Radiolabelled CCK2R antagonists containing PEG linkers: design, synthesis and evaluation.
U, Plavec J Abstract 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 ...
Source: ChemMedChem - July 9, 2020 Category: Chemistry Authors: Anderluh M, Novak D, Krošelj M, Tomašič T, Kolenc Peitl P, Javornik U, Plavec J Tags: ChemMedChem Source Type: research

Phospholipid Cyclosporine Prodrugs Targeted at Inflammatory Bowel Disease (IBD) Treatment: Design, Synthesis, and In Vitro Validation.
This study represents a proof-of-concept for our hypothesis and a first step towards a truly targeted IBD treatment with cyclosporine that could be administered throughout the GI tract. PMID: 32618133 [PubMed - as supplied by publisher] (Source: ChemMedChem)
Source: ChemMedChem - July 2, 2020 Category: Chemistry Authors: Manda JN, Markovic M, Zimmermann EM, Ben-Shabat S, Dahan A, Aponick A Tags: ChemMedChem Source Type: research

First-Generation Bispidine Chelators for 213 BiIII Radiopharmaceutical Applications.
Abstract 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 BiIII coordination chemistry. Crystal structure and solution spectroscopic data (NMR spectroscopy and mass spectrometry) confirm that the rigid and relatively large bispidine cavity with an axially distorted geometry is well suited for BiIII and in all cases forms nine-coordinate complexes; this is supported by an established hole size and shape analysis. It follows th...
Source: ChemMedChem - July 2, 2020 Category: Chemistry Authors: Bruchertseifer F, Comba P, Martin B, Morgenstern A, Notni J, Starke M, Wadepohl H Tags: ChemMedChem Source Type: research

A Dual Inhibitor of DYRK1A and GSK3 β for β-Cell Proliferation: Aminopyrazine Derivative GNF4877.
A Dual Inhibitor of DYRK1A and GSK3β for β-Cell Proliferation: Aminopyrazine Derivative GNF4877. ChemMedChem. 2020 Jul 02;: Authors: Liu YA, Jin Q, Ding Q, Hao X, Mo T, Yan S, Zou Y, Huang Z, Zhang X, Gao W, Wu TY, Li C, Bursalaya B, Di Donato M, Zhang YQ, Deaton L, Shen W, Taylor B, Kamireddy A, Harb G, Li J, Jia Y, Schumacher AM, Laffitte B, Glynne R, Pan S, McNamara P, Molteni V, Loren J Abstract 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 insul...
Source: ChemMedChem - July 2, 2020 Category: Chemistry Authors: Liu YA, Jin Q, Ding Q, Hao X, Mo T, Yan S, Zou Y, Huang Z, Zhang X, Gao W, Wu TY, Li C, Bursalaya B, Di Donato M, Zhang YQ, Deaton L, Shen W, Taylor B, Kamireddy A, Harb G, Li J, Jia Y, Schumacher AM, Laffitte B, Glynne R, Pan S, McNamara P, Molteni V, Lo Tags: ChemMedChem Source Type: research

Rationally Designed Polypharmacology: α-Helix Mimetics as Dual Inhibitors of the Oncoproteins Mcl-1 and HDM2.
Rationally Designed Polypharmacology: α-Helix Mimetics as Dual Inhibitors of the Oncoproteins Mcl-1 and HDM2. ChemMedChem. 2020 Jun 25;: Authors: Conlon IL, Drennen B, Lanning ME, Hughes S, Rothhaas R, Wilder PT, MacKerell AD, Fletcher S Abstract 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, neuro...
Source: ChemMedChem - June 25, 2020 Category: Chemistry Authors: Conlon IL, Drennen B, Lanning ME, Hughes S, Rothhaas R, Wilder PT, MacKerell AD, Fletcher S Tags: ChemMedChem Source Type: research

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.
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.e., MAO-A and MAO-B. Interestingly, MO10 showed a remarkable inhibition against MAO-B with an IC 50 value of 0.044 µM along with a selectivity index of 366.13. The IC 50 value was better than that of lazabemide (IC 50 value of 0.063 µM), used as a reference. Kinetics studies revealed that MO10 acted as a competit...
Source: ChemMedChem - June 25, 2020 Category: Chemistry Authors: Mathew B Tags: ChemMedChem Source Type: research

Functionalized Cannabinoid Subtype 2 Receptor Ligands: Fluorescent, PET, Photochromic and Covalent Molecular Probes.
Abstract Cannabinoid subtype 2 receptors (CB2 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, CB2 Rs are strongly up-regulated in pathological conditions correlated with the onset of inflammatory events like cancer and neurodegenerative diseases. Therefore, CB2 Rs represent an important biological target for therapeutic as well as diagnostic purposes. No CB2 R-selective drugs are yet on the market, thus underlining a that deeper comprehension of CB2 Rs' complex acti...
Source: ChemMedChem - June 24, 2020 Category: Chemistry Authors: Basagni F, Rosini M, Decker M Tags: ChemMedChem Source Type: research

