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Computational study for three isomeric nitroanilines was carried out to find a nonempirical model to predict their relative ionization efficiencies compared to the corresponding experimental logIE values. The CBS-QB3 method was used for the gas-phase calculations of protonated nitroanilines, and the SCC-DFTB method for the calculations of spherical droplets, containing one protonated nitroaniline molecule, one hydronium cation, and 48 acetonitrile molecules, randomly generated by the PACKMOL program. The obtained results show that neither the gas-phase energy of protonated nitroaniline (or gas-phase basicity) nor the average energy of droplets can be used to predict the ionization efficiency ordering of those isomers. However, the difference of gas-phase and droplet energies gives a good correlation with logIE values and, thus, can be used for the prediction of relative ionization efficiencies.

Chikungunya fever results from an infection with Chikungunya virus (CHIKV, genus Alphavirus) that is prevalent in tropical regions and is spreading fast to temperate climates with documented outbreaks in Europe and the Americas. Currently, there are no available vaccines or antiviral drugs for prevention or treatment of Chikungunya fever. The nonstructural proteins (nsPs) of CHIKV responsible for virus replication are promising targets for the development of new antivirals. This study was attempted to find out new potential inhibitors of CHIKV nsP2 protease using the ligand-based drug design. Two compounds 10 and 10c, identified by molecular docking, showed antiviral activity against CHIKV with IC50 of 13.1 and 8.3 μM, respectively. Both compounds demonstrated the ability to inhibit the activity of nsP2 in a cell-free assay, and the impact of compound 10 on virus replication was confirmed by western blot. The molecular dynamics study of the interactions of compounds 10 and 10c with CHIKV nsP2 showed that a possible mechanism of action of these compounds is the blocking of the active site and the catalytic dyad of nsP2.

To find out potential GDNF family receptor alpha 1 (GFR alpha 1) agonists, small molecules were built up by molecular fragments according to the structure-based drug design approach. Molecular docking was used to identify their binding modes to the biological target GFRa1 in GDNF-binding pocket. Thereafter, commercially available compounds based on the best predicted structures were searched from ZINC and MolPort databases (similarity >= 80%). Five compounds from the ZINC library were tested in phosphorylation and luciferase assays to study their ability to activate GFR alpha 1-RET. A bidental compound with two carboxyl groups showed the highest activity in molecular modeling and biological studies. However, the relative position of these groups was important. The meta-substituted structure otherwise identical to the most active compound 2-[4-(5-carboxy-1H-1,3-benzodiazol-2-yl) phenyl]-1H-1,3-benzodiazole-5-carboxylic acid was inactive. A weaker activity was detected for a compound with a single carboxyl group, that is, 4-(1,3-benzoxazol-2-yl) benzoic acid. The substitution of the carboxyl group by the amino or acetamido group also led to the loss of the activity.

Mechanism of an efficient and easily applicable catalytic system for the copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC) reaction, consisting of phosphane-ligated CuI carboxylates and apolar/aprotic solvent was investigated by means of 1H NMR reaction monitoring techniques, isotope exchange studies, and DFT calculations (at the M06L/6-311++G(d,p)//B97D/cc-pVDZ (SDD) level of theory). Kinetic analysis indicates 1st order kinetics with respect to [Azide] and nonlinear positive order in [Cu]. H/D scrambling between alkynes reveals a quickly reached equilibrium existing between CuI–carboxylates and CuI–acetylides and that proton transfer processes are mediated by acetate/acetic acid system. According to the computational results, the Cu–triazolide forms a dinuclear structure that equalizes the copper atoms in the catalytic complex.

The glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) support the survival and functioning of various neuronal populations. Thus, they could be attractive therapeutic agents against a multitude of neurodegenerative diseases caused by progressive death of GFLs responsive neurons. Small-molecule ligands BT13 and BT18 show an effect on GDNF family receptor GFR alpha 1 and RET receptor tyrosine kinase RetA function. Thus, their potential binding sites and interactions were explored in the GDNF-GFR alpha 1-RetA complex using molecular docking calculations as well as molecular dynamics (MD) simulations. Three possible regions were examined: the interface between GDNF and GFR alpha 1 (region A), the RetA interface with GFR alpha 1 (region B), and a possible allosteric site in GFR alpha 1 (region C). The results obtained by the docking calculations and the MD simulations indicate that the preferable binding occurs at the allosteric site. A less preferable binding site was detected on the RetA surface interfacing GFR alpha 1. In the membrane-bound state of RetA this can enable compounds BT13 and BT18 to act as direct RetA agonists. The analysis of the MD simulations shows hydrogen bonds for BT13 and significant hydrophobic interactions with GFR alpha 1 for BT13 and BT18 at the allosteric site.

