Static and Dynamical Quantum Studies of CX3-AlX2 and CSiX3-BX2 (X = F, Cl, Br) Complexes with Hydrocyanic Acid: Unusual Behavior of Strong π-Hole at Triel Center.

The set of TX3-TrX2 (T = C, Si, Ge; Tr = B, Al, Ga; X = F, Cl, Br) molecules offers a rather unique opportunity to study both σ-hole and π-hole dimerization on the tetrel and triel ends, respectively. According to the molecular electrostatic potential (MEP) distribution, the π-hole extrema (acidic sites) were more intense than their σ-hole counterparts. The molecules owning the most (CX3-AlX2) and least (SiX3-BX2) intense π-holes were chosen to evaluate their capacities to attract one and two HCN molecules (Lewis bases). We discovered that the energetic characteristics of π-hole dimers severely conflict with the monomers MEP pattern since the weakest π-hole monomer forms a dimer characterized by interaction energy compared to those created by the monomers with noticeably greater power in the π-hole region. This outcome is due to the deformation of the weakest π-hole donor. Furthermore, the MEP analysis for monomers in the geometry of respective dimers revealed a "residual π-hole" site that was able to drive second ligand attachment, giving rise to the two "unusual trimers" examined further by the NCI and QTAIM analyses. Apart from them, the π-hole/π-hole and σ-hole/π-hole trimers have also been obtained throughout this study and described using energetic and geometric parameters. The SAPT approach revealed details of the bonding in one of the "unusual trimers". Finally, Born-Oppenheimer Molecular Dynamics (BOMD) simulations were carried out to investigate the time evolution of the interatomic distances of the studied complexes as well as their stability.

Heterobimetallic 21,23-dimetallaporphyrin: activation of metal-metal interactions within the porphyrinoid macrocycle.

Two core-modified porphyrins containing metal atoms, namely platinum(II) or platinum(IV) and rhodium(III), in place of two NH units, have been obtained by a post-synthetic modification of the 21,23-ditelluraporphyrin. The products of the tellurium-to-metal exchange, 21-platina-23-rhodaporphyrins, incorporate rhodacyclopentadiene and platinacyclopentadiene units with the metal atoms facing each other. The two molecules exhibit different degrees of metal-metal interaction depending on the oxidation state of platinum, with the NBO bond order being 0.04 for platinum(IV) and 0.15 for platinum(II). Consistently, the Quantum Theory of Atoms in Molecules analysis revealed the presence of the bond determinant, the bond critical point, in the platinum(II) species, in contrast to the platinum(IV) congener. The two porphyrinoids are interconvertible in redox reactions. They both exhibit fluxional behaviour in solution, studied by 1H NMR, involving alteration in the metal ion coordination sphere accompanied by the macrocyclic skeleton conformation change.

Inter- vs. Intra-Molecular Hydrogen Bond in Complexes of Nitrophthalic Acids with Pyridine.

This study covers the analysis of isomeric forms of nitrophthalic acids with pyridine. This work dwells on the complementary experimental (X-ray, IR and Raman) and theoretical (Car-Parrinello Molecular Dynamics (CPMD) and Density Functional Theory (DFT)) studies of the obtained complexes. The conducted studies showed that steric repulsion between the nitro group in ortho-position and the carboxyl group causes significant isomeric changes. Modeling of the nitrophthalic acid-pyridine complex yielded a short strong intramolecular hydrogen bond (SSHB). The transition energy from the isomeric form with an intermolecular hydrogen bond to the isomeric form with an intramolecular hydrogen bond was estimated.

Unraveling the Nature of Hydrogen Bonds of "Proton Sponges" Based on Car-Parrinello and Metadynamics Approaches.