Peptidyl Vinyl Ketones Irreversible Inhibitors of Rhodesain: Modifications of the P2 Fragment.
ve; M Abstract In this paper, we report the design, synthesis and biological investigations of a series of peptidyl vinyl ketones obtained modifying the P2 fragment of previously reported highly potent inhibitors of rhodesain, the main cysteine protease of Trypanosoma brucei rhodesiense . An investigation on the structure-activity relationship is now described, leading us to identify new rhodesain inhibitors endowed with an improved selectivity profile (i.e. 3f ), which showed a selectivity index of 22000 towards the target enzyme and/or an improved antitrypanosomal activity in the submicromolar range (i.e. 3b and...
Source: ChemMedChem - June 21, 2020 Category: Chemistry Authors: Maiorana S, Ettari R, Previti S, Amendola G, Wagner A, Cosconati S, Hellmich UA, Schirmeister T, Zappalà M Tags: ChemMedChem Source Type: research

Exploring Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) Autoproteolysis Process by Molecular Simulations: Hints for Drug Design.
This study could facilitate the identification of ligands capable of interfering with the PCSK9 maturation process. PMID: 32558225 [PubMed - as supplied by publisher] (Source: ChemMedChem)
Source: ChemMedChem - June 17, 2020 Category: Chemistry Authors: Sgrignani J, Fassi EMA, Lammi C, Roda G, Grazioso G Tags: ChemMedChem Source Type: research

Synthesis of N-aryl and N-alkyl substituted imidazolium silver complexes. Cytotoxic screening using human cell lines modelling acute myeloid leukemia.
;rsvik HR Abstract A series of N- aryl and N- alkyl substituted imidazoles were synthesized and complexed with Ag + to obtain silver-NHC complexes of the form [Ag(NHC)2 ]X. These silver-NHC complexes were tested in-vitro versus the human cell lines HL-60 and MOLM-13 that both model acute myeloid leukemia (AML). A substantial difference in cytotoxicity was revealed varying in the range 13 - 4 μ M (for HL-60) and 22 - 9 μ M (for MOLM-13), respectively. Furthermore, this study revealed that when an alkyl group was installed on the imidazole scaffold, its position influenced substantially the cytotoxicity of the...
Source: ChemMedChem - June 17, 2020 Category: Chemistry Authors: Alme E, Törnroos KW, Gjertsen BT, Bjørsvik HR Tags: ChemMedChem Source Type: research

Discovery of an Orally Active and Long-acting DPP-IV Inhibitor through Property-based Optimization with an in silico Biotransformation Prediction Tool.
Abstract Long-acting dipeptidyl peptidase IV inhibitors have emerged as promising interventions for type 2 diabetes. The once weekly dosing brings greater patient compliance and more stable glycemic control. Started from our previously disclosed highly potent but severe hepatic biotransformed hit compound with thienoprimidine scaffold, lead compound was rapidly generated by drawing on the experience of our former discovered long-acting compounds bearing pyrrolopyrimidine scaffold. With the aid of an in silico biotransformation prediction tool, (R)-2-((2-(3-aminopiperidin-1-yl)-4-oxo-6-(pyridin-3-yl)thieno[3,2-d]py...
Source: ChemMedChem - June 17, 2020 Category: Chemistry Authors: Zeng S, Dou W, Li M, Zhou Y, Guo J, Zhao N, Huang H, Zhou Q, Hu W, Ma Y, Zhao X, Xie H Tags: ChemMedChem Source Type: research

Controlling PROTACs With Light.
Abstract 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 which detaches only on irradiation of specific wavelength, releasing the active PROTAC. These modified PROTACs are ...
Source: ChemMedChem - June 17, 2020 Category: Chemistry Authors: Manna D, Verma S Tags: ChemMedChem Source Type: research

Short Photoswitchable Antibacterial Peptides.
In this study, net positive charge, hydrophobicity, position of the azobenzene, secondary structure, and amphiphilicity were all found to contribute to antibacterial activity, with each of these factors likely facilitating the peptide to disrupt the negatively charged bacterial lipid membrane. Hence, these short photoswitchable antibacterial tetrapeptides provide insights for the future design and synthesis of antibiotics for S. aureus infections. PMID: 32558320 [PubMed - as supplied by publisher] (Source: ChemMedChem)
Source: ChemMedChem - June 17, 2020 Category: Chemistry Authors: Yeoh YQ, Horsley J, Yu J, Polyak SW, Jovcevski B, Abell AD Tags: ChemMedChem Source Type: research

