3,200 results match your criteria ChemMedChem[Journal]


Synthesis of antiviral perfluoroalkyl derivatives of teicoplanin and vancomycin.

ChemMedChem 2020 Jul 11. Epub 2020 Jul 11.

Debreceni Egyetem, Pharmaceutical Chemistry, HUNGARY.

The limited scope of antiviral drugs and increasing problem of antiviral drug resistance represent a global health threat. Glycopeptide antibiotics and their lipophilic derivatives have emerged as relevant inhibitors of diverse viruses. Here, we describe a new strategy for the synthesis of dual hydrophobic and lipophobic derivatives of glycopeptides, to produce selective antiviral agents without membrane-disrupting activity. Read More

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http://dx.doi.org/10.1002/cmdc.202000260DOI Listing

Radiolabelled CCK2R antagonists containing PEG linkers: design, synthesis and evaluation.

ChemMedChem 2020 Jul 9. Epub 2020 Jul 9.

Kemijski institut, NMR centre, SLOVENIA.

The cholecystokinin-2/gastrin receptor (CCK2R) is considered a suitable target for the development of radiolabelled antagonists, due to its overexpression in various tumours, but no such compounds are available in clinical use. Therefore, we designed novel 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid conjugated ligands based on CCK2R antagonist Z360/nastorazepide. As a proof of concept that CCK2R antagonistic activity can be retained by extending Z360/nastorazepide structure using suitable linker, herein we present three compounds containing various PEG linkers synthesized on solid phase and in solution. Read More

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http://dx.doi.org/10.1002/cmdc.202000392DOI Listing

Phospholipid Cyclosporine Prodrugs Targeted at Inflammatory Bowel Disease (IBD) Treatment: Design, Synthesis, and In Vitro Validation.

ChemMedChem 2020 Jul 2. Epub 2020 Jul 2.

University of Florida, Department of Chemistry, P.O. Box 11720, 32611, Gainesville, UNITED STATES.

Novel phospholipid (PL)-cyclosporine conjugates, were prepared and studied as potential prodrugs for IBD. Our approach relies on Phospholipase A 2 (PLA 2 ), which is overexpressed in the inflamed intestinal tissues, as the prodrug-activator to potentially release cyclosporine at the site of inflammation. PL-cyclosporine prodrug conjugates with varying methylene linker lengths between the sn-2 position of the PL and cyclosporine were synthesized and evaluated for in vitro activation. Read More

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http://dx.doi.org/10.1002/cmdc.202000317DOI Listing

A Dual Inhibitor of DYRK1A and GSK3β for β-Cell Proliferation: Aminopyrazine Derivative GNF4877.

ChemMedChem 2020 Jul 2. Epub 2020 Jul 2.

Genomics Institute of the Novartis Research Foundation (GNF), 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA.

Loss of β-cell mass and function can lead to insufficient insulin levels and ultimately to hyperglycemia and diabetes mellitus. The mainstream treatment approach involves regulation of insulin levels; however, approaches intended to increase β-cell mass are less developed. Promoting β-cell proliferation with low-molecular-weight inhibitors of dual-specificity tyrosine-regulated kinase 1A (DYRK1A) offers the potential to treat diabetes with oral therapies by restoring β-cell mass, insulin content and glycemic control. Read More

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http://dx.doi.org/10.1002/cmdc.202000183DOI Listing
July 2020
2.968 Impact Factor

First-Generation Bispidine Chelators for Bi Radiopharmaceutical Applications.

ChemMedChem 2020 Jul 2. Epub 2020 Jul 2.

Universität Heidelberg, Anorganisch-Chemisches Institut, Neuenheimer Feld 270, 69120, Heidelberg, Germany.

Hepta- and octadentate bispidines (3,7-diazabicyclo[3.3.1]nonane, diaza-adamantane) with acetate, methyl-pyridine, and methyl-picolinate pendant groups at the amine donors of the bispidine platform have been prepared and used to investigate Bi coordination chemistry. Read More

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http://dx.doi.org/10.1002/cmdc.202000361DOI Listing

1-[4-(morpholin-4-yl)phenyl]-5-phenylpenta-2,4-dien-1-one as a new potent and selective monoamine oxidase-B inhibitor with extended conjugation in chalcone framework.

Authors:
Bijo Mathew

ChemMedChem 2020 Jun 25. Epub 2020 Jun 25.

Ahalia School of Pharmacy, Pharmaceutical Chemistry, Kozhippara, 678557, Palakkad, INDIA.

The general blueprint of the design of monoamine oxidase-B (MAO-B) inhibitor has been based on two phenyl or hetero nucleus linked via proper length spacer. In this study, 1-[4-(morpholin-4-yl)phenyl]-5-phenylpenta-2,4-dien-1-one ( MO10 ) was prepared by the condensation of 4'-morpholinoacetophenone and cinnamaldehyde in the presence of basic alcoholic medium . The title compound MO10 was assessed for inhibitory activities against two human MAO isoforms, i. Read More

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http://dx.doi.org/10.1002/cmdc.202000305DOI Listing

Rationally Designed Polypharmacology: α-Helix Mimetics as Dual Inhibitors of the Oncoproteins Mcl-1 and HDM2.

ChemMedChem 2020 Jun 25. Epub 2020 Jun 25.

Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD, 21201, USA.