The nature of intra- and intermolecular non-covalent interactions was studied in four naphthalene derivatives commonly referred to as "proton sponges". Special attention was paid to an intramolecular hydrogen bond present in the protonated form of the compounds. The unsubstituted "proton sponge" served as a reference structure to study the substituent influence on the hydrogen bond (HB) properties. We selected three compounds substituted by methoxy, amino, and nitro groups. The presence of the substituents either retained the parent symmetry or rendered the compounds asymmetric. In order to reveal the non-covalent interaction properties, the Hirshfeld surface (HS) was computed for the crystal structures of the studied compounds. Next, quantum-chemical simulations were performed in vacuo and in the crystalline phase. Car-Parrinello molecular dynamics (CPMD), Path Integral Molecular Dynamics (PIMD), and metadynamics were employed to investigate the time-evolution changes of metric parameters and free energy profile in both phases. Additionally, for selected snapshots obtained from the CPMD trajectories, non-covalent interactions and electronic structure were studied. Quantum theory of atoms in molecules (QTAIM) and the Density Overlap Regions Indicator (DORI) were applied for this purpose. It was found based on Hirshfeld surfaces that, besides intramolecular hydrogen bonds, other non-covalent interactions are present and have a strong impact on the crystal structure organization. The CPMD results obtained in both phases showed frequent proton transfer phenomena. The proton was strongly delocalized in the applied time-scale and temperature, especially in the PIMD framework. The use of metadynamics allowed for tracing the free energy profiles and confirming that the hydrogen bonds present in "proton sponges" are Low-Barrier Hydrogen Bonds (LBHBs). The electronic and topological analysis quantitatively described the temperature dependence and time-evolution changes of the electronic structure. The covalency of the hydrogen bonds was estimated based on QTAIM analysis. It was found that strong hydrogen bonds show greater covalency, which is additionally determined by the proton position in the hydrogen bridge.

Chalcogen Bond as a Factor Stabilizing Ligand Conformation in the Binding Pocket of Carbonic Anhydrase IX Receptor Mimic.

It is postulated that the overexpression of Carbonic Anhydrase isozyme IX in some cancers contributes to the acidification of the extracellular matrix. It was proved that this promotes the growth and metastasis of the tumor. These observations have made Carbonic Anhydrase IX an attractive drug target. In the light of the findings and importance of the glycoprotein in the cancer treatment, we have employed quantum-chemical approaches to study non-covalent interactions in the binding pocket. As a ligand, the acetazolamide (AZM) molecule was chosen, being known as a potential inhibitor exhibiting anticancer properties. First-Principles Molecular Dynamics was performed to study the chalcogen and other non-covalent interactions in the AZM ligand and its complexes with amino acids forming the binding site. Based on Density Functional Theory (DFT) and post-Hartree-Fock methods, the metric and electronic structure parameters were described. The Non-Covalent Interaction (NCI) index and Atoms in Molecules (AIM) methods were applied for qualitative/quantitative analyses of the non-covalent interactions. Finally, the AZM-binding pocket interaction energy decomposition was carried out. Chalcogen bonding in the AZM molecule is an important factor stabilizing the preferred conformation. Free energy mapping via metadynamics and Path Integral molecular dynamics confirmed the significance of the chalcogen bond in structuring the conformational flexibility of the systems. The developed models are useful in the design of new inhibitors with desired pharmacological properties.

Comprehensive Empirical Model of Substitution-Influence on Hydrogen Bonding in Aromatic Schiff Bases.

In this work, over 500 structures of tri-ring aromatic Schiff bases with different substitution patterns were investigated to develop a unified description of the substituent effect on the intramolecular hydrogen bridge. Both proximal and distal effects were examined using Density Functional Theory (DFT) in the gas phase and with solvent reaction field (Polarizable Continuum Model (PCM) and water as the solvent). In order to investigate and characterize the non-covalent interactions, a topological analysis was performed using the Quantum Theory of Atoms In Molecules (QTAIM) theory and Non-Covalent Interactions (NCI) index. The obtained results were summarized as the generalized, empirical model of the composite substituent effect, assessed using an additional group of simple ring-based Schiff bases. The composite substituent effect has been divided into separate increments describing the different interactions of the hydrogen bridge and the substituent: the classical substituent effect, involving resonance and induction mediated through the ring, steric increment based on substituent proximity to the bridge elements, and distal increment, derived from substitution on the distal ring.

A new mixed-valence CuI/CuII three-dimensional coordination polymer constructed with an N,O-donor ligand generated via solvothermal synthesis: structural features and magnetic properties.

