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Daniel Laengle, Tessa R Werner, Fabian Wesseler, Elena S Reckzeh, Niklas Schaumann, Lauren Drowley, Magnus Polla, Alleyn T Plowright, Marc N Hirt, Thomas Eschenhagen, Dennis Schade
Innovative therapeutic modalities for pharmacological intervention of TGFβ-dependent diseases are of great value. b-Annelated 1,4-dihydropyridines (DHPs) might be such a class as they induce TGFβ receptor type-II degradation. However, intrinsic drawbacks are associated with this compound class and were systematically addressed in the presented study. It was possible to install polar functionalities and bioisosteric moieties at distinct sites of the molecules while keeping TGFβ inhibiting activities. The introduction of a 2-amino group or 7-N-alkyl modification proved successful strategies...
February 15, 2019: ChemMedChem
Alexandra Manos-Turvey, Guillaume Becker, Pierre Francotte, Maria Elisa Serrano, André Luxen, Bernard Pirotte, Alain Plenevaux, Christian Lemaire
Alzheimer's disease (AD) remains a significant burden on society. In the search for new AD drugs, modulators of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are of particular interest as loss of synaptic AMPARs has been linked to AD learning and memory deficits. Previously reported fluorine-containing BPAM121, an AMPA positive allosteric modulator (pam) with high activity, low toxicity and slow metabolism, was considered to be a perfect 18F-labelled candidate for positron emission tomography (PET) AD diagnostic investigations...
February 11, 2019: ChemMedChem
Ricardo L Mancera, Giuseppe Luna, Anton V Dolzhenko
Xanthine oxidase (XO) is the enzyme responsible for the catabolism of purines in the body and their conversion to uric acid. XO is thus the target enzyme for the treatment of hyperuricemia and gout. For more than 50 years the only drug inhibitor of XO available on the market was the purine analogue allopurinol. In the last decade there has been a resurgence in the search for new inhibitors of XO as the activity of XO and hyperuricemia have also been associated with a variety of conditions like diabetes, hypertension and other cardiovascular diseases...
February 10, 2019: ChemMedChem
Miguel M Santos, Luís R Raposo, Alexandra Costa, Madalena Dionísio, Pedro V Baptista, Alexandra R Fernandes, Luis C Branco
Herein we report the synthesis of novel ionic liquids (ILs) by combination of Ibuprofen as anion with biocompatible ammonium, imidazolium and pyridinium cations. The synthetic methodology consisted in the acid-base reaction of neutral Ibuprofen with cation hydroxides, which were previously prepared by anion exchange from the corresponding halide salts with Amberlyst A-26(OH). In comparison with the parent drug, the plethora of synthesized compounds display very attractive physicochemical properties such as higher solubility in water and biological fluids and a smaller degree of polymorphism which in some cases was completely eliminated...
February 8, 2019: ChemMedChem
Nicole A Spiegelman, Jun Young Hong, Jing Hu, Hui Jing, Miao Wang, Ian R Price, Ji Cao, Min Yang, Xiaoyu Zhang, Hening Lin
SIRT2, a member of the sirtuin family of protein lysine deacylases, has been identified as a promising therapeutic target. In addition to catalyzing deacetylation, SIRT2 has recently been shown to remove fatty acyl groups from K-Ras4a and promote its transforming activity. Among the SIRT2 specific inhibitors, only the thiomyristoyl lysine compound, TM, can weakly inhibit the demyristoylation activity of SIRT2. Thus, more potent small molecule SIRT2 inhibitors are needed to further evaluate the therapeutic potential of SIRT2 inhibition, and to understand the function of protein lysine defatty-acylation...
February 7, 2019: ChemMedChem
Maria Luisa Navacchia, Elena Marchesi, Nicola Chinaglia, Massimo Luigi Capobianco, Paolo Marchetti, Tzu-En Huang, Cheng Weng, Jih-Hwa Guh, Lih-Ching Hsu, Daniela Perrone
A series of hybrid compounds based on natural products bile acids and dihydroartemisinin (DHA) were prepared by different synthetic methodologies and investigated for their in vitro biological activity against HL-60 leukemia and HepG2 hepatocellular carcinoma cell lines. Most synthesized hybrids presented significantly improved antiproliferative activities respect to DHA and parent bile acids. Compounds 2 and 13 were the most potent hybrids of the series with a 10.5- and 15.4-fold increase in cytotoxic activity respect to DHA alone in HL-60 and HepG2 cells, respectively...