Protein-protein interactions (PPIs), many of which are dominated by α-helical recognition domains, play key roles in many essential cellular processes, and the dysregulation of these interactions can cause detrimental effects. For instance, aberrant PPIs involving the Bcl-2 protein family can lead to several diseases including cancer, neurodegenerative diseases, and diabetes. Interactions between Bcl-2 pro-life proteins, such as Mcl-1, and pro-death proteins, such as Bim, regulate the intrinsic pathway of apoptosis. Read More

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http://dx.doi.org/10.1002/cmdc.202000278DOI Listing

Functionalized Cannabinoid Subtype 2 Receptor Ligands: Fluorescent, PET, Photochromic and Covalent Molecular Probes.

ChemMedChem 2020 Jun 24. Epub 2020 Jun 24.

Pharmaceutical and Medicinal Chemistry Institute of Pharmacy and Food Chemistry, Julius Maximilian University of Würzburg, Am Hubland, 97074, Würzburg, Germany.

Cannabinoid subtype 2 receptors (CB Rs) are G protein-coupled receptors (GPCRs) belonging to the endocannabinoid system, a complex network of signalling pathways leading to the regulation of key physiological processes. Interestingly, CB Rs are strongly up-regulated in pathological conditions correlated with the onset of inflammatory events like cancer and neurodegenerative diseases. Therefore, CB Rs represent an important biological target for therapeutic as well as diagnostic purposes. Read More

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http://dx.doi.org/10.1002/cmdc.202000298DOI Listing

Peptidyl Vinyl Ketone Irreversible Inhibitors of Rhodesain: Modifications of the P2 Fragment.

ChemMedChem 2020 Jun 21. Epub 2020 Jun 21.

Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Annunziata, 98168, Messina, Italy.

In this paper, we report the design, synthesis and biological investigation of a series of peptidyl vinyl ketones obtained by modifying the P2 fragment of previously reported highly potent inhibitors of rhodesain, the main cysteine protease of Trypanosoma brucei rhodesiense. Investigation of the structure-activity relationship led us to identify new rhodesain inhibitors endowed with an improved selectivity profile (a selectivity index of up to 22 000 towards the target enzyme), and/or an improved antitrypanosomal activity in the sub-micromolar range. Read More

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http://dx.doi.org/10.1002/cmdc.202000360DOI Listing

Short Photoswitchable Antibacterial Peptides.

ChemMedChem 2020 Jun 17. Epub 2020 Jun 17.

Institute of Photonics and Advanced Sensing (IPAS) School of Physical Sciences, The University of Adelaide, North Terrace, Adelaide, SA 5005, Australia.

Three photoswitchable tetrapeptides, based on a known synthetic antibacterial, were designed and synthesized to determine activity against Staphylococcus aureus. Each peptide contains an azobenzene photoswitch incorporated into either the N-terminal side chain (1), C-terminal side chain (2), or the C-terminus (3) to allow reversible switching between cis- and trans-enriched photostationary states. Biological assays revealed that the C-terminus azobenzene (3) possessed the most potent antibacterial activity, with an MIC of 1 μg/mL. Read More

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http://dx.doi.org/10.1002/cmdc.202000280DOI Listing

Controlling PROTACs with Light.

ChemMedChem 2020 Jun 17. Epub 2020 Jun 17.

Department of Chemistry, Indian Institute of Science Education and Research Bhopal, Bhopal Bypass Road, Bhauri, Bhopal, 462066, MP, India.

Proteolysis targeting chimeras, PROTACs, are emerging as a powerful strategy for exerting exogenous control over protein levels, allowing small molecules to exploit the ubiquitin-proteasome pathway for targeted protein degradation. This highlight focuses on the fusion of photochemistry with these bifunctional compounds, which has provided a novel pathway for spatiotemporally tuning the activation of PROTACs in the form of their photocaged and photoswitchable versions. Photocaged PROTACs consist of a hindered optolabile group that detaches only upon irradiation at a specific wavelength, releasing the active PROTAC. Read More

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http://dx.doi.org/10.1002/cmdc.202000249DOI Listing

Discovery of an Orally Active and Long-Acting DPP-IV Inhibitor through Property-Based Optimization with an in Silico Biotransformation Prediction Tool.

ChemMedChem 2020 Jun 17. Epub 2020 Jun 17.

Department of Pharmacy, The First Affiliated Hospital of Guangzhou Medical University, 151 Yanjiang Road, 510120, Guangzhou, P. R. China.

Long-acting dipeptidyl peptidase IV inhibitors have emerged as promising molecules for interventions for type 2 diabetes. Once weekly dosing brings greater patient compliance and more stable glycemic control. Starting from our previous highly potent compound with a thienoprimidine scaffold, which is unfortunately severely hit by hepatic biotransformation, a lead compound was rapidly generated by drawing on the experience of our previously discovered long-acting compounds with pyrrolopyrimidine scaffold. Read More

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http://dx.doi.org/10.1002/cmdc.202000175DOI Listing

Synthesis of N-Aryl- and N-alkyl-Substituted Imidazolium Silver Complexes: Cytotoxic Screening by Using Human Cell Lines Modelling Acute Myeloid Leukaemia.

ChemMedChem 2020 Jun 17. Epub 2020 Jun 17.

Department of Chemistry, University of Bergen, Allégaten 41, 5007, Bergen, Norway.

