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In the present study, four O-substituted oximes of quinuclidin-3-one were synthesized using appropriate O-substituted hydroxylamine hydrochlorides. In order to perform these reactions in a solvent, a mixture of (E) and (Z) products was yielded. Using mechanochemical and microwave synthesis, we then obtained pure (E) oximes. In almost all cases, the conversion to oxime ethers was completed. Reactions were monitored by ATR spectroscopy and the ratios of (E) and (Z) oxime ethers were deduced from 1H NMR data. Several reactions were very rapid (1 min) with 100% conversion and stereospecificity. To investigate the reaction mechanisms, full conformational analyses of the reaction intermediates were performed and the lowest energy conformers were determined. These conformers differed in spatial arrangement around the nitrogen atom of the amino group and were in the correct orientation for reactions to occur. Calculated standard Gibbs energies of the formation were in agreement with the experimentally obtained ratios of (E) and (Z) isomers. This work shows alternatives to the classical synthesis of O-substituted oxime ether precursors and highlights the fast reaction rate and stereoselectivity of microwave synthesis as well as the “green” aspects of mechanochemistry.

The propensity of 4-hydroxybenzhydrazone-related ligands derived from 3-methoxysalicylaldehyde (H2L3OMe), 4-methoxysalicylaldehyde (H2L4OMe), and salicylaldehyde (H2LH) to act as chelating and/or bridging ligands in Ni(II) complexes was investigated. Three clusters of different nuclearities, [Ni3(L3OMe)2(OAc)2(MeOH)2]∙2MeOH∙MeCN (1∙2MeOH∙MeCN), [Ni2(HL4OMe)(L4OMe)(OAc)(MeOH)2]∙4.7MeOH (2∙4.7MeOH), and [Ni4(HLH)2(LH)2(OAc)2]∙4MeOH·0.63H2O·0.5MeCN·HOAc (3∙4MeOH·0.63H2O·0.5MeCN·HOAc), were prepared from Ni(OAc)2∙4H2O and the corresponding ligand in the presence of Et3N. The hydrazones in these acetato- and phenoxido-bridged clusters acted as singly or doubly deprotonated ligands. When pyridine was used, mononuclear complexes with the square-planar geometry seemed to be favoured, as found for complexes [Ni(L3OMe)(py)] (4), [Ni(L4Ome)(py)] (5) and [Ni(LH)(py)] (6). Ligand substituent effects and the stability of square-planar complexes were investigated and quantified by extensive quantum chemical analysis. Obtained results showed that standard Gibbs energies of binding were lower for square-planar than for octahedral complexes. Starting from [MoO2(L)(EtOH)] complexes as precursors and applying the metal-exchange procedure, the mononuclear complexes [Ni(HL3OMe)2]∙MeOH (7∙MeOH) and [Ni(HLH)]∙2MeOH (9∙2MeOH) and hybrid organic–inorganic compound [Ni2(HL4OMe)2(CH3OH)4][Mo4O10(OCH3)6] (10) were achieved. The octahedral complexes [Ni(HL)2] (7–9) can also be obtained by the direct synthesis from Ni(Oac)2∙4H2O and the appropriate ligand under specific reaction conditions. Crystal and molecular structures of 1∙2MeOH∙MeCN, 2∙4.7MeOH, 3∙4MeOH∙0.63H2O∙0.5MeCN∙HOAc, 4, 5, 9∙2MeOH, and 10 were determined by the single-crystal X-ray diffraction method.

Structure and hydrogen bonding interactions of bioactive oxazolidinones have been studied by means of NMR and vibrational spectroscopies and quantum chemical calculations. We have demonstrated that oxazolidinone derivatives form hydrogen bonds in solution and solid state. Conformational space search has revealed predominant conformations in solution. In low polarity solvents, such as chloroform, dimers are formed presumably by intermolecular hydrogen bonds between two oxazolidinone molecules forming the most stable complexes, which has also been found in the solid state by IR spectroscopy and crystallography. In solvents of higher polarities, like methanol and dimethylsulfoxide, intermolecular interactions with solvent molecules and in dimers are present. As expected, raising the temperature broke hydrogen bonds, which was reflected in down-field chemical shifts of corresponding resonances. On the other hand, raising the solution concentration considerably affected oxazolidinone resonances only in chloroform, corroborating the formation of oxazolidinone dimers. These results may help in better understanding oxazolidinone structure, properties and interactions when designing new bioactive compounds and pharmaceutical products.

International audience; This contribution describes the synthesis, characterization, and catalytic implementation of the highly constrained molybdenum(VI) polymers [MoO2(LR)]n (with R = H (1), 3OMe (2), and 4OMe (3)) and cyclic tetramer [MoO2(L4OMe)]4·0.5MeCN (3′·0.5MeCN) with nicotinoyl hydrazonato ligands (LR) derived from salicylaldehyde (LH), 3-methoxy-2-hydroxybenaldehyde (L3OMe), or 4-methoxy-2-hydroxybenzaldehyde (L4OMe). In order to determine the most stable geometries, conformational analysis of the free and coordinated ligands in these assemblies was carried out through the potential energy surface scans using quantum-chemical methods. The mononuclear analogues [MoO2(HLR)(MeOH)]Cl (R = H (1a) and 3OMe (2a)), [MoO2(HLR)Cl] (R = 3OMe (2b) and 4OMe (3b)), and [MoO2(LR)(MeOH)] (R = H (1c), and 4OMe (3c-α and 3c-β)) were also synthesized and evaluated as potential precursors for reactions in the solid state. Vapor induced transformation of 2a quantitatively afforded complex 2b. The chemometric analysis using principal component analysis was applied to provide insight into the reaction profile. Thermally induced solid-state reactions resulted in the transformation of metallocycle 3′·0.5MeCN and monomeric complexes 1c, 2a, 3c-α, and 3c-β into the corresponding coordination polymers. The structural features responsible for these conversions are discussed in detail. Lastly, the metallosupramolecular architectures were tested as catalysts for cyclooctene epoxidation by using tert-butyl hydroperoxide as an oxidant in water or decane. Compound 3′ is shown to be the most effective and selective catalyst.