A new mixed-valence CuI/CuII three-dimensional coordination polymer, poly[[diaquabis[µ4-2-(pyrazin-2-yl)quinoline-4-carboxylato]dicopper(I)copper(II)] bis(tetrafluoridoborate)], {[Cu3(C14H8N3O2)2(H2O)2](BF4)2}n, was synthesized and characterized, with 2-(pyrazin-2-yl)quinoline-4-carboxylic acid being employed as a linker ligand. The ligand was isolated as its hydrochloride salt, 4-carboxy-2-(pyrazin-2-yl)quinolin-1-ium chloride dihydrate, C14H10N3O2+·Cl-·2H2O. The compounds show luminescence at 550 nm for the ligand and at 565 nm for the polymer at 297 K. The ligand structure was rationalized by means of quantum-chemical calculations, which led to a similar conformation to that determined from X-ray diffraction studies.

Revealing Intra- and Intermolecular Interactions Determining Physico-Chemical Features of Selected Quinolone Carboxylic Acid Derivatives.

The intra- and intermolecular interactions of selected quinolone carboxylic acid derivatives were studied in monomers, dimers and crystals. The investigated compounds are well-recognized as medicines or as bases for further studies in drug design. We employed density functional theory (DFT) in its classical formulation to develop gas-phase and solvent reaction field (PCM) models describing geometric, energetic and electronic structure parameters for monomers and dimers. The electronic structure was investigated based on the atoms in molecules (AIM) and natural bond orbital (NBO) theories. Special attention was devoted to the intramolecular hydrogen bonds (HB) present in the investigated compounds. The characterization of energy components was performed using symmetry-adapted perturbation theory (SAPT). Finally, the time-evolution methods of Car-Parrinello molecular dynamics (CPMD) and path integral molecular dynamics (PIMD) were employed to describe the hydrogen bond dynamics as well as the spectroscopic signatures. The vibrational features of the O-H stretching were studied using Fourier transformation of the autocorrelation function of atomic velocity. The inclusion of quantum nuclear effects provided an accurate depiction of the bridged proton delocalization. The CPMD and PIMD simulations were carried out in the gas and crystalline phases. It was found that the polar environment enhances the strength of the intramolecular hydrogen bonds. The SAPT analysis revealed that the dispersive forces are decisive factors in the intermolecular interactions. In the electronic ground state, the proton-transfer phenomena are not favourable. The CPMD results showed generally that the bridged proton is localized at the donor side, with possible proton-sharing events in the solid-phase simulation of stronger hydrogen bridges. However, the PIMD enabled the quantitative estimation of the quantum effects inclusion-the proton position was moved towards the bridge midpoint, but no qualitative changes were detected. It was found that the interatomic distance between the donor and acceptor atoms was shortened and that the bridged proton was strongly delocalized.

Intermolecular Interactions and Spectroscopic Signatures of the Hydrogen-Bonded System-n-Octanol in Experimental and Theoretical Studies.

n-Octanol is the object of experimental and theoretical study of spectroscopic signatures and intermolecular interactions. The FTIR measurements were carried out at 293 K for n-octanol and its deuterated form. Special attention was paid to the vibrational features associated with the O-H stretching and the isotope effect. Density Functional Theory (DFT) in its classical formulations was applied to develop static models describing intermolecular hydrogen bond (HB) and isotope effect in the gas phase and using solvent reaction field reproduced by Polarizable Continuum Model (PCM). The Atoms in Molecules (AIM) theory enabled electronic structure and molecular topology study. The Symmetry-Adapted Perturbation Theory (SAPT) was used for energy decomposition in the dimers of n-octanol. Finally, time-evolution methods, namely classical molecular dynamics (MD) and Car-Parrinello Molecular Dynamics (CPMD) were employed to shed light onto dynamical nature of liquid n-octanol with emphasis put on metric and vibrational features. As a reference, CPMD gas phase results were applied. Nuclear quantum effects were included using Path Integral Molecular Dynamics (PIMD) and a posteriori method by solving vibrational Schrödinger equation. The latter applied procedure allowed to study the deuterium isotope effect.

