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ChemMedChem

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https://www.readbyqxmd.com/read/30430750/-18-f-labeled-derivatives-of-irbesartan-for-angiotensin-ii-receptor-pet-imaging
#1
Matthias Hoffmann, Xinyu Chen, Mitsuru Hirano, Kenji Arimitsu, Hiroyuki Kimura, Takahiro Higuchi, Michael Decker
The renin angiotensin aldosterone system (RAAS) is a hormonal cascade involved in the regulation of blood pressure and electrolyte balance, and represents a common target for the treatment of various diseases including hypertension, heart failure, and diabetes. Herein we present a novel 18 F-labeled derivative of the drug irbesartan, one of the most prescribed angiotensin II type 1 receptor (AT1 R) antagonists, for in vivo positron emission tomography (PET). This allows the in vivo measurement of AT1 R expression, and thus the evaluation of functional changes in its expression under pathophysiological conditions...
November 15, 2018: ChemMedChem
https://www.readbyqxmd.com/read/30430749/a-two-step-multicomponent-synthetic-approach-and-anti-inflammatory-evaluation-of-n-substituted-2-oxopyrazines
#2
Eduardo Hernández-Vázquez, Alejandra Chávez-Riveros, Antonio Nieto-Camacho, Luis D Miranda
Inflammation is widely reported as a main factor for the development of chronic diseases such as cancer, diabetes and even metabolic syndrome. Thus, the search for novel anti-inflammatory compounds is required. Herein, we describe the synthesis of a collection of peptidic pyrazinones by a convenient approach which involved a multicomponent isocyanide-based reaction followed by a tandem deprotection/oxidative cyclization step. The series was tested for its potential anti-inflammatory capacity in an in vivo murine model, where 4 compounds were identified that inhibited tetradecanoylphorbol acetate-induced (TPA) edema more than 75%...
November 14, 2018: ChemMedChem
https://www.readbyqxmd.com/read/30422389/assembly-of-fully-substituted-2h-indazoles-catalyzed-by-cu2o-rhombic-dodecahedra-and-evaluation-of-anti-cancer-activity
#3
Kaushik Chanda, Venkatraman Manickam, Rajeeva Lochana P
Simultaneous C-N, and N-N bond forming methods for the one-pot transformation are highly demanding in synthetic organic chemistry. In this report, we demonstrated the Cu2O rhombic dodecahedra catalyzed synthesis of 2H-indazoles with very good to excellent yields from readily available chemicals. This one-pot procedure involves the Cu2O nanoparticle catalyzed consecutive C-N, and N-N bond formation followed by the cyclization to obtain 2H-indazoles with broad substrate scope and high functional group tolerance...
November 13, 2018: ChemMedChem
https://www.readbyqxmd.com/read/30417561/recent-advances-in-the-design-and-development-of-nnrti-scaffolds
#4
Pouria Shirvani, Afshin Fassihi, Lotfollah Saghaei
The non-nucleoside reverse transcriptase inhibitors have been always as important part of combination therapy called highly active antiretroviral therapy (HAART) since 1996. About twenty-two years usage of NNRTIs led to some mutations in reverse transcriptase active site amino acids and consequently emerging drug-resistance viruses. Thus, looking for novel potent NNRTIs with improved safety profile and activity against drug-resistant strains is indispensable and lots of hit and lead NNRTIs have been discovered in the last decade...
November 12, 2018: ChemMedChem
https://www.readbyqxmd.com/read/30403833/design-synthesis-and-biological-evaluation-of-novel-polyaminocarboxylate-ligand-based-theranostic-conjugate-for-antibody-targeted-cancer-therapy-and-near-infrared-optical-imaging
#5
Hyun-Soon Chong
We report design, synthesis, and evaluation of polyaminocarboxylate ligand-based antibody conjugate for potential application in targeted cancer therapy and near infrared fluorescent imaging. We synthesized a new polyaminocarboxylate chelate (CAB-NE3TA) as a potential anti-cancer agent. CAB-NE3TA displayed potent inhibitory activities against different cancer cell lines. We then designed a multifunctional theranostic platform (CAB-NE3TA-PAN-IR800) constructed on an EGFR-targeted antibody (panitumumab, PAN) labeled with a near IR fluorescent dye...
November 7, 2018: ChemMedChem
https://www.readbyqxmd.com/read/30403831/discovery-of-new-cdk8-cycc-ligands-with-a-novel-virtual-screening-tool
#6
Wei Chen, Xiaodong Ren, Chia-En Chang
Selective inhibition of Cyclin-dependent kinase 8 and cyclin C (CDK8/CycC) has been suggested as a promising strategy for reducing mitogenic signals in cancer cells with reduced toxic effects on normal cells. We developed a novel virtual screening protocol for drug development and applied it to discovering new CDK8/CycC type II ligands, which is likely to achieve long residence time and specificity. We first analyzed binding thermodynamics of 11 published pyrazolourea ligands using molecular dynamics simulations and a free energy calculation method, VM2, and extracted the key binding information to assist virtual screening...
