On the use OF 1H-NMR chemical shifts and thermodynamic data for the prediction of the predominant conformation of organic molecules in solution: the example of the flavonoid rutin.

Conformational analyses of organic compounds in solution still represent a challenge to be overcome. The traditional methodology uses the relative energies of the conformations to decide which one is most likely to exist in the experimental sample. The goal of this work was to deepen the approach of conformational analysis of flavonoid rutin (a well-known antioxidant agent) in DMSO solution. The methodology we used in this paper involves expanding the sample configuration space to a total of 44 possible geometries, using Molecular Dynamics (MD) simulations, which accesses structures that would hardly be considered with our chemical perception, followed by DFT geometry optimizations using the ωB97X-D/6-31G(d,p) - PCM level of theory. Spectroscopic and thermodynamic analyses were done, by calculating the relative energies and nuclear magnetic resonance (1H-NMR) chemical shifts, comparing the theoretical and experimental 1H-NMR spectra (DMSO-d 6) and evaluating Mean Absolute Error (MAE). The essence of this procedure lies in searching for patterns, like those found in traditional DNA tests common in healthcare. Here, the theoretical spectrum plays the role of the analyzed human sample, while the experimental spectrum acts as the reference standard. In solution, it is natural for the solute to dynamically alter its geometry, going through various conformations (simulated here by MD). However, our DFT/PCM results show that a structure named 32 with torsion angles ϕ 1 and ϕ 2 manually rotated by approx. 20° showed the best theoretical-experimental agreement of 1H-NMR spectra (in DMSO-d 6). Relative energies benchmarking involving 16 DFT functionals revealed that the ωB97X-D is very adequate for estimating energies of organic compounds with dispersion of charge (MAE < 1.0 kcal mol-1, using ab initio post-Hartree-Fock MP2 method as reference). To describe the stability of the conformations, calculations of Natural Bonding Orbitals (NBO) were made, aiming to reveal possible intramolecular hydrogen bonds that stabilize the structures. Since van der Waals (vdW) interactions are difficult to be identified by NBO donations, the Reduced Density Gradient (RDG) were calculated, which provides 2D plots and 3D surfaces that describe Non-Covalent Interactions (NCI). These data allowed us to analyze the effect of dispersion interactions on the relative stability of the rutin conformations. Our results strongly indicate that a combination of DFT (ωB97X-D)-PCM relative energies and NMR spectroscopic criterion is a more efficient strategy in conformational analysis of organic compounds in solution.

Quantum chemical investigation of predominant conformation of the antibiotic azithromycin in water and DMSO solutions: thermodynamic and NMR analysis.

Azithromycin (AZM) is a macrolide-type antibiotic used to prevent and treat serious infections (mycobacteria or MAC) that significantly inhibit bacterial growth. Knowledge of the predominant conformation in solution is of fundamental importance for advancing our understanding of the intermolecular interactions of AZM with biological targets. We report an extensive density functional theory (DFT) study of plausible AZM structures in solution considering implicit and explicit solvent effects. The best match between the experimental and theoretical nuclear magnetic resonance (NMR) profiles was used to assign the preferred conformer in solution, which was supported by the thermodynamic analysis. Among the 15 distinct AZM structures, conformer M14, having a short intramolecular C6-OH … N H-bond, is predicted to be dominant in water and dimethyl sulfoxide (DMSO) solutions. The results indicated that the X-ray structure backbone is mostly conserved in solution, showing that large flexible molecules with several possible conformations may assume a preferential spatial orientation in solution, which is the molecular structure that ultimately interacts with biological targets.

Quantum Chemical Investigation of the Interaction of Thalidomide Monomeric, Dimeric, Trimeric, and Tetrameric Forms with Guanine DNA Nucleotide Basis in DMSO and Water Solution: A Thermodynamic and NMR Spectroscopy Analysis.

