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.     

Novel Synthesis of Agaritine,a 4-Hydrazinobenzyl-Alcohol Derivative Occurring in Agaricaceae

The 4-hydrazinobenzyl alcohol ( 3 was prepared (58%)) by diiobutylaluminiumhydride reduction of methyl 4-hydrazinobenzoate ( 4 ), whereas LiA1H₄ or LiBh₄ reduction of 4 proceeded further to yield (via intermediate 3 ) (4-tolyl)hydrazine ( 5 ). The alcohol 3 was stable under O₂-free conditions and exhibited no tendency to eliminate H₂O, neither thermally nor with H⁺ catalysis. Oxidation of 3 with SeO₂ yielded 4-(hydroxymethyl)benzine-diazonium ion ( 8 ), identified by its azo coupling product 9 with 2-naphthol. Condensation of 3 with 1-benzyl 5-Hydrogen N-(benzyloxycarbonyl)-L-glutamate ( 10 ) in presence of dicyclohexylcarbodiimide afforded 81% of N²-(benzyloxycarbonyl)-L- glutamic acid 1-(benzyl-ester) 5-{2-[4-(hydroxymethyl)phenyl]hydrazide} ( 11 ) which upon controlled hydrogenolysis (quinoline-sulfur-poisoned Pd/C catalyst) gave 82% of L-Glutamic acid 5-{2-[4-(hydroxymethyl)phenyl] hydrazide} ( 1 ), i. e. agaritine, a metabolite of Agaricus bisporus. Without poisoning of the catalyst, hydrogenolysis of ( 11 ) yielded L-glutamic acid 5-[2-(4-tolyl)hydrazide] ( 12 ).     

Triaziridine 7. Mitteilung. Stabile pyramidale Konfigurationen an den Stickstoff-Atomen von Dialkyl-und Trialkyl-triaziridinen

Stable Pyramidal configurations at the Nitrogen Atoms of Dialkyl-and Trialkyl-triaziridines Stereochemical features of the recently synthesized nine samples of di- and trialkyl-triaziridines, namely the 1,3-cyclopentylen-(series a ) and the two stereoisomers of the diisopropyl derivatives (series b and c ), containing as the third substituent an H-atom ( 2 ), a CH₃ group ( 3 )or a CH₂OH group ( 4 ), were elaborated on the basis of the ¹H-, ¹³C-, and ¹⁵N-NMR spectra. The three N-atoms of the saturated N₃-homocycle were found to be stable to pyramidal inversion in all cases. According to their NMR spectra, 2 – 4 of the series a and b possess twofold symmetry (C_s), while 2 – 4 of series c are asymmetric. Thus, series c has the trans-configuration at N(2)/N(3) and, consequently, the cis-configuration at N(1)/N(2), while series a and b have the cis-configuration at N(2)/N(3) and -since the all-cis-arrangement is excluded-the trans-configuration at N(1)/N(2). The asymmetry of the trans-configurated 2c turned into twofold symmetry (C₂), when a little CF₃COOH was added. The ¹H- and ¹³C-NMR data of series b and c of our alkyl-triaziridines exhibit a shielding effect, according to which there are two types of i-Pr groups, i-Pr(a) and i-Pr(b). They differ in the NMR signals of the H- and the C-atoms of their CH groups: the H-atoms of i-Pr(a) are more deshielded by 0.75–1.111 ppm and its C-atoms are more shielded by 10.0–160.0 ppm as compared to the corresponding atoms of i-Pr(b). i-Pr(a) is cis (on the N₃-homocycle) to a large substituent (such as i-Pr, Me, CH₂OH) and to a lone pair, while i-Pr(b)is cis only to a small (H) or to no substituent and to one or two lone pairs. An analogous effect appears in the NMR signals of the CH₃ and CH₂OH groups at N(1) of 3 and 4 in the series b and c .     

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.     

pH tunable self-assembly of chicoric acid and their biocompatibility studies

We report for the first time, the pH tunable self-assembly of chicoric acid, an HIV-I integrase inhibitor, which displayed a remarkable tendency to self-assemble at room temperature into varying nano- and microstructures. Furthermore, those assemblies were then functionalised with gold (Au) nanoparticles. We then investigated the biocompatibility of the materials by conducting in vitro cell attachment and cytotoxicity studies using normal rat kidney cells. The studies revealed that the biomaterials were non-toxic and biocompatible, and showed considerable adhesion to the cells. These results suggest that the assemblies could potentially be used for a variety of applications, such as carriers for targeted drug delivery as well as optoelectronics and sensors. Furthermore, the formation of highly organised nano- and microstructures of medicinally significant phytohormones such as chicoric acid is of particular interest as it might help in further understanding the supramolecular assembly mechanism of higher organised biological structures for the development of building blocks for various device fabrications.     

Total and inorganic mercury determination in fish tissue by flow injection cold vapour atomic fluorescence spectrometry

A simple and reliable method for Hg determination in fish samples has been developed. Lyophilised fish tissue samples were extracted in a 25% (w/v) tetramethylammonium hydroxide (TMAH) solution; the extracts were then analysed by FI-CVAFS. This method can be used to determine total and inorganic Hg, using the same FI manifold. For total Hg determination, a 0.1% (w/v) KMnO₄ solution was added to the FI manifold at the sample zone, followed by the addition of a 0.5% (w/v) SnCl₂ solution, whereas inorganic Hg was determined by adding a 0.1% (w/v) L-cysteine solution followed by a 1.0% (w/v) SnCl₂ solution to the FI system. The organic fraction was determined as the difference between total and inorganic Hg. Sample preparation, reagent consumption and parameters that can influence the FI-CVAFS performance were also evaluated. The limit of detection for this method is 3.7 ng g^?1 for total Hg and 4.3 ng g^?1 for inorganic Hg. The relative standard deviation for a 1.0 µg L^?1 CH₃Hg standard solution (n = 20) was 1.1%, and 1.3% for a 1.0 µg L^–1 Hg²⁺ standard solution (n = 20). Accuracy was assessed by the analysis of Certified Reference Material (dogfish: DORM-2, NRCC). Recoveries of 99.1% for total Hg and 93.9% inorganic Hg were obtained. Mercury losses were not observed when sample solutions were re-analysed after a seven day period of storage at 4°C.