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Keywords = local electrophilicity

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15 pages, 1994 KiB  
Article
Modeling of the General Trends of Reactivity and Regioselectivity in Cyclopentadiene–Nitroalkene Diels–Alder Reactions
by Adrianna Fałowska, Stanisław Grzybowski, Daniel Kapuściński, Karol Sambora and Agnieszka Łapczuk
Molecules 2025, 30(11), 2467; https://doi.org/10.3390/molecules30112467 - 4 Jun 2025
Cited by 1 | Viewed by 1134
Abstract
This study presents a theoretical investigation of the electronic properties of mono- and pentasubstituted cyclopentadiene analogs and variously substituted conjugated nitroalkenes bearing electron-donating and electron-withdrawing groups. Conceptual Density Functional Theory (CDFT) and Electron Localization Function (ELF) analyses were employed to characterize the global [...] Read more.
This study presents a theoretical investigation of the electronic properties of mono- and pentasubstituted cyclopentadiene analogs and variously substituted conjugated nitroalkenes bearing electron-donating and electron-withdrawing groups. Conceptual Density Functional Theory (CDFT) and Electron Localization Function (ELF) analyses were employed to characterize the global and local reactivity indices of the reactants. The obtained data provided insights into the nucleophilic and electrophilic nature of the investigated systems, allowing for the prediction of their reactivity patterns in Diels–Alder reactions. A reactivity model for conjugated alkenes toward cyclopentadienes was developed based on correlation analysis using Hammett substituent constants. This approach enabled the prediction of reaction polarity in (4+2) cycloaddition processes, providing insight into how the electronic effects of substituents influence the reaction course. These findings contribute to a deeper understanding of structure–reactivity relationships in Diels–Alder processes. Full article
(This article belongs to the Special Issue Cyclization Reactions in Organic Synthesis: Recent Developments)
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15 pages, 6194 KiB  
Article
Towards Imaging Tau Hyperphosphorylation: Is DYRK1A a Potential Target for Imaging Hyperphosphorylation of Tau? Molecular Modeling Assessment and Synthesis of [125I]Radioiodinated DYRK1A Inhibitor
by Cayz G. Paclibar, Deanna M. Schafer, Agnes P. Biju, Fariha Karim, Stephanie A. Sison, Christopher Liang, Shamiha T. Ahmed and Jogeshwar Mukherjee
Molecules 2025, 30(5), 990; https://doi.org/10.3390/molecules30050990 - 21 Feb 2025
Cited by 2 | Viewed by 859
Abstract
Dual specificity tyrosine-phosphorylation regulated kinase 1A (DYRK1A), a phosphorylation kinase, is localized within the central nervous system and is linked to hyperphosphorylation of Tau. Imaging of DYRK1A may provide an earlier biomarker for Tauopathies, including Alzheimer’s disease (AD). We have used Chimera-Autodock to [...] Read more.
Dual specificity tyrosine-phosphorylation regulated kinase 1A (DYRK1A), a phosphorylation kinase, is localized within the central nervous system and is linked to hyperphosphorylation of Tau. Imaging of DYRK1A may provide an earlier biomarker for Tauopathies, including Alzheimer’s disease (AD). We have used Chimera-Autodock to evaluate potential molecules for binding to the binding site of DYRK1A. Five molecules, 10-bromo-2-iodo-11H-indolo[3,2-c]quinoline-6-carboxylic acid (4E3), 10-iodo-11H-indolo[3,2-c]quinoline-6-carboxylic acid (KuFal184), harmine, 6-(fluoro-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine (MK-6240), and 6-iodo-3-(1H-pyrrolo[2,3-c]pyridine-1-yl)isoquinoline (IPPI), were found to have binding energies of −10.4, −10.1, −9.0, −9.1, and −9.4 kcal/mole, respectively. Two molecules, 4E3 and KuFal184, were selective for DYRK1A, while harmine also had a monoamine oxidase A affinity, and MK-6240 and IPPI had affinity for Tau. Tau present in the brain slices of AD subject were labeled with [125I]IPPI. KuFal184 had no effect on the binding of [125I]IPPI, suggesting the absence of binding overlap of the two molecules. MK-6240, a known Tau agent was, however, able to compete with [125I]IPPI. The binding energies of harmine, MK-6240, and IPPI for the DYRK1A site suggest affinities of approximately 80–100 nM, which is insufficient to serve as an imaging agent. The higher affinity of KuFal184 (6 nM for DYRK1A) suggested that [125I]KuFal184 may be a potential imaging agent. Electrophilic radioiodination was used to synthesize [125I]KuFal184 in modest yields (25%) and high radiochemical purity (>95%). Preliminary binding studies with [125I]KuFal184 in AD brain slices showed some selectivity for cortical grey matter regions containing Tau. Full article
(This article belongs to the Special Issue Molecular Modeling: Advancements and Applications, 3rd Edition)