February 6, 2019: ChemMedChem
Beat Ernst, Wojciech Schönemann, Jonathan Cramer, Tobias Mühlethaler, Brigitte Fiege, Marleen Silbermann, Said Rabbani, Philipp Dätwyler, Pascal Zihlmann, Roman P Jakob, Christoph P Sager, Martin Smieško, Oliver Schwardt, Timm Maier
Antimicrobial resistance has become a serious concern for the treatment of urinary tract infections. In this context, an anti-adhesive approach targeting FimH, a bacterial lectin enabling the attachment of E. coli to host cells, attracted considerable interest. FimH can adopt a low/medium-affinity state in the absence and a high-affinity state in the presence of shear forces. Until recently, mostly the high-affinity state has been investigated, despite the fact that a therapeutic antagonist should bind predominantly to the low-affinity state...
February 1, 2019: ChemMedChem
Andreia Daniela Veloso, Ana M Ferraria, Ana Botelho do Rego, Pedro Tavares B Tavares, Patrícia Valentão, David M David M Pereira, Paula B Andrade, António J Fernandes, Maria C Oliveira, Romeu A Videira
A highly hydrophilic carbon nanomaterial was generated by an electrochemical approach, and its structure, chemical composition, redox properties, antioxidant activity and cells effects were characterized. It was found that the nanomaterial possesses a structure dominated by sp2 carbons in a non-order carbon network formed by small clusters (< 2 nm) of a carbonaceous material. This nanomaterial has an outstanding capability for electron-donating and an unusual ability to retain cations. Antioxidant activity assays showed that it displays a high scavenging activity against both DPPH and ABTS radicals, and a concentration-dependent ability to protect the mitochondrial lipids and intracellular thiol groups from oxidation promoted by external oxidant agents...
February 1, 2019: ChemMedChem
Aoi Isono, Mieko Tsuji, Yu Sanada, Akari Matsushita, Shinichiro Masunaga, Tasuku Hirayama, Hideko Nagasawa
We developed new 10B carriers for boron neutron capture therapy (BNCT) that can effectively transport and accumulate boron clusters into cells. These carriers consist of lipopeptide, mercaptoundecahydrododecaborate (BSH) and a disulfide linker. The carriers were conceived according to the structure of pepducine, a membrane-penetrating lipopeptide targeting protease-activated receptor 1 (PAR1). To improve the membrane permeability of BSH, the structure was optimised using various lipopeptides possessing different peptides and lipid moieties...
February 1, 2019: ChemMedChem
Karl Scheidt, Kristine K Deibler, Gary E Schiltz, Matthew R Clutter, Rama K Mishra, Purav P Vagadia, Matthew O'Connor, Mariam Donny George, Ryan Gordon, Graham Fowler, Raymond Bergan
Herein we report the discovery of a novel series of highly potent and selective mitogen-activated protein kinase kinase 4 (MEK4) inhibitors. MEK4 is an upstream kinase in MAPK signalling pathways that phosphorylates p38 MAPK and JNK in response to mitogenic and cellular stress queues. MEK4 is over-expressed and induces metastasis in advanced prostate cancer lesions. However, the value of MEK4 as an oncology target has not been pharmacologically validated because selective chemical probes targeting MEK4 have not been developed...