Dynamic Combinatorial Chemistry Affords Sugar-Based Molecules Targeting Bacterial Glucosyltranseferase as Potential Dental Biofilm Inhibitors.
Abstract 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. Synthesis of the required mono- and disaccharide-based aldehydes set the stage for DCC experiments. Analysis of the dynamic combinatorial libraries (DCLs) via UPLC-MS revealed major amplificat...
Source: ChemMedChem - June 16, 2020 Category: Chemistry Authors: Hartman AM, Jumde VR, Elgaher WAM, Te Poele EM, Dijkhuizen L, Hirsch AKH Tags: ChemMedChem Source Type: research

Evaluation of 5H-thiazolo[3,2-a]pyrimidin-5-ones as potential GluN2A PET tracers.
We describe here our efforts to develop a PET tracer for imaging GluN2A-containing NMDA receptors, based on 5 H -thiazolo[3,2-a]pyrimidin-5-one scaffold. Metabolic stability and overall properties could be optimized satisfactorily, while 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-5 H -thiazolo-[3,2-a]pyrimidin-5-one ([ 18 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...
Source: ChemMedChem - June 16, 2020 Category: Chemistry Authors: He Y, Whitehead D, Briard E, Numao S, Mu L, Schibli R, Ametamey S, Auberson YP Tags: ChemMedChem Source Type: research

Macrocyclic imino-peptides diversify to better target proteins.
Abstract Among the many methods available for accessing conformationally diverse cyclic peptides, the derivatization of macrocyclic imino-peptides 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 imino-peptides using 1,3-cycloaddition reactions. A proof-of-c...
Source: ChemMedChem - June 9, 2020 Category: Chemistry Authors: Rivera DG, Reguera L Tags: ChemMedChem Source Type: research

Surface modification of luminescent Ln(III) fluoride core-shell nanoparticles with acetyl salicylic acid (aspirin) - synthesis, spectroscopic and in vitro hemocompatibility studies.
This study demonstrates that the LaF3: Tb3+ 5%, Ce3+ 10%@SiO2-NH2 nanoparticles with acetyl salicylic acid (aspirin) coated on the surface, are very good precursors for multifunctional drug-delivery systems or bio-imaging probe, which can be used safely in potential biomedical applications. PMID: 32510839 [PubMed - as supplied by publisher] (Source: ChemMedChem)
Source: ChemMedChem - June 8, 2020 Category: Chemistry Authors: Kwiatek D, Mrówczyńska LM, Stopikowska N, Runowski M, Lesicki A, Lis S Tags: ChemMedChem Source Type: research

Structure-based macrocyclization of substrate analog NS2B-NS3 protease inhibitors of Zika, West Nile and Dengue viruses.
Abstract A series of cyclic active-site directed inhibitors of the NS2B-NS3 proteases from Zika- (ZIKV), West Nile- (WNV), and Dengue-4 (DENV4) viruses was designed. The most potent compounds contain a reversely incorporated d-lysine residue in P1 position, where its side chain is connected to the P2 backbone, its a-amino group is converted into a guanidine for interaction with the conserved Asp129 side chain in the S1 pocket, and its carboxyl group is used for cyclization to the P3 lysine residue via an appropriate linker segment. The most potent compounds inhibit the ZIKV protease with K i values between 1.5 - 5...
Source: ChemMedChem - June 5, 2020 Category: Chemistry Authors: Braun NJ, Quek JP, Huber S, Kouretova J, Rogge D, Lang-Henkel H, Cheong ZKE, Chew BLA, Heine A, Luo D, Steinmetzer T Tags: ChemMedChem Source Type: research

O-GlcNAcase: emerging mechanism, substrate recognition and small molecule inhibitors.
This article also focuses on the catalytic mechanism and substrate recognition by OGA. In addition, we present an updated overview on small molecule OGA inhibitors, either of carbohydrate or noncarbohydrate scaffolds, regarding their structures, binding modes and selectivity towards the enzyme, and potential therapeutic outcomes in probing O -GlcNAcylation at cellular levels. This minireview is believed to be a good starting point to develop more potent and selective OGA drug candidates. PMID: 32496638 [PubMed - as supplied by publisher] (Source: ChemMedChem)
Source: ChemMedChem - June 4, 2020 Category: Chemistry Authors: Elbatrawy AA, Kim EJ, Nam G Tags: ChemMedChem Source Type: research

Design, synthesis, radiosynthesis and biological evaluation of Fenretinide analogues as anticancer and metabolic syndrome-preventive agents.
Abstract 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 evidenced 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. However, although 4-HPR displays quite well-understood multi-target promiscuity with regards to pharmacology, interpreting its precise p...
Source: ChemMedChem - June 4, 2020 Category: Chemistry Authors: Zanda M, Patruno I, Thompson D, Dall'Angelo S, Windhorst AD, Vugts DJ, Poot AJ, Mody N Tags: ChemMedChem Source Type: research