Thalidomide (TLD) was used worldwide as a sedative, but it was revealed to cause teratogenicity when taken during early pregnancy. It has been stated that the (R) enantiomer of TLD has therapeutic effects, while the (S) form is teratogenic. Clinical studies, however, demonstrated the therapeutic efficacy of thalidomide in several intractable diseases, so TLD and its derivatives have played an important role in the development and therapy of anticancer drugs. Therefore, it is important to know the molecular mechanism of action of the TLD, although this is still not clear. In what molecular interactions are concerned, it is known that drug molecules can interact with DNA in different ways, for example, by intercalation between base pairs. Furthermore, the ability of the TLD to interact with DNA has been confirmed experimentally. In this work, we report a theoretical investigation of the interaction of the R and S enantiomers of TLD, in its monomeric, dimeric, trimeric, and tetrameric forms, with guanine (GUA) DNA nucleotide basis in solution using density functional theory (DFT). Our initial objective was to evaluate the interaction of TLD-R/S with GUA through thermodynamic and spectroscopic study in dimethyl sulfoxide (DMSO) solvent and an aqueous solution. Comparison of the experimental 1H nuclear magnetic resonance (NMR) spectrum in DMSO-d6 solution with calculated DFT-PCM-DMSO chemical shifts revealed that TLD can undergo molecular association in solution, and interaction of its dimeric form with a DNA base ((TLD)2-GUA and (TLD)2-2GUA, for example) through H-bond formation is likely to take place. Our results strongly indicated that we must consider the plausibility of the existence of TLD associations in solution when modeling the complexation of the TLD with biological targets. This is new information that may provide further insight into our understanding of drug binding to biological targets at the molecular level.

Theoretical Investigation of Regiodivergent Addition of Anilines and Phenolates to p-Benzoquinone Ring.

Two different products were obtained by the regiodivergent reaction of benzoquinone derivatives with phenolates and anilines: 3-aryloxybenzoquinone and 2-phenylamino-3-bromobenzoquinone. Calculated density functional theory free energies of reaction values corroborate the experimental observation of the formation of the substitution product in the reaction with phenolates in acetonitrile and the product of addition/oxidation for the reaction with aniline in water. Calculated charges and Fukui functions are similar for C2 and C3 atoms, indicating an equal possibility to suffer a nucleophilic attack. The calculated energy barriers for nucleophilic attack steps indicated that the first steps of the substitution with phenolates and addition/oxidation with anilines are faster, which justifies the formation of the respective products. The natural bond order analysis for the transition states revealed that there is a strong interaction between lone pairs of N and O atoms and the πC2C3 * for the O → C2 and N → C3 attacks and a weak interaction for the O → C3 and N → C2 attacks, which also agrees with experimental observations.

An investigation of the predominant structure of antibiotic azithromycin in chloroform solution through NMR and thermodynamic analysis.

Azithromycin (AZM) is a well-known macrolide-type antibiotic that has been used in the treatment of infections and inflammations. Knowledge of the predominant molecular structure in solution is a prerequisite for an understanding of the interactions of the drug in biological media. Experimental structural determination can be carried out for samples in solid-state (X-ray diffraction technique) and gas phase (electron diffraction experiment). In solution, spectroscopic methods can be used to extract valuable information which combined with quantum chemical calculations can lead to the determination of the preferred molecular structures to be observed when a given solute is dissolved in each solvent. That is precisely the aim of this work. We used experimental NMR chemical shift data (in CDCl3) as a reference for comparison with Density Functional Theory (DFT) NMR calculations, with geometry optimized having as guess input two crystallographic structures available in the literature with the configuration of all chiral carbon atoms inverted, named here A and B. The Polarizable Continuum Model (PCM) was used to describe the solvent effects (chloroform) including five explicit CHCl3 solvent molecules, which we believe can account for short and long-range solute-solvent interactions. Analysis of calculated thermodynamic, NMR chemical shift, MAE (Mean Absolute Error), and spin-spin coupling constant values revealed that both supposable C3R-C5S (named M2-A) and C3S-C5R (named M2-B) structures are equally probable to exist in chloroform solution. In addition, we found that the heavy atoms' conformation is reasonably similar in the solid-state and chloroform solution; however, regarding the OH groups, the spatial orientations are rather different with intramolecular OH⋯N and OH⋯O hydrogen bonds present in solution and with some of them being absent in the X-ray structure probably due to crystal packing effects.