A series of N-aryl- and N-alkyl substituted imidazoles has been synthesised and complexed with Ag to obtain silver-NHC complexes of the form [Ag(NHC) ]X. These silver-NHC complexes were tested in vitro against the human cell lines HL-60 and MOLM-13, which both model acute myeloid leukaemia (AML). A substantial difference in cytotoxicity was revealed varying in the range 13-4 μM and 22-9 μM for HL-60 and MOLM-13, respectively. Read More

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http://dx.doi.org/10.1002/cmdc.202000138DOI Listing

Exploring Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) Autoproteolysis Process by Molecular Simulations: Hints for Drug Design.

ChemMedChem 2020 Jun 17. Epub 2020 Jun 17.

Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via L. Mangiagalli 25, 20133, Milano, Italy.

Proprotein convertase subtilisin/kexin 9 (PCSK9) is a notable target for the treatment of hypercholesterolemia because it regulates the population of the low-density lipoprotein receptor (LDLR) on liver cells. The PCSK9 zymogen is a serine protease that spontaneously undergoes a double self-cleavage step. Available X-ray structures depict the PCSK9 mature state, but the atomic details of the zymogen state of the enzyme are still unknown. Read More

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http://dx.doi.org/10.1002/cmdc.202000431DOI Listing

Evaluation of 5H-Thiazolo[3,2-α]pyrimidin-5-ones as Potential GluN2A PET Tracers.

ChemMedChem 2020 Jun 16. Epub 2020 Jun 16.

Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Fabrikstrasse 2, 4056, Basel, Switzerland.

We describe here our efforts to develop a PET tracer for imaging GluN2A-containing NMDA receptors, based on a 5H-thiazolo[3,2-α]pyrimidin-5-one scaffold. The metabolic stability and overall properties could be optimized satisfactorily, although binding affinities remained a limiting factor for in vivo imaging. We nevertheless identified 7-(((2-fluoroethyl)(3-fluorophenyl)amino)-methyl)-3-(2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo-[3,2-α]pyrimidin-5-one ([ F]7b) as a radioligand providing good-quality images in autoradiographic studies, as well as a tritiated derivative, 2-(7-(((2-fluoroethyl)(4-fluorophenyl)amino)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-α]pyrimidin-3-yl)cyclopropane-1-carbonitrile ([ H ]15b), which was used for the successful development of a radioligand binding assay. Read More

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http://dx.doi.org/10.1002/cmdc.202000340DOI Listing

Potential Dental Biofilm Inhibitors: Dynamic Combinatorial Chemistry Affords Sugar-Based Molecules that Target Bacterial Glucosyltransferase.

ChemMedChem 2020 Jun 16. Epub 2020 Jun 16.

Department of Drug Design and Optimization Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), Campus Building E8.1, 66123, Saarbrücken, Germany.

We applied dynamic combinatorial chemistry (DCC) to find novel ligands of the bacterial virulence factor glucosyltransferase (GTF) 180. GTFs are the major producers of extracellular polysaccharides, which are important factors in the initiation and development of cariogenic dental biofilms. Following a structure-based strategy, we designed a series of 36 glucose- and maltose-based acylhydrazones as substrate mimics. Read More

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http://dx.doi.org/10.1002/cmdc.202000222DOI Listing
June 2020
2.968 Impact Factor

Macrocyclic Iminopeptides Diversify To Better Target Proteins.

ChemMedChem 2020 Jul 15;15(13):1111-1112. Epub 2020 Jun 15.

Faculty of Chemistry, University of Havana, Zapata y G, Havana, 10400, Cuba.

Among the many methods available for accessing conformationally diverse cyclic peptides, the derivatization of macrocyclic iminopeptides has remained notably underexplored. Now, a relevant complexity-generating method expands the repertoire of synthetic strategies exploiting the reactivity of an imino bond embedded in the cyclic peptide skeleton. Here we highlight a recent report describing the on-resin construction of a new family of macrocyclic peptide/natural product-inspired hybrids, namely "PepNats", by derivatization of cyclic iminopeptides through 1,3-cycloaddition reactions. Read More

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http://dx.doi.org/10.1002/cmdc.202000261DOI Listing

Surface Modification of Luminescent Ln Fluoride Core-Shell Nanoparticles with Acetylsalicylic acid (Aspirin): Synthesis, Spectroscopic and in Vitro Hemocompatibility Studies.

ChemMedChem 2020 Jun 8. Epub 2020 Jun 8.

Department of Rare Earths, Faculty of Chemistry, Adam Mickiewicz University, Uniwersytetu Poznańskiego 8, 61-614, Poznań, Poland.

Luminescent lanthanide fluoride core-shell (LaF :Tb ,Ce @SiO -NH ) nanoparticles, with acetylsalicylic acid (aspirin) coated on the surface have been obtained. The synthesized products, which combine the potential located in the silica shell with the luminescent activity of the core, were characterized in detail with the use of luminescence spectroscopy, Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), and transmission electron microscopy (TEM) methods. The in vitro effects of the modified luminescent nanoparticles on human red blood cell (RBC) membrane permeability, RBC shape, and sedimentation rate were investigated to assess the hemocompatibility of the obtained compounds. Read More

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http://dx.doi.org/10.1002/cmdc.202000269DOI Listing

Structure-Based Macrocyclization of Substrate Analogue NS2B-NS3 Protease Inhibitors of Zika, West Nile and Dengue viruses.

ChemMedChem 2020 Jun 5. Epub 2020 Jun 5.

