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Hezhen Wang, Bader Huwaimel, Kshitij Verma, James Miller, Todd Germain, Nihar Kinarivala, Dimitri Pappas, Paul Brookes, Paul Charles Trippier
Mitochondrial complex II (CII) is an emerging target for numerous human diseases. Sixteen analogues of the CII inhibitor natural product atpenin A5 were prepared to evaluate the structure-activity relationship of the C-5 pyridine side chain. The side chain ketone moiety was determined to be pharmacophoric, engendering a bioactive conformation. Analogue 16c displayed CII IC50 = 64 nM, retained selectivity for CII over mitochondrial complex I (>156-fold) and possessed a ligand-lipophilicity efficiency of 5...
May 18, 2017: ChemMedChem
Francescsa Aiello, Gabriele Carullo, Francesca Giordano, Elena Spina, Alessandra Nigro, Antonio Garofalo, Sabrina Tassini, Gabriele Costantino, Paolo Vincetti, Agostino Bruno, Marco Radi
Together with ERα/β, GPER (G protein-coupled estrogen receptor) mediates important pathophysiological signaling pathways induced by estrogens and is currently regarded as a promising target for ER-negative and triple-negative breast cancer. Only a few selective GPER modulators have been reported to date and their use in cancer cell lines has often led to contradictory results. Here we report the application of virtual screening and cell-based studies for the identification of new chemical scaffolds with a specific anti-proliferative effect against GPER-expressing breast cancer cell lines...
May 18, 2017: ChemMedChem
Giuseppe Deganutti, Ajith Welihinda, Stefano Moro
Adenosine deaminase converts adenosine to inosine. Differently by adenosine, modest attention has been dedicated to the physiological roles of inosine. Nevertheless, recent studies demonstrate that inosine has neuroprotective, cardioprotective immunomodulatory, and antidepressive effects. It has been recently reported by Welihinda and collaborators that inosine is a less potent agonist than adenosine at the A2A AR. To better depict the differences in receptor recognition mechanism of both adenosine and inosine, in this work supervised molecular dynamics (SuMD) simulations have been performed and analyzed...
May 18, 2017: ChemMedChem
Hang Zhang, Xiao-Feng Xiong, Michael W Boesgaard, Christina R Underwood, Hans Bräuner-Osborne, Kristian Strømgaard
Extracellular signals perceived by G protein-coupled receptors are transmitted via G proteins, and subsequent intracellular signaling cascades result in a plethora of physiological responses. The natural product cyclic depsipeptides YM-254890 and FR900359 are the only known compounds that specifically inhibit signaling mediated by the Gq subfamily. In this study we exploit a newly developed synthetic strategy for this compound class in the design, synthesis, and pharmacological evaluation of eight new analogues of YM-254890...
May 16, 2017: ChemMedChem
Laurent Sevaille, Laurent Gavara, Carine Bebrone, Filomena De Luca, Lionel Nauton, Maud Achard, Paola Mercuri, Silvia Tanfoni, Luisa Borgianni, Carole Guyon, Pauline Lonjon, Gülhan Turan-Zitouni, Julia Dzieciolowski, Katja Becker, Lionel Bénard, Ciaran Condon, Ludovic Maillard, Jean Martinez, Jean-Marie Frère, Otto Dideberg, Moreno Galleni, Jean-Denis Docquier, Jean-François Hernandez
Metallo-β-lactamases (MBL) cause resistance of Gram-negative bacteria to β-lactam antibiotics and are of serious concern because they can inactivate the last-resort carbapenems and because MBL inhibitors of clinical value are still lacking. We have previously identified the original binding mode of a 4-amino-1,2,4-triazole-3-thione compound, IIIA, within the di-zinc active site of the L1 MBL. Here, we present the crystallographic structure of a complex of L1 with the corresponding non-amino compound IIIB...
May 15, 2017: ChemMedChem
Guang Liang, Lingfeng Chen, Yiyi Jin, Weitao Fu, Siyang Xiao, Chen Feng, Bo Fang, Yugui Gu, Chenglong Li, Yunjie Zhao, Zhiguo Liu
Acute lung injury (ALI) results in high lethality rate, and interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) contribute most to tissue deterioration in ALI. In this study, we designed and synthesized a new series of thiazolo[3,2-a]pyrimidine derivatives based on lead compound 6, and evaluated their anti-inflammatory activities. The structure-activity relationship studies led to the discovery of two highly potent inhibitors. The promising compounds 11e and 11l inhibited lipopolysaccharide (LPS)-induced IL-6 and TNF-α release in a dose-dependent manner in mouse primary peritoneal macrophages (MPMs)...