Unveiling the Molecular Structure of Antimalarial Drugs Chloroquine and Hydroxychloroquine in Solution through Analysis of 1H NMR Chemical Shifts.

Chloroquine (CQ) and hydroxychloroquine (HCQ) have been standard antimalarial drugs since the early 1950s, and very recently, the possibility of their use for the treatment of COVID-19 patients has been considered. To understand the drug mode of action at the submicroscopic level (atoms and molecules), molecular modeling studies with the aid of computational chemistry methods have been of great help. A fundamental step in such theoretical investigations is the knowledge of the predominant drug molecular structure in solution, which is the real environment for the interaction with biological targets. Our strategy to access this valuable information is to perform density functional theory (DFT) calculations of 1H NMR chemical shifts for several plausible molecular conformers and then find the best match with experimental NMR profile in solution (since it is extremely sensitive to conformational changes). Through this procedure, after optimizing 30 trial distinct molecular structures (ωB97x-D/6-31G(d,p)-PCM level of calculation), which may be considered representative conformations, we concluded that the global minimum (named M24), stabilized by an intramolecular N-H hydrogen bond, is not likely to be observed in water, chloroform, and dimethyl sulfoxide (DMSO) solution. Among fully optimized conformations (named M1 to M30, and MD1 and MD2), we found M12 (having no intramolecular H-bond) as the most probable structure of CQ and HCQ in water solution, which is a good approximate starting geometry in drug-receptor interaction simulations. On the other hand, the preferred CQ and HCQ structure in chloroform (and CQ in DMSO-d6) solution was assigned as M8, showing the solvent effects on conformational preferences. We believe that the analysis of 1H NMR data in solution can establish the connection between the macro level (experimental) and the sub-micro level (theoretical), which is not so apparent to us and appears to be more appropriate than the thermodynamic stability criterion in conformational analysis studies.

Conformational Analysis of 5,4'-Dihydroxy-7,5',3'-trimethoxyisoflavone in Solution Using 1H NMR: A Density Functional Theory Approach.

Among 20 compounds isolated from the extracts of Ouratea ferruginea the 5,4'-dihydroxy-7,5',3'-trimethoxyisoflavone (9) showed the best inhibitory effect on glutathione S-transferase (GST) and so deserves our attention. In this work we investigated the preferred molecular structure of 9 in chloroform solution using the density functional theory (DFT) and molecular dynamics simulation. Comparison between experimental 1H NMR data in CDCl3 solution and calculated chemical shifts enabled us to precisely determine the conformation adopted by 9 in solution, which can be used in further theoretical studies involving interaction with biological targets. Moreover, the experimental NMR data were used as reference to assess the ability of DFT based methods to predict 1H NMR spectrum in solution for organic compounds. Among various DFT functionals the hybrid B3LYP was the most adequate for the calculation of chemical shifts in what CHn protons are concerned. Regarding the OH hydrogen, inclusion of explicit CHCl3 solvent molecules adequately placed around the solute led to good agreement with the experimental chemical shifts (in CDCl3). It is a well-known fact that theoretical prediction of chemical shifts for OH hydrogens poses as a challenge and also revealed that the way the solvent effects are included in the DFT calculations is crucial for the right prediction of the whole 1H NMR spectrum. It was found in this work that a supermolecule solute-solvent calculation with a minimum of four CHCl3 molecules is enough to correctly reproduce the 1H NMR experimental profile observed in solution, revealing that the calculated solvated structure used to reproduce the NMR chemical shifts is not unique.

Determination of Anticancer Zn(II)-Rutin Complex Structures in Solution through Density Functional Theory Calculations of 1H NMR and UV-VIS Spectra.

