213 research outputs found
Long-lived polymer-supported dimeric Cinchona alkaloid organocatalyst in the asymmetric α-amination of 2-oxindoles
Nearly quantitative yields and high enantiomeric purity (89–95% ee) were attained in the course of 100 reaction cycles of a polystyrene resin-supported Cinchona alkaloid organocatalyst in the enantioselective α-amination of 2-oxindoles with diethyl azodicarboxylate. The catalytic material proved stable for >5300 h operation time over 8 months
Pathoblockers or antivirulence drugs as a new option for the treatment of bacterial infections
The rapid development of antimicrobial resistance is threatening mankind to such an extent that the World Health Organization
expects more deaths from infections than from cancer in 2050 if current trends continue. To avoid this scenario, new classes of antiinfectives must urgently be developed. Antibiotics with new modes of action are needed, but other concepts are also currently being
pursued. Targeting bacterial virulence as a means of blocking pathogenicity is a promising new strategy for disarming pathogens.
Furthermore, it is believed that this new approach is less susceptible towards resistance development. In this review, recent examples of anti-infective compounds acting on several types of bacterial targets, e.g., adhesins, toxins and bacterial communication, are
described
SUPPORTED LIGANDS AND ORGANOCATALYSTS FOR ENANTIOSELECTIVE TRANSFORMATIONS: A PRACTICAL FEASIBILITY PERSPECTIVE
A new approach for the immobilization onto organic insoluble polymers of Cinchona alkaloid derivatives was developed and the resulting insoluble polymer-bound (IPB) systems were used as enantioselective organocatalysts in different metal-free asymmetric transformations. Landmarks of this work were the scalable preparation of the IPB derivatives, the attainment of excellent catalytic performance (up to 97% ee) in selected enantioselective processes (dimerization of ketenes and a-amination of 2-oxindoles) and extended serviceability (up to 100 reaction cycles and 5300 h reaction time) of the supported catalysts
Aminopropyl-silica-supported Cu nanoparticles: An efficient catalyst for continuous-flow Huisgen azide-alkyne cycloaddition (CuAAC)
Cu nanoparticles prepared by metal vapor synthesis (MVS) were immobilized on 3-aminopropyl-functionalized silica at room temperature. HRTEM analysis of the catalyst showed that the copper nanoparticles are present with mean diameters limited in the range 1.0-4.5 nm. TPR analysis was performed in order to study the oxidation state of the supported copper nanoparticles. The supported catalyst was used both in batch and in a packed-bed reactor for continuous-flow CuAAC reaction. The activation of the copper catalyst by reduction using phenyl hydrazine in continuous-flow conditions was demonstrated. Along with the high catalytic activity (productivity up to 1689 mol/mol), the catalyst can be used several times with negligible Cu leaching in the product (<9 ppm), less than allowed Cu contaminant in pharmaceuticals. The applicability of packed-bed flow reactor was showed by sequentially converting different substrates in their corresponding products using same column
New Polymer-Supported Mono- and Bis-Cinchona Alkaloid Derivatives: Synthesis and Use in Asymmetric Organocatalyzed Reactions
The straightforward synthesis of polystyrene-supported Chinchona alkaloids and their application in the asymmetric dimerization of ketenes is reported. Six different immobilized derivatives, consisting of three dimeric and two monomeric 9-O ethers, were prepared by “click” anchoring of soluble alkaloid precursors on to azidomethyl resins. The resulting insoluble polymer-bound (IPB) organocatalysts were employed for promoting the dimerization of in-situ generated ketenes. After opening of the ketene dimer intermediates with N,O-dimethylhydroxylamine, valuable Weinreb amides were eventually obtained in good yield (up to 81 %) and excellent enantiomeric purity (up to 96 % ee). All of the IPB catalysts could be recycled effectively without significant loss of activity and enantioselectivity. The extension to other asymmetric transformations (meso-anhydride desymmetrization and α-amination of 2-oxindoles) is also briefly discussed
Ultrafine palladium nanoparticles immobilized into poly(4-vinylpyridine)-based porous monolith for continuous-flow Mizoroki-Heck reaction