May 14, 2017: ChemMedChem
Zhiyang Liu, Shutao Ma
For the past few years, there are more and more people with type 2 diabetes due to unhealthy diet, less exercise and overweight. To find novel and efficient anti-diabetes agents becomes an urgent task for scientists. Among those anti-diabetes drugs, α-glucosidase inhibitor drugs are proved to have many advantages which are inaccessible for other drugs, therefore, large amounts of new compounds as α-glucosidase inhibitors have been reported lately. In this review, we summarized those newly found α-glucosidase inhibitors and their structure-activity relationship in anti-diabetic studies, wishing to provide better structures as α-glucosidase inhibitors or even pre-clinical candidates...
May 12, 2017: ChemMedChem
Clelia Mariangiola Luisa Dallanoce, Marta Quadri, Carlo Matera, Almin Silnović, Maria Chiara Pismataro, Nicole Alana Horenstein, Clare Stokes, Roger Lee Papke
Compound 11 (3-(benzyloxy)-1'-methyl-1'-azonia-4H-1'-azaspiro[isoxazole-5,3'-bicyclo[2.2.2]octane] iodide) was selected from a previous set of nicotinic ligands as a suitable model ligand for the design of new silent agonists of α7 nAChRs. Silent agonists evoke little or no channel activation but can induce the α7 desensitized Ds state, sensitive to a type II positive allosteric modulator (PAM) such as PNU-120596. Introduction of meta-substituents into the benzyloxy moiety of 11 led to the two sets of tertiary amines and quaternary ammonium salts based on the spirocyclic quinuclidinyl-Δ2-isoxazoline scaffold...
May 11, 2017: ChemMedChem
Salimeh Amidi, Marjan Esfahanizadeh, Kimia Tabib, Zohreh Soleimani, Farzad Kobarfard
Based on the previous studies indicating the pharmacophoric role of hydrazone group and azole rings for antiplatelet aggregation activity, a few series of compounds with both hydrazone and azole (imidazole) ring in their structures were synthesized and their platelet aggregation inhibitory effect was evaluated. Two compounds among the 1-(arylideneamino)-4-aryl-1H-imidazole-2-amine derivatives compound 4a and 4p showed IC50 values comparable to that of aspirin against collagen as platelet aggregation inducer...
May 11, 2017: ChemMedChem
Daniel Meibom, Barbara Albrecht-Küpper, Nicole Diedrichs, Walter Hübsch, Raimund Kast, Thomas Krämer, Ursula Krenz, Hans-Georg Lerchen, Joachim Mittendorf, Peter G Nell, Frank Süssmeier, Alexandros Vakalopoulos, Katja Zimmermann
Adenosine is known to be released under a variety of physiological and pathophysiological conditions to facilitate the protection and regeneration of injured ischemic tissues. The activation of myocardial adenosine A1 receptors (A1 Rs) has been shown to inhibit myocardial pathologies associated with ischemia and reperfusion injury, suggesting several options for new cardiovascular therapies. When full A1 R agonists are used, the desired protective and regenerative cardiovascular effects are usually overshadowed by unintended pharmacological effects such as induction of bradycardia, atrioventricular (AV) blocks, and sedation...
May 10, 2017: ChemMedChem
Ramaiah Muthyala, Woo Shik Shin, Yuk Yin Sham, Alexander Bergstrom, Michael W Crowder, Robert A Bonomo
VIM-2 is one of the most common carbapenem-hydrolyzing metallo lactamase (MBL) found in many drug resistant Gram-negative bacteria. Currently, there is a lack of effective lead compounds with optimal therapeutic potential within our drug development pipeline. Here we report the discovery of 1-hydroxypyridine-2(1H)-thione-6-carboxylic acid (3) as a first-in class metallo lactamase inhibitor (MBLi) with a potent inhibition Ki of 13 nM against VIM-2 that corresponds to a remarkable 0.99 ligand efficiency...
May 8, 2017: ChemMedChem
Margherita Di Pisa, Oliver Seitz
Nucleic acid directed bioorthogonal reactions offer the fascinating opportunity to potentially unveil and redirect a plethora of intracellular mechanisms. Nano- to picomolar amounts of specific RNA molecules serve as templates and catalyze the selective formation of molecules that i) exert biological effects or ii) provide measurable signals for RNA detection. Turnover of reactants on the template is a valuable asset when concentrations of RNA templates are low. The idea is to use RNA templated reactions to fully control biodistribution of drugs as well as pushing the detection limits of DNA or RNA analytes to extraordinary sensitivities...
May 8, 2017: ChemMedChem
Eva Toth, Sara Lacerda
Lanthanide complexes have attracted continuous attention in the biomedical field and today various imaging applications make use of their versatile magnetic and luminescence properties. In this minireview, we give insights into the mechanistic aspects that allow modulating the relaxation or chemical exchange saturation transfer (CEST) features, thus the MRI efficiency of paramagnetic lanthanide chelates in order to create agents that are capable of providing an MRI response as a function of a specific biomarker...