The interaction between the cesium cation and fulvic or humic acids is supposed to play a role in cesium mobility in the environment, which is of importance in the context of geographical dispersion or concentration of the corresponding radionuclides. Among the singly charged positive clusters generated by electrospray ionization of mixtures of carboxylic acids (AH) and cesium salts (nitrate, iodide, or trifluoroacetate), the cluster [A- Cs+ ]Cs+ [A'- Cs+ ] was subjected to collision-induced dissociation. The fragmentation into Cs+ [A- Cs+ ] and Cs+ [A'- Cs+ ] was treated using the kinetic method. A gas-phase basicity ladder was built by a step-by-step addition of the relative basicity data. The relative basicity scale deduced from the kinetic method was calibrated using the affinity and basicity (the enthalpy and Gibbs energy scales, respectively) obtained from DFT calculations. The enhanced basicity of the polyacid salts, relative to their monoacid salts, as well as the substituent effects on aliphatic and aromatic structures, are discussed.

The copper-free Sonogashira cross-coupling reaction consisting of oxidative addition, cis–trans isomerization, deprotonation, and reductive elimination was computationally modeled using the DFT B97D/cc-pVDZ method for reaction between phenyl bromide and phenylacetylene. Tetrakis(triphenylphosphano)palladium was used as a catalyst and sec-butylamine as a base. The reaction mechanism was studied in dichloromethane solution. Oxidative addition proceeds through the biligated pathway, and the catalytically active palladium species is Pd(PPh3)3. Amines, present in the reaction mixture, can inhibit oxidative addition by coordinating to Pd(PPh3)3.

Substituent effects on the formation of cesium cation complexes with a series of 17 benzoic acids (AH), benzoates (A–), and the ion pairs (Cs+A–) are studied by density functional theory (DFT) and mass spectrometry. This study is positioned in the context of the fate of cesium in the environment, with emphasis of the influence of natural organic matter and humic substances. The bond length Cs+-(carboxylic O) in the various adduct geometries are discussed as regards the interaction strength, but quantitative relationships are limited by secondary effects arising mostly from long-distance interactions in systems bearing polar groups in meta-position. Relative cesium cation affinities of [Cs+A–] were experimentally determined by the kinetic method, i.e. by dissociating the required cesium cluster formed by electrospray ionization in a quadrupole ion-trap. Experiments and calculations are in agreement, except for the adducts derived from 3- and 4-hydroxybenzoic acids. A change in the localization of the negative charge is proposed as a possible explanation for the divergence.

This review focuses on the quantitative data related to cesium cation interaction with neutral or negatively charged ligands. The techniques used for measuring the cesium cation affinity (enthalpies, CCA), and cesium cation basicities (Gibbs free energies, CCB) are briefly described. The quantum chemical calculations methods that were specifically designed for the determination of cesium cation adduct structures and the energetic aspects of the interaction are discussed. The experimental results, obtained essentially from mass spectrometry techniques, and complemented by thermochemical data, are tabulated and commented. In particular, the correlations between cesium cation affinities and lithium cation affinities for the various kinds of ligands (rare gases, polyatomic neutral molecules, among them aromatic compounds and negative ions) serve as a basis for the interpretation of the diverse electrostatic modes of interaction. A brief account of some recent analytical applications of ion/molecule reactions with Cs+, as well as other cationization approaches by Cs+, is given.

The complexation of MgX 2 , MeMgX, and Me 2 Mg (X=Cl, Br) with propyne have been studied both in the gas phase and in the presence of dimethyl ether (Me 2 O) by means of the density functional theory B3LYP/6-31+G* method. Solvation was modeled using the supermolecule approach. The complex formation between disolvated magnesium compound and alkyne is connected with replacement of a coordinated solvent molecule by the alkyne, being necessary for the reaction to proceed to the end. The reaction towards end products, an acetylenic Grignard reagent and an alkane, is exothermic. The transition state has a cyclic structure, which is almost triangular with practically linear proton transfer. The transition state resembles more the reagents than the products.

The Schlenk equilibrium involving RMgX, R2Mg, and MgX2 (R = Me, Et, Ph and X = Cl, Br) has been studied both in the gas phase and in diethyl ether (Et2O) and tetrahydrofuran (THF) solutions by means of the density functional theory (DFT) B3LYP/6-31+G* method. Solvation was modeled using the supermolecule approach. The stabilization due to interaction with solvent molecules decreases in the order MgX2 > RMgX > R2Mg and among the groups (R and X) Ph > Me > Et and Cl > Br. Studied magnesium compounds are more strongly solvated by THF compared to Et2O. The magnesium halide is solvated with up to four solvent molecules in THF solution, assuming that trans-dihalotetrakis(tetrahydrofurano)magnesium(II) complex forms. The formation of cis-dihalotetrakis(tetrahydrofurano)magnesium(II) is energetically less favorable than the formation of corresponding disolvated complexes. The predominant species in the Schlenk equilibrium are RMgX in Et2O and R2Mg + MgX2 in THF, which is consistent with experimental data.