Institute of Pharmaceutical Chemistry, Philipps University, Marbacher Weg 6, 35032, Marburg, Germany.

A series of cyclic active-site-directed inhibitors of the NS2B-NS3 proteases from Zika (ZIKV), West Nile (WNV), and dengue-4 (DENV4) viruses has been designed. The most potent compounds contain a reversely incorporated d-lysine residue in the P1 position. Its side chain is connected to the P2 backbone, its α-amino group is converted into a guanidine to interact with the conserved Asp129 side chain in the S1 pocket, and its C terminus is connected to the P3 residue via different linker segments. Read More

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http://dx.doi.org/10.1002/cmdc.202000237DOI Listing

Expanding the Spectrum of Antibiotics Capable of Killing Multidrug-Resistant Staphylococcus aureus and Pseudomonas aeruginosa.

ChemMedChem 2020 Jun 4. Epub 2020 Jun 4.

Department of Chemistry and Biochemistry, University of Oklahoma, 101 Stephenson Parkway, Norman, OK 73019, USA.

Infections from antibiotic-resistant Staphylococcus aureus and Pseudomonas aeruginosa are a serious threat because reduced antibiotic efficacy complicates treatment decisions and prolongs the disease state in many patients. To expand the arsenal of treatments against antimicrobial-resistant (AMR) pathogens, 600-Da branched polyethylenimine (BPEI) can overcome antibiotic resistance mechanisms and potentiate β-lactam antibiotics against Gram-positive bacteria. BPEI binds cell-wall teichoic acids and disables resistance factors from penicillin binding proteins PBP2a and PBP4. Read More

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http://dx.doi.org/10.1002/cmdc.202000239DOI Listing

Synthesis of Tetramic Acid Fragments Derived from Vancoresmycin Showing Inhibitory Effects towards S. aureus.

ChemMedChem 2020 Jun 4. Epub 2020 Jun 4.

Kekulé-Institut für Organische Chemie und Biochemie, Rheinische Friedrich-Wilhelms-Universität Bonn, Gerhard-Domagk-Str. 1, 53121, Bonn, Germany.

An efficient route to various vancoresmycin-type tetramic acids has been developed. The modular route is based on an effective Fries-type rearrangement to introduce various appending acetyl residues. The minimum inhibitory concentration (MIC) values of the new tetramic acids against Staphylococcus aureus and Escherichia coli were determined, revealing that three of the new compounds exhibit antimicrobial activity against S. Read More

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http://dx.doi.org/10.1002/cmdc.202000241DOI Listing

Design, Synthesis, Radiosynthesis and Biological Evaluation of Fenretinide Analogues as Anticancer and Metabolic Syndrome-Preventive Agents.

ChemMedChem 2020 Jun 4. Epub 2020 Jun 4.

Institute of Medical Sciences, University of Aberdeen, Aberdeen, AB25 2ZD, UK.

Fenretinide (4-HPR) is a synthetic derivative of all-trans-retinoic acid (ATRA) characterised by improved therapeutic properties and toxicological profile relative to ATRA. 4-HPR has been mostly investigated as an anti-cancer agent, but recent studies showed its promising therapeutic potential for preventing metabolic syndrome. Several biological targets are involved in 4-HPR's activity, leading to the potential use of this molecule for treating different pathologies. Read More

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http://dx.doi.org/10.1002/cmdc.202000143DOI Listing

O-GlcNAcase: Emerging Mechanism, Substrate Recognition and Small-Molecule Inhibitors.

ChemMedChem 2020 Jun 4. Epub 2020 Jun 4.

Center for Neuro-Medicine Brain Science Institute, Korea Institutes of Science and Technology, Seoul, 02792 (Republic of, Korea.

O-GlcNAcylation is the dynamic and ubiquitous post-translational glycosylation of nucleocytoplasmic proteins on serine/threonine residues; it is implicated in regulation of the cell cycle. This protein modification is mainly governed by a pair of enzymes: O-GlcNAc transferase (OGT) adds the N-acetylglucosamine moiety to acceptor proteins, and O-GlcNAcase (OGA) hydrolyses the sugar moiety from protein acceptors. Irregular O-GlcNAcylation is linked to several diseases including cancer, diabetes and neurodegeneration. Read More

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http://dx.doi.org/10.1002/cmdc.202000077DOI Listing

Enantiomerically Pure Quinoline-Based κ-Opioid Receptor Agonists: Chemoenzymatic Synthesis and Pharmacological Evaluation.

ChemMedChem 2020 Jun 3. Epub 2020 Jun 3.

Institut für Pharmazeutische und Medizinische Chemie der Universität Münster, Corrensstraße 48, 48149, Münster, Germany.

Racemic -opioid receptor (KOR) agonist 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aSR)-8-(pyrrolidin-1-yl)-3,4,4a,5,6,7,8,8a-octahydroquinolin-1(2H)-yl]ethan-1-one ((±)-4) was prepared in a diastereoselective synthesis. The first key step of the synthesis was the diastereoselective hydrogenation of the silyl ether of 1,2,3,4-tetrahydroquinoin-8-ol ((±)-9) to afford cis,cis-configured perhydroquinoline derivative (±)-10. Removal of the TBDMS protecting group led to a β-aminoalcohol that reacted with SO Cl to form an oxathiazolidine. Read More

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http://dx.doi.org/10.1002/cmdc.202000300DOI Listing
June 2020
2.968 Impact Factor

Platinum(II) Complexes Bearing Triphenylphosphine and Chelating Oximes: Antiproliferative Effect and Biological Profile in Resistant Cells.

