Aromaticity of six-membered nitro energetic compounds through molecular electrostatic potential, magnetic, electronic delocalization and reactivity-based indices.

The electron density depletion associated with π-hole at the ring center typical of energetic compounds was clearly revealed by the molecular electrostatic potential (ESP). In addition, the spatial arrangement of NO2 groups appears to affect the ESP value in the ring center, and therefore sensitivity to detonation. Indeed, for monocyclic nitrobenzene compounds with the same number of NO2 groups, the ESP value in the ring center decreases as the NO2 groups are more closely spaced. As expected, the central rings become less aromatic as NO2 groups are added. The MCI, PDI, PLR, NICSzz(1), FLU indices are all strongly correlated with the ESP values observed in the ring center of the set of nitrobenzenes. Aromaticity indices based on electron delocalization criteria appear to be very sensitive to small variations in aromaticity. Among magnetic-based indices, only NICSzz(1) is capable to predict small changes in aromaticity. The PLR index derived from conceptual DFT is quite relevant for predicting small variations in aromaticity. According to our results, the most suitable aromaticity index is not based on a single criterion, and that selecting it is more subtle. Therefore, it is important to combine information from several criteria to obtain a more complete description of the aromaticity of the studied compounds.

The effect of {O,N}=X⋯M={Ti,Zr,Hf} interactions on the sensitivity of CNO2 trigger bonds in FOX-7: Approach based on the QTAIM/EDA-NOCV analysis.

The local chemical reactivity of FOX-7 (1,1-diamino-2,2-nitroethylene, also known as DADNE from DiAminoDiNitroEthylene) was elucidated through a quantitative study of the electrostatic potential on the molecular surface, topological analysis based on Bader's theory, and the EDA-NOCV method. Unlike (O2N)2CC(NH2)H2N⋯Cp2MCH3+ complexes, which exhibit both σ-donor and π-acceptor features, the situation is different concerning the (H2N)2CC(NO2)(O)NO⋯Cp2MCH3+ complexes, where both charge transfers correspond to the σ-donation. The two charge transfers reinforce each other, resulting in increased stability for (H2N)2CC(NO2)(O)NO⋯Cp2MCH3+. This seems to strengthen the (H2N)2CC(NO2)(O)NO⋯M={Ti,Zr,Hf} bond, which may explain the high stability of (H2N)2CC(NO2)(O)NO⋯Cp2MCH3+ compared to (O2N)2CC(NH2)-H2N⋯Cp2MCH3+. Results from topological analysis revealed that the decreased sensitivity to decomposition of CNO2 bonds depends on the chemical nature of the interacting metal, and the best achievements are obtained for the Hf-based complex. Our results demonstrate that the interaction of M={Ti,Zr,Hf} with CNO2 is more favourable than that with CNH2, this specific action on the trigger bond may support the use of Metallocene Methyl Cations (MMC) as possible neutralisers.

Molecular docking/dynamics simulations, MEP analysis, bioisosteric replacement and ADME/T prediction for identification of dual targets inhibitors of Parkinson's disease with novel scaffold.

Monoamine oxidase B and Adenosine A2A receptors are used as key targets for Parkinson's disease. Recently, hMAO-B and hA2AR Dual-targets inhibitory potential of a novel series of Phenylxanthine derivatives has been established in experimental findings. Hence, the current study examines the interactions between 38 compounds of this series with hMAO-B and hA2AR targets using different molecular modeling techniques to investigate the binding mode and stability of the formed complexes. A molecular docking study revealed that the compounds L24 ((E)-3-(3-Chlorophenyl)-N-(4-(1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) phenyl) acrylamide and L32 ((E)-3-(3-Chlorophenyl)-N-(3-(1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)phenyl)acrylamide) had a high affinity (S-score: -10.160 and -7.344 kcal/mol) with the pocket of hMAO-B and hA2AR targets respectively, and the stability of the studied complexes was confirmed during MD simulations. Also, the MEP maps of compounds 24 and 32 were used to identify the nucleophilic and electrophilic attack regions. Moreover, the bioisosteric replacement approach was successfully applied to design two new analogs of each compound with similar biological activities and low energy scores. Furthermore, ADME-T and Drug-likeness results revealed the promising pharmacokinetic properties and oral bioavailability of these compounds. Thus, compounds L24, L32, and their analogs can undergo further analysis and optimization in order to design new lead compounds with higher efficacy toward Parkinson's disease. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-023-00139-3.

