NMR Calculations Research Articles

New poly heterocyclic compounds based on pyrimidine-2-thiones: synthesis, evaluation of putative antiviral agents, DFT calculation, and molecular modeling

Owing to the enormous increase in viral infections in recent years, novel antiviral candidates are both eagerly awaited and unquestionably essential for the treatment of a variety of deadly and incapacitating viral disorders. As a part of our program in this area, a new series of thiazolopyrimidine, pyrimidothiazine, [1,2,4]triazolopyrimidine and N-substituted pyrimidinethione 6–17 have been synthesized in good yields (82–91%) through a facile method using new pyrimidinethione 4 as a building block and several reagents as halo acids/ketones or hydrazonyl halids in one framework. By using several spectroscopic methods, including IR, 1H NMR, 13C NMR, elemental analysis, and DFT calculations, the chemical structures of the novel derivatives were confirmed. The synthetic compounds' cytotoxicity and in vitro antiviral efficacy were examined against HSV-1. Results demonstrated that compounds 6, 7b, 14b,c, and 17 have been found to have significant antiviral activity against HSV-1. Additionally, after examining compounds (6 and 7b)' mechanisms of action, we discovered that compound 6 had a virucidal effect and a mild effect on replication at higher concentrations, whereas compound 7b had activity in all three modes of action, with the virucidal effect being the most potent, followed by the replication effect, and then adsorption. In order to comprehend these results, we investigated the thermal and electrical stability of the generated compounds, where their chemical and thermal properties, dipole moment, subtraction of the highest occupied molecular orbital from the lowest unoccupied molecular orbital (HOMO-LUMO gap), and molecular electrostatic potential were computed. We also, examined the binding mechanism, binding affinity, and non-bonding contacts of the generated derivatives using molecular docking against the Herpes simplex virus type-1 thymidine kinase (PDB ID: 2KI5). A hypothetical pharmacophore model was made using the Molecular Operating Environment (MOE) tool and 10 compounds with structural resemblances to those synthesized with known antiviral activity. The current work recommends compounds 6 and 7b as potential lead structures for future research and development of novel anti-HSV-1 medicines.

Weak, Broken, but Working-Intramolecular Hydrogen Bond in 2,2'-bipyridine.

From an academic and practical point of view, it is desirable to be able to assess the possibility of the proton exchange of a given molecular system just by knowing the positions of the proton acceptor and the proton donor. This study addresses the difference between intramolecular hydrogen bonds in 2,2'-bipyridinium and 1,10-phenanthrolinium. Solid-state 15N NMR and model calculations show that these hydrogen bonds are weak; their energies are 25 kJ/mol and 15 kJ/mol, respectively. Neither these hydrogen bonds nor N-H stretches can be responsible for the fast reversible proton transfer observed for 2,2'-bipyridinium in a polar solvent down to 115 K. This process must have been caused by an external force, which was a fluctuating electric field present in the solution. However, these hydrogen bonds are the grain that tips the scales precisely because they are an integral part of a large system of interactions, including both intramolecular interactions and environmental influence.

New cyclic dipeptide discovered from deep-sea derived Aspergillus sp. HDN20-1401

A new alkaloid named aspergilalkaloid A (1) with pyridoindole hydroxymethyl piperazine dione structure along with six known compounds 2-7 were isolated from deep-sea derived fungus Aspergillus sp. HDN20-1401. The structure including absolute configuration was elucidated by extensive NMR analyses, HRESIMS, ECD calculation, and theoretical NMR calculation with DP4+ analysis. All isolated compounds were tested for antimicrobial and anticancer activity. Aspergilalkaloid A (1) showed inhibitive activity against Bacillus cereus with MIC value of 12.5 μM and weak activity against MRCNS.