Five hexamolybdate and five octamolybdate-based organic–inorganic hybrid assemblies, with dioxomolybdenum(VI) hydrazonato complex cations, were synthesized from the [MoO2(acac)2] and isonicotinoyl hydrazone ligands bearing OH (H2L1, 2) and OMe (H2L3, 4) electron-donating groups. They can be classified into four categories including one known (i) [MoO2(HL1–4 ) (D)]2[Mo6O19]·xMeCN·yH2O, where D=H2O or MeCN, and three novel (ii) [Mo2O2(μ- O)2(HL3 )2][Mo6O19], (iii) [MoO2(HL1, 2)(H2O)]4[Mo8- O26]·xMeCN·yH2O, and (iv) [MoO2(H2L2, 4) (H2O)]2[Mo8O26]·xMeCN·yH2O, thus extending the structural landscape of Mo-complex–POM hybrids. Characterization of the hybrids, employing X-ray crystallography, IR-ATR, and TG analysis, was carried out. The effects of the reaction conditions and coordination nature of the Mo(VI) complex cations on the structure of the hybrid compounds were investigated. Relative differences in the standard Gibbs energies of formation (ΔΔfG°rel) of the structures were calculated to determine the possibility of developing the covalently anchored POM–Mo-complex hybrids. The impact of the metal–organic components and various solvents on the particular type of hybrid formation was evaluated.

Bacterial infections that do not respond to current treatments are increasing, thus there is a need for the development of new antibiotics. Series of 20 N-substituted quaternary salts of cinchonidine (CD) and their quasi-enantiomer cinchonine (CN) were prepared and their antimicrobial activity was assessed against a diverse panel of Gram-positive and Gram-negative bacteria. All tested compounds showed good antimicrobial potential (minimum inhibitory concentration (MIC) values 1.56 to 125.00 μg/mL), proved to be nontoxic to different human cell lines, and did not influence the production of reactive oxygen species (ROS). Seven compounds showed very strong bioactivity against some of the tested Gram-negative bacteria (MIC for E. coli and K. pneumoniae 6.25 μg/mL, MIC for P. aeruginosa 1.56 μg/mL). To establish a connection between antimicrobial data and potential energy surfaces (PES) of the compounds, activity/PES models using principal components of the disc diffusion assay and MIC and data towards PES data were built. An extensive machine learning procedure for the generation and cross-validation of multivariate linear regression models with a linear combination of original variables as well as their higher-order polynomial terms was performed. The best possible models with predicted R2(CD derivatives) = 0.9979 and R2(CN derivatives) = 0.9873 were established and presented. This activity/PES model can be used for accurate prediction of activities for new compounds based solely on their potential energy surfaces, which will enable wider screening and guided search for new potential leads. Based on the obtained results, N-quaternary derivatives of Cinchona alkaloids proved to be an excellent scaffold for further optimization of novel antibiotic species.

The two red centrosymmetric Ni(II) tetrameric complexes with defective double-cubane core, [Ni2L2(H2O)]2·0.75 CH3OH (1) and [Ni2L2(CH3CN)]2 (2) (H2L = N-(2-hydroxy-5-methylphenyl)- salicylideneimine), have been isolated and magnetically characterized, emphasizing the effect of the reaction temperature on structural and magnetic properties of isolated complexes. Prevailing antiferromagnetic interactions in the complexes are observed leading to the non- magnetic ground state. Comparation with the known magneto-structural correlations in nickel cubane and dicubane complexes is discussed.

Crude oils are extremely complex organic mixtures, composed of various constituents ranging in size, shape and polarity. Obtaining a detailed insight into the petroleum composition is of highest priority for quality evaluation of crude oils and crude oil product performances. The stability of crude oils and their components represents one of the major challenges in petroleum industry, since there is no existing single method to determine the stability of all fractions. In this study, statistical multi-way analysis (MWA) and machine learning (ML) methods were coupled with diffusion-ordered NMR spectroscopy (DOSY) and compared to different crude oil stability affecting parameters in order to explore possibilities to predict crude oil stability. The potential of this approach was explored to identify and classify the crude oils of different origin according to their composition, stability, density and diffusion properties. With the application of MWA using the TUCKER3 decomposition model for a set of DOSY NMR spectra, the principal components were determined for the model (5,5,5), which described 99.89 % of the total variance. The reduced space of the first 3 principal components was used for the sample classification. Similar samples were identified, and reduced space was further utilized for the regression of measured stabilities. Extensive ML multivariate linear regression was carried out for modeling crude oil stability in relation to DOSY NMR spectra and other measured properties, such as aromaticity, API gravity, percentage of aliphatic chains, asphaltene content and relative diffusivities. In both MWA and ML cases the best predictive models were determined. For such complex mixtures as crude oils are, exceptionally good correlations were obtained, proving that this new and robust model can accurately predict crude oil stability and other important parameters relevant for petroleum industry thus showing a great potential for practical applications.

Synthesis of hydrazones was performed via both conventional and solvent-free routes using the corresponding hydrazide (isonicotinic hydrazide, nicotinic hydrazide, 2- aminobenzhydrazide or 4- aminobenzhydrazide) and appropriate aldehyde (salicylaldehyde, 3- methoxysalicylaldehyde or 4- methoxysalicylaldehyde). A systematic study dedicated to solvatomorphism or polymorphism screening resulted in the formation of twelve novel crystalline forms, and eight of these were characterized via the single crystal X-ray diffraction method. In all studied structures, the molecules were assembled into endless supramolecular chains, discrete rings, chains of rings or nets. The mechanochemical synthesis employing liquid-assisted grinding was also applied and the nicotinic- and isonicotinic- based hydrazones were found to form readily from their corresponding precursors. The chemometric study using principal component analysis for mechanochemical synthesis monitoring was implemented for the first time to provide an insight into the reaction profiles. A thoughtful combination of ex situ powder X-ray diffraction and chemometric analysis was essential to identify a stepwise mechanism for the hydrazone formation via an intermediate phase. In five investigated reactions the first principal component accounted for at least 75% of the total variance, whereas in the case of two reactions this component accounted for 69.72 and 46.23% of the total variance. The hydrazones were also evaluated for cytotoxic activity in vitro. All compounds exhibited weak to moderate cytotoxicity against THP-1 and no cytotoxicity against HepG2 cells. Substantial antibacterial activity was obtained against Moraxella catarrhalis while no growth inhibition of Staphylococcus aureus, Enterococcus faecalis and Escherichia coli was observed.