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17 pages, 8670 KiB  
Article
A New Insight into the Molecular Mechanism of the Reaction between 2-Methoxyfuran and Ethyl (Z)-3-phenyl-2-nitroprop-2-enoate: An Molecular Electron Density Theory (MEDT) Computational Study
by Mikołaj Sadowski, Ewa Dresler, Aneta Wróblewska and Radomir Jasiński
Molecules 2024, 29(20), 4876; https://doi.org/10.3390/molecules29204876 - 14 Oct 2024
Cited by 7 | Viewed by 1731
Abstract
The molecular mechanism of the reaction between 2-methoxyfuran and ethyl (Z)-3-phenyl-2-nitroprop-2-enoate was investigated using wb97xd/6-311+G(d,p)(PCM) quantum chemical calculations. It was found that the most probable reaction mechanism is fundamentally different from what was previously postulated. In particular, six possible zwitterionic intermediates [...] Read more.
The molecular mechanism of the reaction between 2-methoxyfuran and ethyl (Z)-3-phenyl-2-nitroprop-2-enoate was investigated using wb97xd/6-311+G(d,p)(PCM) quantum chemical calculations. It was found that the most probable reaction mechanism is fundamentally different from what was previously postulated. In particular, six possible zwitterionic intermediates were detected on the reaction pathway. Their formation is determined by the nature of local nucleophile/electrophile interactions. Additionally, the channel involving the formation of the exo-nitro Diels–Alder cycloadduct was completely ruled out. Finally, the electronic nature of the five- and six-membered nitronates as potential TACs was evaluated. Full article
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14 pages, 2639 KiB  
Article
Theoretical Investigation of the Effects of Aldehyde Substitution with Pyran Groups in D-π-A Dye on Performance of DSSCs
by Suzan K. Alghamdi, Abdulaziz I. Aljameel, Rageh K. Hussein, Khalled Al-heuseen, Mamduh J. Aljaafreh and Dina Ezzat
Molecules 2024, 29(17), 4175; https://doi.org/10.3390/molecules29174175 - 3 Sep 2024
Cited by 2 | Viewed by 1189
Abstract
This work investigated the substitution of the aldehyde with a pyran functional group in D-π-aldehyde dye to improve cell performance. This strategy was suggested by recent work that synthesized D-π-aldehyde dye, which achieved a maximum absorption wavelength that was only slightly off the [...] Read more.
This work investigated the substitution of the aldehyde with a pyran functional group in D-π-aldehyde dye to improve cell performance. This strategy was suggested by recent work that synthesized D-π-aldehyde dye, which achieved a maximum absorption wavelength that was only slightly off the threshold for an ideal sensitizer. Therefore, DFT and TD-DFT were used to investigate the effect of different pyran substituents to replace the aldehyde group. The pyran groups reduced the dye energy gap better than other known anchoring groups. The proposed dyes showed facile intermolecular charge transfer through the localization of HOMO and LUMO orbitals on the donor and acceptor parts, which promoted orbital overlap with the TiO2 surface. The studied dyes have HOMO and LOMO energy levels that could regenerate electrons from redox potential electrodes and inject electrons into the TiO2 conduction band. The lone pairs of oxygen atoms in pyran components act as nucleophile centers, facilitating adsorption on the TiO2 surface through their electrophile atoms. Pyrans increased the efficacy of dye sensitizers by extending their absorbance range and causing the maximum peak to redshift deeper into the visible region. The effects of the pyran groups on photovoltaic properties such as light harvesting efficiency (LHE), free energy change of electron injection, and dye regeneration were investigated and discussed. The adsorption behaviors of the proposed dyes on the TiO2 (1 1 0) surface were investigated by means of Monte Carlo simulations. The calculated adsorption energies indicates that pyran fragments, compared to the aldehyde in the main dye, had a greater ability to induce the adsorption onto the TiO2 substrate. Full article
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18 pages, 4137 KiB  
Article
Synthesis, X-ray Crystallography, Spectroscopic Characterizations, Density Functional Theory, and Hirshfeld Surface Analyses of a Novel (Carbonato) Picket Fence Iron(III) Complex
by Mondher Dhifet, Bouzid Gassoumi, Maxim A. Lutoshkin, Anna S. Kazachenko, Aleksandr S. Kazachenko, Omar Al-Dossary, Noureddine Issaoui and Habib Nasri
Molecules 2024, 29(16), 3722; https://doi.org/10.3390/molecules29163722 - 6 Aug 2024
Cited by 2 | Viewed by 1498
Abstract
An Fe(III)-carbonato six-coordinate picket fence porphyrin complex with the formula [K(2,2,2-crypt)][FeIII(TpivPP)(CO3)]·C6H5Cl·3H2O (I) has been synthesized and characterized by UV-Vis and FT-IR spectra. The structure of (carbonato)(α,α,α,α-tetrakis(o-pivalamidophenyl)porphinato)ferrate(III) was also established [...] Read more.
