ABSTRACT
The occurrence of resistances in Gram negative bacteria is steadily increasing to reach extremely worrying levels and one of the main causes of resistance is the massive spread of very efficient ß-lactamases which render most ß-lactam antibiotics useless. Herein, we report the development of a series of imino-analogues of ß-lactams (namely azetidinimines) as efficient non-covalent inhibitors of ß-lactamases. Despite the structural and mechanistic differences between serine-ß-lactamases KPC-2 and OXA-48 and metallo-ß-lactamase NDM-1, all three enzymes can be inhibited at a submicromolar level by compound 7dfm, which can also repotentiate imipenem against a resistant strain of Escherichia coli expressing NDM-1. We show that 7dfm can efficiently inhibit not only the three main clinically-relevant carbapenemases of Ambler classes A (KPC-2), B (NDM-1) and D (OXA-48) with Ki's below 0.3 µM, but also the cephalosporinase CMY-2 (class C, 86% inhibition at 10 µM). Our results pave the way for the development of a new structurally original family of non-covalent broad-spectrum inhibitors of ß-lactamases.
Subject(s)
Anti-Bacterial Agents/chemistry , Azetidines/chemistry , beta-Lactamase Inhibitors/chemistry , beta-Lactamases/chemistry , Anti-Bacterial Agents/metabolism , Anti-Bacterial Agents/pharmacology , Azetidines/metabolism , Binding Sites , Catalytic Domain , Cell Line , Cell Proliferation/drug effects , Escherichia coli Proteins/antagonists & inhibitors , Escherichia coli Proteins/genetics , Escherichia coli Proteins/metabolism , Gram-Negative Bacteria/drug effects , Humans , Inhibitory Concentration 50 , Microbial Sensitivity Tests , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Molecular Docking Simulation , Structure-Activity Relationship , beta-Lactamase Inhibitors/metabolism , beta-Lactamase Inhibitors/pharmacology , beta-Lactamases/genetics , beta-Lactamases/metabolismABSTRACT
Ynamides were used as precursors for the inâ situ generation of highly reactive ketenimines that could be trapped with imines in a [2+2] cycloaddition. This imino-Staudinger synthesis led to a variety of imino-analogs of ß-lactams, namely azetidinimines (20â examples), that could be further functionalized through a broad range of transformations.
ABSTRACT
Herein, the use of a well-defined low-valent cobalt(I) catalyst [HCo(PMe3)4] capable of performing the highly regio- and stereoselective hydrosilylation of internal alkynes is reported. The reaction can be applied to a variety of hydrosilanes, symmetrical and unsymmetrical alkynes, giving in many cases a single hydrosilylation isomer. Experimental and theoretical studies suggest the key step to be a hydro-cobaltation and that the reaction proceeds through a classical Chalk-Harrod mechanism.
ABSTRACT
The direct conversion of aliphatic carboxylic acids to the corresponding alkyl fluorides has been achieved via visible light-promoted photoredox catalysis. This operationally simple, redox-neutral fluorination method is amenable to a wide variety of carboxylic acids. Photon-induced oxidation of carboxylates leads to the formation of carboxyl radicals, which upon rapid CO2-extrusion and F(â¢) transfer from a fluorinating reagent yield the desired fluoroalkanes with high efficiency. Experimental evidence indicates that an oxidative quenching pathway is operable in this broadly applicable fluorination protocol.
Subject(s)
Carboxylic Acids/chemistry , Hydrocarbons, Fluorinated/chemical synthesis , Catalysis , Decarboxylation , Halogenation , Hydrocarbons, Fluorinated/chemistry , Molecular Structure , Oxidation-Reduction , Photochemical ProcessesABSTRACT
Go cyclic! The use of [Co(H)(PMe3)4] as a cobalt catalyst allows the previously unattainable catalytic version of the cobalt-mediated cycloaddition of enediynes without the requirement of thermal or light activation (see scheme). The importance of a chelating group on the substrate that can selectively direct the reaction pathway toward the classical polycyclic 1,3-cyclohexadienes or a new family of bicyclic trienes is also demonstrated.