- Structure–Activity and Structure–Toxicity Relationships of Peptoid-Based Histone Deacetylase Inhibitors with Dual-Stage Antiplasmodial Activity
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Novel malaria intervention strategies are of great importance, given the development of drug resistance in malaria-endemic countries. In this regard, histone deacetylases (HDACs) have emerged as new and promising malaria drug targets. In this work, we present the design, synthesis, and biological evaluation of 20 novel HDAC inhibitors with antiplasmodial activity. Based on a previously discovered peptoid-based hit compound, we modified all regions of the peptoid scaffold by using a one-pot multicomponent pathway and submonomer routes to gain a deeper understanding of the structure–activity and structure–toxicity relationships. Most compounds displayed potent activity against asexual blood-stage P. falciparum parasites, with IC50 values in the range of 0.0052–0.25 μm and promising selectivity over mammalian cells (SIPf3D7/HepG2: 170–1483). In addition, several compounds showed encouraging sub-micromolar activity against P. berghei exo-erythrocytic forms (PbEEF). Our study led to the discovery of the hit compound N-(2-(benzylamino)-2-oxoethyl)-N-(4-(hydroxycarbamoyl)benzyl)-4-isopropylbenzamide (2 h) as a potent and parasite-specific dual-stage antiplasmodial HDAC inhibitor (IC50 Pf3D7=0.0052 μm, IC50 PbEEF=0.016 μm).
- Mackwitz, Marcel K. W.,Hesping, Eva,Antonova-Koch, Yevgeniya,Diedrich, Daniela,Woldearegai, Tamirat Gebru,Skinner-Adams, Tina,Clarke, Mary,Sch?ler, Andrea,Limbach, Laura,Kurz, Thomas,Winzeler, Elizabeth A.,Held, Jana,Andrews, Katherine T.,Hansen, Finn K.
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- Thermodynamic and structural properties of Gd3+ complexes with functionalized macrocyclic ligands based upon 1,4,7,10-tetraazacyclododecane
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The co-ordination properties toward Na+, Ca2+, Zn2+, Cu2+ and Gd3+ of six ligands containing pendant functionalities attached to the common 1,4,7,10-tetraazacyclododecane macrocyclic ring have been studied by means of potentiometric and microcalorimetric methods. Stability constants for the l,4,7,10-tetra(methylcarbamoylmethyl) ligand (DTMA), and for the new 10-(2-hydroxypropyl) 1,4,7-tri(2-hydroxymethylacetic acid) (HPDO3A-3HM) and 1,4,7-tri(2-hydroxymethylacetic acid) ligand (DO3A-3HM) are reported for the first time, while analogous data for the remaining ligands have been redetermined under the same experimental conditions (0.1 mol dm-3 NMe4Cl, 298.1 ±0.1 K). The synthesis of DTMA is also described. The stability of the GdL complexes follows the order DOTA (1,4,7,10-tetraacetic acid) ≈ HPDO3A [10-(2-hydroxypropyl) 1,4,7-triacetic acid] > DO3A (1,4,7-triacetic acid) > HPDO3A-3HM > DO3A-3HM > DTMA, although considering both complex formation and ligand basicity the binding selectivity of these ligands at physiological pH follows the order HPDO3A > DOTA > HPDO3A-3HM > DO3A-3HM > DO3A > DTMA. The thermodynamic resistance of the Gd3+ complexes, at a plasma concentration of clinical administrations, toward demetallation in the presence of important components of blood plasma, such as Na+, Ca2+, Cu2+, Zn2+, phosphate and carbonate, has been evaluated: the results are consistent with the previous trend of binding selectivity. The formation of intermediate complexed species formed in the first minutes of the complexation reactions has been studied from a thermodynamic point of view. The crystal structure of [Gd(DTMA)(H2O)][ClO4]3-NaClO43H2O) solved by X-ray analysis, displays the Gd3+ ion in a 9-co-ordinated environment defined by four nitrogens of the tetraazamacrocyclic moiety, eight amidic oxygen atoms of the side arms and by an oxygen atom of a water molecule. The Royal Society of Chemistry 2000.