An Fe(III)-carbonato six-coordinate picket fence porphyrin complex with the formula [K(2,2,2-crypt)][FeIII(TpivPP)(CO3)]·C6H5Cl·3H2O (I) has been synthesized and characterized by UV-Vis and FT-IR spectra. The structure of (carbonato)(α,α,α,α-tetrakis(o-pivalamidophenyl)porphinato)ferrate(III) was also established by XRD. The iron atom is hexa-coordinated by the four nitrogen atoms of the pyrrol rings and the two oxygen atoms of the CO32− group. Complex I, characterized as a ferric high-spin complex (S = 5/2), presented higher Fe-Np (2.105(6) Å) and Fe-PC (0.654(2) Å) distances. Both X-ray molecular structure and Hirshfeld surface analysis results show that the crystal packing of I is made by C-H⋯O and C-H⋯Cg weak intermolecular hydrogen interactions involving neighboring [FeIII(TpivPP)(CO3)] ion complexes. Computational studies were carried out at DFT/B3LYP-D3/LanL2DZ to investigate the HOMO and LUMO molecular frontier orbitals and the reactivity within the studied compound. The stability of compound I was investigated by analyzing both intra- and inter-molecular interactions using the 2D and 3DHirshfeld surface (HS) analyses. Additionally, the frontier molecular orbital (FMO) calculations and the molecular electronic potential (MEP) analyses were conducted to determine the electron localizations, electrophilic, and nucleophilic regions, as well as charge transfer (ECT) within the studied system. Full article
(This article belongs to the Section Computational and Theoretical Chemistry)
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15 pages, 3065 KiB  
Article
Energetic Aspects and Molecular Mechanism of 3-Nitro-substituted 2-Isoxazolines Formation via Nitrile N-Oxide [3+2] Cycloaddition: An MEDT Computational Study
by Ewa Dresler, Aneta Wróblewska and Radomir Jasiński
Molecules 2024, 29(13), 3042; https://doi.org/10.3390/molecules29133042 - 26 Jun 2024
Cited by 15 | Viewed by 2560
Abstract
Regioselectivity and the molecular mechanism of the [3+2] cycloaddition reaction between nitro-substituted formonitrile N-oxide 1 and electron-rich alkenes were explored on the basis of the wb97xd/6-311+G(d) (PCM) quantum chemical calculations. It was established that the thermodynamic factors allow for the formation of stable [...] Read more.