February 1, 2019: ChemMedChem
Kyla M Frohlich, Spencer Weintraub, Janeen T Bell, Gabrielle C Todd, Ville Yp Väre, Ryan Schneider, Zachary A Kloos, Ebot S Tabe, William A Cantara, Caren Stark, Ureena Onwuanaibe, Bryan C Duffy, Maria Basanta-Sanchez, Douglas B Kitchen, Kathleen McDonough, Paul F Agris
The emergence of multi-drug resistant bacteria necessitates identifying unique targets of intervention and compounds that inhibit their function. Gram-positive bacteria use a well-conserved tRNA-responsive transcriptional regulatory element in mRNAs, the T-box, to regulate transcription of multiple operons controlling amino acid metabolism. T-box regulatory elements are found only in the 5'UTR of mRNAs of Gram-positive bacteria, not Gram-negative bacteria or the human host. Using the structure of the 5'-untranslated sequence of the Bacillus subtilis tyrosyl-tRNA synthetase mRNA T-box as a model, in silico docking of 305,000 small compounds yielded initially 700 as potential binders that could inhibit the binding of the tRNA ligand...
February 1, 2019: ChemMedChem
Jakub Modranka, Jiahong Li, Anastasia Parchina, Michiel Vanmeert, Shrinivas Dumbre, Mayla Salman, Hannu Myllykallio, Hubert F Becker, Roeland Vanhoutte, Lia Margamuljana, Hoai Nguyen, Rania Abu El Asrar, Jef Rozenski, Piet Herdewijn, Steven Dejonghe, Eveline Lescrinier
Since the discovery of a flavin-dependent thymidylate synthase (ThyX or FDTS), that is absent in humans but crucial for DNA biosynthesis in a diverse group of pathogens, the enzyme has been pursued for the development of new antibacterial agents against Mycobacterium tuberculosis, the causative agent of the widespread infectious disease tuberculosis (TB). In response to a growing need for more effective anti-TB drugs, we have built upon our previous screening efforts and report here an optimization campaign of a novel series of inhibitors with a unique inhibition profile...
January 31, 2019: ChemMedChem
Adhan Pilon, Julia Lorenzo, Sergi Rodriguez-Calado, Pedro Adão, Ana M Martins, Andreia Valente, Luis G Alves
New cyclam derivatives (HOCH2CH2CH2)2(PhCH2)2Cyclam and (HOCH2CH2CH2)2(4-CF3PhCH2)2Cyclam as well as their Cu(II) and Fe(III) complexes were synthesised and characterized and their stability in cellular media was assessed. The cytotoxic effect of all the compounds was examined on human cervical cancer cells (HeLa) revealing strong anticancer activity. After 24 h, only complexes bearing the (HOCH2CH2CH2)2(4-CF3PhCH2)2Cyclam ligand are cytotoxic, while at 72 h incubation all the compounds show significant antiproliferative effects...
January 29, 2019: ChemMedChem
Thuy Van Lam van, Teodora Ivanova, Kornelia Hardes, Miriam Ruth Heindl, Rory E Morty, Eva Böttcher-Friebertshäuser, Iris Lindberg, Manuel E Than, Sven O Dahms, Torsten Steinmetzer
The activation of viral glycoproteins by the host protease furin is an essential step in the replication of numerous pathogenic viruses. Thus, effective inhibitors of furin could serve as broad-spectrum antiviral drugs. A crystal structure of an inhibitory hexapeptide derivative in complex with furin served as template for the rational design of various types of new cyclic inhibitors. Most of the prepared derivatives are relatively potent furin inhibitors with inhibition constants in the low nanomolar or even subnanomolar range...
January 25, 2019: ChemMedChem
Gerhard Klebe
The incorporation of diamondoid amino acids (DAAs) into peptide-like drugs is a general strategy to improve lipophilicity, membrane permeability and metabolic stability of peptidomimetic pharmaceuticals. We designed and synthesized five novel peptidic DAA-containing kinase inhibitors of protein kinase A using a sophisticated molecular dynamics protocol and solid phase peptide synthesis. By means of a thermophoresis binding assay, NMR, and crystal structure analysis, we determined the influence of the DAAs on the secondary structure and binding affinity in comparison to the native protein kinase inhibitor, which is purely composed of proteinogenic amino acids...