Ultrafine Pd nanoparticles (dm = 2.3 nm), obtained by metal vapor synthesis technique, were immobilized into a poly(4-vinylpyridine)-based porous monolith by means of a new synthetic approach. The synthesis involves stabilization of Pd nanoparticles with 4-vinylpyridine ligand and their subsequent immobilization into the monolith by radical co-polymerization of the resulting metal-embedding monomer with ethylene glycol dimethacrylate in presence of porogenic agents (i.e. DMF and PEG-400) inside stainless-steel columns (HPLC type). The hybrid monolithic reactors containing highly dispersed Pd nanoparticles were effectively used as catalyst for Mizoroki-Heck cross-coupling reactions carried out under continuous-flow conditions. The devices showed long life-time (>65 h) and very low Pd leaching (<2 ppm)
Potential Dental Biofilm Inhibitors: Dynamic Combinatorial Chemistry Affords Sugar-Based Molecules that Target Bacterial Glucosyltransferase
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) by UPLC-MS revealed major amplification of four compounds in the presence of GTF180. Moreover, we found that derivatives of the glucose-acceptor maltose at the C1-hydroxy group act as glucose-donors and are cleaved by GTF180. The synthesized hits display medium to low binding affinity (KD values of 0.4–10.0 mm) according to surface plasmon resonance. In addition, they were investigated for inhibitory activity in GTF-activity assays. The early-stage DCC study reveals that careful design of DCLs opens up easy access to a broad class of novel compounds that can be developed further as potential inhibitors
Inverting Small Molecule-Protein Recognition by the Fluorine Gauche Effect: Selectivity Regulated by Multiple H→F Bioisosterism
Fluorinated motifs have a venerable history in drug
discovery, but as C(sp3
)@F-rich 3D scaffolds appear with
increasing frequency, the effect of multiple bioisosteric changes
on molecular recognition requires elucidation. Herein we
demonstrate that installation of a 1,3,5-stereotriad, in the
substrate for a commonly used lipase from Pseudomonas
fluorescens does not inhibit recognition, but inverts stereoselectivity. This provides facile access to optically active,
stereochemically well-defined organofluorine compounds (up
to 98% ee). Whilst orthogonal recognition is observed with
fluorine, the trend does not hold for the corresponding
chlorinated substrates or mixed halogens. This phenomenon
can be placed on a structural basis by considering the
stereoelectronic gauche effect inherent to F@C@C@X systems
(s!s*). Docking reveals that this change in selectivity (H
versus F) with a common lipase results from inversion in the
orientation of the bound substrate being processed as a consequence of conformation. This contrasts with the stereochemical interpretation of the biogenetic isoprene rule, whereby
product divergence from a common starting material is also
a consequence of conformation, albeit enforced by two discrete
enzymes
Highly enantioselective catalytic synthesis of chiral pyridines
General methods to prepare chiral pyridine derivatives are greatly sought after due to their significance in medicinal chemistry. Here, we report highly enantioselective catalytic transformations of poorly reactive β-substituted alkenyl pyridines to access a wide range of alkylated chiral pyridines. The simple methodology involves reactivity enhancement via Lewis acid (LA) activation, the use of readily available and highly reactive Grignard reagents, and a copper-chiral diphosphine ligand catalyst. Apart from allowing the introduction of different linear, branched, cyclic, and functionalised alkyl chains at the β-position of alkenyl pyridines, the catalytic system also shows high functional group tolerance
Rapid Discovery of Aspartyl Protease Inhibitors Using an Anchoring Approach
Pharmacophore searches that include anchors, fragments
contributing above average to receptor binding, combined with
one-step syntheses are a powerful approach for the fast
discovery of novel bioactive molecules. Here, we are presenting
a pipeline for the rapid and efficient discovery of aspartyl
protease inhibitors. First, we hypothesized that hydrazine could
be a multi-valent warhead to interact with the active site Asp
carboxylic acids. We incorporated the hydrazine anchor in a
multicomponent reaction and created a large virtual library of
hydrazine derivatives synthetically accessible in one-step. Next,
we performed anchor-based pharmacophore screening of the
libraries and resynthesized top-ranked compounds. The inhibitory potency of the molecules was finally assessed by an
enzyme activity assay and the binding mode confirmed by
several soaked crystal structures supporting the validity of the
hypothesis and approach. The herein reported pipeline of tools
will be of general value for the rapid generation of receptor
binders beyond Asp proteases
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