Regioselectivity and the molecular mechanism of the [3+2] cycloaddition reaction between nitro-substituted formonitrile N-oxide 1 and electron-rich alkenes were explored on the basis of the wb97xd/6-311+G(d) (PCM) quantum chemical calculations. It was established that the thermodynamic factors allow for the formation of stable cycloadducts along all considered models. The analysis of the kinetic parameters of the main processes show that all [3+2] cycloadditions should be realized with full regioselectivity. In all cases, the formation of 5-substituted 3-nitro-2-isoxazolidines is clearly preferred. It is interesting that regiodirection is not determined by the local electrophile/nucleophile interactions but by steric effects. From a mechanistic point of view, all considered reactions should be treated as polar, one-step reactions. All attempts to locate the hypothetical zwitterionic intermediates along the cycloaddition paths were, however, not successful. Full article
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25 pages, 27606 KiB  
Article
Structural Analysis of the Drosophila melanogaster GSTome
by Nicolas Petiot, Mathieu Schwartz, Patrice Delarue, Patrick Senet, Fabrice Neiers and Adrien Nicolaï
Biomolecules 2024, 14(7), 759; https://doi.org/10.3390/biom14070759 - 26 Jun 2024
Cited by 2 | Viewed by 1981
Abstract
Glutathione transferase (GST) is a superfamily of ubiquitous enzymes, multigenic in numerous organisms and which generally present homodimeric structures. GSTs are involved in numerous biological functions such as chemical detoxification as well as chemoperception in mammals and insects. GSTs catalyze the conjugation of [...] Read more.
Glutathione transferase (GST) is a superfamily of ubiquitous enzymes, multigenic in numerous organisms and which generally present homodimeric structures. GSTs are involved in numerous biological functions such as chemical detoxification as well as chemoperception in mammals and insects. GSTs catalyze the conjugation of their cofactor, reduced glutathione (GSH), to xenobiotic electrophilic centers. To achieve this catalytic function, GSTs are comprised of a ligand binding site and a GSH binding site per subunit, which is very specific and highly conserved; the hydrophobic substrate binding site enables the binding of diverse substrates. In this work, we focus our interest in a model organism, the fruit fly Drosophila melanogaster (D. mel), which comprises 42 GST sequences distributed in six classes and composing its GSTome. The goal of this study is to describe the complete structural GSTome of D. mel to determine how changes in the amino acid sequence modify the structural characteristics of GST, particularly in the GSH binding sites and in the dimerization interface. First, we predicted the 3D atomic structures of each GST using the AlphaFold (AF) program and compared them with X-ray crystallography structures, when they exist. We also characterized and compared their global and local folds. Second, we used multiple sequence alignment coupled with AF-predicted structures to characterize the relationship between the conservation of amino acids in the sequence and their structural features. Finally, we applied normal mode analysis to estimate thermal B-factors of all GST structures of D. mel. Particularly, we extracted flexibility profiles of GST and identify key residues and motifs that are systematically involved in the ligand binding/dimerization processes and thus playing a crucial role in the catalytic function. This methodology will be extended to guide the in silico design of synthetic GST with new/optimal catalytic properties for detoxification applications. Full article
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19 pages, 12152 KiB  
Article
Theoretical Analysis of Coordination Geometries in Transition Metal–Histidine Complexes Using Quantum Chemical Calculations
by Dapeng Zhang and Naoki Kishimoto
Molecules 2024, 29(13), 3003; https://doi.org/10.3390/molecules29133003 - 25 Jun 2024
Cited by 1 | Viewed by 1938
Abstract
A theoretical investigation utilizing density functional theory (DFT) calculations was conducted to explore the coordination complexes formed between histidine (His) ligands and various divalent transition metal ions (Mn2+, Fe2+, Co2+, Ni2+, Cu2+, and [...] Read more.