Explaining the High Catalytic Activity in Bis(indenyl)methyl Zirconium Cation Using Combined EDA-NOCV/QTAIM Approach.

The main purpose of this study is to elucidate some discrepancies already observed in the catalytic activity values of some zirconocene methyl cations. The EDA-NOCV scheme was employed for a theoretical description of the interactions between an ethylene molecule and five catalysts of zirconocene methyl cation. The nature of the chemical interactions has been elucidated through the QTAIM topological analysis. The steric hindrance due to the ligands was evaluated qualitatively by means of an IRI-based analysis and quantitively through Fisher information. The findings prove that the indenyl ligand seems to favor the orbital interaction between the ethylene molecule and the metal centre of zirconocene methyl cation. Both electrostatic and orbital contributions play a crucial role in stabilising the studied complexes. Based on the NOCV deformation density contributions, the strongest orbital interaction is reached with the bis(indenyl)methyl zirconium cation, which is the only one exhibiting covalent interactions. Especially, the strong contribution of π-back donation (occurring from the occupied orbitals of the zirconium atom to the π* anti-bonding orbital of ethylene) may be a key to understand why this catalyst has a higher polymerisation yield than the other studied catalysts. This work suggests a perspective for predicting values of catalytic activity when theoretically designing novel catalysts of zirconocene type.

Investigation of [3H]diazepam derivatives as allosteric modulators of GABAA receptor α1ß2γ2 subtypes: combination of molecular docking/dynamic simulations, pharmacokinetics/drug-likeness prediction, and QSAR analysis.

In this paper, a data set of [3H] diazepam derivatives was analyzed using various computational methods: molecular docking/dynamic simulations, and QSAR analysis. The main aims of these studies are to understand the binding mechanisms by which benzodiazepines allosterically modulate GABAA receptor α1ß2γ2 subtypes, from inducing neuronal inhibition at lower doses to the anesthetic effect at higher doses, and also, to define the structural requirements that contribute to improving the response of GABAA/α1ß2γ2 receptor to benzodiazepine drugs. The results of the molecular docking study allowed selecting Ro12-6377 and proflazepam as the best modulators for the four binding sites simultaneously. Subsequently, the stability of the selected complexes was investigated by performing molecular dynamics simulation. The latter confirmed the features of both modulators to exert direct effects on the chloride-channel lining residues. Pharmacokinetics and drug-likeness profile were assessed through in silico tool. Furthermore, a QSAR analysis was conducted using an improved vemolecular dynamics simulations proposed byrsion of PLS regression. The goodness of fit and the predictive power of the resulting PLS model were estimated according to internal and external validation parameters: R2 = 0.632, R2adj = 0.584, F = 12.806; p-value = 6.2050e - 07, Q2loo = 0.639, and Q2F3 = 0.813. Clearly, the obtained results ensure the predictive ability of the developed QSAR model for the design of new high-potency benzodiazepine drugs. Supplementary Information: The online version contains supplementary material available at 10.1007/s11224-022-02029-4.

A computational study of potent series of selective estrogen receptor degraders for breast cancer therapy.

A detailed multistep framework combining quantitative structure-activity relationship, global reactivity, absorption, distribution, metabolism and elimination properties, molecular docking and molecular dynamics simulation (MD) on a series of Selective Estrogen Receptor Down-Regulators (SERDs) interacting with Estrogen Receptor α (ERα) has been performed. The partial least squares regression method derived an empirical model with better predictive capability. The results of global reactivity descriptors revealed that all the compounds are considered strong electrophiles, allowing them to participate in polar reactions more easily. The Brain Or IntestinaL EstimateD permeation diagram revealed that compounds 49 and 31 were predicted to be well absorbed by the human gastrointestinal tract and would not enter the brain. The elucidation of the binding mode between the most active compounds that comply with Lipinski's and Veber's rules from the dataset and ERα targets was explored by molecular docking. The MD simulations were performed for 100 ns on the best compounds, which indicated their stability state under dynamics simulations. These findings are expected to help predict the anticancer activities of the studied SERD compounds and better understand their binding mechanism with ERα targets.Communicated by Ramaswamy H. Sarma.