ChemMedChem 2020 Jun 3. Epub 2020 Jun 3.

Department of Pharmaceutical and Pharmacological Sciences, Università di Padova, Via F. Marzolo, 5, 35131, Padova, Italy.

Platinum(II) complexes of the type [Pt(Cl)(PPh ){(κ -N,O)-(1{C(R)=N(OH)-2(O)C H })}] with R=Me, H, (1 and 2) were synthesized and characterized. Single-crystal X-ray diffraction confirmed the proposed (SP4-3) configuration for 1. Study of the antiproliferative activity, performed on a panel of human tumor cell lines and on mesothelial cells, highlighted complex 2 as the more effective. Read More

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http://dx.doi.org/10.1002/cmdc.202000165DOI Listing

Synthesis and Anticancer Properties of Oxazepines Related to Azaisoerianin and IsoCoQuines.

ChemMedChem 2020 Jun 2. Epub 2020 Jun 2.

Université Paris-Saclay, CNRS, BioCIS, 92290, Châtenay-Malabry, France.

In this article, we report the synthesis and biological properties of a series of novel oxazepines related to isoCA-4 having significant antitumor properties. Among them, three oxazepin-9-ol derivatives display a nanomolar or a sub-nanomolar cytotoxicity level against five human cancer cell lines (HCT116, U87, A549, MCF7, and K562). It was demonstrated that the lead compound in this series inhibits tubulin assembly with an IC value of 1 μM and totally arrests the cellular cycle in the G2/M phase at the low concentration of 5 nM in HCT116 and K562 cells. Read More

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http://dx.doi.org/10.1002/cmdc.202000197DOI Listing

Simplified Novel Muraymycin Analogues; using a Serine Template Strategy for Linking Key Pharmacophores.

ChemMedChem 2020 May 31. Epub 2020 May 31.

Menzies Health Institute Queensland, Griffith University, Gold Coast, QLD 4222, Australia.

The present status of antibiotic research requires the urgent invention of novel agents that act on multidrug-resistant bacteria. The World Health Organization has classified antibiotic-resistant bacteria into critical, high and medium priority according to the urgency of need for new antibiotics. Naturally occurring uridine-derived "nucleoside antibiotics" have shown promising activity against numerous priority resistant organisms by inhibiting the transmembrane protein MraY (translocase I), which is yet to be explored in a clinical context. Read More

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http://dx.doi.org/10.1002/cmdc.202000033DOI Listing

Synthesis and Antibacterial Activity of New N-Alkylammonium and Carbonate-Triazole Derivatives within Desosamine of 14- and 15-Membered Lactone Macrolides.

ChemMedChem 2020 May 27. Epub 2020 May 27.

Faculty of Chemistry, Adam Mickiewicz University, Uniwersytetu Poznańskiego 8, 61-614, Poznań, Poland.

Desosamines of azithromycin (AZM) and clarithromycin (CLA) were modified by N-alkylation or nucleophilic substitution at the carbonyl/CuAAC sequence. Biological studies revealed a higher antibacterial potency of quaternary N-alkylammonium bromides of CLA as compared to AZM. SAR studies of CLA salts, including biological, conformation and molecular-docking analysis, enriched by physicochemical parameters, showed the importance of less bulky and unsaturated substituent for an efficient docking mode at the ribosomal tunnel and good antibacterial potency against clinical and standard Streptococcus pneumoniae and Streptococcus pyogenes strains (MICs 0. Read More

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http://dx.doi.org/10.1002/cmdc.202000273DOI Listing

α-Triazolylboronic Acids: A Promising Scaffold for Effective Inhibitors of KPCs.

ChemMedChem 2020 May 27. Epub 2020 May 27.

Departments of Medicine.

Boronic acids are known reversible covalent inhibitors of serine β-lactamases. The selectivity and high potency of specific boronates bearing an amide side chain that mimics the β-lactam's amide side chain have been advanced in several studies. Herein, we describe a new class of boronic acids in which the amide group is replaced by a bioisostere triazole. Read More

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http://dx.doi.org/10.1002/cmdc.202000126DOI Listing

Diphenylene Iodonium Is a Noncovalent MAO Inhibitor: A Biochemical and Structural Analysis.

ChemMedChem 2020 May 27. Epub 2020 May 27.

Department of Biology and Biotechnology "Lazzaro Spallanzani", University of Pavia, Via Ferrata 9, 27100, Pavia, Italy.

Diphenylene iodonium (DPI) is known for its inhibitory activities against many flavin- and heme-dependent enzymes, and is often used as an NADPH oxidase inhibitor. We probed the efficacy of DPI on two well-known drug targets, the human monoamine oxidases MAO A and B. UV-visible spectrophotometry and steady-state kinetics experiments demonstrate that DPI acts as a competitive and reversible MAO inhibitor with K values of 1. Read More

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http://dx.doi.org/10.1002/cmdc.202000264DOI Listing

Small-Molecule Inhibitors Targeting Sterol 14α-Demethylase (CYP51): Synthesis, Molecular Modelling and Evaluation Against Candida albicans.

ChemMedChem 2020 May 27. Epub 2020 May 27.