November 7, 2018: ChemMedChem
https://www.readbyqxmd.com/read/30394699/bacteria-hunt-bacteria-through-an-intriguing-cyclic-peptides
#7
Fernando Albericio, Shimaa A H Abdel Monaim, Anou M Somboro, Ayman El-Faham, Beatriz G de la Torre
In the last few decades, peptides have been victorious over small molecules as therapeutics due to their broad range of applications, high biological activity and high specificity. However, the main challenges to overcome if peptides are to become effective drugs is their low oral bioavailability and instability in physiological conditions. Cyclic peptides play a vital role in this context as they show higher stability under physiological conditions, higher membrane permeability, and greater oral bioavailability than their corresponding linear analogues...
November 5, 2018: ChemMedChem
https://www.readbyqxmd.com/read/30381909/in-vitro-anti-atherogenic-properties-of-n-heterocyclic-carbene-aurate-i-compounds
#8
Steven Patrick Nolan, Ronan Lordan, Eleni Soriki, Ioannis Zabetakis, Fady Nahra, Kristof Vanhecke
The anti-atherogenic (anti-inflammatory) properties of various aurate(I) salts, of the general formula [NHC·H][AuCl2] (NHC = N-heterocyclic carbene) have been investigated. The aurates are easily synthesized and obtained in analytically pure form. In addition, the biological activity of these compounds against atheromatosis via in vitro inhibition of platelet-activating factor (PAF) induced platelet aggregation was probed. All complexes were found to possess anti-aggregatory properties in vitro with [IPr*·H][AuCl2] 6 being the most potent inhibitor of PAF in micromolar concentration...
November 1, 2018: ChemMedChem
https://www.readbyqxmd.com/read/30380199/a-fluorescent-benzo-g-isoquinoline-based-hif-prolyl-hydroxylase-inhibitor-for-cellular-imaging
#9
Marleen Mayer, Kerstin Fey, Eva Heinze, Christian Rainer Wick, Martine I Abboud, Tzu-Lan Yeh, Anthony Tumber, Nicole Orth, Gunnar Schley, Björn Buchholz, Timothy Clark, Christopher J Schofield, Carsten Willam, Nicolai Burzlaff
Prolyl hydroxylation domain enzymes (PHD) catalyze the hydroxylation of the transcription factor Hypoxia Inducible Factor (HIF) and serve as cellular oxygen sensors. HIF and the PHD enzymes regulate numerous potentially tissue protective target genes which can adapt cells to metabolic and ischemic stress. We describe a fluorescent PHD inhibitor (1-chloro-4-hydroxybenzo[g]isoquinoline-3-carbonyl)-glycine which is suited to fluorescent based detection assays and for monitoring PHD inhibitors in biological systems...
October 31, 2018: ChemMedChem
https://www.readbyqxmd.com/read/30380198/the-role-of-bridging-water-and-hydrogen-bonding-as-key-determinants-of-non-covalent-protein-carbohydrate-recognition
#10
Anatoly Ruvinsky, Hans Matter
Mechanisms of protein-carbohydrate recognition attract a lot of interest due to their roles in various cellular processes and metabolism disorders. We have performed a large-scale analysis of protein structures solved in complex with glucose, galactose and their substituted analogs. We found that, on average, sugar molecules establish five hydrogen bonds (HBs) in the binding site, including one to two HBs with bridging water molecules. The free energy contribution of bridging and direct HBs was estimated using the free energy perturbation (FEP+) methodology for mono- and disaccharides that bind to L-ABP, ttGBP, TrmB, hGalectin-1 and hGalectin-3...
October 31, 2018: ChemMedChem
https://www.readbyqxmd.com/read/30380184/targeted-nanoswitchable-inhibitors-of-protein-protein-interactions-involved-in-apoptosis
#11
Laura Nevola, Monica Varese, Andrés Martín-Quirós, Giacomo Mari, Kay Eckelt, Pau Gorostiza, Ernest Giralt
Progress in drug delivery is hampered by the lack of efficient strategies to target drugs with high specificity and precise spatiotemporal regulation. The remote control of nanoparticles and drugs with light allows controlling their action site and dosage. Peptide-based drugs are very specific, non-immunogenic and can be designed to cross the plasma membrane. In order to combine target specificity and remote control of drug action, here we describe a versatile strategy based on a generalized template to design nanoswitchable peptides that modulate protein-protein interactions with light...