Coordination compounds formed by flavonoid ligands are recognized as promising candidates as novel drugs with enhanced antioxidant and anticancer activity. Zn(II)-Rutin complexes have been described in the literature and distinct coordination modes proposed based on 1H NMR/MS and IR/UV-VIS experimental spectroscopic data: 1:1/1:2 (Zn(II) binding to A-C rings) and 2:1 (Zn(II) binding to A-C-B rings) stoichiometry. Aiming to clarify these experimental findings and provide some physical insights into the process of complex formation in solution, we carried out density functional theory calculations of NMR and UV-VIS spectra for 25 plausible Zn(II)-Rutin molecular structures including solvent effect using the polarizable continuum model approach. The studied complexes in this work have 1:1, 1:2, 2:1, and 3:1 metal-ligand stoichiometry for all relevant Zn(II)-Rutin configurations. The least deviation between theoretical and experimental spectroscopic data was used as an initial criterion to select the probable candidate structures. Our theoretical spectroscopic results strongly indicate that the experimentally suggested modes of coordination (1:2 and 2:1) are likely to exist in solution, supporting the two distinct experimental findings in DMSO and methanol solution, which may be seen as an interesting result. Our predicted 1:2 and 2:1 metal complexes are in agreement with the experimental stoichiometry; however, they differ from the proposed structure. Besides the prediction of the coordination site and molecular structure in solution, an important contribution of this work is the determination of the OH-C5 deprotonation state of rutin due to metal complexation at the experimental conditions (pH = 6.7 and 7.20). We found that, in the two independent synthesis of metal complexes, distinct forms of rutin (OH-C5 and O(-)-C5) are present, which are rather difficult to be assessed experimentally.

1H and 195Pt NMR prediction for inclusion compounds formed by cisplatin and oxidized carbon nanostructures.

Prediction of NMR chemical shifts can assist experimentalists in the characterization of drug delivery systems based on carbon nanocomposites. Chemical shifts are strongly correlated to the nucleus position and its chemical neighborhood. Therefore, to predict structures and NMR properties of complex chemical models, choosing a more consistent theoretical level capable of providing more realistic results and moderate computational demand is a major challenge. In this work, we predicted the NMR spectra of inclusion compounds formed by cisplatin (cDDP) and an oxidized carbon nanotube (CNTox) and nanocone (CNCox) considered by specialists as potential drug delivery systems. The 195Pt NMR chemical shifts calculated at the DFT level with the new relativistic NMR-DKH basis set were -2314 ppm and -2192 ppm for cDDP@CNTox and cDDP@CNCox complexes, respectively, which are both high-field shifted relative to the free cDDP (-2110 ppm). 1H NMR chemical shifts are also sensitive to the inclusion process. The H (NH3) signals are found on average at +4.3 (cDDP), -5.1 (cDDP@CNTox) and +6.6 ppm (cDDP@CNCox). Interestingly, despite the similar inclusion modes in CNTox and CNCox cavities, the 1H NMR shifts were in opposite directions. A possible reason might be the higher stability of cDDP@CNTox (ΔE F = -19.9 kcal mol-1) than that of cDDP@CNCox (ΔE F = -5.7 kcal mol-1), which suggests a short guest-host contact in the former and consequently, a more efficient shielding of hydrogen atoms due to the electron-rich carbon structure. These results may be helpful as comparison data in the NMR spectra assignment in solution and the inclusion compounds' structural elucidation.

Chemically Modified Carbon Nanohorns as Nanovectors of the Cisplatin Drug: A Molecular Dynamics Study.