- Blanchi, Antonio,Calabi, Luisella,Claudia Giorgi, Pietro Losi,Mariani, Palma,Paoli, Paola,Rossi, Patrizia,Valtancoli, Barbara,Virtuani, Mario
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- In Vitro Anti-Toxoplasma gondii Activity Evaluation of a New Series of Quinazolin-4(3H)-one Derivatives
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Toxoplasmosis post serious threaten to human health, leading to severely eye and brain disease, especially for immunocompromised patients and pregnant women. The multiple side effects and long dosing period of current main treatment regiments calls for high effective and low toxicity anti-toxoplasmosis drugs. Herein, we report our efforts to synthesize a series of 2-(piperazin-1-yl)quinazolin-4(3H)-one derivatives and investigate their activity against Toxoplasma gondii tachyzoites in vitro based on cell phenotype screening. Among the 26 compounds, 8w and 8x with diaryl ether moiety at the side chain of piperazine exhibited good efficacy to inhibit T. gondii, with IC50 values of 4 μM and 3 μM, respectively. Structure-activity relationship (SAR) studies implies that hydrophobic aryl at the side chain would be preferred for improvement of activity. Molecular docking study reveals these two compounds appeared high affinity to TgCDPK1 by interaction with the hydrophobic pocket of ATP-binding cleft.
- Deng, Yu,Fu, Li-Zhi,Huang, Shu-Heng,Li, Cheng-Hong,Li, Hong-Bo,Mu, Hao,Tang, Da,Wu, Tao
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- Synthesis and preliminary evaluation of novel 11C-labeled GluN2B-selective NMDA receptor negative allosteric modulators
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N-methyl-D-aspartate receptors (NMDARs) play critical roles in the physiological function of the mammalian central nervous system (CNS), including learning, memory, and synaptic plasticity, through modulating excitatory neurotransmission. Attributed to et
- Sun, Ji-yun,Kumata, Katsushi,Chen, Zhen,Zhang, Yi-ding,Chen, Jia-hui,Hatori, Akiko,Fu, Hua-long,Rong, Jian,Deng, Xiao-yun,Yamasaki, Tomoteru,Xie, Lin,Hu, Kuan,Fujinaga, Masayuki,Yu, Qing-zhen,Shao, Tuo,Collier, Thomas Lee,Josephson, Lee,Shao, Yi-han,Du, Yun-fei,Wang, Lu,Xu, Hao,Zhang, Ming-rong,Liang, Steven H
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p. 491 - 498
(2020/07/16)
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- GluN2B subunit targeting central nervous system positron tracer and preparation thereof
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The existing GluN2B selective positron tracer has relatively high affinity and selectivity, but does not show ideal tracer properties in an in vivo experiment, has the problems of overquick metabolism, lower brain uptake, undifferentiated distribution in the whole brain, overquick degradation of C-11 labeled probe and off-target phenomenon caused by influence of other target spots in the brain, which limit the further translational research. The invention designs a novel GluN2B subunit targeting central nervous system positron tracer, reduces the metabolism rate of the tracer and prolongs theservice time by utilizing the characteristics that a methylamino structure is stable and not easy to metabolize. Meanwhile, the tracer of the invention is easy to be detected and traced through experiments, and has a better electron tracing effect. In addition, a preparation method provided by the invention is mild in conditions, and can quickly obtain a high-purity C11-labeled tracer injection,so as to effectively solve the problem of overquick degradation of the C-11 labeled probe.
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Paragraph 0042-0047
(2019/10/15)
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- TRICYCLIC COMPOUNDS HAVING SULFINYL AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
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It is intended to provide a compound that exhibits a wide antibacterial spectrum against various bacteria including gram-negative bacteria, and a pharmaceutical composition having an antibacterial activity against carbapenem-resistant bacteria.
