Room-temperature catalytic hydrodefluorination of C(sp3)-F bonds

Room-temperature catalytic hydrodefluorination of the strong C(sp3)-F bonds in benzotrifluorides and fluoropentane is catalyzed by Et3Si[B(C6F5)4] and uses Et3SiH as the source of H. Ar-CF3 compounds are converted to Ar-CH3 and fluropentane to pentane. The reaction is thought to proceed via abstraction of F- by Et3Si[B(C6F5)4], and the substituent effects are consistent with this hypothesis.     

The molecular mechanism of stabilization of proteins by TMAO and its ability to counteract the effects of urea

Trimethylamine n-oxide (TMAO) is a naturally occurring osmolyte that stabilizes proteins and offsets the destabilizing effects of urea. To investigate the molecular mechanism of these effects, we have studied the thermodynamics of interaction between TMAO and protein functional groups. The solubilities of a homologous series of cyclic dipeptides were measured by differential refractive index and the dissolution heats were determined calorimetrically as a function of TMAO concentration at 25 degrees C. The transfer free energy of the amide unit (-CONH-) from water to 1 M TMAO is large and positive, indicating an unfavorable interaction between the TMAO solution and the amide unit. This unfavorable interaction is enthalpic in origin. The interaction between TMAO and apolar groups is slightly favorable. The transfer free energy of apolar groups from water to TMAO consists of favorable enthalpic and unfavorable entropic contributions. This is in contrast to the contributions for the interaction between urea and apolar groups. Molecular dynamics simulations were performed to provide a structural framework for the interpretation of these results. The simulations show enhancement of water structure by TMAO in the form of a slight increase in the number of hydrogen bonds per water molecule, stronger water hydrogen bonds, and long-range spatial ordering of the solvent. These findings suggest that TMAO stabilizes proteins via enhancement of water structure, such that interactions with the amide unit are discouraged.     

Partial-filling affinity capillary electrophoresis

Partial-filling affinity capillary electrophoresis (PFACE) is used to examine the binding interactions between two model biological systems: D-Ala-D-Ala terminus peptides to the glycopeptide antibiotic vancomycin (Van) from Streptomyces orientalis, and arylsulfonamides to carbonic anhydrase B (CAB, EC 4.2.1.1, bovine erythrocytes). Using these two systems, modifications in the PFACE technique are demonstrated including flow-through PFACE (FTPFACE), competitive flow-through PFACE (CFTPFACE), on-column ligand synthesis PFACE (OCLSPFACE), and multiple-step ligand injection PFACE (MSLIPFACE). In PFACE small plugs of sample are injected into the capillary column and an equilibrium is established between receptor and ligand during electrophoresis. Binding constants are then obtained by Scatchard analysis using changes in the migration time of the receptor/ligand on changing the concentration of the ligand/receptor. Data demonstrating the quantitative potential of these methods are presented. This review focuses on the unique capabilities of the different PFACE techniques as applied to two model biological systems.     

Synthesis of [Ni(η-CH2C6H4R-4){PPh(CH2CH2PPh2)2}] (R = H, Me or MeO) and protonation reactions with HCl

The complexes [Ni(η²-CH₂C₆H₄R-4)(triphos)]BPh₄ {R = H, Me or MeO; triphos = PhP(CH₂CH₂PPh₂)₂} have been prepared and characterised by spectroscopy and X-ray crystallography. In all cases the coordination geometry of the nickel is best described as square-planar with an η²-benzyl ligand occupying one of the positions. The orientation of the η²-benzyl ligand is dictated by the steric restrictions imposed by the phenyl groups on the triphos ligand, so that the phenyl group on the unique secondary phosphorus and the aromatic group of the benzyl ligand (which are trans to one another) are oriented in the same direction. [Ni(η²-CH₂C₆H₄R-4)(triphos)]⁺ react with an excess of anhydrous HCl in MeCN to form [NiCl(triphos)]⁺ (characterised as the [BPh₄]⁻ salt by X-ray crystallography) and the corresponding substituted toluene. The kinetics of the reaction of all [Ni(η²-CH₂C₆H₄R-4)(triphos)]⁺ and HCl in the presence of Cl⁻ have been determined using stopped-flow spectrophotometry. All reactions exhibit a first-order dependence on the concentration of complex and a first-order dependence on the ratio [HCl]/[Cl⁻]. Varying the 4-R-substituent on the benzyl ligand shows that electron-withdrawing substituents facilitate the rate of the reaction. It is proposed that the mechanism involves initial rapid protonation at the nickel to form [NiH(η²-CH₂C₆H₄R-4)(triphos)]²⁺, followed by intramolecular proton migration from nickel to carbon to yield the products.     

Enhancing the effectiveness of virtual screening by fusing nearest neighbor lists: a comparison of similarity coefficients

This paper evaluates the effectiveness of various similarity coefficients for 2D similarity searching when multiple bioactive target structures are available. Similarity searches using several different activity classes within the MDL Drug Data Report and the Dictionary of Natural Products databases are performed using BCI 2D fingerprints. Using data fusion techniques to combine the resulting nearest neighbor lists we obtain group recall results which, in many cases, are a considerable improvement on standard average recall values obtained for individual structures. It is shown that the degree of improvement can be related to the structural diversity of the activity class that is searched for, the best results being found for the most diverse groups. The group recall of active compounds using subsets of the class is also investigated: for highly self-similar activity classes, the group recall improvement saturates well before the full activity class size is reached. A rough correlation is found between the relative improvement using the group recall and the square of the number of unique compounds available in all of the merged lists. The Tanimoto coefficient is found unambiguously to be the best coefficient to use for the recovery of active compounds using multiple targets. Furthermore, when using the Tanimoto coefficient, the "MAX" fusion rule is found to be more effective than the "SUM" rule for the combination of similarity searches from multiple targets. The use of group recall can lead to improved enrichment in database searches and virtual screening.     

