- Structure-Activity Studies with Bis-Amidines That Potentiate Gram-Positive Specific Antibiotics against Gram-Negative Pathogens
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Pentamidine, an FDA-approved antiparasitic drug, was recently identified as an outer membrane disrupting synergist that potentiates erythromycin, rifampicin, and novobiocin against Gram-negative bacteria. The same study also described a preliminary structure-activity relationship using commercially available pentamidine analogues. We here report the design, synthesis, and evaluation of a broader panel of bis-amidines inspired by pentamidine. The present study both validates the previously observed synergistic activity reported for pentamidine, while further assessing the capacity for structurally similar bis-amidines to also potentiate Gram-positive specific antibiotics against Gram-negative pathogens. Among the bis-amidines prepared, a number of them were found to exhibit synergistic activity greater than pentamidine. These synergists were shown to effectively potentiate the activity of Gram-positive specific antibiotics against multiple Gram-negative pathogens such as Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Escherichia coli, including polymyxin- and carbapenem-resistant strains.
- Wesseling, Charlotte M. J.,Slingerland, Cornelis J.,Veraar, Shanice,Lok, Samantha,Martin, Nathaniel I.
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p. 3314 - 3335
(2021/11/24)
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- General and Facile Route to Isomerically Pure Tricyclic Peptides Based on Templated Tandem CLIPS/CuAAC Cyclizations
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We report a one-pot ligation/cyclization technology for the rapid and clean conversion of linear peptides into tricyclic peptides that is based on using tetravalent scaffolds containing two benzyl bromide and two alkyne moieties. These react via CLIPS/CuAAC reactions with cysteines and azides in the peptide. Flexibility in the scaffolds is key to the formation of isomerically pure products as the flexible scaffolds T41 and T42 mostly promote the formation of single isomeric tricycles while the rigid scaffolds T43 and T44 do not yield clean products. There seems to be no limitation to the number and types of amino acids present as 18 canonical amino acids were successfully implemented. We also observed that azides at the peptide termini and cysteine residues in the center gave better results than compounds with the functional groups placed the other way round.
- Richelle, Gaston J. J.,Ori, Sumeet,Hiemstra, Henk,van Maarseveen, Jan H.,Timmerman, Peter
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supporting information
p. 501 - 505
(2017/12/26)
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- MULTICYCLIC PEPTIDES AND METHODS FOR THEIR PREPARATION
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The invention relates to methods for preparing a compound comprising a peptide attached to a molecular scaffold whereby multiple peptide loops are formed, to compounds that can be obtained with such methods and uses thereof.
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Page/Page column 76; 77; 82
(2018/06/30)
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- ENDOSOMOLYTIC AGENTS FOR GENE THERAPY
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Compounds of formula (I), wherein Ar is an aryl group optionally further substituted with one or more groups R3; A is a lipophilic, hydrophobic moiety; R1 is a phosphodiester, phosphotriester, thioether or amide group; X is an unsubs
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Page/Page column 26
(2018/04/17)
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- ZINC COMPLEX
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A zinc complex characterized in exhibiting an octahedral structure and being configured from repeating units represented by general formula (I): wherein L represents a linker region, and R1 represents a C1-4 alkyl group, which can have a halogen atom.
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- AROMATIC RING-CONTAINING COMPOUND AND CANCER PREVENTIVE AND/OR THERAPEUTIC AGENT
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PROBLEM TO BE SOLVED: To provide cancer preventive/therapeutic means that can exhibit cancer cell-specific therapeutic effect on many cancers. SOLUTION: According to one embodiment of the present invention, an aromatic ring-containing compound represented
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Paragraph 0070
(2017/01/02)
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- Structure-guided design of selective inhibitors of neuronal nitric oxide synthase
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Nitric oxide synthases (NOSs) comprise three closely related isoforms that catalyze the oxidation of l-arginine to l-citrulline and the important second messenger nitric oxide (NO). Pharmacological selective inhibition of neuronal NOS (nNOS) has the potential to be therapeutically beneficial in various neurodegenerative diseases. Here, we present a structure-guided, selective nNOS inhibitor design based on the crystal structure of lead compound 1 in nNOS. The best inhibitor, 7, exhibited low nanomolar inhibitory potency and good isoform selectivities (nNOS over eNOS and iNOS are 472-fold and 239-fold, respectively). Consistent with the good selectivity, 7 binds to nNOS and eNOS with different binding modes. The distinctly different binding modes of 7, driven by the critical residue Asp597 in nNOS, offers compelling insight to explain its isozyme selectivity, which should guide future drug design programs.
- Huang, He,Li, Huiying,Martásek, Pavel,Roman, Linda J.,Poulos, Thomas L.,Silverman, Richard B.
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p. 3024 - 3032
(2013/06/04)
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- Construction of hexanuclear macrocycles by a coupling strategy from polyfunctionalized bis(terpyridines)
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The construction of a heteronuclear (Ru4Fe2) hexameric metallomacrocycle with methyl- and carbonyl-functionalized bis(terpyridyl) moieties was achieved by a self-assembly of a dinuclear trimer, which was prepared in high yield via Pd
- Eryazici, Ibrahim,Newkome, George R.