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Paragraph 0062
(2020/01/02)
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- PHARMACEUTICAL COMPOSITION CONTAINING TRICYCLIC COMPOUND HAVING SULFINYL OR SULFONYL
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PROBLEM TO BE SOLVED: To provide a pharmaceutical composition that has antibacterial activity against carbapenem-resistant bacteria. SOLUTION: A pharmaceutical composition contains a compound represented by formula (I), its ester body or their pharmaceutically acceptable salts, or their hydrates (W is S(=O) or S(=O)2; T is CR4AR4B or CR5AR5B-CR6AR6B; R4A, R4B, R5A, R5B, R6A and R6B independently represent halogen, hydroxy, carbonyl, alkyl, cycloalkyl, aryl or the like; R1 is a carbocycle or heterocycle; R2A and R2B independently represent H, amino, hydroxy and the like, or R2A and R2B together form methylidene, hydroxyimino and the like; R3 is H, methoxy or the like). SELECTED DRAWING: None COPYRIGHT: (C)2018,JPOandINPIT
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Paragraph 0285
(2018/08/02)
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- Conformational Features of Thioamide-Containing Dipeptoids and Peptoid-Peptide Hybrids - Computational and Experimental Approaches
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The effects of thioamide incorporation into N,N-dimethyl-2-(N-methylacetamido)acetamide and N-methyl-2-(N-methylacetamido)acetamide as the simplest models of a dipeptoid structure and a peptoid-peptide hybrid are discussed. The solvent-modulated conformational features of model compounds were examined by computations enhanced by natural bond orbital (NBO) analysis and experimentally by kinetic and equilibrium measurements using NMR spectroscopy. The computations supported by NBO analysis showed that intrinsic stability of the predominant trans isomer (αD and C7β forms) of the dipeptoid model results from an indirect n → π? interaction, occurring between the carbonyl oxygen lone pair (n) and the π? orbital of the adjacent amide carbonyl through the C-H antibond (σ?). The direct n → π? interaction constitutes a negligible contribution to trans stabilization. The N-terminal thioxo substitution increases this indirect electron delocalization, making the αD isomer prevalent. The nX → σN′C-H? interaction is an additional source of stability of the trans-C7β form relevant for the underivatized dipeptoid model and its C-terminal thioamide counterpart. In the peptoid-peptide hybrid, the trans preference is perturbed by subtle differences in the H-bond donor-acceptor abilities between the thioxo and oxo groups. The cis isomer becomes more populated with an increase in the strength of polarity and the hydrogen bonding acceptor ability of the solvent molecules. While thioxo substitution slightly shifts the trans-cis equilibrium in polar solvents, it effectively allows for increasing or decreasing the barrier to trans-cis rotation with respect to underivatized model compounds depending on N- vs C-terminal thioamide backbone substitution.
- Zimnicka, Magdalena M.
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p. 7819 - 7831
(2018/10/05)
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- A 4 - phenyl quinoline compound, preparation method and application thereof (by machine translation)
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The invention discloses a 4 - phenyl quinoline compound, its preparation method and application, the invention of the 4 - phenyl quinoline compound to, its structure (I) shown in the diimmonium: Wherein R1 Is - OH, - Cl, - OCH3 Or -
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Paragraph 0037
(2017/08/31)
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- A silver triflate-catalyzed cascade of in situ-oxidation and allylation of arylbenzylamines
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A silver-triflate catalyzed cascade of in situ-oxidation and allylation of arylbenzylamines is reported. The 2,2,6,6-tetramethylpiperidine-1-oxoammonium tetrafluoroborate is employed as a mild oxidant which is compatible with both catalyst and ligand. Racemic BINAP is also utilized to assist with the catalyst in regulating the yields of products. Various homoallylic amines are obtained in 39–99% yields.
- Wang, Junjiao,Yang, Shangdong
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supporting information
p. 3444 - 3448
(2016/07/18)
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- Phosphorylation of Glycine Derivatives via Copper(I)-Catalyzed Csp3?H Bond Functionalization
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A simple and efficient one-pot approach has been developed for a copper-catalyzed phosphorylation of glycine derivatives under air and at room temperature. The present cross-dehydrogenative coupling allows various methoxyphenyl-protected glycine derivativ
- Zhi, Huizhen,Ung, Sosthene Pierre-Marie,Liu, Yun,Zhao, Liang,Li, Chao-Jun
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supporting information
p. 2553 - 2557
(2016/08/16)
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- Promiscuity and selectivity in covalent enzyme inhibition: A systematic study of electrophilic fragments
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Covalent ligand-target interactions offer significant pharmacological advantages. However, off-target reactivity of the reactive groups, which usually have electrophilic properties, must be minimized, and the selectivity of irreversible inhibitors is a crucial requirement. We therefore performed a systematic study to determine the selectivity of several electrophilic groups that can be used as building blocks for covalently binding ligands. Six reactive groups with modulated electrophilicity were combined with 11 nonreactive moieties, resulting in a small combinatorial library of 72 fragment-like compounds. These compounds were screened against a group of 11 enzyme targets to assess their selectivity and their potential for promiscuous binding to proteins. The assay results showed a considerably lower degree of promiscuity than initially expected, even for those members of the screening collection that contain supposedly highly reactive electrophiles.
- J?st, Christian,Nitsche, Christoph,Scholz, Therese,Roux, Lionel,Klein, Christian D.