Synthesis of Tetramic Acid Fragments Derived from Vancoresmycin Showing Inhibitory Effects Towards S. aureus.
Abstract 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 S. aureus and E. coli were determined, revealing three of the new compounds to exhibit antimicrobial activity against S. aureus . These bioactive compounds were structurally most closely related to the authentic vancoresmycin building block. Additionally, the compounds induced a lial - lux bioreporter, which responds to cell w...
Source: ChemMedChem - June 4, 2020 Category: Chemistry Authors: Wingen LM, Rausch M, Schneider T, Menche D Tags: ChemMedChem Source Type: research

Expanding the spectrum of antibiotics capable of killing multi-drug resistant Staphylococcus aureus and Pseudomonas aeruginosa.
Abstract 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. The present study describes...
Source: ChemMedChem - June 4, 2020 Category: Chemistry Authors: Lam AK, Panlilio H, Pusavat J, Wouters CL, Moen EL, Brennan RE, Rice C Tags: ChemMedChem Source Type: research

Platinum(II) complexes bearing triphenylphosphine and chelating oximes: antiproliferative effect and biological profile in resistant cells.
Abstract Platinum(II) complexes of the type [Pt(Cl)(PPh3){(κ2-N,O)-(1{C(R)=N(OH)-2(O)C6H4})}] with R = Me, H, (1 and 2) were synthesized and characterized. Single crystal X-ray diffraction confirmed for 1 the proposed (SP4-3) configuration. The study of the antiproliferative activity, performed on a panel of human tumor cell lines and on mesothelial cells, highlighted complex 2 as the most effective. In particular, it showed a remarkable cytotoxicity on ovarian carcinoma cells (A2780) and interestingly, a significant antiproliferative effect on cisplatin resistant cells (A2780cis). The investigation on the i...
Source: ChemMedChem - June 3, 2020 Category: Chemistry Authors: Hyeraci M, Colalillo M, Labella L, Marchetti F, Samaritani S, Scalcon V, Rigobello MP, Dalla Via L Tags: ChemMedChem Source Type: research

Chemoenzymatic synthesis and pharmacological evaluation of enantiomerically pure quinoline-based κ-opioid receptor (KOR) agonists.
Chemoenzymatic synthesis and pharmacological evaluation of enantiomerically pure quinoline-based κ-opioid receptor (KOR) agonists. ChemMedChem. 2020 Jun 03;: Authors: Wünsch B, Martin B, Schepmann D, Bernal FA, Schmidt TJ, Che T, Loser K Abstract The perhydroquinoline-based KOR agonist (±)-4 was prepared in a diastereoselective synthesis. The first key step of the synthesis was the diastereoselective hydrogenation of silyl ether (±)-9 affording cis,cis-configured perhydroquinoline (±)-10. Nucleophilic substitution of (±)-12 with pyrrolidine resulted in the desire...
Source: ChemMedChem - June 3, 2020 Category: Chemistry Authors: Wünsch B, Martin B, Schepmann D, Bernal FA, Schmidt TJ, Che T, Loser K Tags: ChemMedChem Source Type: research

Synthesis and Anticancer Properties of Oxazepines Related to Azaisoerianin and IsoCoQuinesSynthesis and Anticancer Properties of Oxazepines Related to Azaisoerianin and IsoCoQuines.
Abstract : In this article, we reported the synthesis and the biological properties of a series of novel oxazepines 1 endowed with antitumor properties. Among them, we found that oxazepin-9-ol 1f and ester derivative 1j displayed a nanomolar level of cytotoxicity. Remarkably, oxazepin-9-ol 1g having in structure a 2-cyanoquinoline linked on C4 to a benzo[b][1,4]oxazepine ring was found to be the lead molecule in this series displaying a (sub)nanomolar cytotoxicity level against five human cancer cell lines (HCT116, U87, A549, MCF7 and K562). Moreover, oxazepin-9-ol 1g inhibited the tubulin assembly with an IC 50 v...
Source: ChemMedChem - June 2, 2020 Category: Chemistry Authors: Provot O, Khelifi I, Pecnard S, Bernadat G, Bignon J, Levaique H, Dubois J, Alami M Tags: ChemMedChem Source Type: research

Simplified Novel Muraymycin Analogues; using a Serine Template Strategy for Linking Key Pharmacophores.
This study will pave the way for the development of novel antibacterial lead compounds based on a simplified serine template. PMID: 32476294 [PubMed - as supplied by publisher] (Source: ChemMedChem)
Source: ChemMedChem - May 31, 2020 Category: Chemistry Authors: Rudrawar S, Patel B, Kerr RV, Malde AK, Zunk M, Bugg TD, Grant G Tags: ChemMedChem Source Type: research