Inside out Approach to Rotator State in Hydrogen-Bonded System-Experimental and Theoretical Cross-Examination in n-Octanol.

The experimental and theoretical description of premelting behavior is one of the most challenging tasks in contemporary material science. In this paper, n-octanol was studied using a multi-method approach to investigate it at macroscopic and molecular levels. The experimental infrared (IR) spectra were collected in the solid state and liquid phase at temperature range from -84∘C to -15 ∘C to detect temperature-related indicators of pretransitional phenomena. Next, the nonlinear dielectric effect (NDE) was measured at various temperatures (from -30 ∘C to -15 ∘C) to provide insight into macroscopic effects of premelting. As a result, a two-step mechanism of premelting in n-octanol was established based on experimental data. It was postulated that it consists of a rotator state formation followed by the surface premelting. In order to shed light onto molecular-level processes, classical molecular dynamics (MD) was performed to investigate the time evolution of the changes in metric parameters as a function of simulation temperature. The applied protocol enabled simulations in the solid state as well as in the liquid (the collapse of the ordered crystal structure). The exact molecular motions contributing to the rotator state formation were obtained, revealing an enabling of the rotational freedom of the terminal parts of the chains. The Car-Parrinello molecular dynamics (CPMD) was applied to support and interpret experimental spectroscopic findings. The vibrational properties of the stretching of OH within the intermolecular hydrogen bond were studied using Fourier transformation of the autocorrelation function of both dipole moments and atomic velocity. Finally, path integral molecular dynamics (PIMD) was carried out to analyze the quantum effect's influence on the bridged proton position in the hydrogen bridge. On the basis of the combined experimental and theoretical conclusions, a novel mechanism of the bridged protons dynamics has been postulated-the interlamellar hydrogen bonding pattern, resulting in an additional OH stretching band, visible in the solid-state experimental IR spectra.

Exploring Intra- and Intermolecular Interactions in Selected N-Oxides-The Role of Hydrogen Bonds.

Intra- and intermolecular interactions have been explored in selected N-oxide derivatives: 2-(N,N-dimethylamino-N-oxymethyl)-4,6-dimethylphenyl (1) and 5,5'-dibromo-3-diethylaminomethyl-2,2'-biphenol N-oxide (2). Both compounds possess intramolecular hydrogen bonding, which is classified as moderate in 1 and strong in 2, and resonance-assisted in both cases. Density Functional Theory (DFT) in its classical formulation as well as Time-Dependent extension (TD-DFT) were employed to study proton transfer phenomena. The simulations were performed in the gas phase and with implicit and explicit solvation models. The obtained structures of the studied N-oxides were compared with experimental data available. The proton reaction path was investigated using scan with an optimization method, and water molecule reorientation in the monohydrate of 1 was found upon the proton scan progress. It was found that spontaneous proton transfer phenomenon cannot occur in the electronic ground state of the compound 1. An opposite situation was noticed for the compound 2. The changes of nucleophilicity and electrophilicity upon the bridged proton migration were analyzed on the basis of Fukui functions in the case of 1. The interaction energy decomposition of dimers and microsolvation models was investigated using Symmetry-Adapted Perturbation Theory (SAPT). The simulations were performed in both phases to introduce polar environment influence on the interaction energies. The SAPT study showed rather minor role of induction in the formation of homodimers. However, it is worth noticing that the same induction term is responsible for the preference of water molecules' interaction with N-oxide hydrogen bond acceptor atoms in the microsolvation study. The Natural Bond Orbital (NBO) analysis was performed for the complexes with water to investigate the charge flow upon the polar environment introduction. Finally, the TD-DFT was applied for isolated molecules as well as for microsolvation models showing that the presence of solvent affects excited states, especially when the N-oxide acceptor atom is microsolvated.

Biological Evaluation and Molecular Docking Studies of Novel 1,3,4-Oxadiazole Derivatives of 4,6-Dimethyl-2-sulfanylpyridine-3-carboxamide.