2-Mercaptomethyl-thiazolidines use conserved aromatic–S interactions to achieve broad-range inhibition of metallo-β-lactamases

Infections caused by multidrug resistant (MDR) bacteria are a major public health threat. Carbapenems are among the most potent antimicrobial agents that are commercially available to treat MDR bacteria. Bacterial production of carbapenem-hydrolysing metallo-β-lactamases (MBLs) challenges their safety and efficacy, with subclass B1 MBLs hydrolysing almost all β-lactam antibiotics. MBL inhibitors would fulfil an urgent clinical need by prolonging the lifetime of these life-saving drugs. Here we report the synthesis and activity of a series of 2-mercaptomethyl-thiazolidines (MMTZs), designed to replicate MBL interactions with reaction intermediates or hydrolysis products. MMTZs are potent competitive inhibitors of B1 MBLs in vitro (e.g., K_i = 0.44 μM vs. NDM-1). Crystal structures of MMTZ complexes reveal similar binding patterns to the most clinically important B1 MBLs (NDM-1, VIM-2 and IMP-1), contrasting with previously studied thiol-based MBL inhibitors, such as bisthiazolidines (BTZs) or captopril stereoisomers, which exhibit lower, more variable potencies and multiple binding modes. MMTZ binding involves thiol coordination to the Zn(ii) site and extensive hydrophobic interactions, burying the inhibitor more deeply within the active site than d/l-captopril. Unexpectedly, MMTZ binding features a thioether–π interaction with a conserved active-site aromatic residue, consistent with their equipotent inhibition and similar binding to multiple MBLs. MMTZs penetrate multiple Enterobacterales, inhibit NDM-1 in situ, and restore carbapenem potency against clinical isolates expressing B1 MBLs. Based on their inhibitory profile and lack of eukaryotic cell toxicity, MMTZs represent a promising scaffold for MBL inhibitor development. These results also suggest sulphur–π interactions can be exploited for general ligand design in medicinal chemistry.

Metallo-β-lactamases (MBLs) are major culprits of resistance to carbapenems in bacteria. A series of thiazolidines are potent MBL inhibitors, restoring the activity of carbapenems. Metal binding and sulphur–π interactions are key to inhibition.     

Measurement of the Rates of Diffusion of Halomethanes into Polymer Films Using ATR-FTIR Spectroscopy

Polymer-modified attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy and FEWS (fibre-optic evanescent wave) spectroscopy have been very successful to date for sensitive detection of organic pollutants in water utilising the mid-infrared (MIR) region of the electromagnetic spectrum (4000-400 cm^?1). This sensing approach involves the use of different polymer films for preconcentration with optimisation of the sensor related to the rate of diffusion of solvent molecules into these polymer films. Compounds such as chloroform, bromoform, bromodichloromethane and dibromochloromethane which are collectively referred to as trihalomethanes (THMs) were analysed in this work. A gaseous phase experimental design was used and from experimental data the rate of diffusion of each of the halomethanes was quantified based on a Fickian type diffusion model. Individual diffusion coefficient values were found to be in the range 3.38 E-10 ± 0.01 E-10 to 4.72 E-08 ± 0.42 E-08 cm² s^?1. Multicomponent effects were observed for mixtures of compounds diffusing into polyisobutylene and ethylene-propylene copolymer.     

Competing Effects of Chlorination on the Strength of Te⋅⋅⋅O Chalcogen Bonds Select the Structure of Mixed Supramolecular Macrocyclic Aggregates of Iso-Tellurazole N-Oxides

Chlorination of 3-methyl-5-phenyl-1,2-tellurazole-2-oxide yielded the λ⁴Te dichloro derivative. Its crystal structure demonstrates that the heterocycle retains its ability to autoassociate by chalcogen bonding (ChB) forming macrocyclic tetramers. The corresponding Te⋅⋅⋅O ChB distances are 2.062 Å, the shortest observed to date in aggregates of this type. DFT−D3 calculations indicate that while the halogenated molecule is stronger as a ChB donor it also is a weaker ChB acceptor; the overall effect is that the ChBs in the chlorinated homotetramer are not significantly stronger. However, partial halogenation or scrambling selectively yield the 2 : 2 heterotetramer with alternating λ⁴Te and λ²Te centers, which calculations identified as the thermodynamically preferred arrangement.     

Synthesis,Structure and Catalytic Activity of NHC–AgI Carboxylate Complexes

A general synthetic route was used to prepare 15 new N‐heterocyclic carbene (NHC)–Ag^I complexes bearing anionic carboxylate ligands [Ag(NHC)(O₂CR)], including a homologous series of complexes of sterically flexible ITent ligands, which permit a systematic spectroscopic and theoretical study of the structural and electronic features of these compounds. The complexes displayed a significant ligand‐accelerated effect in the intramolecular cyclisation of propargylic amides to oxazolidines. The substrate scope is highly complementary to that previously achieved by NHC–Au and pyridyl–Ag^I complexes.     

Synthesis by FVT and Characterization of Unhindered Silanethiones

The retro-ene reaction of allylthio- and propargylthiosilanes led, under flash vacuum thermolysis (FVT) conditions, to unhindered silanethiones, characterized by their derivatives, and also directly by coupling of the FVT with gas-phase spectrometries. Monomeric silicon oxysulfide has been generated similarly. The unsubstituted silanethione was not obtained, but dehydrogenated into silicon monosulfide during FVT.