Small molecule inhibitors targeting sterol 14 α-demethylase (CYP51): synthesis, molecular modelling and evaluation against Candida albicans.
Small molecule inhibitors targeting sterol 14α-demethylase (CYP51): synthesis, molecular modelling and evaluation against Candida albicans. ChemMedChem. 2020 May 27;: Authors: Simons C, Binjubair F, Warrilow AG, Puri K, Braidley PJ, Tatar E, Kelly SL, Kelly DE, Parker J Abstract 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. Two serie...
Source: ChemMedChem - May 27, 2020 Category: Chemistry Authors: Simons C, Binjubair F, Warrilow AG, Puri K, Braidley PJ, Tatar E, Kelly SL, Kelly DE, Parker J Tags: ChemMedChem Source Type: research

Diphenylene iodonium is a non-covalent MAO inhibitor: a biochemical and structural analysis.
Abstract 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 MAO inhibitor with Ki values of 1.7 µM and 0.3 µM for MAO A and MAO B, respectively. Elucidation of the crystal structure of human MAO B bound to the inhibitor revealed that DPI binds deeply in the active-site cavity to est...
Source: ChemMedChem - May 27, 2020 Category: Chemistry Authors: Iacovino LG, Reis J, Mai A, Binda C, Mattevi A Tags: ChemMedChem Source Type: research

α-triazolylboronic acids: a promising scaffold for effective inhibitors of KPCs.
α-triazolylboronic acids: a promising scaffold for effective inhibitors of KPCs. ChemMedChem. 2020 May 27;: Authors: Introvigne ML, Taracila MA, Prati F, Caselli E, Bonomo RA Abstract Boronic Acids are known reversible covalent inhibitors of serine β-lactamases. The selectivity and high potency of specific boronates bearing an amide side chain mimicking the β-lactam's amide side chain have been advanced in several studies. Herein, we describe a new class of boronic acids where the amide group is replaced by a bioisostere triazole. The boronic acids were obtained in a two steps synthesi...
Source: ChemMedChem - May 27, 2020 Category: Chemistry Authors: Introvigne ML, Taracila MA, Prati F, Caselli E, Bonomo RA Tags: ChemMedChem Source Type: research

Synthesis and antibacterial activity of new N-alkylammonium and carbonate-triazole derivatives within desosamine of 14- and 15-membered lactone macrolides.
Abstract Desosamine of azithromycin ( AZM ) and clarithromycin ( CLA ) was modified via S N 2 and CuAAC dipolar cycloaddition. The biological studies revealed 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 physico-chemical parameters, showed the importance of less bulky and unsaturated substituent for efficient docking mode at the ribosomal tunnel and good antibacterial potency against clinical and standard Streptococcus pneumoniae and Streptococcus pyogenes str...
Source: ChemMedChem - May 27, 2020 Category: Chemistry Authors: Janas A, Pecyna P, Gajecka M, Bartl F, Przybylski P Tags: ChemMedChem Source Type: research

Design and synthesis of fluorescent-methylphenidate analogues for FRET-based assay of Synapsin III binding.
Abstract We previously described Synapsin III (Syn III) as a synaptic phosphoprotein that controls dopamine release in cooperation with alpha-synuclein (aSyn). Moreover, we found that in Parkinson's disease (PD), Syn III also participates in alpha-synuclein (aSyn) aggregation and toxicity. Our recent observations point to threo -methylphenidate (MPH), a monoamine reuptake inhibitor that efficiently counteracts the freezing gait characteristic of advanced PD, as a ligand for Syn III. Here, we designed and synthesized two different fluorescently-labelled MPH derivatives, one with Rhodamine Red (RHOD) and one with 5-...
Source: ChemMedChem - May 26, 2020 Category: Chemistry Authors: Casiraghi A, Longhena F, Straniero V, Faustini G, Newman AH, Bellucci A, Valoti E Tags: ChemMedChem Source Type: research

Physicochemical properties of zwitterionic drugs in therapy.
e;l B Abstract In solutions amphoteric compounds exist in anionic, non-charged, zwitterionic and cationic forms. The importance of zwitterionic drugs is currently underrepresented in the literature. The acid-base parameters, lipophilicity and solubility of such compounds are discussed to deepen the molecular-level understanding of their pharmacokinetic and pharmacodynamic behaviour. Our recent studies show there are many drug molecules, including thyroid hormones and 5-hydroxytryptophan, the precursor of the neurotransmitter serotonin, where contribution of the zwitterionic microspecies to the overall lipophilicit...
Source: ChemMedChem - May 20, 2020 Category: Chemistry Authors: Mazak K, Noszál B Tags: ChemMedChem Source Type: research

