Marija Antić

Effect of benzo-annelation on local aromaticity in heterocyclic conjugated compounds.

The effect of benzo-annelation on the local aromaticity of the central ring of acridine (1), 9H-carbazole (2), dibenzofuran (3), and dibenzothiophene (4) was analyzed by means of the energy effects (ef), pairwise energy effects (pef), multicenter delocalization index (MCI), electron density at ring critical points (ρ(r(C))), harmonic oscillator model of aromaticity (HOMA), and nucleus independent chemical shifts (NICS). According to energetic, electron delocalization, and geometrical indices, angular benzo-annelation increases, whereas linear benzo-annelation decreases, the extent of the local aromaticity of the central ring containing heteroatoms. The local aromaticity of the central heterocyclic ring in the examined molecules can significantly vary by applying different modes of benzo-annelation. The NICS values do not always support the results obtained by the other aromaticity indices and, in some cases, lead to completely opposite conclusions.

Importance of hydrogen bonding and aromaticity indices in QSAR modeling of the antioxidative capacity of selected (poly)phenolic antioxidants

The quantitative structure-activity relationship (QSAR) models for predicting antioxidative capacity of 21 structurally similar natural and synthetic phenolic antioxidants was considered. The one-, two- and three-descriptor QSAR models were developed. For this purpose the literature data on the vitamin C equivalent antioxidative capacity (VCEAC) values were used as experimental descriptor of antioxidative capacity. Some thermodynamic and aromaticity properties, as well as the natural bond analysis (NBO) based quantities aimed at measuring the strength of intramolecular hydrogen bonds, were used as independent variables. It was examined whether a combination of these variables can yield a mathematical function that is in good correlation with the VCEAC values. It was shown that a combination of a certain thermodynamic descriptor (related to the single proton loss electron transfer mechanism) with the NBO-based quantities results in several two-descriptor models with the correlation coefficient greater than 0.950. Thus, a significant influence of internal hydrogen bonds on the antioxidative capacity of the studied molecules was confirmed. The best correlation with the VCEAC values was achieved within a three-descriptor QSAR model. This model was obtained by including a magnetic aromaticity index. It was found that aromaticity has only secondary effects on the antioxidative capacity.

Mononuclear gold(III) complexes with phenanthroline ligands as efficient inhibitors of angiogenesis: A comparative study with auranofin and sunitinib

Gold(III) complexes with 1,7- and 4,7-phenanthroline ligands, [AuCl3(1,7-phen-κN7)] (1) and [AuCl3(4,7-phen-κN4)] (2) were synthesized and structurally characterized by spectroscopic (NMR, IR and UV-vis) and single-crystal X-ray diffraction techniques. In these complexes, 1,7- and 4,7-phenanthrolines are monodentatedly coordinated to the Au(III) ion through the N7 and N4 nitrogen atoms, respectively. In comparison to the clinically relevant anti-angiogenic compounds auranofin and sunitinib, gold(III)-phenanthroline complexes showed from 1.5- to 20-fold higher anti-angiogenic potential, and 13- and 118-fold lower toxicity. Among the tested compounds, complex 1 was the most potent and may be an excellent anti-angiogenic drug candidate, since it showed strong anti-angiogenic activity in zebrafish embryos achieving IC50 value (concentration resulting in an anti-angiogenic phenotype at 50% of embryos) of 2.89μM, while had low toxicity with LC50 value (the concentration inducing the lethal effect of 50% embryos) of 128μM. Molecular docking study revealed that both complexes and ligands could suppress angiogenesis targeting the multiple major regulators of angiogenesis, such as the vascular endothelial growth factor receptor (VEGFR-2), the matrix metalloproteases (MMP-2 and MMP-9), and thioredoxin reductase (TrxR1), where the complexes showed higher binding affinity in comparison to ligands, and particularly to auranofin, but comparable to sunitinib, an anti-angiogenic drug of clinical relevance.