Carbon nanohorns (CNH) have been considered potential anticancer drug carriers, such as the cisplatin drug (cddp), due to their low toxicity, high purity, drug-loading capacity, and biodegradation routes. However, when it comes to nanomedicine applications, chemical functionalization is an essential step in order to overcome undesirable properties of these nanomaterials, such as the high hydrophobicity, low reactivity, and low dispersibility in polar solvents. In this context, the present study involved the modeling of new CNH topologies based on chemical oxidation and reduction mechanisms and the investigation of the influence of these modified structures on the dynamics and stability of inclusion complexes with cddp. The results indicated that these functionalization strategies lead to the opening of nanowindows on the CNH surfaces, which would constitute the main route for drug release, as reported by experimentalists. Also, our results showed that the insertion of polar functional groups on the oxidized CNH (CNHox-N) contributed to an improvement of the cddp@CNHox-N biocompatibility due to the greater number of hydrogen bonds formed with the solvent. Despite the favorable formation of all complexes, the binding free energies pointed out that the oxidation process made the cddp@CNHox-N complexes slightly less stable than the ones with pristine and reduced CNH. Besides, the results suggest the possibility to tune the complex stability by controlling the oxidation degree, which could be explored by the experimentalists in order to design controlled drug delivery systems based on CNH nanocarriers.

Molecular dynamics of carbon nanohorns and their complexes with cisplatin in aqueous solution.

The medication with Pt-based antitumor drug cisplatin has demonstrated effective results against cancer cells, despite the severe side effects due to the high toxicity associated with the low selectivity of these anticancer agents. An alternative to overcome or decrease the side effects is to use drug delivery systems, which can carry high doses of the anticancer drug and promote its slow and targeted release to the tumor sites. Herein, we used molecular dynamics to study prototypes of the complexes formed by the encapsulated cisplatin and carbon nanohorns (CNH), with the purpose to characterize its structures and dynamical behavior in aqueous solution, an important feature to assess the potentiality of using CNH as carrier systems. The results indicated the presence of up to 36 water molecules inside the empty CNH cavity, depending on the cone angle and the presence of the cisplatin. Some of these solvent molecules are expelled out to the bulk upon cisplatin inclusion, although more than 10 molecules remain even for the narrow structures. Moreover, the calculated binding free energy (ΔbG) pointed out that the inclusion complexes formation between CNH structures and up to two cisplatin molecules was thermodynamically favorable in aqueous media, which suggests the potentiality of these carbon nanostructures as drug carriers. For the most likely and narrow host structure the average ΔbG was -92.0 kcal mol-1 for inclusion of two cisplatin, with most of the complex stability coming from the van der Waals contribution.

Structural Determination of Antioxidant and Anticancer Flavonoid Rutin in Solution through DFT Calculations of 1H†NMR Chemical Shifts.

As the knowledge of the predominant molecular structure of antioxidant and anticancer flavonoid rutin in solution is very important for understanding the mechanism of action, a quantum chemical investigation of plausible rutin structures including solvent effects is of relevance. In this work, DFT calculations were performed to find possible minimum energy structures for the rutin molecule. 1H NMR chemical shift DFT calculations were carried out in DMSO solution using the polarizable continuum model (PCM) to simulate the solvent effect. Analysis of the experimental and theoretical 1H NMR chemical shift profiles offers a powerful fingerprint criterion to determine the predominant molecular structure in solution. Therefore, our aim is to find the best match between experimental (in DMSO-d) and theoretical (PCM-DMSO) 1H NMR spectrum profiles. Among 34 optimized structures located on the potential energy surface, we found that structure 32, with a B-ring deviated 30° from a planar configuration (geometry usually assumed for polyphenols), showed an almost perfect agreement with experimental the 1H NMR pattern when compared to the corresponding fully optimized planar geometry. This structure is also predicted as the global minimum based on room-temperature Gibbs free energy calculations in solution and, therefore, should be experimentally observed. This is new and valuable structural information regarding structure-activity relationship studies, and such information is hard to obtain by experimentalists without the aid of the X-ray diffraction technique.

Inclusion complexes between cisplatin and oxidized carbon nanostructures: A theoretical approach.