A theoretical investigation utilizing density functional theory (DFT) calculations was conducted to explore the coordination complexes formed between histidine (His) ligands and various divalent transition metal ions (Mn2+, Fe2+, Co2+, Ni2+, Cu2+, and Zn2+). Conformational exploration of the His ligand was initially performed to assess its stability upon coordination. Both 1:1 and 1:2 of metal-to-ligand complexes were scrutinized to elucidate their structural features and the relative stability of the complexes. This study examined the ability of His to act as a bidentate or tridentate coordinating ligand, along with the differences in coordination geometry when solvent effects were incorporated. The reduced density gradient (RDG) analysis and local electron attachment energy (LEAE) analysis were employed to elucidate the interaction planes and the nucleophilic and electrophilic properties. The electronic properties were analyzed through electrostatic potential (ESP) maps and natural population analysis (NPA) of atomic charge distributions. This computational study provides valuable insights into the diverse coordination modes of His and its interactions with divalent transition metal ions, contributing to a better understanding of the role of this amino acid ligand in the formation of transition metal complexes. The findings can aid in the design and construction of self-assembled structures involving His-metal coordination. Full article
(This article belongs to the Special Issue Exclusive Feature Papers on Molecular Structure)
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16 pages, 2062 KiB  
Article
Design of β-Keto Esters with Antibacterial Activity: Synthesis, In Vitro Evaluation, and Theoretical Assessment of Their Reactivity and Quorum-Sensing Inhibition Capacity
by Maximiliano Martínez-Cifuentes, Emmanuel Soto-Tapia, Camila Linares-Pipón, Ben Bradshaw, Paulina Valenzuela-Hormazabal, David Ramírez, Patricio Muñoz-Torres and Claudio Parra
Pharmaceuticals 2023, 16(10), 1339; https://doi.org/10.3390/ph16101339 - 22 Sep 2023
Viewed by 2328
Abstract
This work proposes the design of β-keto esters as antibacterial compounds. The design was based on the structure of the autoinducer of bacterial quorum sensing, N-(3-oxo-hexanoyl)-l-homoserine lactone (3-oxo-C6-HSL). Eight β-keto ester analogues were synthesised with good yields and were spectroscopically characterised, showing [...] Read more.
This work proposes the design of β-keto esters as antibacterial compounds. The design was based on the structure of the autoinducer of bacterial quorum sensing, N-(3-oxo-hexanoyl)-l-homoserine lactone (3-oxo-C6-HSL). Eight β-keto ester analogues were synthesised with good yields and were spectroscopically characterised, showing that the compounds were only present in their β-keto ester tautomer form. We carried out a computational analysis of the reactivity and ADME (absorption, distribution, metabolism, and excretion) properties of the compounds as well as molecular docking and molecular dynamics calculations with the LasR and LuxS quorum-sensing (QS) proteins, which are involved in bacterial resistance to antibiotics. The results show that all the compounds exhibit reliable ADME properties and that only compound 7 can present electrophile toxicity. The theoretical reactivity study shows that compounds 6 and 8 present a differential local reactivity regarding the rest of the series. Compound 8 presents the most promising potential in terms of its ability to interact with the LasR and LuxS QS proteins efficiently according to its molecular docking and molecular dynamics calculations. An initial in vitro antimicrobial screening was performed against the human pathogenic bacteria Pseudomonas aeruginosa and Staphylococcus aureus as well as the phytopathogenic bacteria Pseudomonas syringae and Agrobacterium tumefaciens. Compounds 6 and 8 exhibit the most promising results in the in vitro antimicrobial screening against the panel of bacteria studied. Full article
(This article belongs to the Special Issue Structural and Computational-Driven Molecule Design in Drug Discovery)
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24 pages, 9997 KiB  
Article
Structural Analysis and Reactivity Insights of (E)-Bromo-4-((4-((1-(4-chlorophenyl)ethylidene)amino)-5-phenyl-4H-1,2,4-triazol-3-yl)thio)-5-((2-isopropylcyclohexyl)oxy) Furan-2(5H)-one: A Combined Approach Using Single-Crystal X-ray Diffraction, Hirshfeld Surface Analysis, and Conceptual Density Functional Theory
by Ahmed H. Bakheit, Mohamed W. Attwa, Adnan A. Kadi and Hamad M. Alkahtani
Crystals 2023, 13(9), 1313; https://doi.org/10.3390/cryst13091313 - 28 Aug 2023
Cited by 15 | Viewed by 2763
Abstract
This study presents a comprehensive exploration of the structure–reactivity relationship of (E)-3-bromo-4-((4-((1-(4-chlorophenyl)ethylidene)amino)-5-phenyl-4H-1,2,4-triazol-3-yl)thio)-5-((2-isopropylcyclohexyl)oxy)furan-2(5H)-one. The study embarked on an in-depth investigation into the solid-state crystal structure of this organic compound, employing computational Density Functional Theory (DFT) and related methodologies, which have not extensively [...] Read more.
