Effects of the aldehyde-derived ring substituent on the properties of two new bioinspired trimethoxybenzoylhydrazones: methyl vs nitro groups.

N-Acylhydrazones are a versatile class of organic compounds with a diversity of potential applications. In this study, two new structure-related 3,4,5-trimethoxybenzoyl-containing N-acylhydrazones were synthesized and fully characterized, both in solution and in the solid state. The compounds differ with respect to the carbonyl precursors, i.e., 3-substituted salicylaldehydes with either a methyl or a nitro group. Single crystals of both compounds were isolated from the respective mother liquors and, in both cases, XRD confirmed the obtention of the (E)-isomer, in an anti-conformation. Computational calculations (gas and water phases) were performed in order to confirm some of the structural and vibrational aspects of the compounds. An important intramolecular H bond involving the phenolic hydroxy group and the azomethine nitrogen was identified in the solid state and seems to be maintained in solution. Moreover, the presence of the electron-withdrawing nitro substituent makes this interaction stronger. However, the contact should probably not subsist for the nitro compound under physiological conditions since the presence of this substituent significantly affects the pKa of the phenol: an apparent value of 5.68 ± 0.02 was obtained. This also impacts the basicity of the azomethine nitrogen and, as a consequence, increases the hydrazone's susceptibility to hydrolysis. Nevertheless, both compounds are stable at physiological-like conditions, especially the methyl-derived one, which qualifies them for further toxicological and activity studies, such as those involving trivalent metal ions sequestering in the context of neurodegenerative diseases.

Molecular dynamics simulations of aqueous systems of inhibitor candidates for adenosine-5'-phosphosufate reductase.

Molecular dynamics (MD) simulations were used to evaluate some chelating agents as potential candidates to inhibitors for dissimilatory adenosine-5'-phosphosulfate reductase (APSrAB). Molecular docking methods were used to evaluate the best binding modes of these molecules to the enzyme at two binding sites: of the substrate (enzyme active site) by mean the redocking protocol of substrate; and of one of the [Fe4S4]2+ groups by mean of the clusterization protocol. The best docking poses were selected by criteria such as low energy and RMSD (redocking) and the cluster with the higher number of similar poses (clusterization), which were submitted to MD simulations. RMSD, RDF, and hydrogen bonds results revelated that all ligands left the cube site, while in the active site, some ligands remained in their docking region, pointing to the enzyme active site as the best target for the selected ligands. The binding energy results of ligands hydroxamic acid (HXA) and catechol (CAT) showed that they bonded favorably to the enzyme and key residues of the active site contributed significantly to the protein-ligand bind, indicating HAX and CAT may compete with the substrate for interactions with these residues and displaying potential as candidates for experimental studies about APSrAB inhibitors.Communicated by Ramaswamy H. Sarma.

Development of parameters compatible with the CHARMM36 force field for [Fe4S4]2+ clusters and molecular dynamics simulations of adenosine-5'-phosphosulfate reductase in GROMACS 2019.

DFT calculations were used to obtain parameters compatible with the CHARMM36 force field for iron-sulfur clusters (Fe-S) of the type [Fe4S4]2+ that are coordinated to dissimilatory adenosine-5'-phosphosulfate reductase (APSrAB). Classical molecular dynamics (MD) simulations were performed on two APSrAB systems to validate the parameters and verify the stability of the studied systems. The time analysis of the parameters inserted into the force field was in reasonable agreement with the experimental X-ray diffraction data. The analysis of the time evolution of the studied systems indicated that these systems and, in particular, the clusters in their respective cavities had a good stability and were in agreement with what was observed in previous works. The parameters obtained provide the basis for the study of APSrAB as well as other systems that contain [Fe4S4]2+ through the CHARMM36 force field.

Electronic investigation of the effect of substituents on the SOD mimic activity of copper (II) complexes with 8-hydroxyquinoline-derived ligands.

Density functional theory (DFT) calculations were used to study the superoxide dismutase (SOD) mimic activity of two Cu2+ complexes with ligands derived from 8-hydroxyquinoline (8-HQ). Electron-donating and -withdrawing substituent groups were inserted into the structures to verify changes in the reactivity. The theoretical parameters obtained were compared and validated with the experimental data available. The results showed that the reduction process occurs with greater participation of the 8-HQ ligand and the oxidation step occurs with participation of the copper atom in the complexes, where the electron received during the reduction step is used to reduce the Cu2+ to Cu+. The calculated electronic affinity showed good correlation with the experimental mimetic activity, and the analysis of this property, of total charge and of molecular orbitals indicated an increase in the mimetic activity with the insertion of electron-withdrawing substituent groups in the structures.