Identification and characterization of asphaltenes, the most polar and predominantly aromatic components of crude oil, still post a challenge for researchers in the oil industry, owing to their complex molecular architecture. Recently, much effort has been devoted to understanding their structure and physicochemical properties. In this paper, a combination of diffusion-ordered NMR spectroscopy (DOSY) and statistical multiway methods was used to investigate petroleum samples and asphaltenes of different origin. Such multiway TUCKER3 decomposition has been used for the first time to analyze the two-dimensional matrix of complex nuclear magnetic resonance (NMR) data for petroleum samples. DOSY NMR spectra of 50 samples (45 for establishing the statistical model and 5 for its validation) were recorded and evaluated by an in-house-developed code incorporating multiway analysis to set up a tool for predicting their identity and origin. A statistical model was developed that can identify and separate asphaltene ...

A study of strong halogen bonding within three series of halogen-bonded complexes, derived from seven para-substituted pyridine derivatives and three N-halosuccinimides (iodo, bromo and chloro), has been undertaken with the aid of single-crystal diffraction, solution complexation and computational methods. The halogen bond was compared with the hydrogen bond in an equivalent series based on succinimide. The halogen-bond energies are in the range −60 to −20 kJ mol−1 and change regularly with pyridine basicity and the Lewis acidity of the halogen. The halogen-bond energies correlate linearly with the product of charges on the contact atoms, which indicates a predominantly electrostatic interaction. The binding enthalpies in solution are around 19 kJ mol−1 less negative due to solvation effects. The optimised geometries of the complexes in the gas phase are comparable to those of the solid-state structures, and the effects of the supramolecular surroundings in the latter are discussed. The bond energies for the hydrogen-bonded series are intermediate between the halogen-bond energies of iodine and bromine, although there are specific differences in the geometries of the halogen- and hydrogen-bonded complexes.

Synthesis of hydrazones (1a–4a and 1b–4b), quinazolines (3c*MeOH and 3d*MeOH), and hydrazone- Schiff bases (4c and 4d) is achieved by combining suitable aldehydes (2, 3- or 2, 4- ihydroxybenzaldehyde) with four hydrazides (isonicotinic, nicotinic, and 2- or 4-aminobenzoic acid hydrazide). A suite of approaches for their preparation is described: solution-based synthesis, mechanosynthesis, and solid-state melt reactions. The mechanochemical approach is generally a better choice for the quinazolines, while the solid-state melt reaction is more efficient for derivatives of (iso)nicotinic based hydrazones. Crystalline amine-functionalised hydrazones 4a and 4b undergo post-synthetic modifications in reactions with 3- or 4- pyridinecarbaldehyde vapours to form hydrazone- Schiff bases 4a-3py, 4b-3py, 4a-4py, and 4b4py. Mechanochemical and vapour-mediated reactions are followed by ex situ powder X-ray diffraction and IR-ATR methods, respectively. The chemometric analysis of these data using principal component analysis provided an insight into the reaction profiles and reaction times. Azines (5a and 5b), achieved from aldehydes and hydrazine, reversibly change colour in response to temperature changes. The structures of all products are ascertained by a combined use of spectroscopic and X-ray diffraction methods. The cytotoxic and antimicrobial activities of all compounds against selected human cancer cell lines and bacterial strains are evaluated.

The treatment of central nervous system (CNS) diseases related to the decrease of neurotransmitter acetylcholine in neurons is based on compounds that prevent or disrupt the action of acetylcholinesterase and butyrylcholinesterase. A series of thirteen quinuclidine carbamates were designed using quinuclidine as the structural base and a carbamate group to ensure the covalent binding to the cholinesterase, which were synthesized and tested as potential human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. The synthesized compounds differed in the substituents on the amino and carbamoyl parts of the molecule. All of the prepared carbamates displayed a time-dependent inhibition with overall inhibition rate constants in the 103 M−1 min−1 range. None of the compounds showed pronounced selectivity for any of the cholinesterases. The in silico determined ability of compounds to cross the blood–brain barrier (BBB) revealed that six compounds should be able to pass the BBB by passive transport. In addition, the compounds did not show toxicity toward cells that represented the main models of individual organs. By machine learning, the most optimal regression models for the prediction of bioactivity were established and validated. Models for AChE and BChE described 89 and 90% of the total variations among the data, respectively. These models facilitated the prediction and design of new and more potent inhibitors. Altogether, our study confirmed that quinuclidinium carbamates are promising candidates for further development as CNS-active drugs, particularly for Alzheimer’s disease treatment.

The in situ condensation reaction of 2-hydrazinobenzothiazole with salicylaldehyde, 3,4-dihydroxybenzaldehyde, 2,4-dihydroxybenzaldehyde, 2,5-dihydroxybenzaldehyde, 2,3-dihydroxybenzaldehyde, 2-hydroxy-1-naphthaldehyde, 2-methoxy-1-naphthaldehyde, 4-methoxy-1-naphthaldehyde and 6-methoxy-2-naphthaldehyde produced 9 hydrazone Schiff bases (L1–L9, respectively) which were identified and characterized by elemental analysis, IR and NMR spectroscopy. The crystal and molecular structures of four Schiff bases (L1, L7–L9) have been determined by the single-crystal X-ray diffraction method confirming the imino form of L1 and the amino tautomeric form of L7–L9 compounds. Molecular structure analysis also confirmed that reported compounds are E-isomers relative to exo C = N imino bond. The Nhydrazino–H group of amino tautomers forms Nhydrazino–H···Nthiazolyl intermolecular hydrogen bonds shaping molecules into R 2 2 (8) rings, while imino tautomer of L1 forms C(4) infinite helical chains via Nthiazolyl–H···Nhydrazino type of intermolecular hydrogen bond. The methoxy group (L7–L9) further shaped these primary supramolecular synthons into different supramolecular arrangements via C–H···O, C–H···N and C–H···S intermolecular hydrogen bonds. The role of aryl substituents in the shaping and stabilization of supramolecular architectures of L1, L7–L9 is supported by quantum chemical calculations. Strong antiproliferative effects on tumor cells and cytotoxic effects on fibroblasts are shown for all ligands L1–L9 with exception of L6 and L7 that had no effect on fibroblast cells.