May 4, 2017: ChemMedChem
Sabrina Taliani, Barbara Costa, Eleonora Da Pozzo, Elisabetta Barresi, Marco Robello, Chiara Cavallini, Sandro Cosconati, Federico Da Settimo, Ettore Novellino, Claudia Martini
Targeting neuroactive steroid biosynthetic pathway by specific 18 kDa Translocator Protein (TSPO) ligands may represent a therapeutic approach in a variety of neurodegenerative and neuropsychiatric diseases. However, the lack of correlation between the binding affinity and the in vitro steroidogenic efficacy has limited the identification of lead compounds by a traditional affinity-based drug discovery strategy. Our recent researches indicate that the key factor for robust steroidogenic TSPO ligand efficacy is not the binding affinity per se, but rather the time the compound spends into the target, namely its Residence Time (RT)...
May 3, 2017: ChemMedChem
Yugen Zhang, Yuan Yuan
A series of imidazolium oligomers with novel planar and stereo core structures were designed and synthesized. These compounds have symmetric structures with different cores, tails and linkers. These novel imidazolium oligomers demonstrated a desirable set of bioactivities against four types of clinically relevant microbes including E. coli, S.aureus, P. aeruginosa and C. albicans. The planar oligomers with three di-imidazolium arms and n-octyl tails showed good antimicrobial activity and biocompatibility. Oligomers with ortho-xylylene linker exhibited higher antimicrobial activity and higher hemolytic ability compared to those oligomers with para-xylylene linker...
May 2, 2017: ChemMedChem
Edmond Differding
This review provides a comprehensive survey of proprietary drug discovery and development efforts performed by Indian companies between 1994 and mid-2016. It is based on the identification and detailed analysis of pharmaceutical, biotechnology and contract research companies active in proprietary New Chemical Entity R&D in India. Information on preclinical and clinical development compounds has been collected by company, therapeutic indication, mode of action, target class, and development status. The analysis focuses on the overall pipeline and its evolution over two decades, contributions by type of company, therapeutic focus, attrition rates, and contribution to Western pharmaceutical pipelines through licensing agreements...
May 2, 2017: ChemMedChem
Alba Velle, Ronan Maguire, Kevin Kavanagh, Pablo J Sanz Miguel, Diego Montagner
The combination of NHC-carbene Au(I) complexes and estrogen derivatives generates a new class of compounds with noteworthy in vivo antibacterial activity (Galleria mellonella model). The synthesis, characterization and antibacterial activity of four novel steroid-Au(I)-NHC complexes is reported.
May 2, 2017: ChemMedChem
Markus Glaffig, Natascha Stergiou, Edgar Schmitt, Horst Kunz
Fully synthetic MUC1 glycopeptide antitumor vaccines have a precisely specified structure and induce a targeted immune response without suppression of the immune response when using an immunogenic carrier protein. However, tumor-associated aberrantly glycosylated MUC1 glycopeptides are endogenous structures, "self-antigens", that exhibit only low immunogenicity. To overcome this obstacle, a fully synthetic MUC1 glycopeptide antitumor vaccine was combined with poly(inosinic acid:cytidylic acid), poly(I:C), as a structurally defined Toll-like receptor 3 (TLR3)-activating adjuvant...
April 25, 2017: ChemMedChem
Balázs Dankó, Szilárd Tóth, Ana Martins, Vágvölgyi Máté, Norbert Kúsz, Joseph Molnár, Fang-Rong Chang, Yang-Chang Wu, Gergely Szakács, Attila Hunyadi
There is a constant need for new therapies against multidrug resistant (MDR) cancer. Natural compounds represent a promising class of novel anticancer agents. Recently, we have shown that protoflavones display activity in multidrug resistant cancer cell lines overexpressing the drug efflux pump P-glycoprotein. In the present study, 52 protoflavones, including 22 new derivatives were synthesized and tested against a panel of sensitive parental cells and their MDR derivatives obtained by transfection with the human ABCB1 or ABCG2 genes, or by adaptation to chemotherapeutics...
April 23, 2017: ChemMedChem
Fabrizio Micheli
This Minireview describes a presentation made at the XXIV National Meeting in Medicinal Chemistry (NMMC) held in Perugia (Italy), September 11-14, 2016. It relates to the discovery of novel templates of the so-called "amino" region of dopamine D3 receptor antagonists. Moving from the early scaffolds, which were modified in the amine portion, this review discusses the variations that led to the discovery of new systems published in 2016, which allowed the identification of compounds endowed with great selectivity over the dopamine D2 receptor and the human ether-à-go-go-related gene (hERG) ion channel...
April 20, 2017: ChemMedChem
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