Salvianolic acids from Salvia miltiorrhiza Bunge and their anti-inflammatory effects through the activation of α7nAchR signaling

Ethnopharmacological relevanceCardiovascular disease (CVD) is a serious disease with a high incidence rate and mortality. Inflammation is closely related to the occurrence of CVDs. As an essential medicine of promoting blood circulation and removing blood stasis in China, Salvia miltiorrhiza Bunge (Danshen) is widely used to treat CVDs due to its anti-inflammatory and cardiovascular protective effects. Salvianolic acids are the most abundant component in the water extract of S. miltiorrhiza, which has a significant effect on the treatment of CVDs. However, due to the complex composition of salvianolic acids, the active molecules and their underlying mechanisms have not been fully explored. Aim of this studyThe present study aims to isolate and identify salvianolic acids from Danshen with anti-inflammatory activity and explore the potential mechanisms of isolates. MethodsThe structures of isolated salvianolic acids were elucidated by UV, IR, NMR, MS and electronic circular dichroism (ECD) calculations. Then anti-inflammatory activities of isolates were screened out by the zebrafish inflammation models. The most active compound was further used to explore the anti-inflammatory mechanisms on LPS-stimulated RAW 264.7 cells. The key inflammatory cytokines IL-6 and TNF-α were measured by enzyme-linked immunosorbent assay (ELISA). The protein expression levels of STAT3, p-STAT3 (Tyr705), NF-κB p65, IκBα, p-IκBα (Ser32) and α7nAchR were determined by Western blotting. The nuclear translocation of p-STAT3 (Tyr705) and NF-κB p65 was evaluated by immunofluorescence assays. Finally, the in vivo anti-inflammatory mechanisms were investigated by observation of neutrophil migration, H&E staining, survival analysis and quantitative PCR (Q-PCR) in LPS-microinjected zebrafish. ResultsTwo new and four known compounds were isolated from Danshen. Among them, isosalvianolic acid A-1 (C1) and ethyl lithospermate (C5) inhibited neutrophil migrations in three zebrafish inflammation models and C1 with the best activities decreased the secretion of IL-6 and TNF-α and inhibited the expression level of p-IκBα (Ser32) in LPS stimulated RAW 264.7 cells. In addition, C1 also reduced the nuclear translocation of NF-κB p65 and p-STAT3 (Tyr705). Moreover, C1 significantly upregulated the protein expression of α7nAchR, and the knockdown of α7nAchR counteracted the effects of C1 on the production of IL-6 and TNF-α and the expression levels of p-STAT3 (Tyr705), NF-κB p65 and p-IκBα (Ser32). In vivo experiments, C1 decreased the migration and infiltration of inflammatory cells, increased the survival ratio and inhibited the mRNA level of IL-6, TNF-α, STAT3, NF-κB and IκBα in LPS-microinjected zebrafish. ConclusionTwo new and four known compounds were isolated from Danshen. Among them, C1 exerted anti-inflammatory activities by activating α7nAchR signaling and subsequently inhibiting STAT3 and NF-κB pathways. This study provided evidence for the clinical application of Danshen and contributed to the development of C1 as a novel in the treatment of cardiovascular disease.

Trichodermatides A–D, four new polyketides from Trichoderma sp. XM-3

Four new polyketides named trichodermatides A–D (1–4), along with five known analogues (5–9), were isolated from the fungus Trichoderma sp. XM-3. Their structures were elucidated on the basis of HRESIMS and NMR analyses, and their absolute configurations were determined by ECD comparison, 1H and 13C NMR calculation, DP4+ analysis, modified Mosher's method, and X-ray crystallography. Trichodermaketone D (9) showed mild antibacterial activity against Pseudomonas aeruginosa.