Halohydrin dehalogenase from Arthrobacter sp. AD2 catalysed azidolysis of epoxides with high regioselectivity and low to moderate (S)-enantioselectivity (E = 1–16). Mutation of the asparagine 178 to alanine (N178A) showed increased enantioselectivity towards styrene oxide derivatives and glycidyl ethers. Conversion of aromatic epoxides was catalysed by HheA-N178A with complete enantioselectivity, however the regioselectivity was reduced. As a result of the enzyme-catalysed reaction, enantiomerically pure (S)-β-azido alcohols and (R)-α-azido alcohols (ee ⩾ 99%) were obtained.

Motivated by diverse biological and pharmacological activity of quinuclidine and oxime compounds we have synthesized and characterized novel class of surfactants, 3-hydroxyimino quinuclidinium bromides with different alkyl chains lengths (CnQNOH ; n = 12, 14 and 16). The incorporation of nonconventional hydroxyimino quinuclidinium headgroup and variation in alkyl chain length affects hydrophilic-hydrophobic balance of surfactant molecule and thereby physicochemical properties important for its application. Therefore, newly synthesized surfactants were characterized by the combination of different experimental techniques: X-ray analysis, potentiometry, electrical conductivity, surface tension and dynamic light scattering measurements, as well as antimicrobial susceptibility tests. Comprehensive investigation of CnQNOH surfactants enabled insight into structure-property relationship, i.e. way in which the arrangement of surfactant molecules in the crystal phase correlates with their solution behavior and biologically activity. The synthesized CnQNOH surfactants exhibited high adsorption efficiency and relatively low critical micelle concentrations. In addition, all investigated compounds showed very potent and promising activity against Gram-positive and clinically relevant Gram-negative bacterial strains compared to conventional antimicrobial agents: tetracycline and gentamicin. The overall results indicate that bicyclic headgroup with oxime moiety, which affects both hydrophilicity and hydrophobicity of CnQNOH molecule in addition to enabling hydrogen bonding, has dominant effect on crystal packing and physicochemical properties. The unique structural features of cationic surfactants with hydroxyimino quinuclidine headgroup along with diverse biological activity have made them promising structures in novel drug discovery. Obtained fundamental understanding how combination of different functionalities in a single surfactant molecule affects its physicochemical properties represents a good starting point for further biological research.

The aim of this study was to investigate the feasibility of FTIR-ATR spectroscopy coupled with the multivariate numerical methodology for qualitative and quantitative analysis of binary and ternary edible oil mixtures. Four pure oils (extra virgin olive oil, high oleic sunflower oil, rapeseed oil, and sunflower oil), as well as their 54 binary and 108 ternary mixtures, were analyzed using FTIR-ATR spectroscopy in combination with principal component and discriminant analysis, partial least-squares, and principal component regression. It was found that the composition of all 166 samples can be excellently represented using only the first three principal components describing 98.29% of total variance in the selected spectral range (3035-2989, 1170-1140, 1120-1100, 1093-1047, and 930-890 cm(-1)). Factor scores in 3D space spanned by these three principal components form a tetrahedral-like arrangement: pure oils being at the vertices, binary mixtures at the edges, and ternary mixtures on the faces of a tetrahedron. To confirm the validity of results, we applied several cross-validation methods. Quantitative analysis was performed by minimization of root-mean-square error of cross-validation values regarding the spectral range, derivative order, and choice of method (partial least-squares or principal component regression), which resulted in excellent predictions for test sets (R(2)0.99 in all cases). Additionally, experimentally more demanding gas chromatography analysis of fatty acid content was carried out for all specimens, confirming the results obtained by FTIR-ATR coupled with principal component analysis. However, FTIR-ATR provided a considerably better model for prediction of mixture composition than gas chromatography, especially for high oleic sunflower oil.

Adulteration of hempseed (H) oil, a well known health beneficial nutrient, is studied in this work by means of 1H NMR spectroscopy. H oil samples were mixed with cheap and widely used oils such as rapeseed (R) oil and sezame (Se) and sunflower (Su) oil. Many samples of different geographic origins were taken into account. Binary mixture sets of hempseed oil with these three oils (HR, HSe and HSu) were considered. 1H NMR spectra of pure oils and their mixtures were recorded and quantitative analyses were performed using Partial Least Squares Regression (PLS), First-Break Forward Interval PLS methods (FB-FiPLS) and Interval Ridge Regression (iRR). The obtained results show that each particular oil can be very successfully quantified (RMSEP 1.4–3.0%), and that NMR coupled with iRR has a great potential in studying signals of low intensity belonging to oil microconstituents. This means that 1H NMR spectroscopy coupled with multivariate methods can rapidly and effectively determine both the fatty acid profile and the level of adulteration in the adulterated hempseed oil for these studied and frequently used adulterant oils.

Full conformational space of cinchonine and cinchonidine has been investigated by means of statistical analysis of quantum chemical molecular dynamics simulations. Recently developed procedure comprising principal component analysis of molecular dynamics trajectories was applied on cinchonine and cinchonidine as well as on their protonated and methylated quaternary derivatives. The method for full conformational analysis includes Cartesian coordinates sampling through quantum chemical molecular dynamics simulations, reduction of dimensionality by principal component analysis, determination of probability distributions in a reduced space of Cartesian coordinates and search for all the strict extrema points in probability distribution functions. In order to gain crucial insight in the understanding of chirality induction of these alkaloids, comparison of the determined conformational spaces of pseudo-enantiomers has been made. It was shown that protonation of the quinuclidine nitrogen atom stabilizes the conformers with the intramolecular 1N–H∙∙∙9O hydrogen bond whereas methylation on the same position results in the reduction of the domain of internal coordinates responsible for the conformational space. This work is licensed under a Creative Commons Attribution 4.0 International License.