October 31, 2018: ChemMedChem
https://www.readbyqxmd.com/read/30378281/discovery-and-structure-activity-relationships-of-n-aryl-6-aminoquinoxalines-as-potent-pfkfb3-kinase-inhibitors
#12
Nicolas Boutard, Arkadiusz Białas, Aleksandra Sabiniarz, Paweł Guzik, Katarzyna Banaszak, Artur Biela, Marcin Bień, Anna Buda, Barbara Bugaj, Ewelina Cieluch, Anna Cierpich, Łukasz Dudek, Hans-Michael Eggenweiler, Joanna Fogt, Monika Gaik, Andrzej Gondela, Krzysztof Jakubiec, Mirek Jurzak, Agata Kitlińska, Piotr Kowalczyk, Maciej Kujawa, Katarzyna Kwiecińska, Marcin Leś, Ralph Lindemann, Monika Maciuszek, Maciej Mikulski, Paulina Niedziejko, Alicja Obara, Henryk Pawlik, Tomasz Rzymski, Magdalena Sieprawska-Lupa, Marta Sowińska, Joanna Szeremeta-Spisak, Agata Stachowicz, Mateusz M Tomczyk, Katarzyna Wiklik, Sylwia Ziemiańska, Łukasz Włoszczak, Adrian Zarębski, Krzysztof Brzózka, Mateusz Nowak, Charles-Henry Fabritius
Energy and biomass production in cancer cell is largely supported by aerobic glycolysis in what is called the "Warburg effect". The process is regulated by key enzymes among which phosphofructokinase PFK-2 plays a significant role by producing fructose-2,6-biphosphate, the most potent activator of the glycolysis rate limiting step performed by phosphofructokinase PFK-1. We report herein the synthesis, biological evaluation and structure-activity relationship of novel inhibitors of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), the ubiquitous and hypoxia-induced isoform of PFK-2...
October 30, 2018: ChemMedChem
https://www.readbyqxmd.com/read/30376607/identification-of-specific-and-non-specific-inhibitors-of-bacillus-anthracis-type-iii-pantothenate-kinase-pank
#13
Justin A Shapiro, John J Varga, Derek Parsonage, William Walton, Matthew R Redinbo, Larry J Ross, E Lucile White, Robert Bostwick, William M Wuest, Al Claiborne, Joanna B Goldberg
Antibiotics with novel mechanisms are desperately needed to combat increasing rates of multi-drug resistant infections. Bacterial pantothenate kinase has emerged as a target of interest to cut off the biosynthesis of coenzyme A. In this work we report the results of an in vitro high-throughput screen of over 10,000 small molecules against Bacillus anthracis pantothenate kinase, as well as a follow up screen of hits against PanK isolated from Pseudomonas aeruginosa and Burkholderia cenocepacia. Nine hits are structurally categorized and analysed to set the stage for future drug development...
October 30, 2018: ChemMedChem
https://www.readbyqxmd.com/read/30371024/designing-two-dimensional-nanosheets-for-improving-drug-delivery-to-fucose-receptor-overexpressing-cancer-cells
#14
Nitin Gupta, Ashok Kumar Jangid, Mandeep Singh, Deep Pooja Kulhari, Hitesh Kulhari
Targeted drug delivery has shown promises in improving the therapeutic efficacy of anticancer drugs. Gemcitabine hydrochloride (GEM) is a broad range chemotherapeutic agent for treating various cancers. However, systemic use of free GEM is restricted because of its poor physicochemical properties and non-specific drug delivery, resulting in dose dependent adverse effects. In this study, a fucose conjugated, graphene oxide-based smart, targeted nanocarrier system was designed to provide high loading, sustained release and targeted high concentration of GEM to cancer cells...
October 29, 2018: ChemMedChem
https://www.readbyqxmd.com/read/30370998/structure-activity-relationships-of-antiplasmodial-pantothenamide-analogs-reveal-a-new-way-by-which-triazoles-mimic-amide-bonds
#15
Jinming Guan, Erick T Tjhin, Vanessa M Howieson, Tanakorn Kittikool, Christina Spry, Kevin J Saliba, Karine Auclair
Pantothenamides are potent growth inhibitors of the malaria parasite Plasmodium falciparum. Their clinical use is, however, hindered due to the ubiquitous presence of pantetheinases in human serum, which rapidly degrade pantothenamides to pantothenate and the corresponding amine. We previously reported that replacement of the labile amide bond with a triazole ring not only imparts stability towards pantetheinases but also improves activity against P. falciparum. A small library of new triazole derivatives was synthesized and their use in establishing structure-activity relationships relevant to antiplasmodial activity of this family of compounds is discussed herein...