Undescribed amino acid-sesquiterpene lactone adducts and sesquiterpene glycosides from the roots of Saussurea lappa and their anti-HBV activity

Saussurea lappa (Asteraceae family), a traditional Chinese medicine, has been found to possess anti-inflammatory, immune-promoting, antibacterial, antitumor, anti-HBV, cholestatic, and hepatoprotective activities. Herein, two undescribed amino acid-sesquiterpene lactone adducts, saussureamines G and H (1 and 2), and two new sesquiterpene glycosides, saussunosids F and G (3 and 4), along with 26 known sesquiterpenoids (5–30) have been isolated from the roots of S. lappa. Their structures and absolute configurations of these compounds were established by physical data analyses such as HRESIMS, IR, 1D and 2D NMR and ECD calculations. All isolated compounds were tested for anti-hepatitis B virus (anti-HBV) activity. Ten compounds (5, 6, 12, 13, 17, 19, 23, 26, 29, and 30) exhibited activities against the secretions of HBsAg and HBeAg. In particular, compound 6 showed inhibition of HBsAg and HBeAg secretion with IC50 values of 11.24 and 15.12 μM, with SI values of 1.25 and 0.93, respectively. Molecular docking studies were also conducted on the anti-HBV compounds. Overall, this study provides insights into the potential therapeutic uses of the compounds found in the roots of S. lappa, particularly in the treatment of hepatitis B virus infections.

A highly selective and sensitive ICT-based Cu2+ fluorescent probe and its application in bioimaging

Cu2+ is an essential trace element for the organism, but its excess can also cause irreversible damage to the organism. As such, a “Turn-Off” fluorescent probe DPAP for the specific detection of Cu2+ was successfully constructed. DPAP exhibits large Stokes shift (120 nm), fast reaction speed (1 min), low detection limit (15.2 nM), low toxicity, and good cell permeability. Cu2+ quenches the fluorescence of DPAP by blocking its intramolecular charge transfer process to achieve the detection of Cu2+ and has been confirmed by HRMS, 1H NMR and DFT calculations. Excitingly, the five-cycle detection of Cu2+ and the successful recovery of trace Cu2+ in environmental water samples fully demonstrate the potential of DPAP for practical applications. In particular, DPAP can observe the distribution and translocation patterns of exogenous Cu2+ in HeLa cells and zebrafish in real-time. This research concept has offered important theoretical support for the study of the environmental behavior of heavy metal ions.

Enantioselective catalysts based on metal-organic framework-supported nucleotides

Adenosine triphosphate (ATP) and other nucleotides can be irreversibly bound to the metal-organic framework (MOF) MIL-101(Cr). Analysis of X-ray diffraction data suggests that the location of the adsorbed ATP molecule is in proximity of the Cr3 clusters. Solid-state NMR and DFT calculations indicate that ATP is bound to MIL-101(Cr) through linkages of the terminal phosphate group with Cr(III) of the framework. In the presence of Cu(II) ions, the MOF-supported nucleotides can function as stable and reusable enantioselective heterogeneous catalysts for reactions like Diels-Alder and Michael addition. Compared to the corresponding homogeneous nucleotide-based artificial metalloenzymes (ArMs), the MOF-supported nucleotide-based ArMs exhibit significantly enhanced activity and selectivity in certain cases, demonstrating their potential as a new class of enantioselective heterogeneous catalysts.

Amine‐Free, Directing‐Group‐Free and Redox‐Neutral α‐Alkylation of Saturated Cyclic Ketones

AbstractThe activation of the α‐C−H bond of ketones typically requires an amine and a directing group to guide the reaction selectivity in amine‐catalysis carbonyl chemistry. For an α‐C−H bond activation of ketone, directing groups are also required to control the reaction selectivity. Reported herein is the first α‐alkylation of cyclic ketones in the absence of an amine catalyst and directing group. 1H NMR, XPS, EPR studies and DFT calculations indicate that an α‐carbon radical intermediate is formed through direct and selective activation of the inert α‐C−H bond of ketones chelating on the surface of colloidal quantum dots (QDs). Such an interaction is essential for weakening the C−H bond, as exemplified, using CdSe QDs as the sole photocatalyst to execute α‐C−H alkylation of cyclic ketones under visible‐light irradiation. Without an amine catalyst and directing group, the high step‐ and atom‐economy transformation under redox‐neutral condition opens a new way for α‐C−H functionalization of ketones in carbonyl chemistry.