This study presents a comprehensive exploration of the structure–reactivity relationship of (E)-3-bromo-4-((4-((1-(4-chlorophenyl)ethylidene)amino)-5-phenyl-4H-1,2,4-triazol-3-yl)thio)-5-((2-isopropylcyclohexyl)oxy)furan-2(5H)-one. The study embarked on an in-depth investigation into the solid-state crystal structure of this organic compound, employing computational Density Functional Theory (DFT) and related methodologies, which have not extensively been used in the examination of such compounds. A single-crystal X-ray diffraction (SCXRD) analysis was initially performed, supplemented by a Hirshfeld surfaces analysis. This latter approach was instrumental in visualizing and quantifying intermolecular interactions within the crystal structures, offering a detailed representation of the molecule’s shape and properties within its crystalline environment. The concept of energy framework calculations was utilized to understand the varied types of energies contributing to the supramolecular architecture of the molecules within the crystal. The Conceptual DFT (CDFT) was applied to predict global reactivity descriptors and local nucleophilic/electrophilic Parr functions, providing a deeper understanding of the compound’s chemical reactivity properties. The aromatic character and π–π stacking ability were also evaluated with the help of LOLIPOP and ring aromaticity measures. This comprehensive approach not only provides a detailed description of the structure and properties of the investigated compound but also offers valuable insights into the design and development of new materials involving 1,2,4-triazole systems. Full article
(This article belongs to the Special Issue Density Functional Theory (DFT) and Beyond for Crystalline Materials)
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19 pages, 4428 KiB  
Article
Efficient Approach for the Synthesis of Aryl Vinyl Ketones and Its Synthetic Application to Mimosifoliol with DFT and Autodocking Studies
by Tummuri Sudheer Reddy, Karreddula Raja, Kishore Reddy Mandapati, Srinivasa Reddy Goli and Manubolu Surya Surendra Babu
Molecules 2023, 28(17), 6214; https://doi.org/10.3390/molecules28176214 - 24 Aug 2023
Cited by 4 | Viewed by 2992
Abstract
An efficient and elegant method was developed for the preparation of substituted phenyl vinyl ketones using low-cost and commercially available ethyl chloroformate and diisopropylethylamine as reagents. This methodology was also applied to the synthesis of natural products such as mimosifoliol and quinolines. Frontier [...] Read more.
An efficient and elegant method was developed for the preparation of substituted phenyl vinyl ketones using low-cost and commercially available ethyl chloroformate and diisopropylethylamine as reagents. This methodology was also applied to the synthesis of natural products such as mimosifoliol and quinolines. Frontier molecular orbital (FMO) studies on mimosifoliol were carried out to understand its chemical reactivity. Electron localization function (ELF) and localized orbital locator (LOL) analysis gave information about localized and delocalized electrons. Reduced density gradient (RDG) analysis gave information on steric, van der Waals, and hydrogen-bonding interactions. Molecular electrostatic potential (MEP) and Fukui functions gave information about nucleophilic and electrophilic attack. Nonlinear optical (NLO) analysis represented the mimosifoliol good NLO material. Molecular docking showed that the mimosifoliol compound had effectively inhibited the aspulvinone dimethylallyltransferase enzyme. Full article
(This article belongs to the Section Organic Chemistry)
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18 pages, 5226 KiB  
Article
Synthesis, Crystal Structure, and Computational Investigations of 2-(2-(4-Fluorophenyl)-2-oxoethyl)-6-methyl-5-(4-methylbenzyl)pyridazin-3(2H)-one as Antiviral Agent
by Fouad El Kalai, Christina Susan Abraham, Sevgi Kansiz, Afaf Oulmidi, Sambantham Muthu, Johanan Christian Prasana, Necmi Dege, Hatem A. Abuelizz, Rashad Al-Salahi, Noureddine Benchat and Khalid Karrouchi
Crystals 2023, 13(7), 1098; https://doi.org/10.3390/cryst13071098 - 13 Jul 2023
Cited by 4 | Viewed by 2503
Abstract
The aim of this work was to scrutinize the physiochemical properties of a new pyridazin-3(2H)-one derivative with potential pharmaceutical effectiveness via density functional theory (DFT) and molecular docking analysis. The compound 2-(2-(4-fluorophenyl)-2-oxoethyl)-6-methyl-5-(4-methylbenzyl)pyridazin-3(2H)-one (FOMMP) was synthesized and characterized by FT-IR, [...] Read more.