Theoretical investigation of the effect of O⋯M={Ti,Zr,Hf} interactions on the sensitivity of energetic N-nitro compounds.

This paper outlines the role of intermolecular interactions involving group 4 transition metals in stabilising the N-NO2 trigger bonds. Minimising sensitivity is the foremost priority in designing energetic compounds. A quantitative analysis with Molecular Electrostatic Potential (MEP) evidenced anomalies arising from the marked depletion of negative charge distribution of RDX and HMX. The Energy Decomposition Analysis with Natural Orbitals for Chemical Valence (EDA-NOCV) results reveal that the electrostatic and orbital contributions are the dominant factors driving the assembly of the M={Ti,Zr,Hf}-based complexes. Sensitivity of the N-NO2 trigger bonds is investigated by using the Quantum Theory of Atoms in Molecules (QTAIM). The QTAIM topological analysis showed that the O⋯M={Ti,Zr,Hf} interaction strengthens these trigger bonds, revealing an increased stability to decomposition. This effect is more marked in the Hf- and Zr-based complexes. Finally, the results based on Interaction Indicator Region (IRI) are fully consistent with those generated from QTAIM analysis.

A combined QTAIM/IRI topological analysis of the effect of axial/equatorial positions of NH2 and CN substituents in the [(PY5Me2)MoO]+ complex.

By means of the Interaction Region Indicator (IRI) and Quantum Theory of Atoms in Molecules (QTAIM), the influence exerted by NH2 (amino) and CN (cyano) as electron donor and electron acceptor substituent groups, respectively, located at para-positions of axial and equatorial pyridine rings of derivatized complexes coming from the [(PY5Me2)MoO]+ complex during the hydrogen molecular release in the gas phase was analyzed. In any case, a H-H covalent bond is forming at the transition state, with a strengthening of the electron density of 5.5% when the substituent group involved is NH2 at the para-position of the axial pyridine ring. However, there was no difference between NH2 and CN when these substituent groups are located at the para-positions of the equatorial pyridine rings. The topological properties of electron densities from the QTAIM are not perturbed by the electron donor and electron acceptor nature of the substituents, even when these substituent groups are located at the axial or equatorial pyridine rings of the Mo-based complex.

Evanescent Waves Nuclear Magnetic Resonance.

Nuclear Magnetic Resonance spectroscopy and imaging can be classified as inductive techniques working in the near- to far-field regimes. We investigate an alternative capacitive detection with the use of micrometer sized probes positioned at sub wavelength distances of the sample in order to characterize and model evanescent electromagnetic fields originating from NMR phenomenon. We report that in this experimental configuration the available NMR signal is one order of magnitude larger and follows an exponential decay inversely proportional to the size of the emitters. Those investigations open a new road to a better understanding of the evanescent waves component in NMR with the opportunity to perform localized spectroscopy and imaging.

Investigation on NMR relaxivity of nano-sized cyano-bridged coordination polymers.

We present the first comparative investigation of the Nuclear Magnetic Resonance (NMR) relaxivity of a series of nanosized cyano-bridged coordination networks stabilized in aqueous solution. These Ln(3+)/[Fe(CN)6](3-) (Ln = Gd, Tb, Y) and M(2+)/[Fe(CN)6](3-) (M = Ni, Cu, Fe) nanoparticles with sizes ranging from 1.4 to 5.5 nm are stabilized by polyethylene glycols (MW = 400 or 1000), polyethylene glycol functionalized with amine groups (MW = 1500), or by N-acetyl-D-glucosamine. The evaluation of NMR relaxivity allowed estimation of the Magnetic Resonance Imaging (MRI) contrast efficiency of our systems. The results demonstrate that Gd(3+)/[Fe(CN)6](3-) nanoparticles have r1p and r2p relaxivities about four times higher than the values observed in the same conditions for the commercial Contrast Agents (CAs) ProHance or Omniscan, regardless of the stabilizing agent used, while nanoparticles of Prussian blue and its analogues M(2+)/[Fe(CN)6](3-) (M = Ni, Cu, Fe) present relatively modest values. The influence of the chemical composition of the nanoparticles, their crystal structure, spin values of lanthanide and transition metal ions, and stabilizing agent on the relaxivity values are investigated and discussed.