Cinchona alkaloids are natural products isolated from bark of the Cinchona tree. They have interesting structures which consist of bicyclic aliphatic quinuclidine ring and aromatic quinoline ring, connected through a chiral carbon atom bearing hydroxyl group. Parent alkaloids and their derivatives have a variety of applications, for example as chiral agents in different chromatography techniques and chiral catalysts in asymmetric synthesis. Because of their structure and stereochemistry, Cinchona alkaloids can have a complex conformational behavior in the solution and the thorough knowledge about the dominant conformers can be crucial for understanding reaction pathways and stereochemical outcome of the catalyzed reactions. Conformational space of a few Cinchona alkaloids has been previously investigated by some techniques in the field of NMR spectroscopy and molecular modeling . In this study, complete and detailed conformational landscape of cinchonidine and its pseudo-enantiomeric pair cinchonine has been determined both experimentally, by the low temperature 1H NMR, 2D NMR spectroscopy (HSQC, COSY, NOESY) and theoretically. Furthermore, their quaternary ammonium salts were also investigated. Tensor decomposition of the ab initio molecular dynamics trajectories was used to determine the full conformational space of the investigated compounds in vacuo and in the water box.

In the search for a new class of potential antimicrobial agents, five novel N-substituted imidazole 2-aldoximes and their six quaternary salts were evaluated. The antimicrobial activity was assessed against a panel of representative Gram-positive and Gram-negative bacteria, including multidrug resistant bacteria. All compounds demonstrated potent in vitro activity against the tested microorganisms, with MIC values ranging from 6.25 to 50.0 μg/mL. Among the tested compounds, two quaternary compounds (N-but-3-enyl- and meta- (10) or para- N-chlorobenzyl (11) imidazolium 2-aldoximes) displayed the most potent and broad-spectrum activity against both Gram-positive and Gram-negative bacterial strains. The broth microdilution assay was also used to investigate the antiresistance efficacy of the both most active compounds against a set of Enterobacteriaceae isolates carried a multiple extended-spectrum β-lactamases (ESBLs) in comparison to eight clinically relevant antibiotics. N-but-3-enyl-N-meta-chlorobenzyl imidazolium 2-aldoxime was found to possess promising antiresistance efficacy against a wide range of β-lactamases producing strains (MIC 2.0 to 16.0 μg/mL). Best results for that compound were obtained against Escherichia coli and Enterobacter cloacae producing multiple β-lactamases form A and C molecular classes, which were 32- and 128-fold more potent than ceftazidime and cefotaxime, respectively. To visualize the results, principal component analysis was used as an additional classification tool. The mixture of ceftazidime and compound 10 (3 μg:2 μg) showed a strong activity and lower the necessary amount (up to 40-fold) of 10 against five of ESBL-producing isolates (MIC ≤ 1 µg/mL).

NMR spectroscopy in combination with statistical methods was used to study vacuum residues and vacuum gas oils from 32 crude oils of different origin. Two chemometric metodes were applied. First- ly, principal component analysis on complete spectra was used to perform classification of samples and clear distinction between vacuum residues and vacuum light and heavy gas oils were obtained. To quanti- tatively predict the composition of asphaltenes, principal component regression models using areas of res- onance signals spaned by 11 frequency bins of the 1 H NMR spectra were build. The first 5 principal com- ponents accounted for more than 94 % of variations in the input data set and coefficient of determination for correlation between measured and predicted values was R 2 = 0.7421. Although this value is not signifi- cant, it shows the underlying linear dependence in the data. Pseudo two-dimensional DOSY NMR exper- iments were used to assess the composition and structural properties of asphaltenes in a selected crude oil and its vacuum residue on the basis of their different hydrodynamic behavior and translational diffusion coefficients. DOSY spectra showed the presence of several asphaltene aggregates differing in size and interactions they formed. The obtained results have shown that NMR techniques in combina- tion with chemometrics are very useful to analyze vacuum residues and vacuum gas oils. Furthermore, we expect that our ongoing investigation of asphaltenes from crude oils of different origin will elucidate in more details composition, structure and properties of these complex molecular systems.

Six non−symmetric enaminones 4-[(2-hydroxy-5-methylphenyl)amino]pent-3-en-2-one ( H 2 L 1 ), 4-[(2-hydroxy-4-methylphenyl)amino]pent-3-en-2-one ( H 2 L 2 ), 4-[(4-hydroxy-2-methylphenyl)amino)]pent-3-en-2-one ( H 2 L 3 ), 3-[(2-hydroxy-5-methylphenyl)amino]-1-phenylbut-2-en-1-one ( H 2 L 4 ), 3-[(2-hydroxy-4-methylphenyl)amino]-1-phenylbut-2-en-1-one ( H 2 L 5 ) and 3-[(4-hydroxy-2-methylphenyl)amino]-1-phenylbut-2-en-1-one ( H 2 L 6 ) have been prepared by solution based method. The enaminones were characterized by elemental and DSC analysis, NMR and IR spectroscopy. Crystal and molecular structures of H 2 L 1 , H 2 L 2 , H 2 L 4 and H 2 L 6 were determined via single crystal X−ray analysis. The prepared enaminones were screened against THP-1 and HepG2 cells, and Staphylococcus aureus , Enterococcus faecalis , Escherichia coli and Moraxella catarrhalis bacteria to assess their cytotoxic and antibacterial activity, respectively. All compounds proved to be non-cytotoxic and showed mild or no antibacterial activity. Quantum mechanical calculations suggest that the presence of hydroxy group in ortho position, combined with the methyl group on the same aromatic ring, has a significant impact on the biological activities.

New fluorescent calix[4]arene derivatives 1, 2, and 3 were synthesized by introducing phenanthridine moieties at a lower calixarene rim. It was shown that due to the prominent fluorescence of compounds 1 and 3, they could be considered as potential sensitive fluorimetric cation sensors. Complexation of the prepared compounds with alkali-metal cations was studied at 25 C in acetonitrile– dichloromethane and methanol–dichloromethane solvent mixtures (4 ¼ 0.5) by means of fluorimetric, spectrophotometric, potentiometric, and microcalorimetric titrations as well as NMR spectroscopy. The stability constants of the corresponding complexes were determined, as were the enthalpies and entropies of the complexation reactions. In addition, equilibrium constants of ion-pairing reactions between alkali-metal cations and several anions in the solvents used were measured conductometrically. It was found that the cation-binding affinity of ligand 1 with four phenanthridine subunits was much higher than that of 2 and 3, with the complex stabilities in all cases being significantly lower in methanol– dichloromethane mixture compared to that in acetonitrile– dichloromethane. These findings were thoroughly discussed by taking into account the determined thermodynamic complexation data, structural properties of the ligand and free and complexed cations, as well as the solvation abilities of the solvents examined. The conclusions made in that way were corroborated by the results of the molecular dynamics simulations of the systems studied. An attempt to get an insight into the possible structures of the alkali- metal cation complexes with ligand 1 was made by carrying out the corresponding density functional theory calculations.

