No abstract

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.

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.

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 CH n 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.

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-d 6) 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.