To date, chronic inflammation is involved in most main human pathologies such as cancer, and autoimmune, cardiovascular or neurodegenerative disorders. Studies suggest that different prostanoids, especially prostaglandin E2, and their own synthase (cyclooxygenase enzyme-COX) can promote tumor growth by activating signaling pathways which control cell proliferation, migration, apoptosis, and angiogenesis. Non-steroidal anti-inflammatory drugs (NSAIDs) are used, alongside corticosteroids, to treat inflammatory symptoms particularly in all chronic diseases. However, their toxicity from COX inhibition and the suppression of physiologically important prostaglandins limits their use. Therefore, in continuation of our efforts in the development of potent, safe, non-toxic chemopreventive compounds, we report herein the design, synthesis, biological evaluation of new series of Schiff base-type hybrid compounds containing differently substituted N-acyl hydrazone moieties, 1,3,4-oxadiazole ring, and 4,6-dimethylpyridine core. The anti-COX-1/COX-2, antioxidant and anticancer activities were studied. Schiff base 13, containing 2-bromobenzylidene residue inhibited the activity of both isoenzymes, COX-1 and COX-2 at a lower concentration than standard drugs, and its COX-2/COX-1 selectivity ratio was similar to meloxicam. Furthermore, the results of cytotoxicity assay indicated that all of the tested compounds exhibited potent anti-cancer activity against A549, MCF-7, LoVo, and LoVo/Dx cell lines, compared with piroxicam and meloxicam. Moreover, our experimental study was supported by density functional theory (DFT) and molecular docking to describe the binding mode of new structures to cyclooxygenase.

How Substitution Combines with Non-Covalent Interactions to Modulate 1,4-Naphthoquinone and Its Derivatives Molecular Features-Multifactor Studies.

Substitution is well-known to modulate the physico-chemical properties of molecules. In this study, a combined, multifactor approach was employed to determine a plethora of substitution patterns using -Br and -O-H in 1,4-naphthoquinone and its derivatives. On the basis of classical Density Functional Theory (DFT), 25 models divided into three groups were developed. The first group contains 1,4-naphthoquinone and its derivatives substituted only by -Br. The second group consists of compounds substituted by -Br and one -O-H group. As a result of the substitution, an intramolecular hydrogen bond was formed. The third group also contains -Br as a substituent, but two -O-H groups were introduced and two intramolecular hydrogen bonds were established. The simulations were performed at the ωB97XD/6-311++G(2d,2p) level of theory. The presence of substituents influenced the electronic structure of the parent compound and its derivatives by inductive effects, but it also affected the geometry of the 2 and 3 groups, due to the intramolecular hydrogen bonding and the formation of a quasi-ring/rings. The static DFT models were applied to investigate the aromaticity changes in the fused rings based on the Harmonic Oscillator Model of Aromaticity (HOMA). The OH stretching was detected for the compounds from groups 2 and 3 and further used to find correlations with energetic parameters. The evolution of the electronic structure was analyzed using Hirshfeld atomic charges and the Substituent Active Region (cSAR) parameter. The proton reaction path was investigated to provide information on the modulation of hydrogen bridge properties by diverse substitution positions on the donor and acceptor sides. Subsequently, Car-Parrinello Molecular Dynamics (CPMD) was carried out in the double-bridged systems (group 3) to assess the cooperative effects in double -O-H-substituted systems. It was determined that the -O-H influence on the core of the molecule is more significant than that of -Br, but the latter has a major impact on the bridge dynamics. The competitive or synergic effect of two -Br substituents was found to depend on the coupling between the intramolecular hydrogen bridges. Thus, the novel mechanism of a secondary (cooperative) substituent effect was established in the double-bridged systems via DFT and CPMD results comparison, consisting of a mediation of the bromine substitutions' influence by the cooperative proton transfer events in the hydrogen bridges.

Naphthazarin Derivatives in the Light of Intra- and Intermolecular Forces.

