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.     

Anti-Inflammatory Dysidazirine Carboxylic Acid from the Marine Cyanobacterium Caldora sp. Collected from the Reefs of Fort Lauderdale,Florida

Dysidazirine carboxylic acid (1) was isolated from the lipophilic extract of a collection of the benthic marine cyanobacterium Caldora sp. from reefs near Fort Lauderdale, Florida. The planar structure of this new compound was determined by spectroscopic methods and comparisons between HRMS and NMR data with its reported methyl ester. The absolute configuration of the single chiral center was determined by the conversion of 1 to the methyl ester and the comparison of its specific rotation data with the two known methyl ester isomers, 2 and 3. Molecular sequencing with 16S rDNA indicated that this cyanobacterium differs from Caldora penicillata (Oscillatoriales) and represents a previously undocumented and novel Caldora species. Dysidazirine (2) showed weak cytotoxicity against HCT116 colorectal cancer cells (IC₅₀ 9.1 µM), while dysidazirine carboxylic acid (1) was non-cytotoxic. Similar cell viability patterns were observed in RAW264.7 cells with dysidazirine only (2), displaying cytotoxicity at the highest concentration tested (50 µM). The non-cytotoxic dysidazirine carboxylic acid (1) demonstrated anti-inflammatory activity in RAW264.7 cells stimulated with LPS. After 24 h, 1 inhibited the production of NO by almost 50% at 50 µM, without inducing cytotoxicity. Compound 1 rapidly decreased gene expression of the pro-inflammatory gene iNOS after 3 h post-LPS treatment and in a dose-dependent manner (IC₅₀ ~1 µM); the downregulation of iNOS persisted at least until 12 h.     

Structure determination and infrared spectroscopy of K(UO2)(SO4)(OH)(H2O) and K(UO2)(SO4)(OH)

Two potassium uranyl sulfate compounds were synthesized, and their crystal structures were determined by single-crystal X-ray diffraction. K(UO2)(SO4)(OH)(H2O) (KUS1) crystallizes in space group P21/c, a = 8.0521(4) A, b = 7.9354(4) A, c = 11.3177(6) A, beta = 107.6780(10) degrees , V = 689.01(6) A3, and Z = 4. K(UO2)(SO4)(OH) (KUS2) is orthorhombic Pbca, a = 8.4451(2) A, b = 10.8058(4) A, c = 13.5406(5)A, V = 1235.66(7)A3, and Z = 8. Both structures were refined on the basis of F2 for all unique data collected with Mo Kalpha radiation and a CCD-based detector to agreement indices R1 = 0.0251 and 0.0206 calculated for 2856 and 2616 reflections for KUS1 and KUS2, respectively. The structures contain vertex-sharing uranyl pentagonal bipyramids and sulfate tetrahedra linked into new chains and sheet topologies. Infrared spectroscopy provides additional information about the linkages between the sulfate and uranyl polyhedra, as well as the hydrogen bonding present in the structures. The U-O-S connectivity is examined in detail, and the local bond angle is impacted by the steric constraints of the crystal structure.     

Chemical Validation of Mycobacterium tuberculosis Phosphopantetheine Adenylyltransferase Using Fragment Linking and CRISPR Interference**

The coenzyme A (CoA) biosynthesis pathway has attracted attention as a potential target for much-needed novel antimicrobial drugs, including for the treatment of tuberculosis (TB), the lethal disease caused by Mycobacterium tuberculosis (Mtb). Seeking to identify inhibitors of Mtb phosphopantetheine adenylyltransferase (MtbPPAT), the enzyme that catalyses the penultimate step in CoA biosynthesis, we performed a fragment screen. In doing so, we discovered three series of fragments that occupy distinct regions of the MtbPPAT active site, presenting a unique opportunity for fragment linking. Here we show how, guided by X-ray crystal structures, we could link weakly-binding fragments to produce an active site binder with a K_D <20 μM and on-target anti-Mtb activity, as demonstrated using CRISPR interference. This study represents a big step toward validating MtbPPAT as a potential drug target and designing a MtbPPAT-targeting anti-TB drug.     

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.     

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.     

GIT-equivalence and semi-stable subcategories of quiver representations

In this paper, we answer the question of when the subcategory of semi-stable representations is the same for two rational vectors for an acyclic quiver. This question has been previously answered by Ingalls, Paquette, and Thomas in the tame case in [14]. Here we take a more invariant theoretic approach, to answer this question in general. We recover the known result in the tame case.     

The Use of a Simple Multiple-Criteria Model to Assist in Selection from a Shortlist

The use of a simple multiple-criteria model to assist in decision making is described. The model, a hierarchical additive weighted value-function, was used as a part of a decision-making process to select, from a shortlist of three, the company with which to place a contract for the development of a computerized financial management system. The multiple-criteria model and its use are described in detail. To conclude, there is a discussion on the contribution of the model to the decision-making process as perceived by the decision-making group.     

The Binary System Tetradecanedioic Acid–Hexadecanedioic Acid: Polymorphism of the Components and Experimental Phase Diagram

Complementary techniques had to be applied to investigate the binary system tetradecanedioic acid (C₁₄H₂₆O₄)–hexadecanedioic acid (C₁₆H₃₀O₄), because all the forms observed have the same space group (P2₁/c; Z = 2). We studied the polymorphism of the two single compounds and of their mixtures by X‐ray powder diffraction, differential‐scanning calorimetry (DSC), infrared spectroscopy (IR), scanning electron microscopy (SEM), and thermo‐optical microscopy (TOM). The two diacids were found to be isopolymorphic. At low temperature, they crystallize in the same ordered C‐form, and, on heating, adopt the ordered C_h‐form, 1° below their melting point. In contrast to similar compounds (unbranched alkanes, alkanols, and fatty acids), the solid–solid and solid–liquid phase‐transition temperatures decrease with increasing chain length. At low temperature, a new monoclinic form, C_i, appears as a result of the disorder of composition in the mixed samples. There are two [C + C_i]‐type solid–solid domains. On heating, the solid domains are related to solid–liquid domains by a peritectic invariant for compositions rich in C₁₄H₂₆O₄, and by a eutectic invariant for compositions rich in C₁₆H₃₀O₄. At higher temperature, there appears a second peritectic invariant for compositions rich in C₁₄H₂₆O₄, together with a metatectic invariant for compositions rich in C₁₆H₃₀O₄. All the solid forms observed in this binary system are isostructural. Nevertheless, the equilibrium between them is complex near the melting point, and their miscibility in the solid state is reduced.     

Entropy Maximization for Markov and Semi-Markov Processes

The literature about maximum of entropy for Markov processes deals mainly with discrete-time Markov chains. Very few papers dealing with continuous-time jump Markov processes exist and none dealing with semi-Markov processes. It is the aim of this paper to contribute to fill this lack. We recall the basics concerning entropy for Markov and semi-Markov processes and we study several problems to give an overview of the possible directions of use of maximum entropy in connection with these processes. Numeric illustrations are presented, in particular in application to reliability.