School of Pharmacy & Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff, CF10 3NB, UK.

Fungal infections are a global issue affecting over 150 million people worldwide annually, with 750 000 of these caused by invasive Candida infections. Azole drugs are the frontline treatment against fungal infections; however, resistance to current azole antifungals in C. albicans poses a threat to public health. Read More

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http://dx.doi.org/10.1002/cmdc.202000250DOI Listing

Structure-Activity Relationships of Butyrophilin 3 Ligands.

Authors:
Andrew J Wiemer

ChemMedChem 2020 Jun 26;15(12):1030-1039. Epub 2020 May 26.

Department of Pharmaceutical Sciences and Institute for Systems Genomics, University of Connecticut, 69N. Eagleville Road, Storrs, CT, 06269, USA.

Phosphoantigens (pAgs) are small phosphorus-containing molecules that stimulate Vγ9Vδ2 T cells with sub-nanomolar cellular potency. Recent work has revealed that these compounds work through binding to the transmembrane immunoglobulin butyrophilin 3A1 (BTN3A1) within its intracellular B30.2 domain. Read More

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http://dx.doi.org/10.1002/cmdc.202000198DOI Listing

Design and Synthesis of Fluorescent Methylphenidate Analogues for a FRET-Based Assay of Synapsin III Binding.

ChemMedChem 2020 May 26. Epub 2020 May 26.

Department of Pharmaceutical Sciences, University of Milan, Via Luigi Mangiagalli, 25, 20133, Milano, Italy.

We previously described synapsin III (Syn III) as a synaptic phosphoprotein that controls dopamine release in cooperation with α-synuclein (aSyn). Moreover, we found that in Parkinson's disease (PD), Syn III also participates in aSyn aggregation and toxicity. Our recent observations point to threo-methylphenidate (MPH), a monoamine re-uptake inhibitor that efficiently counteracts the freezing-gait characteristic of advanced PD, as a ligand for Syn III. Read More

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http://dx.doi.org/10.1002/cmdc.202000128DOI Listing

Physicochemical Properties of Zwitterionic Drugs in Therapy.

ChemMedChem 2020 Jul 9;15(13):1102-1110. Epub 2020 Jun 9.

Semmelweis University Department of Pharmaceutical Chemistry Hungarian Academy of Sciences, Hőgyes E. u. 9., 1092, Budapest, Hungary.

In solution, amphoteric compounds exist in anionic, uncharged, zwitterionic and cationic forms. The importance of zwitterionic drugs is currently under-represented in the literature. Herein, the acid-base parameters, lipophilicity and solubility of such compounds are discussed to deepen the molecular-level understanding of their pharmacokinetic and pharmacodynamic behaviour. Read More

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http://dx.doi.org/10.1002/cmdc.202000164DOI Listing

Design and Synthesis of New Pyrazole-Based Heterotricycles and their Derivatization by Automated Library Synthesis.

ChemMedChem 2020 May 19. Epub 2020 May 19.

Department of Chemistry, University of Sheffield, Sheffield, S3 7HF, UK.

Small-molecule heterocycles bearing orthogonal functionality have the potential to deliver diverse structural motifs that aid the drug-discovery effort. This work highlights how a readily assembled N-hydroxyethyl pyrazole trifluoroborate offers rapid access to architecturally distinct 5-6-6- and 5-7-6-fused tricyclic compounds. This chemistry is not only amenable to single compound synthesis, but also to high-throughput experimentation. Read More

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http://dx.doi.org/10.1002/cmdc.202000187DOI Listing

Divergent Synthesis of Novel Cylindrocyclophanes that Inhibit Methicillin-Resistant Staphylococcus aureus (MRSA).

ChemMedChem 2020 May 18. Epub 2020 May 18.

Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.

The cylindrocyclophanes are a family of macrocyclic natural products reported to exhibit antibacterial activity. Little is known about the structural basis of this activity due to the challenges associated with their synthesis or isolation. We hypothesised that structural modification of the cylindrocyclophane scaffold could streamline their synthesis without significant loss of activity. Read More

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http://dx.doi.org/10.1002/cmdc.202000179DOI Listing

Pharmacological Profile and Molecular Modeling of Cyclic Opioid Analogues Incorporating Various Phenylalanine Derivatives.

ChemMedChem 2020 May 15. Epub 2020 May 15.

Department of Biomolecular Chemistry Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215, Lodz, Poland.

Peptide-based agonists of the μ opioid receptor (μOR) are promising therapeutic candidates for pain relief with reduced side effects compared to morphine. A deep understanding of μOR-ligand interactions is necessary for future design of peptide-based opioid analgesics. To explore the requirements of the μOR binding pocket, eight new analogues of our cyclic peptide Tyr-c[d-Lys-Phe-Phe-Asp]NH displaying high μOR affinity were synthesized, in which Phe in either the third or fourth position was replaced by various derivatives of this amino acid (β -Phe, homoPhe, β -homoPhe and PhGly). Read More

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http://dx.doi.org/10.1002/cmdc.202000248DOI Listing

Plumbagin-Serum Albumin Interaction: Spectral, Electrochemical, Structure-Binding Analysis, Antiproliferative and Cell Signaling Aspects with Implications for Anticancer Therapy.

ChemMedChem 2020 May 14. Epub 2020 May 14.

Vaccine Research Institute of San Diego (VRISD), 3030 Bunker Hill Street, San Diego, CA 92109, USA.

Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) is a small molecule with potent anticancer activity. Like other 1,4-naphthoquinones, it exhibits electrophilic reactivity towards biological nucleophiles. We demonstrate that plumbagin and structurally related 1,4-naphthoquinones with at least one unsubstituted quinoid carbon (C2 or C3) bind to albumin, an ubiquitously present nucleophile, with minimum recovery of free drug. Read More

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http://dx.doi.org/10.1002/cmdc.202000157DOI Listing

Polysubstituted Pyrimidines as mPGES-1 Inhibitors: Discovery of Potent Inhibitors of PGE Production with Strong Anti-inflammatory Effects in Carrageenan-Induced Rat Paw Edema.

ChemMedChem 2020 May 15. Epub 2020 May 15.

Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo nám. 2, 166 10, Prague 6, Czech Republic.

We report an extensive structure-activity relationship optimization of polysubstituted pyrimidines that led to the discovery of 5-butyl-4-(4-benzyloxyphenyl)-6-phenylpyrimidin-2-amine, and its difluorinated analogue. These compounds are sub-micromolar inhibitors of PGE production (IC as low as 12 nM). In order to identify the molecular target of anti-inflammatory pyrimidines, we performed extensive studies including enzymatic assays, homology modeling and docking. Read More

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http://dx.doi.org/10.1002/cmdc.202000258DOI Listing
May 2020
2.968 Impact Factor

The Synthesis and Anti-tumour Properties of Poly Ethoxy Ethyl Glycinamide (PEE-G) Scaffolds with Multiple PD-1 Peptides Attached.

ChemMedChem 2020 Jul 2;15(13):1128-1138. Epub 2020 Jun 2.

Victoria University of Wellington PO Box 33 436, Petone, 5046, New Zealand.

Multivalent structures can provide multiple interactions at a target site and improve binding affinity. The multivalent presentation of the anti-tumour heptapeptide, SNTSESF, was investigated. This peptide's activity has been attributed to blockade of the PD-1 receptor-mediated signalling pathway. Read More

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http://dx.doi.org/10.1002/cmdc.202000221DOI Listing

Design, Synthesis, Structure-Activity Relationship and Docking Studies of Novel Functionalized Arylvinyl-1,2,4-Trioxanes as Potent Antiplasmodial as well as Anticancer Agents.

ChemMedChem 2020 Jul 3;15(13):1216-1228. Epub 2020 Jun 3.

Laboratory of Organic and Medicinal Chemistry, Department of Chemistry, Malaviya National Institute of Technology, Jawaharlal Nehru Marg, Jaipur, 302017, India.

A novel series of synthetic functionalized arylvinyl-1,2,4-trioxanes (8 a-p) has been prepared and assessed for their in vitro antiplasmodial activity against the chloroquine-resistant Pf INDO strain of Plasmodium falciparum by using a SYBR green-I fluorescence assay. Compounds 8 g (IC =0.051 μM; SI=589. Read More

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http://dx.doi.org/10.1002/cmdc.202000045DOI Listing
July 2020
2.968 Impact Factor

Design, Synthesis, and Characterization of Novel CXCR4 Antagonists Featuring Cyclic Amines.

ChemMedChem 2020 Jul 29;15(13):1150-1162. Epub 2020 May 29.

Jiangsu Key Laboratory of Neuropsychiatric Diseases, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, 215123, P. R. China.

Chemokine receptor CXCR4 and its natural ligand CXCL12 (also known as stromal cell-derived factor-1, or SDF-1) regulate a broad range of physiological functions. Dysregulation of the CXCL12/CXCR4 axis is involved in numerous pathological conditions such as HIV infection, inflammation and cancer. Herein, we report the design, synthesis, and characterization of novel CXCR4 antagonists based on cyclic amine scaffolds. Read More

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http://dx.doi.org/10.1002/cmdc.202000268DOI Listing

Pharmacokinetic Parameters of HIV-1 Protease Inhibitors.

ChemMedChem 2020 Jun 26;15(12):1018-1029. Epub 2020 May 26.

School of Pharmaceutical Sciences, São Paulo State University (UNESP), 14800-903, Araraquara, São Paulo, Brazil.

Since the beginning of the HIV epidemic, research has been carried out to control the virus. Understanding the mechanisms of replication has given access to the various classes of drugs that over time have transformed AIDS into a manageable chronic disease. The class of protease inhibitors (PIs) gained notice in anti-retroviral therapy, once it was found that peptidomimetic molecules act by blocking the active catalytic center of the aspartic protease, which is directly related to HIV maturation. Read More

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http://dx.doi.org/10.1002/cmdc.202000101DOI Listing

A Library of Thiazolidin-4-one Derivatives as Protein Tyrosine Phosphatase 1B (PTP1B) Inhibitors: An Attempt To Discover Novel Antidiabetic Agents.

ChemMedChem 2020 Jul 3;15(13):1229-1242. Epub 2020 Jun 3.

Department of Pharmaceutical Science Sushruta School of Medical and Paramedical Sciences, Assam University (A Central University), Silchar, Assam, 788011, India.

Protein tyrosine phosphatase 1B (PTP1B) is an important target for the treatment of diabetes. A series of thiazolidin-4-one derivatives 8-22 was designed, synthesized and investigated as PTP1B inhibitors. The new molecules inhibited PTP1B with IC values in the micromolar range. Read More

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http://dx.doi.org/10.1002/cmdc.202000055DOI Listing

Structural Consequences of the 1,2,3-Triazole as an Amide Bioisostere in Analogues of the Cystic Fibrosis Drugs VX-809 and VX-770.