Design and Synthesis of Novel Pyrazole Based Heterotricycles and their Derivatization via Automated Library Synthesis.
Abstract 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. It enables easy access to diverse compound arrays with varying physchem and ADME profiles by fully automated library synthesis. The combination of the high throughput expe...
Source: ChemMedChem - May 19, 2020 Category: Chemistry Authors: Harrity JPA, Fricero P, Bialy L, Czechtizky W, Mendez M Tags: ChemMedChem Source Type: research

Divergent synthesis of novel cylindrocyclophanes that inhibit methicillin-resistant Staphylococcus aureus (MRSA).
Abstract 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 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. Herein we report a divergent synthesis of the cylindrocyclophane core enabling access to symmetrical macrocycles by means of a catalytic, domino cross-metathesis-ring-closing metathesis cascade, followed by late-stage divers...
Source: ChemMedChem - May 18, 2020 Category: Chemistry Authors: Freudenreich J, Bartlett S, Kidd S, Forrest S, Spring D, Robertson N, Sore H, Galloway W, Welch M Tags: ChemMedChem Source Type: research

Polysubstituted Pyrimidines as mPGES-1 Inhibitors: Discovery of Potent Inhibitors of PGE2 Production with a Strong Anti-inflammatory Effects in Carrageenan-Induced Rat Paw Edema.
We report an extensive structure-activity relationship optimization of polysubstituted pyrimidines that led to a discovery of 5-butyl-4-(4-benzyloxyphenyl)-6-phenylpyrimidin-2-amine, and its difluorinated analogue. These compounds are submicromolar inhibitors of PGE 2 production (IC 50 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. The difluorinated analogue simultaneously inhibits two key enzymes of the arachidonic acid cascade, namely mPGES-1 and COX-2, where the mPGES-1 inhibition repr...
Source: ChemMedChem - May 15, 2020 Category: Chemistry Authors: Kalčic F, Kolman V, Ajani H, Zídek Z, Janeba Z Tags: ChemMedChem Source Type: research

Pharmacological profile and molecular modeling of cyclic opioid analogs incorporating various phenylalanine derivatives.
Abstract 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 analogs of our cyclic peptide Tyr-c[D-Lys-Phe-Phe-Asp]NH 2 displaying high µOR affinity were synthesized, in which Phe in either third or fourth position was replaced by various derivatives of this amino acid (β 3 -Phe, homoPhe, β 3 -hom...
Source: ChemMedChem - May 15, 2020 Category: Chemistry Authors: Adamska-Bartłomiejczyk A, Lipiński PFJ, Piekielna-Ciesielska J, Kluczyk A, Janecka A Tags: ChemMedChem Source Type: research

Plumbagin-Serum Albumin Interaction: Spectral, Electrochemical, Structure-Binding  Analysis, Anti-proliferative and Cell Signaling Aspects with Implications for Anticancer Therapy.
Plumbagin-Serum Albumin Interaction: Spectral, Electrochemical, Structure-Binding Analysis, Anti-proliferative and Cell Signaling Aspects with Implications for Anticancer Therapy. ChemMedChem. 2020 May 14;: Authors: Baron V, Chrastina A, Welsh J, Rondeau G, Abedinpour P, Borgstrom P Abstract 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 unsubstitute...
Source: ChemMedChem - May 14, 2020 Category: Chemistry Authors: Baron V, Chrastina A, Welsh J, Rondeau G, Abedinpour P, Borgstrom P Tags: ChemMedChem Source Type: research

The Synthesis and Anti-tumour Properties of Poly Ethoxy Ethyl Glycinamide (PEE-G) Scaffolds with Multiple PD-1 Peptides Attached.
Abstract 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. Two and four peptide units were conjugated to poly ethoxy ethyl glycinamide (PEE-G) scaffolds to prepare high purity products. These conjugates and the peptide were examined in a mouse model implanted with GL261 tumours which indicated that presenting more than two copies of peptide SNTSESF on the dendritic scaf...
Source: ChemMedChem - May 12, 2020 Category: Chemistry Authors: Shrestha R, Petley EV, Farrand KJ, Jamieson SA, Jiao W, Teesdale-Spittle PH, Hermans IF, Mace PD, Rendle PM Tags: ChemMedChem Source Type: research

Design, Synthesis, and Characterization of Novel CXCR4 Antagonists Featuring Cyclic Amines.
Abstract 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. Compound 24 was identified as a potent CXCR4 receptor antagonist (competitive inhibition of 12G5 binding, IC 50 = 24 nM; functional inhibition of CXCL12 induced cytosolic calcium increase, IC 5...
Source: ChemMedChem - May 11, 2020 Category: Chemistry Authors: Zhang X, Lin Y, Li Z, Ma H, Wang Y, Wang X, Song S, Zhao L, Wu S, Tian S, Fu C, Luo L, Zhu F, He S, Zheng J Tags: ChemMedChem Source Type: research

