against Ca3.1 and Ca3. Read More

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http://dx.doi.org/10.1016/j.bmcl.2019.03.026DOI Listing
May 2019
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Identification of ortho-hydroxy anilide as a novel scaffold for lysine demethylase 5 inhibitors.

Bioorg Med Chem Lett 2019 May 21;29(10):1173-1176. Epub 2019 Mar 21.

Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 1-5 Shimogamohangi-cho, Sakyo-ku, Kyoto 606-0823, Japan; CREST, Japan Science and Technology Agency (JST), 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan. Electronic address:

Fe(II)/α-ketoglutarate-dependent lysine demethylases (KDMs) are attractive drug targets for several diseases including cancer. In this study, we designed and screened ortho-substituted anilides that are expected to function as Fe(II) chelators, and identified ortho-hydroxy anilide as a novel scaffold for KDM5A inhibitors. Treatment of human lung cancer A549 cells with a prodrug form of 4-carboxy-2-hydroxy-formanilide (9c) increased trimethylated lysine 4 on histone H3 level, suggesting KDM5 inhibition in the cells. Read More

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http://dx.doi.org/10.1016/j.bmcl.2019.03.028DOI Listing
May 2019
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Further sesquiterpenoids from the rhizomes of Homalomena occulta and their anti-inflammatory activity.

Bioorg Med Chem Lett 2019 May 22;29(10):1162-1167. Epub 2019 Mar 22.

CAS Key Laboratory of Chemistry of Northwestern Plant Resources and Key Laboratory for Natural Medicine of Gansu Province, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences (CAS), Lanzhou 730000, People's Republic of China. Electronic address:

The rhizomes of Homalomena occulta are called Qian-nian-jian in Traditional Chinese Medicine (TCM), which is widely consumed in China owing to its health benefits for the treatment of rheumatoid arthritis and for strengthening tendons and bones. A phytochemical investigation on this famous TCM yielded 19 sesquiterpenoids (1-19) with various carbocyclic skeletons including isodaucane (2, 8, and 9), guaiane (3), eudesmane (4 and 10-15), oppositane (5, 16, and 17), and aromadendrane (18 and 19) types. The structures of new compounds, Homalomenins A-E (1-5), were determined by diverse spectroscopic data. Read More

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http://dx.doi.org/10.1016/j.bmcl.2019.03.031DOI Listing
May 2019
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Benzimidazole-based DGAT1 inhibitors with a [3.1.0] bicyclohexane carboxylic acid moiety.

Bioorg Med Chem Lett 2019 May 21;29(10):1182-1186. Epub 2019 Mar 21.

Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.

Previously disclosed benzimidazole-based DGAT1 inhibitors containing a cyclohexane carboxylic acid moiety suffer from isomerization at the alpha position of the carboxylic acid group, generating active metabolites which exhibit DGAT1 inhibition comparable to the corresponding parent compounds. In this report, we describe the design, synthesis and profiling of benzimidazole-based DGAT1 inhibitors with a [3.1. Read More

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http://dx.doi.org/10.1016/j.bmcl.2019.03.025DOI Listing
May 2019
2.420 Impact Factor

Radiosynthesis of a carbon-11-labeled AMPAR allosteric modulator as a new PET radioligand candidate for imaging of Alzheimer's disease.

Bioorg Med Chem Lett 2019 May 20;29(10):1177-1181. Epub 2019 Mar 20.

Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, College of Chemistry and Environmental Science, Hebei University, Baoding, Hebei 071002, China; College of Chemical & Pharmaceutical Engineering, Key Laboratory of Molecular Chemistry for Medicine of Hebei Province, Hebei University of Science & Technology, Shijiazhuang, Hebei 050018, China; Shijiazhuang Vince Pharmatech Co., Ltd., Shijiazhuang, Hebei 050030, China. Electronic address:

To develop PET tracers for imaging of Alzheimer's disease, a new carbon-11-labeled AMPAR allosteric modulator 4-cyclopropyl-7-(3-[C]methoxyphenoxy)-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide ([C]8) has been synthesized. The reference standard 4-cyclopropyl-7-(3-methoxyphenoxy)-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (8) and its corresponding desmethylated precursor 4-cyclopropyl-7-(3-hydroxyphenoxy)-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (9) were synthesized from 4-methoxyabiline and chlorosulfonyl isocyanate in eight and nine steps with 3% and 1% overall chemical yield, respectively. The target tracer [C]8 was prepared from the precursor 9 with [C]CHOTf through O-[C]methylation and isolated by HPLC combined with SPE in 10-15% radiochemical yield, based on [C]CO and decay corrected to end of bombardment (EOB). Read More

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http://dx.doi.org/10.1016/j.bmcl.2019.03.027DOI Listing
May 2019
2 Reads
2.420 Impact Factor

Discovery of 1,3-diphenyl-1H-pyrazole derivatives containing rhodanine-3-alkanoic acid groups as potential PTP1B inhibitors.

Bioorg Med Chem Lett 2019 May 20;29(10):1187-1193. Epub 2019 Mar 20.

Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Yanbian University College of Pharmacy, Yanji 133000, PR China. Electronic address:

Two series of 1,3-diphenyl-1H-pyrazole derivatives containing rhodanine-3-alkanoic acid groups were identified as competitive protein tyrosine phosphatase 1B (PTP1B) inhibitors. Among the compounds studied, IIIv was found to have the best in vitro inhibition activity against PTP1B (IC = 0.67 ± 0. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S0960894X193016
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http://dx.doi.org/10.1016/j.bmcl.2019.03.023DOI Listing
May 2019
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Thiazolyl-pyrazole derivatives as potential antimycobacterial agents.

Bioorg Med Chem Lett 2019 May 19;29(10):1199-1202. Epub 2019 Mar 19.

Department of Chemistry, S. P. Mandali's Sir Parashurambhau College, Tilak Road, Pune 411 030, India. Electronic address:

Mycobacterium tuberculosis (Mtb) is an obligate aerobe that is capable of long-term persistence under conditions of low oxygen tension. A series of thiazolyl-pyrazole derivatives (6a-f, 7a-f, 8c, 8e) were screened for antimycobacterial activity against dormant M. tuberculosis H37Ra (D-MTB) and M. Read More

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http://dx.doi.org/10.1016/j.bmcl.2019.03.020DOI Listing
May 2019
2.420 Impact Factor