ChemMedChem 2020 May 8. Epub 2020 May 8.

Department of Chemistry and Biochemistry, Berry College, Mount Berry, GA 30149, USA.

Although the 1,2,3-triazole is a commonly used amide bioisostere in medicinal chemistry, the structural implications of this replacement have not been fully studied. Employing X-ray crystallography and computational studies, we report the spatial and electronic consequences of replacing an amide with the triazole in analogues of cystic fibrosis drugs in the VX-770 and VX-809 series. Crystallographic analyses quantify subtle differences in the relative positions and conformational preferences of the R and R substituents attached to the amide and triazole bioisosteres. Read More

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http://dx.doi.org/10.1002/cmdc.202000220DOI Listing

Synthesis, Radiosynthesis and Biological Evaluation of Buprenorphine-Derived Phenylazocarboxamides as Novel μ-Opioid Receptor Ligands.

ChemMedChem 2020 Jul 2;15(13):1175-1186. Epub 2020 Jun 2.

Department of Chemistry and Pharmacy, Pharmaceutical Chemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Nikolaus-Fiebiger-Str. 10, 91058, Erlangen, Germany.

Targeted structural modifications have led to a novel type of buprenorphine-derived opioid receptor ligand displaying an improved selectivity profile for the μ-OR subtype. On this basis, it is shown that phenylazocarboxamides may serve as useful bioisosteric replacements for the widely occurring cinnamide units, without loss of OR binding affinity or subtype selectivity. This study further includes functional experiments pointing to weak partial agonist properties of the novel μ-OR ligands, as well as docking and metabolism experiments. Read More

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http://dx.doi.org/10.1002/cmdc.202000180DOI Listing

Synthesis of Tamoxifen-Artemisinin and Estrogen-Artemisinin Hybrids Highly Potent Against Breast and Prostate Cancer.

ChemMedChem 2020 May 6. Epub 2020 May 6.

Organic Chemistry Chair I and Interdisciplinary Center for Molecular Materials (ICMM), Friedrich-Alexander University of Erlangen-Nürnberg, Nikolaus-Fiebiger-Straße 10, 91058, Erlangen, Germany.

In the search for new and effective treatments of breast and prostate cancer, a series of hybrid compounds based on tamoxifen, estrogens, and artemisinin were successfully synthesized and analyzed for their in vitro activities against human prostate (PC-3) and breast cancer (MCF-7) cell lines. Most of the hybrid compounds exhibit a strong anticancer activity against both cancer cell lines - for example, EC (PC-3) down to 1.07 μM, and EC (MCF-7) down to 2. Read More

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http://dx.doi.org/10.1002/cmdc.202000174DOI Listing

Synthesis and Biological Evaluation of Endocannabinoid Uptake Inhibitors Derived from WOBE437.

ChemMedChem 2020 May 5. Epub 2020 May 5.

Department of Chemistry and Applied Biosciences, ETH Zürich HCI H405, Vladimir-Prelog-Weg 4, 8093, Zürich, Switzerland.

WOBE437 ((2E,4E)-N-(3,4-dimethoxyphenethyl)dodeca-2,4-dienamide, 1) is a natural product-derived, highly potent inhibitor of endocannabinoid reuptake. In this study, we synthesized almost 80 analogues of 1 with different types of modifications in the dodecadienoyl domain as well as the dimethoxyphenylethyl head group, and we investigated their effects on anandamide uptake into U937 cells. Intriguingly, none of these analogues was a more potent inhibitor of anandamide uptake than WOBE437 (1). Read More

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http://dx.doi.org/10.1002/cmdc.202000153DOI Listing

Synthetic Guaiacol Derivatives as Promising Myeloperoxidase Inhibitors Targeting Atherosclerotic Cardiovascular Disease.

ChemMedChem 2020 Jul 20;15(13):1187-1199. Epub 2020 May 20.

Department of Chemistry, School of Advanced Science, Vellore Institute of Technology-Vellore, Tamilnadu, 632014, India.

Myeloperoxidase (MPO) is known to cause oxidative stress and inflammation leading to cardiovascular disease (CVD) complications. MPO-mediated oxidation of lipoproteins leads to dysfunctional entities altering the landscape of lipoprotein functionality. The specificity of guaiacol derivatives toward preventing MPO-mediated oxidation to limit MPO's harmful effects is unknown. Read More

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http://dx.doi.org/10.1002/cmdc.202000084DOI Listing

In vitro Biological Tests as the First Tools To Validate Magnetic Nanotheranostics for Colorectal Cancer Models.

ChemMedChem 2020 Jun 26;15(12):1003-1017. Epub 2020 May 26.

INQUISUR, Departamento de Química, Universidad Nacional del Sur (CONICET-UNS), Alem 1253, Bahía Blanca, Argentina.

Colorectal cancer (CRC) remains a leading cause of cancer death. Nanotechnology has focused on reaching more effective treatments. In this concern, magnetic nanoparticles (MNPs) have been studied for a wide range of biomedical applications related to CRC, such as diagnostic imaging, drug delivery and thermal therapy. Read More

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http://dx.doi.org/10.1002/cmdc.202000119DOI Listing