The structure and hydrogen bonding in solution of acetylacetone and benzoylacetone derived enaminone derivatives, 1a – 1d and 2a – 2d , have been studied by a combination of experimental (NMR and UV spectroscopies) and theoretical (PM6 and DFT) methods. It has been shown that all studied compounds predominantly existed in the localised keto-amine tautomeric form in solution as found also in the solid state. Significant line-broadening and down-field chemical shifts of NH and OH protons have strongly indicated that both groups formed hydrogen bonds, which has further been supported by quantum chemical calculations. Temperature and concentration dependent NMR measurements have pointed towards the fact that NH protons are engaged in strong intramolecular hydrogen bonds of the NH⋯O C type in both solvents. On the other hand, OH protons are involved in weaker intermolecular hydrogen bonding with solvent molecules in DMSO, while in chloroform intermolecular interactions between two molecules dominate. The results presented in this paper can be used for better understanding and further exploiting properties these ligands possess, especially their bioactivity.

A new procedure for full conformational analyses comprising the statistical analysis of molecular dynamics trajectories was developed and applied. This method included a coordinate space for sampling using molecular dynamics simulations, reduction of dimensionality using tensor decomposition tools, determination of probability distributions in a reduced space, and finally the search for all of the strict extrema points of probability distributions. These extracted extrema points formed an initial guess for geometry optimization and clustering of conformers. A complete conformational space of 1-oxaspiro[2, 5]octane and its cis- and trans-4-, 5- and 6-methyl substituted derivatives was also determined. In each case, eight conformers were found with two chair-like conformers predominant at room temperature. It was found that chair-like conformers with an epoxide ring oxygen atom in the pseudo-axial position had less strain, as well as all of their conformers with the methyl substituent in an equatorial position on a cyclohexane moiety.

An example of commercially available product, 2-(methylideneamino)acetonitrile (MAAN). This paper will address problems in discerning monomer–polymer ambiguity in organic compounds. Reliable three-step analysis of organic polymers will be proposed using the synergy of computational [density functional theory (DFT)] and experimental [infrared spectroscopy (IR); X-ray powder diffraction (XRPD)] techniques. First, possible conformations of monomeric and trimeric MAAN were calculated using stochastic search and DFT. Second, identification of the commercial sample was performed by comparing the measured IR spectrum with those calculated for monomer and trimer. Third, the examination of sample purity and structural analysis were carried out using XRPD data.

Structural alterations of the aglycon portions of amannosides influence their inhibitory potency toward type 1-fimbriated Escherichia coli. The aim of our work was to prepare and explore inhibitory properties of novel mannosylated N-aryl-substituted 3- hydroxypyridine-4-ones because they possess needed structural characteristics as possible FimH antagonists. Hemagglutination inhibitory tests showed that the examined 3- hydroxypyridine-4-one a-mannosides exhibited better inhibitory activity than methyl a-D- mannopyranoside used as a reference compound. Molecular modeling studies revealed the specific interactions responsible for the observed binding activities toward the mannosespecific FimH lectin. The activity depends on the substituent in p-position on the aglycon aromatic ring.

Three polymorphic forms of the molybdenum- (VI) complex [MoO2(L)(EtOH)] (1α, 1β, and 1γ) (L2− = 4- methoxy-2-oxybenzaldehyde isonicotinylhydrazonate) were synthesized by the reaction of H2L with the dioxobis- (acetylacetonato)molybdenum(VI) complex, [MoO2(acac)2], in ethanol. Removal of the coordinated ethanol molecule upon grinding or heating led to the solid-state transformation of the polymorphs 1α, 1β, or 1γ into the coordination polymer [MoO2(L)]n (2a). The square inclusion complex [MoO2(L)]4⊃CH2Cl2·4CH2Cl2 (2b⊃CH2Cl2·4CH2Cl2) was obtained by a self-assembly reaction in dichloromethane. Standard Gibbs energies of binding for molybdenum(VI) compounds [MoO2(L)(D)] with the sixth coordination site occupied by a nitrogen or an oxygen donor D were estimated using quantum chemical calculations. Crystal and molecular structures of the molybdenum(VI) compounds [MoO2(L)(EtOH)] (1α, 1β, and 1γ), [MoO2(L)]4⊃CH2Cl2·4CH2Cl2 (2b⊃CH2Cl2·4CH2Cl2), [MoO2(L)(γ-pic)]·γ-pic (3·γ-pic), [MoO2(L)(py)] (4), and [MoO2(L)(DMSO)] (5) were determined by the single crystal X-ray diffraction method. The compounds were further characterized by chemical analysis, thermogravimetric, and differential scanning calorimetry measurements, IR, UV−vis, one- and two-dimensional NMR spectroscopies, and the powder X-ray diffraction method.

Two novel fluorescent calix[4]arenes comprising diphenylanthracene moiety at the lower rim were synthetized and their complexation with alkali metal cations in acetonitrile/dichloromethane and methanol/dichloromethane mixtures (φ = 0.5) was studied experimentally and by classical molecular dynamics and quantum chemical calculations. The monosubstituted calixarene derivative (L1) proved to be a poor cation receptor, whereas the ester-based macrocycle (L2) exhibited rather high affinity towards lithium, sodium and potassium cations, particularly in MeCN/CH2Cl2. All complexation reactions were enthalpically controlled, whereby the overall stability was the largest in the case of sodium complex. The computational investigations provided an additional insight into the complexation properties and structures of complex species. The molecular dynamics simulations indicated the occurrence of inclusion of solvent molecules in the calixarene hydrophobic cavity of the free and complexed ligand, which was found to significantly affect the complexation equilibria. This work is licensed under a Creative Commons Attribution 4.0 International License.

