AIM/NBO Analysis of the Geminal Coupling Constants in the Stabilization of A-Type Dimeric Proanthocyanidin: Angular Dependence.

The angular dependence of the indirect short-range spin-spin coupling constants (SSCC), the geminal J ( C 3 , C 1 ' ) $$ J\left({C}_3,{C}_{1^{\prime }}\right) $$ , J ( O 1 , O ) $$ J\left({O}_1,O\right) $$ , and J ( O , C 1 ' ) $$ J\left(O,{C}_{1^{\prime }}\right) $$ in A-type dimeric proanthocyanidin, was investigated using density functional theory. We studied the rotation of ring B around the C 2 - C 1 ' $$ {C}_2\hbox{--} {C}_{1^{\prime }} $$ bond. Therefore, we calculated hyperconjugative charge transfers and bond polarizations within the natural bond orbital (NBO) approach, performing a topological study based on Bader's theory, AIM (atoms in molecules), and analyzing the angular dependence of AIM/NBO parameters. The results describe a relationship between the geminal coupling that changes with angular variation and NBO charge transfers to the bonds involved in the coupling pathways that can explain the behavior of the former property. Based on AIM/NBO data, inductive and mesomeric effects were described and quantified, showing a clear correlation with the stabilization of the structure, demonstrating a resonance-assisted inductive effect. We also set out strong hyperconjugative interactions (anomeric effect) involving nonbonding electron pairs of oxygen atoms. This analysis of coupling constants supports previous models by other authors and shows the application in this particular case. Moreover, the SSCCs studied herein are used for identifying stable structures and conformational search analysis of flavonoids. Finally, our results show the relationship between SSCCs and the structure stabilization and charge delocalization effects.

Structural and functional computational analysis of nicotine analogs as potential neuroprotective compounds in Parkinson disease.

As the mechanism of interaction between nicotinic receptors with nicotine analogs is not yet fully understood, information at molecular level obtained from computational calculations is needed. In this sense, this work is a computational study of eight nicotine analogs, all with pyrrolidine ring modifications over a nicotine-based backbone optimized with B3LYP-D3/aug-cc-pVDZ. A molecular characterization was performed focusing on geometrical parameters such as pseudo-rotation angles, atomic charges, HOMO and LUMO orbitals, reactivity indexes and intermolecular interactions. Three analogs, A2 (3-(1,3-dimethyl-4,5-dihydro-1h-pirazole-5-yl) pyridine), A3 (3-(3-methyl-4,5-dihydro-1H-pyrazol-5-yl)-pyridine) and A8 (5-methyl-3-(pyridine-3-yl)-4,5-dihydroisoxazole), were filtered suggesting putative neuroprotective activity taking into account different reactivity values, such as their lowest hardness: 2.37 eV (A8), 2.43 eV (A2) and 2.56 eV (A3), compared to the highest hardness value found: 2.71 eV for A5 (3-((2S,4R)-4-(fluoromethyl)-1-methylpyrrolidine-2-il) pyridine), similar to the value of nicotine (2.70 eV). Additionally, molecular docking of all 8 nicotine analogs with the α 7 nicotinic acetylcholine receptor (α 7 nAChR) was performed. High values of interaction between the receptor and the three nicotine analogs were obtained: A3 (-7.1 kcal/mol), A2 (-6.9 kcal/mol) and A8 (-6.8 kcal/mol); whereas the affinity energy of nicotine was -6.4 kcal/mol. Leu116 and Trp145 are key residues in the binding site of α 7 nAChR interacting with nicotine analogs. Therefore, based upon these results, possible application of these nicotine analogs as neuroprotective compounds and potential implication at the design of novel Parkinson's treatments is evidenced.

A topological assessment of the electronic structure of mesoionic compounds.

Mesoionic compounds belonging to the 1,3-oxazol-5-one, 1,3-diazole-4-thione and 1,3-thiazole-5-thione rings have been evaluated by a combination of Density Functional Theory, Quantum Theory of Atoms in Molecules, Electron Localization Function, Natural Bond Orbitals and Geodesic Electrostatic Potential Charge calculations. Atomic, bond, and ring properties have been considered to describe the electronic structure of mesoionic compounds. The results show that not only the ring type, but also the substituent groups have great influence on these properties. In addition, there is a significant and heterogeneous π-bonding contribution throughout the mesoionic rings. Finally, we conclude that some classical conceptions of charge localization and π-bonding contribution in these compounds are misleading or incomplete. © 2015 Wiley Periodicals, Inc.