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Bhupinder Kumar, Mohit Kumar, Ashish Ranjan Dwivedi, Vinod Kumar
Monoamine oxidase B (MAO-B) inhibitors are potential drug candidates for the treatment of various neurological disorders including Parkinson's disease. A total of 20 new propargyl-containing 2,4,6-trisubstituted pyrimidine derivatives were synthesized and screened for MAO inhibition using Amplex Red assays. All the synthesized compounds were found to be reversible and selective inhibitors of the MAO-B isoform at sub-micromolar concentrations. MVB3 was the most potent MAO-B inhibitor with an IC50 value of 0...
March 13, 2018: ChemMedChem
Christian Andreas Kuttruff, Margit Haile, Johannes Kraml, Christofer Siegfried Tautermann
Late Stage Functionalization (LSF) is a powerful method to quickly generate new analogs of a lead structure without resorting to de novo synthesis. We have leveraged Baran Diversinates to carry out late stage functionalizations on lead structures from internal drug discovery projects and accurately predicted regioselectivities using computational methods. Our functionalization successfully afforded specific regioisomers which were in line with our predictions. To enhance reactivity, reduce reaction time, and increase reaction yields we have developed new functionalization conditions involving Iron(III) catalysis...
March 13, 2018: ChemMedChem
Marvin Pollum, Minh Lam, Steffen Jockusch, Carlos E Crespo-Hernández
Sulfur-substituted nucleobases (i.e. thiobases) are a prospective class of compounds for clinical and cosmetic topical phototherapies. Recent investigations of several thiobases have revealed the ultrafast and efficient population of reactive triplet states upon UVA irradiation and the subsequent generation of singlet oxygen in high yield. In this contribution, we examine the photosensitizing activities of three of the most promising thiobase derivatives discovered to date, 2,4-dithiothymine, 2,4-dithiouracil, and 2,6-dithiopurine...
March 12, 2018: ChemMedChem
Bernhard Wünsch, Marina Szermerski, Frederik Börgel, Dirk Schepmann, Thomas Betzel, Simon Ametamey, Ahmed Haider
In order to analyze the NMDA receptor distribution in the central nervous system, fluorinated ligands selectively addressing the ifenprodil binding site of GluN2B subunit containing NMDA receptors were developed. Various strategies to introduce a fluorine atom into the potent GluN2B ligand 2 were pursued including the replacement of the benzylic OH moiety by a F-atom (13) and introduction of fluoroethoxy moieties at different positions (14, 17 18a-c). With respect to GluN2B affinity and selectivity over related receptors, the fluoroethoxy derivatives 14 and 18a represent the most promising ligands...
March 9, 2018: ChemMedChem
Stephanie Häfner, Finn Burg, Martina Kannler, Nicole Urban, Peter Mayer, Alexander Dietrich, Dirk Trauner, Johannes Broichhagen, Michael Schaefer
Natural products have many health benefits and their application can improve the quality of life. Recently, the diterpene (+) larixol and its acetylated congeners demonstrated a selective inhibition of the second messenger-gated cation channel transient receptor potential canonical 6 (TRPC6) over its close isoforms TRPC3 and TRPC7. Building on this knowledge, we expand these findings by chemical diversification of (+)-larixol mostly at position C6. Implementing High-Throughput Ca2+ FLIPR screening assays and electrophysiological patch-clamp recordings, we showcase larixyl N-methylcarbamate, dubbed SH045, as a compound with nanomolar affinity and a 13-fold subtype selectivity over TRPC3 in stably expressing HEK293 cells...
March 9, 2018: ChemMedChem
Bo Chen, Diego A Gianolio, James E Stefano, Charlene M Manning, Richard C Gregory, Michelle M Busch, William H Brondyk, Robert J Miller, Pradeep K Dhal
A series of novel multivalent drug linkers (MDLs) containing cytotoxic agents were synthesized and conjugated to antibodies to yield highly potent antibody-drug conjugates (ADCs) with drug/antibody ratios (DARs) higher than those typically reported in the literature (10 vs. ≈4). These MDLs contain two copies of a cytotoxic agent attached to biocompatible scaffolds composed of a branched peptide core and discrete polyethylene glycol (PEG) chains to enhance solubility and decrease aggregation. These drug linkers produced well-defined ADCs, whose DARs could be accurately determined by LC-MS...
March 8, 2018: ChemMedChem
Cheng-He Zhou, Ya-Nan Wang, Rammohan R Yadav Bheemanaboina, Wei-Wei Gao, Jie Kang, Gui-Xin Cai
A series of benzimidazole quinolone hybrids as new potential antimicrobial agents were designed and synthesized, and their bioactive assay indicated that some prepared compounds exhibited potent antibacterial and antifungal activities. Notably, 2-fluorobenzyl derivative 5b showed remarkable antimicrobial activities against the resistant P. aeruginosa and C. tropicalis isolated from infected patients. The active molecule 5b could not only rapidly kill the tested strains, but also exhibit low toxicity towards Hep-2 cells...