Design, Synthesis, Structure-Activity Relationship and Docking Studies of Novel Functionalized Arylvinyl-1,2,4-Trioxanes as Potent Antiplasmodial as well as Anticancer Agents.
Abstract A novel series of functionalized synthetic substituted arylvinyl-1,2,4-trioxanes ( 8a-p ) has been prepared and assessed for in vitro antiplasmodial activity against chloroquine-resistant Pf INDO strain of Plasmodium falciparum using SYBR green-I fluorescence assay. Compounds 8g (IC 50 = 0.051 µ M; SI = 589.41) and 8m (IC 50 = 0.059 µ M; SI = 55.93) showed 11-fold and> 9-fold more potent antiplasmodial activity, respectively as compared to chloroquine (IC 50 = 0.546 µ M; SI = 36.63). In addition, 8a-p were also assessed for their in vitro anticancer activity against human lung (A549) ...
Source: ChemMedChem - May 11, 2020 Category: Chemistry Authors: Tiwari MK, Coghi P, Agrawal P, Shyamlal BRK, Yang LJ, Yadav L, Peng Y, Sharma R, Yadav DK, Sahal D, Wong VKW, Chaudhary S Tags: ChemMedChem Source Type: research

Design and Synthesis of a Library of Thiazolidin-4-one Derivatives as Protein Tyrosine Phosphatase 1B (PTP1B) Inhibitors: An Attempt to Discover Novel Anti-diabetic Agents.
Abstract Protein tyrosine phosphatase 1B (PTP1B) is an important target for treatment of diabetes. A series of thiazolidin-4-one derivatives 8-22 was designed, synthesized and investigated as PTP1B inhibitors. New molecules inhibited PTP1B with IC 50 in micromolar ranges. 5-(Furan-2-ylmethylene)-2-(4-nitrophenylimino)thiazolidin-4-one ( 17 ) exhibited maximum potency with competitive type of enzyme inhibition. SAR studies revealed various structural facets substantial for potency of these analogues. The findings revealed requirement of nitro group including hydrophobic heteroaryl ring for PTP1B inhibition. Molecul...
Source: ChemMedChem - May 10, 2020 Category: Chemistry Authors: Tripathi RKP, Patel AD, Pasha TY, Lunagaria P, Shah U, Bhambharoliya T Tags: ChemMedChem Source Type: research

Pharmacokinetic parameters of HIV-1 Protease Inhibitors.
Abstract Since the beginning of the HIV epidemic, research on controlling the virus has been carried out. 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 highlight in antiretroviral therapy, once that peptidomimetic molecules act by blocking the active catalytic center of the aspartic protease enzyme, which is directly related to HIV maturation. However, the mutations in enzymatic internal residues are the biggest issue in these drugs, because a small ch...
Source: ChemMedChem - May 10, 2020 Category: Chemistry Authors: Nascimento A, Fernandes RP, Quijia C, Araujo VH, Pereira J, Garcia JS, Trevisan MG, Chorilli M Tags: ChemMedChem Source Type: research

Structural Consequences of the 1,2,3-Triazole as an Amide Bioisostere in Analogs of Cystic Fibrosis Drugs VX-809 and VX-770.
Abstract While the 1,2,3-triazole is a commonly utilized 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 the amide with the triazole in analogs 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 R1 and R2 substituents attached to the amide and triazole bioisosteres. Computational studies derived from t...
Source: ChemMedChem - May 8, 2020 Category: Chemistry Authors: Doiron JE, Le CA, Bacsa J, Breton GW, Martin KL, Aller SG, Turlington M Tags: ChemMedChem Source Type: research

Synthesis, biological evaluation and radiosynthesis of buprenorphine-derived phenylazocarboxamides as novel μ-opioid receptor ligands.
Synthesis, biological evaluation and radiosynthesis of buprenorphine-derived phenylazocarboxamides as novel μ-opioid receptor ligands. ChemMedChem. 2020 May 06;: Authors: Krüll J, Fehler SK, Hofmann L, Nebel N, Maschauer S, Prante O, Gmeiner P, Lanig H, Hübner H, Heinrich MR Abstract Targeted structural modifications led to a novel type of buprenorphine-derived opioid receptor ligands 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 widely occuring cinnamide units, wi...
Source: ChemMedChem - May 6, 2020 Category: Chemistry Authors: Krüll J, Fehler SK, Hofmann L, Nebel N, Maschauer S, Prante O, Gmeiner P, Lanig H, Hübner H, Heinrich MR Tags: ChemMedChem Source Type: research