The aim of this work was to scrutinize the physiochemical properties of a new pyridazin-3(2H)-one derivative with potential pharmaceutical effectiveness via density functional theory (DFT) and molecular docking analysis. The compound 2-(2-(4-fluorophenyl)-2-oxoethyl)-6-methyl-5-(4-methylbenzyl)pyridazin-3(2H)-one (FOMMP) was synthesized and characterized by FT-IR, UV-Vis, 1H-NMR, 13C-NMR, ESI-MS, and single-crystal XRD analysis. In addition, the geometrical structure of the molecule was analyzed. Frontier molecular orbital (FMO) analysis showed a low energy gap that suggests the chemical reactivity of the title compound. The electrophilicity index (ω) points towards the probable biological activity of FOMMP. The molecular electrostatic potential (MEP) was used to assess the local reactivity properties and suggests that the nitrogen atom sites are electronegative. Computational and experimental UV-spectral analyses were performed to attain the bandgap associated with electronic transitions while the charge transfer length helped us determine that the excitation mode associated with the electronic transitions is long-ranged. Natural hybrid orbital (NHO) and natural bond orbital (NBO) analyses depicted the prominent acceptor-donor interactions in terms of the stabilization energies. Hirshfeld surface analysis was performed to analyze the intermolecular interactions in the crystal structure. In addition, a molecular docking study was executed to evaluate the potential of the protease inhibitors (PIs) against SARS-CoV-2. Full article
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23 pages, 10764 KiB  
Article
A DFT Study and Hirshfeld Surface Analysis of the Molecular Structures, Radical Scavenging Abilities and ADMET Properties of 2-Methylthio(methylsulfonyl)-[1,2,4]triazolo [1,5-a]quinazolines: Guidance for Antioxidant Drug Design
by Ahmed H. Bakheit, Hatem A. Abuelizz and Rashad Al-Salahi
Crystals 2023, 13(7), 1086; https://doi.org/10.3390/cryst13071086 - 12 Jul 2023
Cited by 11 | Viewed by 2004
Abstract
Optimisation at B3LYP/6-311G(d,p) was used in a DFT study of the characteristics of 2-methylthio(methylsulfonyl)-triazoloquinazolines (1, 2). The design-critical role of intramolecular hydrogen bonding in stabilising both structures is emphasised. The stability of a crystal is a consequence of interactions between [...] Read more.
Optimisation at B3LYP/6-311G(d,p) was used in a DFT study of the characteristics of 2-methylthio(methylsulfonyl)-triazoloquinazolines (1, 2). The design-critical role of intramolecular hydrogen bonding in stabilising both structures is emphasised. The stability of a crystal is a consequence of interactions between its molecules. According to the global index, 2-methylthio-triazoloquinazoline (1) is more electrophilic and reactive, while 2-methylsulfonyl-triazoloquinazoline (2) is more electrophilic and less reactive. Electrophilic, nucleophilic, and radicalophilic sites, polarizable atoms, and charge distributions are all identified by local descriptors. Consistent with crystal structures, negative potentials imply 1 and 2 hydrogen bond acceptors, whereas positive potentials indicate donor capabilities. Antioxidant activity may be enabled via radical stabilisation, as suggested by radicalophilic features such as hydrogen atom donors, resonance, and antioxidants. H7, H8, and H9 atoms in triazoloquinazolines 1 and 2 have been hypothesised to contribute to the compounds’ antioxidant activity through HAT, SPLET, and SET-PT mechanisms. Calculations provide insights into stability, reactivity, electrostatic profiles, radical stabilization ability, toxicity risks. Radical stabilizing ability, reactive site hierarchies suggest possible antioxidant mechanisms. ADMET profiles identify challenges impacting candidate suitability. Full article
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18 pages, 4661 KiB  
Article
Role of Non-Covalent Interactions in Novel Supramolecular Compound, Bis(4-phenylpiperazin-1-ium) Oxalate Dihydrate: Synthesis, Molecular Structure, Thermal Characterization, Spectroscopic Properties and Quantum Chemical Study
by Mahdi Jemai, Marwa Khalfi, Noureddine Issaoui, Thierry Roisnel, Aleksandr S. Kazachenko, Omar Al-Dossary, Houda Marouani, Anna S. Kazachenko and Yuriy N. Malyar
Crystals 2023, 13(6), 875; https://doi.org/10.3390/cryst13060875 - 26 May 2023
Cited by 17 | Viewed by 2586
Abstract
The stoichiometric ratio 2:1 mix of 1-phenylpiperazine and oxalic acid dihydrate followed by slow evaporation results in a new material, bis(4-phenylpiperazin-1-ium) oxalate dihydrate, with the general chemical formula (C10H15N2)2(C2O4).2H2O, [...] Read more.