March 7, 2018: ChemMedChem
Ana Rita Duarte, Enrico Cadoni, Ana S Ressurreição, Rui Moreira, Alexandra Paulo
Guanine rich nucleic acid sequences able to form four-stranded structures (G-quadruplexes, G4) play key cellular regulatory roles and are considered as promising drug targets for anticancer therapy. Based on the organization of their structural elements, G4 ligands can be divided into three major families: 1) fused hetero-aromatic polycyclic systems; 2) macrocycles and 3) modular aromatic compounds. The design of modular G4 ligands emerged as the answer to achieve not only more drug-like compounds, but also more selective ligands by targeting G4 loops and grooves diversity...
March 7, 2018: ChemMedChem
Kayla M Pate, Brandon J Kim, Eric V Shusta, Regina M Murphy
β-amyloid (Aβ) aggregation is causally linked to neuronal pathology in Alzheimer's disease; therefore, several small molecules, antibodies, and peptides have been tested as anti-Aβ agents. We developed two compounds based on the Aβ-binding domain of transthyretin (TTR), a cyclic peptide cG8 and an engineered protein mTTR, and compared them for therapeutically relevant properties. Both mTTR and cG8 inhibit fibrillogenesis of Aβ, with mTTR inhibiting at a lower concentration than cG8. Both inhibit aggregation of amylin but not of α-synuclein...
March 7, 2018: ChemMedChem
Łukasz Joachimiak, Aleksandra Marchwicka, Edyta Gendaszewska-Darmach, Katarzyna M Błażewska
Rab geranylgeranyl transferase (RGGT) is an interesting therapeutic target, as it ensures proper functioning of Rab GTPases, a class of enzymes responsible for the regulation of vesicle trafficking. Relying on our previous studies, we synthesized a set of new α-phosphonocarboxylic acids as potential RGGT inhibitors, with emphasis on the elaboration of imidazole-containing analogues. We identified two compounds with activity similar to that of previously reported RGGT inhibitors, showing structural similarity to imidazo[1,2-a]pyridine-containing analogues in terms of their substitution pattern...
March 2, 2018: ChemMedChem
Weiyang Dai, Wenmin Chen, Bikash Debnath, Wu Yong, Nouri Neamati
Herein, we describe the synthesis and structure-activity relationship of 3-aminocyclohex-2-en-1-one derivatives as novel CXCR2 antagonists. Thirteen out of 44 derivatives inhibit CXCR2 down-stream signaling in a Tango assay specific for CXCR2 with IC50 values less than 10 µM. In silico ADMET prediction suggests that all active compounds possess drug-like properties. None of these compounds show cytotoxicity, suggesting their potential application in inflammatory mediated diseases. A structure-activity relationship (SAR) map has been generated to gain better understanding of their binding mechanism to guide further optimization of these new CXCR2 antagonists...
February 28, 2018: ChemMedChem
Hartmut Beck, Mario Jeske, Kai Thede, Friederike Stoll, Ingo Flamme, Metin Akbaba, Jens-Kerim Ergüden, Gunter Karig, Jörg Keldenich, Felix Oehme, Hans-Christian Militzer, Ingo V Hartung, Uwe Thuss
Small molecule inhibitors of hypoxia inducible factor prolyl hydroxylases (HIF-PHs) are currently under clinical development as novel treatment option for chronic kidney disease (CKD) associated anemia. Inhibition of HIF-PH mimics hypoxia and leads to increased EPO expression and subsequently increased erythropoiesis. Herein we describe the discovery, synthesis, SAR and proposed binding mode of novel 2,4-diheteroaryl-1,2-dihydro-3H-pyrazol-3-ones as orally bioavailable HIF-PH inhibitors for the treatment of anemia...
February 27, 2018: ChemMedChem
Harichandra D Tagad, Subrata Debnath, Victor Clausse, Mrinmoy Saha, Sharlyn Mazur, Ettore Appella, Daniel H Appella
The wild-type p53 induced phosphatase 1, Wip1 (PP2Cδ), is a PP2C family Ser/Thr phosphatase that negatively regulates the function of multiple proteins such as p53, ATM, Chk1, Chk2, Mdm2 and p38 MAPK involved in a DNA damage response. Wip1 dephosphorylates and inactivates its protein targets which are critical for cellular stress responses. Additionally, Wip1 frequently amplified and overexpressed in several human cancer types. Because of its negative role in regulating the function of essential proteins, Wip1 has been identified as a potential therapeutic target in various types of cancers...
February 23, 2018: ChemMedChem
Michael Przybylski
Alpha-galactosidase (αGal) is a lysosomal enzyme that hydrolyses the alphagalactosyl moiety from glycosphingo-lipids. Mutations in the αGal genes lead to defect enzyme resulting in substrate accumulation and pathophysiology. The deficiency of αGal, called Fabry's Disease (FD), belongs to the lysosomal storage diseases. Effective treatment of FD has been developed by enzyme replacement therapy (ERT) by infusion of recombinant enzyme to increase enzyme levels and reduce accumulated substrate. Immuno-reactivity and IgG antibody formation are major, therapy-limiting complications of ERT...