The toxicity of inclusion compounds formed by carbon nanostructures depends on its functionalized surface, use of solvents, dosage and other properties. Molecular modeling has potentially contributed to the understanding of the chemical nature of the formation of these systems and allows advancement in studies of the mechanism of transport, release of drugs and their biological implications. This work reports a quantum chemical investigation of the inclusion complexes formation between oxidized carbon nanotube (CNTox)/nanocone (CNCox) structure and cisplatin molecule, using the density functional theory (DFT) with the B3LYP functional and 6-31G(d,p)/LanL2DZ standard basis sets. Our results indicate that the cDDP@CNTox (inclusion complex - cisplatin into oxidized carbon nanotube) and cDDP@CNCox (inclusion complex - cisplatin into oxidized carbon nanocone) systems form stable molecular complexes that can be used as drug delivery devices. Our theoretical simulation of molecular spectra (IR, Raman and 1H NMR) reveals substantial changes due to complex formation that can be easily experimentally observed.

Water Solvent Effect on Theoretical Evaluation of 1H NMR Chemical Shifts: o-Methyl-Inositol Isomer.

In this paper, density functional theory calculations of nuclear magnetic resonance (NMR) chemical shifts for l-quebrachitol isomer, previously studied in our group, are reported with the aim of investigating in more detail the water solvent effect on the prediction of 1H NMR spectra. In order to include explicit water molecules, 20 water-l-quebrachitol configurations obtained from Monte Carlo simulation were selected to perform geometry optimizations using the effective fragment potential method encompassing 60 water molecules around the solute. The solvated solute optimized geometries were then used in B3LYP/6-311+G(2d,p) NMR calculations with PCM-water. The inclusion of explicit solvent in the B3LYP NMR calculations resulted in large changes in the 1H NMR profiles. We found a remarkable improvement in the agreement with experimental NMR profiles when the explicit hydrated l-quebrachitol structure is used in B3LYP 1H NMR calculations, yielding a mean absolute error (MAE) of only 0.07 ppm, much lower than reported previously for the gas phase optimized structure (MAE = 0.11 ppm). In addition, a very improved match between theoretical and experimental 1H NMR spectrum measured in D2O was achieved with the new hydrated optimized l-quebrachitol structure, showing that a fine-tuning of the theoretical NMR spectra can be accomplished once solvent effects are properly considered.

Computational investigation on the host-guest inclusion process of norfloxacin into ß-cyclodextrin.

A theoretical (1)H NMR spectroscopy and thermodynamic analysis of the host-guest inclusion process involving the norfloxacin (NFX) into ß-cyclodextrin (ß-CD) was carried out. DFT structure and stabilization energies were obtained in both gas and aqueous phases. We could establish that the complex formation is enthalpy driven, and the hydrogen bonds established between NFX and ß-CD play a major role in the complex stabilization. Besides, a theoretical (1)H NMR analysis has shown to be a supplementary proceeding to predict appropriately the inclusion mode of norfloxacin molecule into the ß-CD. In this work, a theoretical study of the NFX@ß-CD complex is reported for the first time, seeking a deep understanding of topology and thermodynamics of the inclusion complex formation. Graphical Abstract Topology, thermodynamic and (1)H NMR analysis of NFX@ß-CD host-guest complexes.

The semiquinone at the Qi site of the bc1 complex explored using HYSCORE spectroscopy and specific isotopic labeling of ubiquinone in Rhodobacter sphaeroides via (13)C methionine and construction of a methionine auxotroph.

Specific isotopic labeling at the residue or substituent level extends the scope of different spectroscopic approaches to the atomistic level. Here we describe (13)C isotopic labeling of the methyl and methoxy ring substituents of ubiquinone, achieved through construction of a methionine auxotroph in Rhodobacter sphaeroides strain BC17 supplemented with l-methionine with the side chain methyl group (13)C-labeled. Two-dimensional electron spin echo envelope modulation (HYSCORE) was applied to study the (13)C methyl and methoxy hyperfine couplings in the semiquinone generated in situ at the Qi site of the bc1 complex in its membrane environment. The data were used to characterize the distribution of unpaired spin density and the conformations of the methoxy substituents based on density functional theory calculations of (13)C hyperfine tensors in the semiquinone of the geometry-optimized X-ray structure of the bc1 complex (Protein Data Bank entry 1PP9 ) with the highest available resolution. Comparison with other proteins indicates individual orientations of the methoxy groups in each particular case are always different from the methoxy conformations in the anion radical prepared in a frozen alcohol solution. The protocol used in the generation of the methionine auxotroph is more generally applicable and, because it introduces a gene deletion using a suicide plasmid, can be applied repeatedly.