Kinetic studies were carried out on the reaction of phenylmagnesium bromide with hex-1-yne in diethyl ether, and in binary mixtures of diethyl ether with toluene, chlorobenzene and dichloromethane. The reaction was accelerated by addition of non-donating solvents. The replacement of a coordinated solvent molecule by the alkyne is necessary for the reaction to proceed, according to density functional theory (DFT) calculations with B3LYP/6–31 + G* method. The non-donating solvents accelerate the reaction by shifting the replacement equilibrium in favour of the complex formation. An analysis in terms of the Koppel–Palm equation revealed a rate decrease with increase in solvent polarity and polarizability. Copyright © 2002 John Wiley & Sons, Ltd.

The solvation, complexation, and disproportionation equilibria, which might be important during titration of a Grignard reagent RMgX with an alcohol in the presence of 1,10-phenanthroline (phen), have been studied both in the gas phase and solution using the density functional theory (DFT) B3LYP/6-31+G* method. Solvation was modeled using the supermolecule approach. NBO atomic charge analyses were performed at the B3LYP/6-31G* level. The absorption spectra of the complexes were calculated by the DFT TD/MPW1PW91/6-311+G** method. According to our calculations the complexation of magnesium halide MgX2 with 1,10-phenanthroline is the reason for the disappearance of the red color of the complex RMgX(phen) near the titration end point.

The interaction between the cesium cation and fulvic or humic acids is supposed to play a role in cesium mobility in the environment, which is of importance in the context of geographical dispersion or concentration of the corresponding radionuclides. Among the singly charged positive clusters generated by electrospray ionization of mixtures of carboxylic acids (AH) and cesium salts (nitrate, iodide, or trifluoroacetate), the cluster [A

The Sonogashira cross-couplig reaction, consisting of oxidative addition, cis-trans isomerization, transmetalation, and reductive elimination, was computationally modeled using the DFT B3LYP/cc-pVDZ method for reaction between bromobenzene and phenylacetylene. Palladium diphosphane was used as a catalyst, copper(I) bromide as a co-catalyst and trimethylamine as a base. The reaction mechanism was studied both in the gas phase and in dichloromethane solution using PCM method. The complete catalytic cycle is thermodynamically strongly shifted toward products (diphenylacetylene and regenerated palladium catalyst) and is exothermic being in accordance with experimental data. The rate-determining step is the oxidative addition, since the highest point on the Gibbs energy graph of the complete reaction is the transition state of this step. This conclusion is also supported by recent experimental data. The computed energy profile suggests that the transmetalation step is initiated by the dissociation of neutral ligand, while the activation Gibbs energy of this step is 0.1 kcal mol(-1) in the gas phase.

The possible reaction pathways between methyllithium and disubstituted 1,2,4,5-tetrazines (bearing methyl, methylthio, phenyl, and 3,5-dimethylpyrazolyl groups) were investigated by means of the density functional theory B3LYP/6-31G* method. Solvation was modeled using the supermolecule approach, adding one tetrahydrofuran molecule to the complexes. Comparison of the calculated energies and structures for the alternate azaphilic and nucleophilic addition pathways showed that the azaphilic addition is kinetically favored over nucleophilic addition, while thermodynamically the nucleophilic addition is usually preferred. The coordination of the tetrazine molecule with methyllithium was found to play a crucial role in the process. These findings provide the first rationale for the experimentally observed unique reactivity of tetrazines toward polar organometallic reagents, suggesting the presence of a kinetically controlled process.

International audience; Collision-induced dissociation (CID) of the Cs(+) heterodimer adducts of the nitrate anion (NO(3)(-)) and a variety of substituted benzoates (XBenz(-)) [(XBenz-)(Cs(+))(NO(3)(-))](-) produces essentially nitrate and benzoate ions. A plot of the natural logarithm of their intensity ratio, In(I(NO(3)(-)/I(XBenz(-))], versus the calculated cesium cation affinity (OFT B3LYP) of the substituted benzoate ions (equivalent to the enthalpy of heterolytic dissociation of the salt) is reasonably linear. This suggests that the kinetic method can be used as a source of data on the intrinsic interaction between the anionic and the cationic moieties in a salt. Copyright (C) 2010 John Wiley & Sons, Ltd.