Our long-term investigations have been devoted the characterization of intramolecular hydrogen bonds in cyclic compounds. Our previous work covers naphthazarin, the parent compound of two systems discussed in the current work: 2,3-dimethylnaphthazarin (1) and 2,3-dimethoxy-6-methylnaphthazarin (2). Intramolecular hydrogen bonds and substituent effects in these compounds were analyzed on the basis of Density Functional Theory (DFT), Møller-Plesset second-order perturbation theory (MP2), Coupled Clusters with Singles and Doubles (CCSD) and Car-Parrinello Molecular Dynamics (CPMD). The simulations were carried out in the gas and crystalline phases. The nuclear quantum effects were incorporated a posteriori using the snapshots taken from ab initio trajectories. Further, they were used to solve a vibrational Schrödinger equation. The proton reaction path was studied using B3LYP, ωB97XD and PBE functionals with a 6-311++G(2d,2p) basis set. Two energy minima (deep and shallow) were found, indicating that the proton transfer phenomena could occur in the electronic ground state. Next, the electronic structure and topology were examined in the molecular and proton transferred (PT) forms. The Atoms In Molecules (AIM) theory was employed for this purpose. It was found that the hydrogen bond is stronger in the proton transferred (PT) forms. In order to estimate the dimers' stabilization and forces responsible for it, the Symmetry-Adapted Perturbation Theory (SAPT) was applied. The energy decomposition revealed that dispersion is the primary factor stabilizing the dimeric forms and crystal structure of both compounds. The CPMD results showed that the proton transfer phenomena occurred in both studied compounds, as well as in both phases. In the case of compound 2, the proton transfer events are more frequent in the solid state, indicating an influence of the environmental effects on the bridged proton dynamics. Finally, the vibrational signatures were computed for both compounds using the CPMD trajectories. The Fourier transformation of the autocorrelation function of atomic velocity was applied to obtain the power spectra. The IR spectra show very broad absorption regions between 700 cm-1-1700 cm-1 and 2300 cm-1-3400 cm-1 in the gas phase and 600 cm-1-1800 cm-1 and 2200 cm-1-3400 cm-1 in the solid state for compound 1. The absorption regions for compound 2 were found as follows: 700 cm-1-1700 cm-1 and 2300 cm-1-3300 cm-1 for the gas phase and one broad absorption region in the solid state between 700 cm-1 and 3100 cm-1. The obtained spectroscopic features confirmed a strong mobility of the bridged protons. The inclusion of nuclear quantum effects showed a stronger delocalization of the bridged protons.

Non-Covalent Forces in Naphthazarin-Cooperativity or Competition in the Light of Theoretical Approaches.

Non-covalent interactions responsible for molecular features and self-assembly in Naphthazarin C polymorph were investigated on the basis of diverse theoretical approaches: Density Functional Theory (DFT), Diffusion Quantum Monte Carlo (DQMC), Symmetry-Adapted Perturbation Theory (SAPT) and Car-Parrinello Molecular Dynamics (CPMD). The proton reaction paths in the intramolecular hydrogen bridges were studied. Two potential energy minima were found indicating that the proton transfer phenomena occur in the electronic ground state. Diffusion Quantum Monte Carlo (DQMC) and other levels of theory including Coupled Cluster (CC) employment enabled an accurate inspection of Potential Energy Surface (PES) and revealed the energy barrier for the proton transfer. The structure and reactivity evolution associated with the proton transfer were investigated using Harmonic Oscillator Model of Aromaticity - HOMA index, Fukui functions and Atoms In Molecules (AIM) theory. The energy partitioning in the studied dimers was carried out based on Symmetry-Adapted Perturbation Theory (SAPT) indicating that dispersive forces are dominant in the structure stabilization. The CPMD simulations were performed at 60 K and 300 K in vacuo and in the crystalline phase. The temperature influence on the bridged protons dynamics was studied and showed that the proton transfer phenomena were not observed at 60 K, but the frequent events were noticed at 300 K in both studied phases. The spectroscopic signatures derived from the CPMD were computed using Fourier transformation of autocorrelation function of atomic velocity for the whole molecule and bridged protons. The computed gas-phase IR spectra showed two regions with OH absorption that covers frequencies from 2500 cm-1 to 2800 cm-1 at 60 K and from 2350 cm-1 to 3250 cm-1 at 300 K for both bridged protons. In comparison, the solid state computed IR spectra revealed the environmental influence on the vibrational features. For each of them absorption regions were found between 2700-3100 cm-1 and 2400-2850 cm-1 at 60 K and 2300-3300 cm-1 and 2300-3200 cm-1 at 300 K respectively. Therefore, the CPMD study results indicated that there is a cooperation of intramolecular hydrogen bonds in Naphthazarin molecule.