Amine-Free, Directing-Group-Free and Redox-Neutral α-Alkylation of Saturated Cyclic Ketones.

The activation of the α-C-H bond of ketones typically requires an amine and a directing group to guide the reaction selectivity in amine-catalysis carbonyl chemistry. For an α-C-H bond activation of ketone, directing groups are also required to control the reaction selectivity. Reported herein is the first α-alkylation of cyclic ketones in the absence of an amine catalyst and directing group. 1 H NMR, XPS, EPR studies and DFT calculations indicate that an α-carbon radical intermediate is formed through direct and selective activation of the inert α-C-H bond of ketones chelating on the surface of colloidal quantum dots (QDs). Such an interaction is essential for weakening the C-H bond, as exemplified, using CdSe QDs as the sole photocatalyst to execute α-C-H alkylation of cyclic ketones under visible-light irradiation. Without an amine catalyst and directing group, the high step- and atom-economy transformation under redox-neutral condition opens a new way for α-C-H functionalization of ketones in carbonyl chemistry.

A highly sensitive and selective fluorescent probe for rapid detection and intracellular imaging of Pd(II)

A novel near-infrared fluorescent probe (SWJT-13) for detecting Pd2+ ions was designed and synthesized using 3-bromopropargyne group as a recognition site. SWJT-13 can detect Pd2+ ions specifically, which can be quickly recognized by naked eye under natural light. SWJT-13 has a large Stokes shift (155 nm) with LOD of 10.5 nM. The mechanism was verified by 1H NMR, MS, and Gaussian calculations. In addition, the detection of Pd2+ ions by the probe was studied in HeLa cells.

Sesquiterpene lactones from Artemisia verlotorum and their anti-inflammatory activities

Seven new sesquiterpenoids (1–7) and 19 known analogues were isolated from the whole plant of Artemisia verlotorum. Their structures were determined by extensive analysis of 1D and 2D NMR and HRESIMS data, electronic circular dichroism (ECD) spectra, density functional theory (DFT) NMR calculations, and time dependent density functional theory (TDDFT) ECD calculations. The absolute configurations of 1, 3, 5 and 7 were confirmed by single crystal X-ray diffraction experiments. Compounds 1 and 2 possess a rarely reported 5/8-bicyclic skeleton, while both compounds 3 and 4 were uncommon iphionane-type sesquiterpenoids. Eudesmane sesquiterpenoids (5–17) reported in this study are all 7,8-cis-lactones, of which, compound 7 represents the first eudesmane sesquiterpene with an oxygen bridge connecting C-5 and C-11. All the compounds were tested in vitro for their anti-inflammatory activities in LPS-stimulated RAW 264.7 murine macrophages. Compound 18 showed a potent inhibitory effect on NO production, with IC50 values of 3.08 ± 0.61 μM.

Investigation of Carbonate Substitution in Hydroxyapatite by Combining Solid‐state NMR and DFT Calculations

AbstractBiological apatites (main constituent of natural bones) correspond to non‐stoichiometric hydroxyapatite HAp, presenting a large variety of ions as substituents (CO32−, F−, SiO44−, Mg2+, Na+…). The precise location and configuration of ionic substitutes in the HAp matrix are generally difficult to identify and characterize. This contribution details the structural characterization based on NMR data of a particular case of hydroxyapatite substitution by carbonates. For this purpose, all substitution mechanisms proposed to our knowledge in the literature are modeled by DFT and the corresponding calculated NMR parameters allowed to propose or confirm some interpretations of a certain number of experimental observations to rationalize the dependencies of the 13C chemical shift and energy on these structural parameters. The presented results open the way for a fast interpretation of 13C NMR experiments on defective HAp materials and will allow to predict the most stable arrangement of CO32− for a given family of defects.

Integrated Computational Study of the Light-Activated Structure of the AppA BLUF Domain and Its Spectral Signatures.