February 23, 2018: ChemMedChem
Paolo Coghi, Ivan A Yaremenko, Parichat Prommana, Peter S Radulov, Mikhail A Syroeshkin, Yu Jun Wu, Jia Ying Gao, Flora M Gordillo-Martinez, Simon Mok, Vincent K W Wong, Chairat Uthaipibull, Alexander O Terent'ev
Twenty six peroxides belonging to bridged 1,2,4,5-tetraoxanes, bridged 1,2,4-trioxolanes (ozonides), and tricyclic monoperoxides were evaluated for the in vitro antimalarial activity against Plasmodium falciparum (3D7) and for their cytotoxic activities against immortalized human normal fibroblast (CCD19Lu), liver (LO2) and lung (BEAS-2B) cell lines as well as human liver (HepG2) and lung (A549) cancer cell lines. Synthetic ozonides were shown to have highest cytotoxicity on HepG2 (IC50 0.19-0.59 µM) and some of these compounds selectively targeted liver cancer (SI for compounds 13a and 14a is 20 and 28 respectively), which in some cases were higher than that of paclitaxel, artemisinin, artesunic acid...
February 22, 2018: ChemMedChem
Alexander Zaykov, Vasily Gelfanov, Fa Liu, Richard Dennis DiMarchi, Richard Dennis DiMarchi
We report the synthesis and in vitro bioactivity assessment for an insulin-like peptide 5 (INSL5) analog that was recently discovered as a genetic mutation in an Amish population. The mutation was associated with improved metabolic status and receptor-based antagonism was proposed as a potential mechanism for the altered phenotype. We determined the specific peptide analog to be fully potent and of maximal efficacy at the human relaxin family peptide receptor 4 (RXFP-4), suggesting an alternative basis for the observed effect...
February 21, 2018: ChemMedChem
Marine Blanchet, Diane Borselli, Anne Rodallec, Franck Peiretti, Nicolas Vidal, Jean Michel Bolla, Carole Digiorgio, Kelly Morrison, William Wuest, Jean Michel Brunel
The emergence of multidrug resistant bacteria/pathogens has highlighted the need for the development of new antibiotics. In this manuscript, we report herein our results dealing with the broad spectrum of antibacterial activity against both sensitive and resistant Gram-negative and Gram-positive bacterial strains of an easily prepared water soluble polyaminosterol compound namely claramine A1. We will also demonstrate its peculiar mechanism of action (different from all the well-known classes of antibiotics) towards Gram-negative and Gram-positive bacteria...
February 21, 2018: ChemMedChem
Ádám Hadházi, Linghui Li, Benjamin Bailly, Andrea Maggioni, Gael Martin, Larissa Dirr, Jeffrey Dyason, Robin Thomson, George Gao, Anikó Borbás, Thomas Ve, Mauro Pascolutti, Mark von Itzstein
Influenza virus infection continues to cause significant, often severe, respiratory illness worldwide. A validated target for development of anti-influenza agents is the viral surface protein sialidase. In the current study, we have discovered a highly potent inhibitor of influenza virus sialidase, based on a novel sialosyl sulfonate template. The synthesised 3-guanidino sialosyl α-sulfonate, a sulfonozanamivir analogue, inhibits virus replication in vitro at a nanomolar level, comparable to that of anti-influenza drug zanamivir...
February 17, 2018: ChemMedChem
Ali Ates, Pierre Burssens, Olivier Lorthioir, Patrick Lo Brutto, Gwenael Dehon, Jean Keyaerts, Francis Coloretti, Lallemand Bénédicte, Verbois Valérie, Gillard Michel, Vermeiren Céline
In the present study, a novel chemical series of serotonin 5-HT7 antagonist is described. The synthesis, structure-activity relationships and selectivity profile are reported. This series includes 5-HT7 antagonists with unprecedented good selectivity for 5-HT7 receptor.
February 16, 2018: ChemMedChem
Mingcheng Qian, Lakshmi Vasudevan, Jelle Huysentruyt, Martijn D P Risseeuw, Christophe Stove, Patrick M L Vanderheyden, Kathleen Van Craenenbroeck, Serge Van Calenbergh
Nowadays, there is mounting evidence that intermolecular receptor-receptor interactions may result in altered receptor recognition, pharmacology and signaling. Heterobivalent ligands have been proven useful molecular probes for confirming and targeting heteromeric receptors. This paper describes the design and synthesis of novel heterobivalent ligands for dopamine D2-like receptors (D2-likeR) and the µ opioid receptor (µOR) and their evaluation using radioactive ligand binding and functional assays.
February 16, 2018: ChemMedChem
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