Synthesis of Tamoxifen-Artemisinin and Estrogen-Artemisinin Hybrids Highly Potent Against Breast and Prostate Cancer.
SB Abstract In 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 towards their in vitro activities against human prostate (PC-3) and breast cancer (MCF-7) cell lines. Most of the hybrid compounds exhibit a strong anti-cancer activity against both cancer cell lines e.g., EC 50 (PC-3) down to 1.07 µM and EC 50 (MCF-7) down to 2.08 µM, thus showing higher activities than their parent compounds 4-hydroxytamoxifen (Afimoxifene, 7 ) (EC 50 (PC-3) = 75.1 µM and EC 5...
Source: ChemMedChem - May 6, 2020 Category: Chemistry Authors: Fröhlich T, Mai C, Bogautdinov R, Morozkina SN, Shavva AG, Friedrich O, Gilbert D, Tsogoeva SB Tags: ChemMedChem Source Type: research

Discovery of novel synthetic hydroxyanisole derivatives as promising myeloperoxidase inhibitors (MPOIs) targeting atherosclerotic CVD.
Abstract Myeloperoxidase (MPO) is known to cause oxidative stress and inflammation leading to CVD complications. MPO mediated oxidation of lipoproteins leads to dysfunctional entities altering the landscape of lipoproteins functionality. The specificity of anisole derivatives toward preventing MPO mediated oxidation to limit its harmful effects is unknown. Diligent in silico studies were accomplished for a portfolio of compounds keeping hydroxyanisole as a building block. Validation of compounds activity toward MPO inhibition is also established. The role of these chemical entities on controlling MPO-mediated oxid...
Source: ChemMedChem - May 5, 2020 Category: Chemistry Authors: Jayaraj P, Parthasarathy S, Rajagopalan S, Aluganti C, Rajagopal D Tags: ChemMedChem Source Type: research

Synthesis and Biological Evaluation of Endocannabinoid Uptake Inhibitors Derived from WOBE437.
In this study, we have synthesized almost 80 analogs of 1 with different types of modifications in the dodecadienoyl domain as well as the dimethoxyphenylethyl head group and we have investigated their effects on anandamide uptake into U937 cells. Intriguingly, none of these analogs was a more potent inhibitor of anandamide uptake than WOBE437 ( 1 ). At the same time, a number of WOBE437 variants exhibited potencies in the sub-100 nM range with high selectivity over inhibition of the endocannabinoid-degrading enzyme fatty acid amide hydrolase; two compounds were virtually equipotent with 1 . Interestingly, profound activit...
Source: ChemMedChem - May 5, 2020 Category: Chemistry Authors: Altmann KH, Mäder P, Bartholomäus R, Nicolussi S, Baumann A, Weis M, Chicca A, Rau M, Simão AC, Gertsch J Tags: ChemMedChem Source Type: research

In vitro biological tests as the first tools to validate magnetic nanotheranostics for colorectal cancer models.
The objective of this contribution is to evaluate the available and recent literature regarding the interactions of MNP and CRC models, aiming to critically analyzing the information given by the commonly used assays, evaluating the data provided by each one, in view of the implementation of this novel technology in CRC diagnostic and therapy. PMID: 32365271 [PubMed - as supplied by publisher] (Source: ChemMedChem)
Source: ChemMedChem - May 4, 2020 Category: Chemistry Authors: Martin MJ, Gentili C, Lassalle V Tags: ChemMedChem Source Type: research

Design, Synthesis and Biological Evaluation of Highly Potent Simplified Archazolids.
üller CE Abstract The archazolids represent potent antiproliferative compounds which have recently emerged as a novel class of promising anticancer agents. Their complex macrolide structures and scarce natural supply render the development of more readily available analogs of high importance. Herein, we report the design, synthesis and biological evaluation of four simplified and partially saturated archazolid derivatives revealing important structure-activity relationship data and insights into the pharmacophore of these complex polyketides. PMID: 32363789 [PubMed - as supplied by publisher] (Source: ChemMedChem)
Source: ChemMedChem - May 3, 2020 Category: Chemistry Authors: Menche D, Rivière S, Vielmuth C, Ennenbach C, Abdelrahman A, Lemke C, Gütschow M, Müller CE Tags: ChemMedChem Source Type: research

Targeting the water network in cyclin G associated kinase (GAK) with 4-anilino-quin(az)oline inhibitors.
Abstract Water networks within kinase inhibitor design and more widely within drug discovery are generally poorly understood. The successful targeting of these networks prospectively has great promise for all facets of inhibitor design, including potency and selectivity on target. Here we describe the design and testing of a targeted library of 4-anilinoquinolines for use as inhibitors of cyclin G associated kinase (GAK). The GAK cellular target engagement assays, ATP binding site modelling and extensive water mapping provide a clear route to access potent inhibitors for GAK and beyond. PMID: 32358915 [PubMed...
Source: ChemMedChem - May 1, 2020 Category: Chemistry Authors: Asquith CRM, Tizzard GJ, Bennett JM, Wells CI, Elkins JM, Willson TM, Poso A, Laitinen T Tags: ChemMedChem Source Type: research