Synthesis, structural characterization and biological evaluation of dinuclear gold(III) complexes with aromatic nitrogen-containing ligands: antimicrobial activity in relation to the complex nuclearity

Dinuclear gold(III) complexes {[AuCl3]2(μ-4,4′-bipy)} (1) and {[AuCl3]2(μ-bpe)} (2) with bridging aromatic nitrogen-containing heterocyclic ligands, 4,4′-bipyridine (4,4′-bipy) and 1,2-bis(4-pyridyl)ethane (bpe), were synthesized and characterized by NMR (1H and 13C), UV-vis and IR spectroscopic techniques. The crystal structure of 1 was determined by single-crystal X-ray diffraction analysis, while the DFT M06-2X method was applied in order to optimize the structures of 1 and 2. A detailed mechanistic study was performed using the same DFT approach in order to shed light on the disparate coordination modes of the presently investigated N-heterocyclic ligands and the monocyclic pyrazine, which contains two nitrogen atoms within one ring, toward the AuCl3 fragment. The investigation of the solution stability of 1 and 2 in DMSO revealed that both complexes were sufficiently stable in this solvent at room temperature. Complexes 1 and 2, along with K[AuCl4] and the N-heterocyclic ligands used for their synthesis, were evaluated by in vitro antimicrobial studies against a panel of Gram-positive and Gram-negative bacteria and the fungus Candida albicans. In most cases, complexes 1 and 2 have higher antibacterial activity than K[AuCl4] (MICs for 1 and 2 were in the range 3.9–62.5 μg mL−1), while both of the N-heterocycles did not affect the bacterial growth at concentrations up to 500 μg mL−1. On the other hand, the antifungal activity of these two complexes against C. albicans was moderate and lower than that of K[AuCl4]. In order to determine the therapeutic potential of 1 and 2, their antiproliferative effect on the normal human lung fibroblast cell line MRC5 and embryotoxicity on zebrafish (Danio rerio) have also been evaluated. To the best of our knowledge, complexes 1 and 2 are the first examples of dinuclear gold(III) complexes with aromatic six-membered heterocycles containing two nitrogen atoms as bridging ligands.

Aromaticity of Nonplanar Fully Benzenoid Hydrocarbons

The Clar aromatic sextet theory can provide a qualitative description of the dominant modes of cyclic π-electron conjugation in benzenoid molecules and of the relative stability among a series of isomeric benzenoid systems. In a series of nonplanar fully benzenoid hydrocarbons, the predictions of the Clar theory were tested by means of several different theoretical approaches: topological resonance energy (TRE), energy effect (ef), harmonic oscillator model of aromaticity (HOMA) index, six center delocalization index (SCI), and nucleus-independent chemical shifts (NICS). To assess deviations from planarity in the examined molecules, four different planarity descriptors were employed. It was shown how the planarity indices can be used to quantify the effect of nonplanarity on the local and global aromaticity of the studied systems.

Electronic structure study of the biradical pleiadene-like molecules

A detailed electronic structure study of singlet and triplet states of a series of biradicaloid pleiadene-like molecules was performed using the DFT and complete active space methods. It was shown that the singlet–triplet gaps obtained with the B3LYP, B2PLYP, and CASSCF methods are not a monotone function of the number of annelated benzene rings. According to the CASSCF results, 9,10-naphthopleiadene is a triplet biradical, whereas all other members of the series are found to be singlet biradicaloids exhibiting very pronounced biradical character. On the other hand, the B2PLYP calculations revealed that 9,10-anthracenopleiadene is a triplet biradical molecule. A detailed analysis of the local aromaticity of singlet and triplet states of the examined molecules was done by means of the multi-centre delocalization indices, harmonic oscillator model of aromaticity index, and nucleus independent chemical shifts. It was shown that the triplet states are more aromatic than the corresponding singlet electronic states. The difference in aromaticity of the singlet and triplet electronic states becomes smaller along the series of benzannelated pleiadenes. The more pronounced aromatic character of the triplet states can compensate the instability coming from the presence of unpaired electrons, which can explain the fact that the mid-size members of the examined series are found to be triplet biradicals.Graphical abstract

The nature of the Au–N bond in gold(III) complexes with aromatic nitrogen-containing heterocycles: the influence of Au(III) ions on the ligand aromaticity

In this work, the nature of the bonding interaction between Au(III) ion and aromatic nitrogen-containing heterocycles (N-heterocycles) in a series of Au(III) complexes was studied by means of the natural bond orbital (NBO), atoms in molecule (AIM), charge decomposition analysis (CDA) and energy decomposition analysis (EDA) methods at the B3LYP/cc-pVTZ + LanL2TZ(f) level of theory. It was found that the Au–N coordinative bond has a higher electrostatic than covalent character. The studied N-heterocycles were found to be strong σ-electron donors, but rather weak π-electron acceptors. In addition, the local aromatic distribution in the studied N-heterocycles, and in their Au(III) complexes, was quantified through several different aromaticity indices: the six center delocalization index (SCI), the harmonic oscillator model of aromaticity (HOMA) index and the nucleus-independent chemical shifts (NICS). It was shown that the aromatic character of the nitrogen-containing ring in gold(III) complexes is decreased in comparison with the same ring of uncoordinated ligands.