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scheme or table
p. 345 - 357
(2009/06/21)
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- Cytotoxic agents comprising new tomaymycin derivatives and their therapeutic use
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The present invention is related to new tomaymycin derivatives having a linking chain between two units of pyrrolo[2,1c][1,4]benzodiazepines, substituted by a non-cleavable linker and their conjugated to cell binding agents, their process of preparation a
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Page/Page column 26-27
(2009/02/10)
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- ALYKYLENE DERIVATIVE HAVING EDG RECEPTOR ANTAGONISM
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PROBLEM TO BE SOLVED: To provide novel compounds having EDG (endothelial differentiation gene) receptor antagonism which are useful as active components of drugs for preventing and/or treating inflammatory diseases or the like. SOLUTION: The compounds are represented by formula (I) (wherein R1 is hydrogen or an alkyl group; R2 is hydrogen present at any substitutable position on ring C or a substituent such as a hydroxy group, a carboxy group, and a nitro group; R3 is hydrogen present at any substitutable position on ring D or a substitutent such as a hydroxy group and an aralkyloxy group; X is an alkylamino group, an amino group or the like; Y is a carboxy group, a sulfo group or a phosphono group; Z is oxygen, sulfur or the like; a ring represented by A is a 5- or 6-membered saturated or unsaturated hydrocarbon ring; and a ring represented by B is a 4- or 7-membered saturated or unsaturated hydrocarbon ring containing one -C=C- as a partial structure shown in the above formula) and include their salts and their esters.
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Page/Page column 141
(2010/02/12)
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- Pyrazolo-[4,3-e]-1,2,4-triazolo-[1,5-c]-pyrimidine adenosine A2a receptor antagonists
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Compounds having the structural formula I or a pharmaceutically acceptable salt thereof, wherein R is optionally substituted phenyl, furanyl, thienyl, pyridyl, pyridyl N-oxide, oxazolyl or pyrrolyl, or cycloalkenyl R1, R2, R3, R4 and R5 are H, alkyl or alkoxyalkyl; and Z is optionally substituted aryl or heteroaryl are disclosed. Also disclosed is the use of compounds of formula I in the treatment of central nervous system diseases, in particular Parkinson's disease, alone or in combination with other agents for treating Parkinson's disease, and pharmaceutical compositions comprising them.
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Page/Page column 22
(2008/06/13)
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- PROCESS FOR PRODUCING 5-(3-CYANOPHENYL)-3-FORMYLBENZOIC ACID COMPOUND
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A 5-(3-cyanophenyl)-3-formylbenzoic acid compound of the formula (IV) is prepared by reacting a 5-bromo-3-(hydroxymethyl)benzoic acid compound of the formula (I) with manganese dioxide to provide a 5-bromo-3-formylbenzoic acid compound of the formula (II)
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- 2-Alkynyl-and 2-alkenyl-pyrazolo-[4,3-e]-1,2,4-triazolo-[1,5-c]-pyrimidine adenosine A2a receptor antagonists
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Compounds having the structural formula I or a pharmaceutically acceptable salt thereof, wherein R is R1, R2, R3, R4 and R5 are H, alkyl or alkoxyalkyl; R6 is H, alkyl, hydroxyalkyl or —CH2F; R7, R8 and R9 are H, alkyl, alkoxy, alkylthio, alkoxyalkyl, halo or —CF3; and Z is optionally substituted aryl, heteroaryl or heteroaryl-alkyl are disclosed. Also disclosed is the use of compounds of formula I in the treatment of central nervous system diseases, in particular Parkinson's disease, alone or in combination with other agents for treating Parkinson's disease, and pharmaceutical compositions comprising them.
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- Cis-imidazolines
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The present invention provides compounds according to formula I and formula II and pharmaceutically acceptable salts and esters thereof, having the designations provided herein and which inhibit the interaction of MDM2 protein with a p53-like peptide and have antiproliferative activity
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- Synthesis of nitronyl- and imino-nitroxide-triradicals interconnected by phenyl ethynyl spacer
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The design and synthesis, as well as solid state and ESR characterisation of three new triradicals based on phenyl ethynyl backbone bearing nitronyl-nitroxide and imino-nitroxide groups, are reported. The synthesis of these compounds was based on palladium-coupling reactions between alkynyl and bromo derivatives. An ESR study showed magnetic interactions between the radicals through the phenyl ethynyl-coupling unit in solution. (C) 2000 Elsevier Science Ltd.
- Catala, Laure,Turek, Philippe,Le Moigne, Jacques,De Cian, André,Kyritsakas, Nathalie
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p. 1015 - 1018
(2007/10/03)
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- Enantioselective catalysis; 123: Octaaldehyde type chelating ligands - A divergent synthesis approach to easily tunable expanded ligands for enantioselective catalysis
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A broad range of optically active two-layer phosphanes was obtained by a divergent reaction sequence. Chirality was introduced into the ligands in the last step by easily performed Schiff base condensation of primary amines from the 'chiral pool' and achiral octaaldehydes containing a bisphosphane core. The two achiral precursors are 1,2-ethylene- and o-phenylene-bridged bisphosphanes with four 3,5-dicarbaldehyde-substituted phenyls, synthesized in six steps. The resulting octaimine ligands have been used in Rh, Pd and Ni complexes in several model reactions of enantioselective catalysis giving low optical inductions.
- Brunner,Janura,Stefaniak
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p. 1742 - 1749
(2007/10/03)
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- Cyclotriveratrylene as preorganizing matrix : A new tripole ligand
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The synthesis of a tripode ligand combining three pyridine rings arranged around a rigid derivative of cyclotriveratrylene is described.
- Wytko, Jennifer A.,Weiss, Jean
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p. 7261 - 7264
(2007/10/02)
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- Circular Dichroism, XCI. - Syntheses and CD of Benzene Derivatives with Several Similar Substituents
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Several optically active 1,2-di and 1,3,5-trisubstituted benzene derivatives have been synthesized, in which one substituent is chiral, the others being methyl, ethyl, or neopentyl.The CD spectra within the α-band can be explained well by making use of Pl
- Netzke, Karl,Snatzke, Guenther
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p. 1365 - 1372
(2007/10/02)
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