We apply an integrated approach combining microsecond MD simulations and (polarizable) QM/MM calculations of NMR, FTIR, and UV-vis spectra to validate the structure of the light-activated form of the AppA photoreceptor, an example of blue light using flavin (BLUF) protein domain. The latter photoactivate through a proton-coupled electron transfer (PCET) that results in a tautomerization of a conserved glutamine residue in the active site, but this mechanism has never been spectroscopically proven for AppA, which has been always considered as an exception. Our simulations instead confirm that the spectral features observed upon AppA photoactivation are indeed directly connected to the tautomer form of glutamine as predicted by the PCET mechanism. In addition, we observe small but significant changes in the AppA structure, which are transmitted from the flavin binding pocket to the surface of the protein.

Seven lower toxicity celastrol derivatives by biotransformation of Pestalotiopsis sp. LGT-1

Biotransformation of toxic components by plant endophytes has become an effective method to reduce the toxicity of target compounds and discover lead compounds. In this context, an endophytic fungus, Pestalotiopsis sp. LGT-1, from Tripterygium wilfordii Hook F. (TwHF), was used to reduce the toxicity of celastrol which is also produced by TwHF and is considered an attractive molecule with a variety of biological activities. Seven celastrol derivatives (1–7) were isolated from the coculture fermentation broth of LGT-1 and celastrol. Their structures were elucidated by spectroscopic data analysis including 1D and 2D NMR, as well as HRESIMS. Their absolute configurations were determined by analysis of NOESY, ECD data and NMR calculations. In cell proliferation experiments, the toxicity of seven compounds was 10.11- to 1.24-fold lower in normal cells than the prototype compound celastrol. These derivatives serve as potential candidates for future pharmaceutical applications.

Substituted Benzalacetophenone Molecules: A Computational Investigation of Structural, PED & Non‐Linear Optical Properties

AbstractThis protocol presents a complete theoretical study on the substituted benzalacetophenone molecules. In this study, eighteen chalcone derivatives 1–18 were evaluated with respect to their first‐ and second‐order hyperpolarizability parameters. For this purpose, the molecular geometries of 1–18 were optimized using set 631 g (d,p) and hybrid functional B3LYP. Spectroscopic characterizations for 1–18 were executed through the calculations of IR, UV‐Vis, 1H NMR and 13C NMR spectra. The quantum chemical parameters such as chemical potential, chemical hardness, electronegativity and electrophilicity indexes were obtained using the frontier molecular orbital (FMO) energies. The potential energy distribution (PED) analysis was used to provide a detailed assignment of vibrational bands. Important contributions to electronic absorption bands from FMOs were also evaluated. The distribution of FMOs to the whole molecule was investigated to determine the nature of electronic charge transfers in the target structures. The static and dynamic first‐ and second‐order hyperpolarizability parameters for 1–18 were calculated by using CAM‐B3LYP/6‐31++G(d,p). The static β and γ were calculated at the ranges of 1.348–2.967×10−29 esu and 82.50–136.2×10−36 esu. This wide range of β and γ values indicates that chalcone derivatives with rational substitution may be promising candidates for first‐ and second‐order NLO applications. The findings of this study contribute to the understanding of the relationships between molecular structure and non‐linear optical properties, thus paving the way for the design of new materials with improved non‐linear optical properties.

Aromaticity in Fully π-Conjugated Multicyclic Macrocycles.

The research on aromaticity has mainly focused on monocyclic [n]annulene-like systems or polycyclic aromatic hydrocarbons. For fully π-conjugated multicyclic macrocycles (MMCs), the electronic coupling between the individual constitutional macrocycles would lead to unique electronic structures and aromaticity. The studies on MMCs, however, are quite limited, presumably due to the great challenges to design and synthesize a fully π-conjugated MMC molecule. Herein, we report the facile synthesis of two MMCs (2TMC and 3TMC) in which two and three thiophene-based macrocycles are fused together by employing both intramolecular and intermolecular Yamamoto coupling reactions of a properly designed precursor (7). The monocyclic macrocycle (1TMC) was also synthesized as a model compound. The geometry, aromaticity, and electronic properties of these macrocycles at different oxidation states were investigated by X-ray crystallographic analysis, NMR, and theoretical calculations, which disclosed how the constitutional macrocycles interplay with each other and lead to unique aromatic/antiaromatic character. This study provides new insights into the complex aromaticity in MMC systems.