Competition of Intra- and Intermolecular Forces in Anthraquinone and Its Selected Derivatives.

Intra- and intermolecular forces competition was investigated in the 9,10-anthraquinone (1) and its derivatives both in vacuo and in the crystalline phase. The 1,8-dihydroxy-9,10-anthraquinone (2) and 1,8-dinitro-4,5-dihydroxy-anthraquinone (3) contain Resonance-Assisted Hydrogen Bonds (RAHBs). The intramolecular hydrogen bonds properties were studied in the electronic ground and excited states employing Møller-Plesset second-order perturbation theory (MP2), Density Functional Theory (DFT) method in its classical formulation as well as its time-dependent extension (TD-DFT). The proton potential functions were obtained via scanning the OH distance and the dihedral angle related to the OH group rotation. The topological analysis was carried out on the basis of theories of Atoms in Molecules (AIM-molecular topology, properties of critical points, AIM charges) and Electron Localization Function (ELF-2D maps showing bonding patterns, calculation of electron populations in the hydrogen bonds). The Symmetry-Adapted Perturbation Theory (SAPT) was applied for the energy decomposition in the dimers. Finally, Car-Parrinello molecular dynamics (CPMD) simulations were performed to shed light onto bridge protons dynamics upon environmental influence. The vibrational features of the OH stretching were revealed using Fourier transformation of the autocorrelation function of atomic velocity. It was found that the presence of OH and NO2 substituents influenced the geometric and electronic structure of the anthraquinone moiety. The AIM and ELF analyses showed that the quantitative differences between hydrogen bonds properties could be neglected. The bridged protons are localized on the donor side in the electronic ground state, but the Excited-State Intramolecular Proton Transfer (ESIPT) was noticed as a result of the TD-DFT calculations. The hierarchy of interactions determined by SAPT method indicated that weak hydrogen bonds play modifying role in the organization of these crystal structures, but primary ordering factor is dispersion. The CPMD crystalline phase results indicated bridged proton-sharing in the compound 2.

Sensitivity of Intra- and Intermolecular Interactions of Benzo[h]quinoline from Car-Parrinello Molecular Dynamics and Electronic Structure Inspection.

The O-H...N and O-H...O hydrogen bonds were investigated in 10-hydroxybenzo[h]quinoline (HBQ) and benzo[h]quinoline-2-methylresorcinol complex in vacuo, solvent and crystalline phases. The chosen systems contain analogous donor and acceptor moieties but differently coupled (intra- versus intermolecularly). Car-Parrinello molecular dynamics (CPMD) was employed to shed light onto principle components of interactions responsible for the self-assembly. It was applied to study the dynamics of the hydrogen bonds and vibrational features as well as to provide initial geometries for incorporation of quantum effects and electronic structure studies. The vibrational features were revealed using Fourier transformation of the autocorrelation function of atomic velocity and by inclusion of nuclear quantum effects on the O-H stretching solving vibrational Schrödinger equation a posteriori. The potential of mean force (Pmf) was computed for the whole trajectory to derive the probability density distribution and for the O-H stretching mode from the proton vibrational eigenfunctions and eigenvalues incorporating statistical sampling and nuclear quantum effects. The electronic structure changes of the benzo[h]quinoline-2-methylresorcinol dimer and trimers were studied based on Constrained Density Functional Theory (CDFT) whereas the Electron Localization Function (ELF) method was applied for all systems. It was found that the bridged proton is localized on the donor side in both investigated systems in vacuo. The crystalline phase simulations indicated bridged proton-sharing and transfer events in HBQ. These effects are even more pronounced when nuclear quantization is taken into account, and the quantized Pmf allows the proton to sample the acceptor area more efficiently. The CDFT indicated the charge depletion at the bridged proton for the analyzed dimer and trimers in solvent. The ELF analysis showed the presence of the isolated proton (a signature of the strongest hydrogen bonds) only in some parts of the HBQ crystal simulation. The collected data underline the importance of the intramolecular coupling between the donor and acceptor moieties.