The reaction of [CoIII(4,4′dmsalen)(CH2Cl)(L)], where 4,4′dmsalen = 4,4′-dimethylsalen and L = solvent, with pyridine led to the isolation of [CoIII(4,4′dmsalen)(CH2py)(Cl)], in a two-step process involving a metallacyclized intermediate, cis β [CoIII(4,4′dmsalenCH2)(py)(L)]+, whereas a parallel direct conversion through the displacement of a Cl atom from the axial CH2Cl group of [CoIII(4,4′dmsalen)(CH2Cl)(L)] may be ruled out. Natural bond orbital analysis of the structures show that the ylide carbon atom has lower orbital occupancies in the cyclized complex, thus making it more susceptible to a nucleophilic attack of pyridine. The calculated potential energy surfaces indicate that the most energy feasible reaction path would be for the complex [CoIII(4,4′dmsalenCH2)(py)ax(H2O)]+, with an entering pyridine molecule and a leaving equatorial water molecule. Experimental kinetic studies of the formation of the ylide complex starting from [CoIII(4,4′dmsalenCH2)(py)eq(H2O)]+ strongly suggest that it is possible to obtain the ylide complex through an alternative, less energetically favourable path.

A series of novel adamantane-substituted guanylhydrazones was synthesized and used in a study of inhibitory potential toward butyrylcholinesterase. The experimental results were further supported by using docking studies to examine the behavior of the inhibitors within the active site regions of the enzyme. The enzyme-inhibitor dissociation constants K(i) were determined from Hunter-Downs diagrams using Ellman's method for cholinesterase activity determination. Compounds 2-(N-guanidino)iminoadamantane hydrochloride (1) and 2,4-bis(N,N'-guanidino)iminoadamantane dihydrochloride (2) were found to be the best BChE inhibitors and their affinities for the enzyme active site were about five times higher compared to the enzyme peripheral site. The strongest interaction observed in complexes obtained by docking studies was the H-bond between the guanidine and the carboxylate of Glu199 and the second guanidine group in bisguanidine compounds was stabilized with additional H-bonds.

In-line Raman spectroscopy and multivariate analysis were used to monitor Knoevenagel condensation reaction, the final step in preparation of drug entacapone. By applying a fiber optical Raman probe immersed into a reaction vessel Raman spectra of the reaction mixture were recorded in situ during the entacapone synthesis in toluene, heptane and isobutyl acetate. Due to the complexity of the measured spectra, the obtained data were analyzed and interpreted by means of principal component analysis. It has been shown that progress of this reaction can be monitored in real-time and reaction end points can be determined in different solvents. The reaction was found to be the fastest in heptane due to the lower loss of the catalyst. For a comparison the reaction was independently monitored by off-line Raman spectroscopy and liquid chromatography which confirmed the results obtained in-line. The results presented here have shown that this in-line approach can be used as a fast, non destructive and reliable method to monitor the Knoevenagel reaction in real time. The knowledge gained in this study can further be exploited for the industrial process control.

A series of electronically tuned trans- [CoIII(chel)(CH2Cl)]2 complexes, where chel is a salen derivative (salen = 2, 2′- ethylenebis(nitrilomethylidene)diphenol) containing either two or four methyl substituents in different positions, has been synthesized and characterized, both in solution and in the solid state. These complexes undergo an intramolecular cyclization reaction in methanolic solution to form the corresponding cis β organometallic derivative containing a seven-membered metallacycle, by replacement of the Cl atom of the axial CH2Cl by the salen phenolate oxygen. The cyclization rate increases on going from two to four methyl substituents in the chelate, in agreement with the electrochemical data that evidence a general shift toward more negative values with an increase in the number of methyl substituents. The cyclization rate is also affected by the substituent position, and both electrochemical and kinetic data evidence a remarkable influence of the methyls on the −C═N– groups of the chelate. The X-ray structures of cyclized complexes, [CoIII(chelCH2)(py)(H2O)]+, show a dependence of the conformation of the seven-membered metallacycle on the different positions of substituents in the chelate. In fact, in the complex having methyls on the −C═N– groups, the conformation is characterized by having the methylene carbon atom significantly displaced (ca. 1.26 Å) from the aromatic ring plane, whereas in the complex lacking methyl groups in those positions, the atoms of the Ph–O–CH2 fragment are coplanar. The standard Gibbs energies obtained by quantum chemical calculation reveal that the different conformations observed in the solid state are mainly the result of the energetically unfavorable setup of the methyls on the −C═N– groups and of the energetically favorable displacement of the CH2 group out of plane of the aromatic ring. 1H NMR data suggest that the different conformations of the metallacycle are, at least partially, retained in solution.

Over the past couple of decades halogen bonds (XB) have transformed from an obscure intermolecular interactions known only to a handful of experts into an indispensable tool of crystal engineering rivalling even to hydrogen bond (HB). However, detailed studies of XB energetics are still quite scarcer than those for HB. In our study we have used commercially available N-iodo, N-bromo- and N-chlorosuccinimide (NIS, NBS, NCS) as halogen bond donors, succinimide (S) as an equivalent HB donor, and 7 p-substituted pyridines as halogen (or hydrogen) bond acceptors. The pyridins have been selected to cover as wide as possible range of Hammet coefficients (-0.88 to 0.66), while avoiding functionalities which could act as hydrogen bond donors. This has ensured a relatively large variability of XB acceptor qualities, while ensuring that the observed XB is the only strong intermolecular interaction. In order to provide a detailed description of the halogen bonding in these systems, N-halosuccinimides were crystallised with the pyridines in order to study the formed complexes in the solid state. Simultaneously, microcalorimetric measurements were made to study the formation of halogen bonded complexes in acetonitrile solution, and, extensive computations in order to study the deformation of electron density upon XB formation, as well as the effect of various geometric parameters on the energy of XB. Solid state studies have shown that NIS and NBS form strong halogen bonds with all 7 pyridine derivatives. NIS is expectedly a better XB donor (N…X distances 29-32% shorter than the sum of van der Waals radii for NIS and 23-29% shorter for NBS). In both cases the more nucleophilic pyridine nitrogen atoms were better XB acceptors forming shorter bonds. The scattering of the datapoints was larger in the case of NBS indicating wider and more shallow potential well for XB with NBS, as confirmed computationally. The differences in the measured bond lengths were mirrored in the stability of the NIS-pyridine complexes in the solution - the stability constants were found to vary by over three orders of magnitude from logK = 4.003(9) for the complex exhibiting the shortest XB to logK = 0.825(3) for the one with the longest bond. In comparisson, S was found to produce hydrogen-bonded cocrystals only with the two strongest nucleophiles used, and the corresponding stability constants were nearly four orders of magnitude lower than those for halogen bonded complexes with NIS.