Fortunilides M-O, anti-inflammatory lindenane sesquiterpenoid dimers from Chloranthus fortunei

Fortunilides M-O (1–3), three new lindenane-type sesquiterpenoid dimers, together with eighteen known dimers (4–21), were isolated from the roots of Chloranthus fortunei. The structures were determined by their NMR, HRESIMS, ECD data and quantum chemical calculations. All compounds were classical [4 + 2] lindenane-type sesquiterpenoid dimers, in which compounds 2–4 and 16–17 had rare additional carbon‑carbon link between C-11 and C-7′. Their anti-inflammatory activity in LPS-induced RAW 264.7 and BV2 microglial cells were screened, and compounds 9 (IC50: 10.70 ± 0.25 μM) and 2 (IC50: 12.26 ± 2.43 μM) showed significant effect, respectively.

Load mechanism and release behaviour of synephrine-loaded calcium pectinate beads: Experiments characterizations, theoretical calculations and mathematical modeling

It is an appropriate strategy to construct the carrier material with polysaccharide pectin, which is the characteristics of good bio-compatible, safe and non-toxic, avoiding the functional loss of bioactive ingredients and achieve sustained release. However, the loading mechanism of the active ingredient and the release behaviour of the active ingredient from the carrier material is still at the stage of conjecture. In this study, a kind of synephrine-loaded calcium pectinate beads (SCPB) with high encapsulation efficiency (95.6 %), loading capacity (11.5 %) and excellent controlled release behaviour was constructed. The interaction between synephrine (SYN) and quaternary ammonium fructus aurantii immaturus pectin (QFAIP) was revealed by FTIR, NMR and density functional theory (DFT) calculation. An inter-molecular hydrogen bond and Van der Waals forces between 7-OH, 11-OH and 10-NH of SYN and -OH, -C=O and N + (CH3)3 of QFAIP were formed. The release experiment in vitro showed that the QFAIP could effectively avoid the release of SYN in gastric fluid, and also realized the slow and full release of SYN in intestinal tract. Moreover, the release mechanism of SCPB in simulated gastric fluid (SGF) was Fickian diffusion, while in simulated intestinal fluid (SIF) was a non-Fickian diffusion controlled by both diffusion and skeleton dissolution.

Ten undescribed eremophilane and guaiane sesquiterpenes from Penicillium roqueforti

Nine undescribed eremophilane sesquiterpenes, one undescribed guaiane sesquiterpene, along with ten known analogues were isolated and identified from fungus Penicillium roqueforti, which was separated from the root soil of Hypericum beanii N. Robson collected from the Shennongjia Forestry District, Hubei Province. Their structures were elucidated on the basis of various spectroscopic analyses, mainly including NMR and HRESIMS data, 13C NMR calculations with DP4+ probability analyses, ECD calculations, and single-crystal X-ray diffraction experiments. Furthermore, all twenty compounds were evaluated for the in vitro cytotoxic activities against seven human tumor cell lines, and the result suggested that 14-hydroxymethylene-1(10)-ene-epi-guaidiol A exhibited considerable cytotoxic activity against the Farage (IC50 < 10 μM, 48 h), SU-DHL-2, and HL-60 cells. Further mechanism study demonstrated that 14-hydroxymethylene-1(10)-ene-epi-guaidiol A could significantly promote apoptosis by inhibiting tumor cell respiration and decreasing intracellular ROS levels, thereby inducing S-phase blockade in tumor cells.