Inter- vs. Intramolecular Hydrogen Bond Patterns and Proton Dynamics in Nitrophthalic Acid Associates.

Noncovalent interactions are among the main tools of molecular engineering. Rational molecular design requires knowledge about a result of interplay between given structural moieties within a given phase state. We herein report a study of intra- and intermolecular interactions of 3-nitrophthalic and 4-nitrophthalic acids in the gas, liquid, and solid phases. A combination of the Infrared, Raman, Nuclear Magnetic Resonance, and Incoherent Inelastic Neutron Scattering spectroscopies and the Car-Parrinello Molecular Dynamics and Density Functional Theory calculations was used. This integrated approach made it possible to assess the balance of repulsive and attractive intramolecular interactions between adjacent carboxyl groups as well as to study the dependence of this balance on steric confinement and the effect of this balance on intermolecular interactions of the carboxyl groups.

New anticandidal Cu(i) complexes with neocuproine and ketoconazole derived diphenyl(aminomethyl)phosphane: luminescence properties for detection in fungal cells.

The search for new antifungals is very important because the large genetic variation of pathogenic organisms has resulted in the development of increasingly effective defense mechanisms by microorganisms. Metal complexes as potential drugs are nowadays gaining interest, because they are characterized by accessible redox states of metal centers and a plethora of easily modifiable geometries. In this work we present two new copper(i) iodide or thiocyanide complexes with 2,9-dimethyl-1,10-phenanthroline (dmp) and a diphenylphosphane derivative of ketoconazole (KeP), where a ketoconazole acetyl group is replaced by the -CH2PPh2 unit, [CuI(dmp)KeP] (1-KeP) and [CuNCS(dmp)KeP] (2-KeP) - their synthesis and structural characteristics. The analysis of the intrinsic fluorescence of the ketoconazole moiety in the coordinated KeP molecule revealed that the copper(i) central atom does not act as a quencher and the observed decrease of fluorescence intensity is a result of a strong inner filter effect caused by the presence of the CuXdmp unit. Moreover, the complexes exhibit a remarkable MLCT (metal-ligand charge transfer) based phosphorescence with the emission maximum at 600-615 nm in aqueous media, which probably results from the formation of dimers and higher order oligomers in the most polar solutions. Both complexes proved to be promising antifungal agents towards Candida albicans, showing a relatively high efficiency towards the fluconazole resistant strains with -CDR1 and CDR2 or MDR1 efflux pump overexpression, which suggests that they overcome at least partially these defense mechanisms. Simulations of docking to the cytochrome P450 14α-demethylase (the azoles' primary molecular target) suggested that the compounds studied were rather incapable of competitively inhibiting this enzyme, unlike ketoconazole and the KeP ligand. On the other hand, the phosphorescence in aqueous solutions allowed recording the confocal micrographs of the complexes which showed that both of them are situated in spherical structures inside the cells, most likely in the vacuoles.

Fluconazole and Lipopeptide Surfactin Interplay During Candida albicans Plasma Membrane and Cell Wall Remodeling Increases Fungal Immune System Exposure.

Recognizing the ß-glucan component of the Candida albicans cell wall is a necessary step involved in host immune system recognition. Compounds that result in exposed ß-glucan recognizable to the immune system could be valuable antifungal drugs. Antifungal development is especially important because fungi are becoming increasingly drug resistant. This study demonstrates that lipopeptide, surfactin, unmasks ß-glucan when the C. albicans cells lack ergosterol. This observation also holds when ergosterol is depleted by fluconazole. Surfactin does not enhance the effects of local chitin accumulation in the presence of fluconazole. Expression of the CHS3 gene, encoding a gene product resulting in 80% of cellular chitin, is downregulated. C. albicans exposure to fluconazole changes the composition and structure of the fungal plasma membrane. At the same time, the fungal cell wall is altered and remodeled in a way that makes the fungi susceptible to surfactin. In silico studies show that surfactin can form a complex with ß-glucan. Surfactin forms a less stable complex with chitin, which in combination with lowering chitin synthesis, could be a second anti-fungal mechanism of action of this lipopeptide.