A well-considered treatment of acute nerve agents poisoning involves the exogenous administration of butyrylcholinesterase (BChE, EC 3.1.1.8) as a stoichiometric bioscavenger efficient in preventing cholinergic crises caused by acetylcholinesterase (AChE, EC 3.1.1.7) inhibition. An additional improvement in medical countermeasures would be to use oximes that could reactivate BChE as well to upgrade bioscavenging from stoichiometric to oxime-assisted catalytic. Therefore, in this paper we investigated the potency of 39 imidazolium and benzimidazolium oximes (36 compounds synthesized for the first time) to be considered as the reactivators specifically designed for reactivation of phosphylated human BChE. Their efficiency in the reactivation of paraoxon-, VX-, and tabun- inhibited human BChE, as well as human AChE was tested and compared with the efficiencies of HI-6 and obidoxime, used in medical practice today. A comprehensive analysis was performed for the most promising oximes defining kinetic parameters of reactivation as well as interactions with uninhibited BChE. Furthermore, experimental data were compared with computational studies (docking, QSAR analysis) as a starting point in future oxime structure refinement. Considering the strict criteria set for in vivo applications, we determined the cytotoxicity of lead oximes on two cell lines. Among the tested oxime library, one imidazolium compound was selected for preliminary in vivo antidotal study in mice. The obtained protection in VX poisoning outlines its potential in development oxime-assisted OP-bioscavenging with BChE.

Based on a new family of NiII cubane-like clusters, this work addresses current challenges in the synthesis, analysis and dynamics of single-molecule-magnet (SMM) systems. Investigation of various synthetic routes and desorption–sorption processes yielded a series of isomorphous compounds: [Ni4L4(CH3OH)4]·xsolv, [Ni4L4(CH3OH)4] and [Ni4L4]. In order to analyze these deceivingly simple materials, several analytical and quantum mechanical methods had to be used. This revealed materials with mixed lattice solvents, statistical disorder of the solvent, and disordered [Ni4L4] cores which offered an insight into the risks of the self-assembly process and interconversion dynamics of the investigated NiII family. These findings also allowed structural–magnetic relationships to be established, and the outcomes were exploited in two ways: first, the effect of the coordinated and lattice solvent on the magnetic properties was examined, and second, magnetic properties were used to facilitate crystal structure determination., New Journal of Chemistry, 40 (8), ISSN:1144-0546, ISSN:0398-9836, ISSN:1369-9261

Monoquaternary N -benzyl-4-hydroxyiminomethylpyridinium bromide (Py-4-H) and its analogous with diverse substituents introduced into the phenyl ring (Py-4-CH 3 , Py-4-Br, Py-4-Cl and Py-4-NO2) were synthesized in order to examine their potency as reactivators of tabun-inhibited human erythrocyte acetylcholinesterase (AChE; EC 3.1.1.7). Within 24 h, the reactivation of tabun-inhibited AChE reached 80% with Py-4-CH 3 , Py-4-Br and Py-4-Cl, 40% with Py-4-NO2, and 30% with Py-4-H. The overall reactivation rate constants were up to 5.0min- 1 M -1 . All oximes inhibited human AChE reversibly, and the inhibition potency increased in the following order Py-4-Br < Py-4-Cl

The first two members of the p-phenylenevinylene- oligomer family (i. e. 1, 4-distyrylbenzene [DSB] and 4, 4'-distyrylstilbene [DSS]) were synthesized and their infrared and Raman spectra recorded and empirically assigned. Molecular geometries were optimized for the planar point group (C2h) by the density functional theory (DFT) method using the B3LYP functional and 6-31G* basis set. Calculations of vibrational spectra, including intensities, were carried out subsequently using the DFT method with the same basis set and linear scaling was applied. Calculated vibrational wavenumbers are in a fair agreement with our own experimental spectra. In order to explore changes in vibrational dynamics that are obtained with the extension of the chain, differences in potential energy distribution (PED) of normal modes are investigated and discussed. It was shown that B3LYP functional well describes the mentioned differences in infrared and Raman spectra and presents a sound basis for a more thorough research. The results are compared with those of trans-stilbene (tSB), a molecule structurally most closely related to the members of the p- phenylenevinylenes family.

Intramolecular proton transfer in malonaldehyde (MA) has been investigated by density functional theory (DFT). The DFT results were used for the construction of a high quality semiempirical potential energy surface with a reparametrized PM3 Hamiltonian. A two-step reparameterization procedure is proposed in which (i) the PM3-MAIS core–core functions for the O–H and H–H interactions were used and a new functional form for the O–O correction function was proposed and (ii) a set of specific reaction parameters (SRP) has been obtained via genetic algorithm optimization. The quality of the reparametrized semiempirical potential energy surfaces was tested by calculating the tunneling splitting of vibrational levels and the anharmonic vibrational frequencies of the system. The applicability to multi-dimensional dynamics in large molecular systems is discussed.

N-Methyl-8-aminophenathridinium–uracil and –adenine conjugates possessing a nucleobase attached at the phenanthridinium 8-amino group by a trimethylene spacer were prepared in the form of water-soluble hydrogensulfate salts. Spectroscopic characteristics of the conjugates reveal the formation of folded conformations in water characterized by intramolecular aromatic stacking between the phenanthridinium unit and the tethered nucleobase. The conjugates form 1:1 complexes in water with either complementary or non-complementary nucleotides, giving log Ks values between 1 and 2 and showing a lack of any base recognition. Also, the binding studies with single-stranded polynucleotides showed no preference of conjugates to polynucleotides containing complementary nucleobases. At pH 5, the N-methylphenanthridinium–adenine conjugate exhibited preferred binding to double-stranded (ds-) polyAH+, whereas its protonated analogue bound preferably to polyU. The results reveal that the presence of protonated or permanently charged intercalator units in the conjugates dramatically changes their binding preferences for polynucleotides. Copyright © 2003 John Wiley & Sons, Ltd.