The gas-phase cesium cation affinities (CsCAs) and basicities (CsCBs) for 56 simple neutral compounds (mostly aromatic molecules) and 41 anions (carboxylates and phenolates) were calculated using density functional theory (DFT), in the context of the interaction of Cs(+) with soil organic matter (SOM). The B3LYP/def2-TZVP method gives in general CsCAs and CsCBs in a good agreement with experimental data. The strong deviations in case of NO(3)(-) and CsSO(4)(-) anions need further experimental investigations as the high-level CCSD(T) calculations support B3LYP results. Different cesium cation complexation patterns between Cs(+) and the neutral and anionic systems are discussed. As expected, the strongest CsCAs are observed for anions. The corresponding quantities are approximately by 4-5 times higher than for the neutral counterparts, being in the range 90-118 kcal/mol. The weakest cesium cation bonding is observed in the case of unsubstituted aromatic systems (11-15 kcal/mol).

Humic substances (HS), including humic and fulvic acids, play a significant role in the fate of metals in soils. The interaction of metal cations with HS occurs predominantly through the ionized (anionic) acidic functions. In the context of the effect of HS on transport of radioactive cesium isotopes in soils, a study of the interaction between the cesium cation and model carboxylic acids was undertaken. Structure and energetics of the adducts formed between Cs+ and cesium carboxylate salts [Cs+RCOO−] were studied by the kinetic method and density functional theory (DFT). Clusters generated by electrospray ionization mass spectrometry from mixtures of a cesium salt (nitrate, iodide, trifluoroacetate) and carboxylic acids were quantitatively studied by CID. By combining the results of the kinetic method and the energetic data from DFT calculations, a scale of cesium cation affinity, CsCA, was built for 33 cesium carboxylates representing the first scale of cation affinity of molecular salts. The structural effects on the CsCA values are discussed.

In relation to the interaction between 137 Cs and soil organic matter, electrospray mass spectrometry experiments and density functional theory (DFT) calculations were carried out on the dissociation of positively charged adducts formed by cesium nitrate and cesium organic salts attached to a cesium cation [Cs(CsNO 3 )(CsA)] + (A = benzoate, salicylate, hydrogen phthalate, hydrogen maleate, hydrogen fumarate, hydrogen oxalate, and hydrogen malonate ion). These mixed clusters were generated by electrospray from methanol solutions containing cesium nitrate and an organic acid. Collision-induced dissociation of [Cs(CsNO 3 )(CsA)] + in a quadrupole ion trap gave [Cs(CsNO 3 )] + and [Cs(CsA)] + as major product ions. Loss of HNO 3 was observed, and also CO 2 loss in the case of A = hydrogen malonate. Branching ratios for the dissociation into [Cs(CsNO 3 )] + and [Cs(CsA)] + were treated by the Cooks' kinetic method to obtain a quantitative order of bonding energetics (enthalpies and Gibbs free energies) between Cs + and the molecular salt (ion pair) CsA, and were correlated with the corresponding values calculated using DFT. The kinetic method leads to relative scales of Cs + affinities and basicities that are consistent with the DFT-calculated values. This study brings new data on the strong interaction between the cesium cation and molecular salts CsA.

The sec-butylammonium salt catalysed oxidative addition of phenyl bromide to tris(triphenylphosphane)palladium and reaction of phenylacetylene with cis-Pd(PPh3)2(Ph)Br were modelled using DFT B97D/cc-pVDZ method to study the mechanism of the copper-free Sonogashira cross-coupling reaction. sec-Butylammonium bromide influences the oxidative addition by coordinating with palladium catalyst and the resulting product is trans-Pd(PPh3)2(Ph)Br, not the corresponding cis-compound, which is formed in the absence of salt. The transition-state energy of this oxidative addition mechanism is very close to the previously reported biligated oxidative addition pathway. Reaction of acetylene with cis-Pd(PPh3)2(Ph)Br can lead to either a transor a cis-Pd(PPh3)2(CCPh)Ph complex, while only the latter is capable of undergoing reductive elimination.

The virtual screening for new scaffolds for TrkA receptor antagonists resulted in potential low molecular weight drug candidates for the treatment of neuropathic pain and cancer. In particular, the compound (Z)-3-((5-methoxy-1H-indol-3-yl)methylene)-2-oxindole and its derivatives were assessed for their inhibitory activity against Trk receptors. The IC50 values were computationally predicted in combination of molecular and fragment-based QSAR. Thereafter, based on the structure-activity relationships (SAR), a series of new compounds were designed and synthesized. Among the final selection of 13 compounds, (Z)-3-((5-methoxy-1-methyl-1H-indol-3-yl)methylene)-N-methyl-2-oxindole-5-sulfonamide showed the best TrkA inhibitory activity using both biochemical and cellular assays and (Z)-3-((5-methoxy-1-methyl-1H-indol-3-yl)methylene)-2-oxindole-5-sulfonamide was the most potent inhibitor of TrkB and TrkC.