The stoichiometric ratio 2:1 mix of 1-phenylpiperazine and oxalic acid dihydrate followed by slow evaporation results in a new material, bis(4-phenylpiperazin-1-ium) oxalate dihydrate, with the general chemical formula (C10H15N2)2(C2O4).2H2O, indicated by PPOXH. The title compound’s asymmetric unit and three-dimensional network have been determined by single crystal X-ray diffraction. Intermolecular O-H…O, N-H…O and C-H…O hydrogen bonding assist in maintaining and stabilization of the crystal structure of this new compound. Hirshfeld surface analysis and two-dimensional fingerprints have been performed to quantify the non-covalent interactions in the PPOXH structure. The vibrational modes of the different characteristic groups of the title chemical were identified using infrared spectrum analysis. The thermal characterization of this product was studied by a coupled TG/DTA analysis. The ultraviolet-visible absorption spectrum has been used to study the optical properties and the energy gap of this compound. DFT calculations were employed to evaluate the composition and properties of PPOXH. The analysis of HOMO-LUMO frontier orbitals analysis allows us to understand the chemical reactivity of this supramolecular compound and to determine the electrophilic and nucleophilic sites responsible for electron transfer. Topological analysis (AIM), reduced density gradient (RDG), molecular electrostatic potential surface (MEPS) and Mulliken population were analyzed to evaluate the types of non-covalent interactions, localization of electrons in space, atomic charges and molecular polarity in depth. Full article
(This article belongs to the Special Issue Density Functional Theory (DFT) and Beyond for Crystalline Materials)
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15 pages, 2393 KiB  
Article
Unveiling the Stereoselectivity and Regioselectivity of the [3+2] Cycloaddition Reaction between N-methyl-C-4-methylphenyl-nitrone and 2-Propynamide from a MEDT Perspective
by Sabir A. Mohammed Salih, Huda A. Basheer, Jesus Vicente de Julián-Ortiz and Haydar A. Mohammad-Salim
Int. J. Mol. Sci. 2023, 24(10), 9102; https://doi.org/10.3390/ijms24109102 - 22 May 2023
Cited by 4 | Viewed by 2336
Abstract
[3+2] cycloaddition reactions play a crucial role in synthesizing complex organic molecules and have significant applications in drug discovery and materials science. In this study, the [3+2] cycloaddition (32CA) reactions of N-methyl-C-4-methyl phenyl-nitrone 1 and 2-propynamide 2, which have not been extensively [...] Read more.
[3+2] cycloaddition reactions play a crucial role in synthesizing complex organic molecules and have significant applications in drug discovery and materials science. In this study, the [3+2] cycloaddition (32CA) reactions of N-methyl-C-4-methyl phenyl-nitrone 1 and 2-propynamide 2, which have not been extensively studied before, were investigated using molecular electron density theory (MEDT) at the B3LYP/6–311++G(d,p) level of theory. According to an electron localization function (ELF) study, N-methyl-C-4-methyl phenyl-nitrone 1 is a zwitterionic species with no pseudoradical or carbenoid centers. Conceptual density functional theory (CDFT) indices were used to predict the global electronic flux from the strong nucleophilic N-methyl-C-4-methyl phenylnitrone 1 to the electrophilic 2-propynamide 2 functions. The 32CA reactions proceeded through two pairs of stereo- and regioisomeric reaction pathways to generate four different products: 3, 4, 5, and 6. The reaction pathways were irreversible owing to their exothermic characters: −136.48, −130.08, −130.99, and −140.81 kJ mol−1, respectively. The enthalpy of the 32CA reaction leading to the formation of cycloadduct 6 was lower compared with the other path owing to a slight increase in its polar character, observed through the global electron density transfer (GEDT) during the transition states and along the reaction path. A bonding evolution theory (BET) analysis showed that these 32CA reactions proceed through the coupling of pseudoradical centers, and the formation of new C-C and C-O covalent bonds did not begin in the transition states. Full article
(This article belongs to the Topic Theoretical, Quantum and Computational Chemistry)
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