The 2-Methoxy Group Orientation Regulates the Redox Potential Difference between the Primary (QA) and Secondary (QB) Quinones of Type II Bacterial Photosynthetic Reaction Centers.

Recent studies have shown that only quinones with a 2-methoxy group can act simultaneously as the primary (QA) and secondary (QB) electron acceptors in photosynthetic reaction centers from purple bacteria such as Rb. sphaeroides. 13C HYSCORE measurements of the 2-methoxy group in the semiquinone states, SQA and SQB, were compared with DFT calculations of the 13C hyperfine couplings as a function of the 2-methoxy dihedral angle. X-ray structure comparisons support 2-methoxy dihedral angle assignments corresponding to a redox potential gap (ΔEm) between QA and QB of 175-193 mV. A model having a methyl group substituted for the 2-methoxy group exhibits no electron affinity difference. This is consistent with the failure of a 2-methyl ubiquinone analogue to function as QB in mutant reaction centers with a ΔEm of ∼160-195 mV. The conclusion reached is that the 2-methoxy group is the principal determinant of electron transfer from QA to QB in type II photosynthetic reaction centers with ubiquinone serving as both acceptor quinones.

Theoretical and experimental study of inclusion complexes formed by isoniazid and modified ß-cyclodextrins: 1H NMR structural determination and antibacterial activity evaluation.

Me-ß-cyclodextrin (Me-ßCD) and HP-ß-cyclodextrin (HP-ßCD) inclusion complexes with isoniazid (INH) were prepared with the aim of modulating the physicochemical and biopharmaceutical properties of the guest molecule, a well-known antibuberculosis drug. The architectures of the complexes were initially proposed according to NMR data Job plot and ROESY followed by density functional theory (DFT) calculations of (1)H NMR spectra using the PBE1PBE functional and 6-31G(d,p) basis set, including the water solvent effect with the polarizable continuum model (PCM), for various inclusion modes, providing support for the experimental proposal. An analysis of the (1)H NMR chemical shift values for the isoniazid (H6',8' and H5',9') and cyclodextrins (H3,5) C(1)H hydrogens, which are known to be very adequately described by the DFT methodology, revealed them to be extremely useful, promptly confirming the inclusion complex formation. An included mode which describes Me-ßCD partially enclosing the hydrazide group of the INH is predicted as the most favorable supramolecular structure that can be used to explain the physicochemical properties of the encapsulated drug. Antibacterial activity was also evaluated, and the results indicated the inclusion complexes are a potential strategy for tuberculosis treatment.

DFT study of cisplatin@carbon nanohorns complexes.

This paper reports a quantum chemical investigation of the inclusion complex formation between a carbon nanohorn structure and cisplatin molecule, using the density functional theory (DFT) with the B3LYP functional and 6-31G(d,p)/LanL2DZ standard basis sets. The inclusion of the drug in host molecules such as carbon nanohorns (CNHs), aims to reduce the toxicity and enhance the effectiveness of cisplatin. In this work we carried out a search for minimum energy structures on the potential energy surface (PES) for CNH-cisplatin interaction, and then calculated the stabilization energy, charge distribution and NMR spectra, which can be of great aid for the experimental identification of the inclusion compound. Our results indicate that the CNH and cisplatin can indeed form stable inclusion complex, with the calculated (1)H NMR and (15)N NMR chemical shifts for cisplatin atoms revealing very substantial changes due to complex formation (~20ppm) that can be easily experimentally observed, which is helpful to the spectra assignment and the inclusion compound structural elucidation.