October 29, 2018: ChemMedChem
https://www.readbyqxmd.com/read/30362667/synthesis-of-a-series-of-non-symmetric-bispyridinium-and-related-compounds-and-their-affinity-characterization-at-the-nicotinic-acetylcholine-receptor
#16
Klaus Theodor Wanner, Sebastian Rappenglück, Sonja Sichler, Georg Höfner, Thomas Wein, Karin V Niessen, Thomas Seeger, Franz F Paintner, Franz Worek, Horst Thiermann
The current standard therapy to counteract organophosphate intoxications is not effective in equal measure against all types of organophosphorus compounds (OPCs) as the outcome of oxime induced reactivation of inactivated acetylcholinesterase (AChE) strongly depends on the particular OPC. In case the reactivation is insufficient, acetylcholine concentrations that rise to pathophysiological levels force the nicotinic acetylcholine receptor (nAChR) into a desensitized state and hence a functionally inactive state...
October 26, 2018: ChemMedChem
https://www.readbyqxmd.com/read/30359484/targeting-protein-kinase-ck1%C3%AE-with-riluzole-could-it-be-one-of-the-possible-missing-bricks-to-interpret-its-effect-in-the-treatment-of-als-from-a-molecular-point-of-view
#17
Maicol Bissaro, Stephanie Federico, Veronica Salmaso, Mattia Sturlese, Giampiero Spalluto, Stefano Moro
Riluzole, approved by FDA in 1995, is the most widespread oral treatment for the fatal neurodegenerative disorder amyotrophic lateral sclerosis (ALS). The drug, which mechanism of action is still obscure, mitigate ill progression with, unfortunately, a limited survival improvement. In the present work, for the first time, it has been demonstrated, using synergistically computational and in vitro studies, that riluzole is an ATP competitive inhibitor of the protein kinase CK1 isoform δ, with an IC50 value of 16...
October 25, 2018: ChemMedChem
https://www.readbyqxmd.com/read/30358105/an-investigation-into-rigidity-activity-relationships-in-bisqac-amphiphilic-antiseptics
#18
Renee C Kontos, Stephanie A Schallenhammer, Brian S Bentley, Kelly R Morrison, Javier A Feliciano, Julia A Tasca, Anna R Kaplan, Mark W Bezpalko, Scott W Kassel, William M Wuest, Kevin P C Minbiole
Twenty-one mono- and biscationic quaternary ammonium amphiphiles (monoQACs and bisQACs) were rapidly prepared in order to investigate the effects of rigidity of a diamine core structure on antiseptic activity. As anticipated, bioactivity against a panel of 6 bacteria including MRSA strains was strong for bisQAC structures, and clearly correlated to the length of non-polar side chains. Modest advantages were noted for amide-containing side chains, as compared to straight-chained alkyl substituents. Surprisingly, antiseptics with more rigidly disposed side chains, such as those in DABCO-12,12, showed the highest level of antimicrobial activity, with single-digit MIC values or better against the entire bacterial panel, including submicromolar activity against a MRSA strain...
October 25, 2018: ChemMedChem
https://www.readbyqxmd.com/read/30358124/antimicrobial-and-antibiofilm-activity-of-disubstituted-bis-benzimidazolium-salts
#19
Andreea R Schmitzer, Jérémie Tessier, Margaux Lecluse, Julien Gravel
The increased prevalence of antibiotic-resistant bacteria is a critical issue for human health. Developing new antibiotic agents is vital in fighting persistent infections and lowering mortality rates. In this study, we designed lutidine-disubstituted bis-benzimidazolium salts (lutidine-bis-benzimidazolium core with octyl, adamantyl, and cholesteryl lipophilic side chains), and tested their antimicrobial activity, their capacity to inhibit planktonic bacterial and fungal growth, and their ability to inhibit the formation of or disrupt mature methicillin-resistant Staphylococcus aureus (MRSA) biofilms...
October 24, 2018: ChemMedChem
https://www.readbyqxmd.com/read/30358112/orally-effective-aminoalkyl-10h-indolo-3-2-b-quinoline-11-carboxamide-kills-the-malaria-parasite-by-inhibiting-host-hemoglobin-uptake
#20
Sandip Bibishan Bharate, Ramesh Mudududdla, Dinesh Mohanakrishnan, Sonali S Bharate, Ram A Vishwakarma, Dinkar Sahal
A series of indolo[3,2-b]quinoline-C11-carboxamides were synthesized by incorporation of amino-alkyl side chains into the core of indolo[3,2-b]quinoline-C11-carboxylic acid. Their in vitro antiplasmodial evaluation against Plasmodium falciparum has led to the identification of 2-(piperidin-1-yl)ethanamine linked analog [2-bromo-N-(2-(piperidin-1-yl)ethyl)-10H-indolo[3,2-b]quinoline-11-carboxamide, 3g] (IC50 1.3 µM) as the most promising compound exhibiting good selectivity-indices against mammalian cell lines...
October 24, 2018: ChemMedChem
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