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supporting information
p. 7590 - 7599
(2014/12/11)
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- Amphiphilic EuDOTA-tetraamide complexes form micelles with enhanced CEST sensitivity
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The synthesis and characterization of four new DOTA-tetraamide ligands having variable alkyl chain lengths (C1, C12, C 14, and C16) and their respective europium(III) complexes are reported. The three EuL comple
- Evbuomwan, Osasere M.,Kiefer, Garry,Sherry, A. Dean
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experimental part
p. 2126 - 2134
(2012/06/15)
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- Strategies for labeling proteins with PARACEST agents
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Reactive surface lysine groups on the monoclonal antibody (3G4) and on human serum albumin (HSA) were labeled with two different PARACEST chelates. Between 7.4 and 10.1 chelates were added per 3G4 molecule and between 5.6 and 5.9 chelates per molecule of
- Vasalatiy, Olga,Zhao, Piyu,Woods, Mark,Marconescu, Andrei,Castillo-Muzquiz, Aminta,Thorpe, Philip,Kiefer, Garry E.,Dean Sherry
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experimental part
p. 1106 - 1114
(2011/03/20)
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- NOVEL MACROCYCLIC INHIBITORS OF HEPATITIS C VIRUS REPLICATION
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The embodiments provide compounds of the general Formulae I, II, III, IV, V, VI, VII, and X, as well as compositions, including pharmaceutical compositions, comprising a subject compound. The embodiments further provide treatment methods, including methods of treating a hepatitis C virus infection and methods of treating liver fibrosis, the methods generally involving administering to an individual in need thereof an effective amount of a subject compound or composition.
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- Structure-activity relationships of 9-substituted-9-dihydroerythromycin- based motilin agonists: Optimizing for potency and safety
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A series of 9-dihydro-9-acetamido-N-desmethyl-N-isopropyl erythromycin A analogues and related derivatives was generated as motilin agonists. The compounds were optimized for potency while showing both minimal antibacterial activity and hERG inhibition. As the substituent on the amide was increased in lipophilicity the potency and hERG inhibition increased, while polar groups lowered potency, without significantly impacting hERG inhibition. The N-methyl acetamide 7a showed the optimal in vitro profile and was probed further by varying the chain length to the macrocycle as well as changing the macrocycle scaffold. 7a remained the compound with the best in vitro properties. 2009 American Chemical Society.
- Shaw, Simon J.,Chen, Yue,Zheng, Hao,Fu, Hong,Burlingame, Mark A.,Marquez, Saul,Li, Yong,Claypool, Mark,Carreras, Christopher W.,Crumb, William,Hardy, Dwight J.,Myles, David C.,Liu, Yaoquan
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supporting information; experimental part
p. 6851 - 6859
(2010/04/04)
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- Functionalizing glycine derivatives by direct C-C bond formation
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(Chemical Equation Presented) Come on glycine: Two different types of glycine derivatives are α-functionalized using cross-dehydrogenative- coupling (CDC) reactions. The method allows the efficient attachment of a malonate or aromatic alkyne group on the α-position of the glycine derivatives under very mild conditions.
- Zhao, Liang,Li, Chao-Jun
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supporting information; experimental part
p. 7075 - 7078
(2009/04/07)
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- Motilide compounds
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Compounds having a structure according to formula (I) where RA, RB, RC, RD, RE, and RF are as defined herein, are useful as prokinetic agents.
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Page/Page column 20-21
(2008/06/13)
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- Indole derivatives as 5-HT1-like agonists for use in migraine
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The present invention relates to 3,5-disubstituted indole compounds which are selective agonists which act on 5-hdroxytryptamine receptors useful in the treatment of migraine.
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- A SIMPLE AND EFFICIENT ONE POT SYNTHESIS OF 4-OXO-SPIRO AND THEIR REACTIONS WITH DDQ
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The treatment of two equivalents of the anion of 3,4-dihydro-1H-quinoline-2-thione (3) with one equivalet of one of the N-substituted 2-bromoacetamides (4a-d) at room temperature afforded the title compounds in good yields (Scheme 1, Table 1).The reaction of the compounds (6a-d) with DDQ at room temperature and 90 deg C was studied.Mechanistic aspects of the processes are briefly discussed.
- Walter, Harald
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p. 2427 - 2436
(2007/10/03)
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- Synthesis of Charged and Uncharged Complexes of Gadolinium and Yttrium with Cyclic Polyazaphosphinic Acid Ligands for in vivo Applications
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The synthesis of 18 new macrocyclic complexing agents incorporating phosphinic acid (and carboxylic acid) groups is reported, based on the 1,4,7,10-tetraazacyclododecane ring.Through selective functionalisation of one ring nitrogen or by changing the natu
- Pulukkody, Kanthi P.,Norman, Timothy J.,Parker, David,Royle, Louise,Broan, Christopher J.
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p. 605 - 620
(2007/10/02)
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