January 24, 2019: ChemMedChem
Phillip L van der Peet, Saman Sandanayake, Bevyn Jarrott, Spencer John Williams
We previously reported that a lipophilic derivative (1) of the voltage-gated sodium channel blocker mexiletine, prepared by coupling di-tert-butyl-phenol to mexiletine via a linker, was a more potent sodium channel blocker in vitro and in vivo. We demonstrate that replacing the methylethylene linker between the amine and di-tert-butyl-phenol with an achiral propylene linker (to give (2)) maintains potency in vitro. We synthesised 25 analogues bearing the propylene linker and found that minor structural changes resulted in pronounced changes in state dependence of blocking human NaV 1...
January 24, 2019: ChemMedChem
Ganna Petruk, Daria Maria Monti, Giarita Ferraro, Andrea Pica, Luigi D'Elia, Francesca Pane, Angela Amoresano, Julien Furrer, Konrad Kowalski, Antonello Merlino
The effects of the encapsulation of the cytotoxic dinuclear trithiolato-bridged arene Ru complex [(η6-p-MeC6H4Pri)2Ru2(μ2-S-p-C6H4But)3]Cl (DiRu-1) within the apoferritin (AFt) nanocage were investigated. The DiRu-1-AFt nanocarrier was characterized by UV-Vis spectroscopy, ICP MS, CD and X-ray crystallography. In contrast to previously reported Au- and Pt- based drug-loaded AFt carriers, no direct interactions between DiRu-1 and AFt were evidenced. DiRu-1-AFt is cytotoxic towards immortalized murine fibroblast BALB/c-3T3 transformed with SV40 virus (SVT2) and human epidermoid carcinoma A431 malignant cells and exhibits a moderate selectivity for these cancer cells over the normal BALB/c-3T3 cells...
January 23, 2019: ChemMedChem
Matthew J Belousoff, Hari Venugopal, Alexander Wright, Samuel Senoner, Isabella Stuart, Christopher Stubenrauch, Rebecca S Bamert, David W Lupton, Trevor Lithgow
While the ribosome is a common target for antibiotics challenges with crystallography can impede the development of new bioactives using structure based drug design approaches. Herein we exploit common structural features present in linezolid-resistant forms of both methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) to redesign the antibiotic. Enabled by rapid and facile cryoEM structures this process has identified LZD-5 and LZD-6, which inhibit the ribosomal function and growth of linezolid-resistant MRSA and VRE...
January 22, 2019: ChemMedChem
Marcel Karl Walter Mackwitz, Eva Hesping, Yevgeniya Antonova-Koch, Daniela Diedrich, Tamirat Gebru, Tina Skinner-Adams, Mary Clarke, Andrea Schöler, Laura Limbach, Thomas Kurz, Elizabeth Ann Winzeler, Jana Held, Katherine Andrews, Finn Kristian Hansen
Novel malaria intervention strategies are of great importance due to the development of drug resistance in malaria endemic countries. In this regard, histone deacetylases (HDACs) have emerged as new and promising malaria drug targets. In this work, we present the design, synthesis and biological evaluation of 20 novel HDAC inhibitors with antiplasmodial activity. Based on a previously discovered peptoid-based hit compound, we modified all regions of the peptoid scaffold by utilizing a one-pot multicomponent pathway and submonomer routes to gain a deeper understanding of the structure-activity as well as structure-toxicity relationships...
January 21, 2019: ChemMedChem
Michela Cerone, Elisa Uliassi, Federica Prati, Godwin U Ebiloma, Leandro Lemgruber, Christian Bergamini, David G Watson, Thais de A M Ferreira, Gabriella Simões Heyn Roth Cardoso, Luiz A Soares Romeiro, Harry P de Koning, Maria Laura Bolognesi
In a search for effective and sustainable treatments for trypanosomiasis, we developed a library of hybrid compounds by merging the structural features of a previously synthesized quinone hit (4) with those of long-chain phenolic constituents from cashew nut shell liquid (CNSL). CNSL is an agro-waste product from cashew nut processing factories with great potential as a precursor for the production of drugs. The synthesized compounds were tested against Trypanosoma brucei brucei, including three multi-drug resistant strains (B48, ISMR1, and aqp2/aqp3-KO), T...
January 21, 2019: ChemMedChem
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