Chemical Shift Values Research Articles

Crystal Structure of Ritonavir Polymorphs I and II Revisited with the Application of NMR Crystallography.

Ritonavir, a protease inhibitor sold under the brand name Norvir®, is an antiviral medication that effectively targets the human immunodeficiency virus (HIV). Being probably the most important and best-known example of the crystal polymorphism in the field of pharmaceutics, ritonavir has been extensively studied in the last 30 years, which eventually led to the discovery of its new polymorph, Form III, in 2023. So far, two crystal structures of both Forms I and II of ritonavir were deposited in CCDC database. The aim of this study was to revisit those crystal structures, using NMR crystallography by recording the 13C CP/MAS NMR spectra and performing GIPAW NMR calculations with CASTEP. The obtained results revealed the major discrepancies between the calculated and experimental NMR chemical shift values. Those differences were explained at the molecular level, as resulting from the differences in the experimentally determined and DFT-optimized positions of some atoms, mostly those forming phenyl and thiazole rings. This work is an example of how NMR crystallography can be used to verify and improve the already published crystal structures.

Pyrochlore-like Local Structure in Globally Disordered Y2Zr2O7: Evidence and Reasoning by Combined Theoretical and Experimental Study.

Even though technological relevance for nuclear and oxide fuel cell application has persuaded a large number of investigations on the Y2Zr2O7 system, its local structure still remains ambiguous and debatable. While diffraction-based investigations claim a lack of local ordering, the MAS NMR and Raman spectroscopic investigations speculate the presence of local ordering. Besides, a correlation between the local and global structures of Y2Zr2O7 is also missing to date. Present work attempts to get deeper insights into the local structure of Y2Zr2O7 and correlate the local structure with global disordering. Complementary investigation using multiple strategies (XRD, RAMAN, electron microscopy, DFT calculations) revealed the presence of pyrochlore-like features in globally disordered Y2Zr2O7. Globally distributed "local probe ions" (Sn4+ by MAS NMR and Eu3+ by photoluminescence (PL)) were utilized for establishing the correlation between local and global structures. The 119Sn MAS NMR spectra possess the shoulder peak bearing chemical shift values, which are improbable under complete cationic randomization. The emission and decay profiles of the Eu3+ ion recommend positioning of few probe ions at the centrosymmetric site, which was further reinforced by crystal field splitting and lifetime values. Thus, both NMR and PL results reaffirm the existence of a pyrochlore-like atomic arrangement in predominantly defective fluorite Y2Zr2O7 phase. These discernible pyrochlore-like features have been envisaged to be emanating from unevenness in bond strength and ionicity/covalency of Y-O and Zr-O bonds. Cationic and anionic randomization energetically endorses global disordering, but the bonding disparity induces short-range ordering. It is believed that the presented findings will guide future research in regulating the physicochemical properties of Y2Zr2O7 for the target applications.

Catalytic Benefits of an Ethynylphenyl-Based PdII Bis(NHC) over a Phenyl-Based PdII Bis(NHC): Insights into the Structural Aspects and Donor Strength Probing.

The amount of cooperation between the metal centers by tailored ligand design is vital to achieve the multimetallic catalytic benefits. Herein, a bimetallic PdII NHC/pyridine complex is synthesized utilizing a novel extended C2-symmetric bis-NHC ligand featuring 1,4-disubstituted ethynylbenzene as a central ligand platform. The complex was further employed for the preparation of a dinuclear complex possessing a combination of NHC and PPh3 ligands. Dinuclear complexes have also been synthesized using a 1,4-di(NHC)-substituted parent benzene ring platform with no acetylene linker units. The donor strengths of both bis-NHC ligands were compared with the help of 13C and 31P chemical shift values as probes. All of the bimetallic complexes were tested as precatalysts in the intermolecular α-arylation of 1-methyl-2-oxindole and Sonogashira coupling reactions. The dinuclear PdII complexes with the ethynylbenzene-bridged bis-NHC ligand showed impressive catalytic outcomes that outweigh the catalytic outcomes obtained with dinuclear bis-NHC complexes possessing no such acetylene linkers. The corresponding mononuclear PdII complexes were synthesized for comparison purposes utilizing both types of central ligand platforms. The dinuclear complexes appeared more active than the corresponding mononuclear complexes in catalysis. Furthermore, higher cooperative index values were obtained in catalysis using the dinuclear PdII complexes with an acetylene-bridged bis-NHC ligand compared to those with no such acetylene linkers.

Aromaticity and Antiaromaticity Reversals between the Electronic Ground State and the Two Lowest Triplet States of Thiophene.

It is shown, by examining the variations in off-nucleus isotropic magnetic shielding around a molecule, that thiophene which is aromatic in its electronic ground state (S0) becomes antiaromatic in its lowest triplet state (T1) and then reverts to being aromatic in T2. Geometry relaxation has an opposite effect on the aromaticities of the ππ* vertical T1 and T2: The antiaromaticity of T1 is reduced whereas the aromaticity of T2 is enhanced. The shielding picture around T2 is found to closely resemble those around certain second singlet ππ* excited states (S2), for example, those of benzene and cyclooctatetraene, thought to be "strongly aromatic" because of their very negative nucleus-independent chemical shift (NICS) values. It is argued that while NICS values correctly follow the changes in aromaticity along the potential energy surface of a single electronic state, the use of NICS values for the purpose of quantitative comparisons between the aromaticities of different electronic states cannot be justified theoretically and should be avoided. "Strongly aromatic" S2 and T2 states should be referred to simply as "aromatic" because detailed comparisons between the properties of these states and those of the corresponding S0 states do not suggest higher levels of aromaticity.

Magnetic Anisotropic Effects in Charged Aza[10]annulene Analogs with a Non-planar Carbon Framework.

Classically, aromaticity portrays the unique stability and peculiar reactivities of cyclic planar conjugated systems with (4n+2) π electrons. Understanding the electronic environments in new chemical frameworks through experimental and theoretical validation is central to this ever-expanding theme in chemical science. Such investigations in curved π-surfaces have special significance as they can unravel the variations when the planarity requirement is slightly lifted. In this report, we discuss the synthesis,spectroscopicand theoretical studies involving a new group of cyclazine analogs having a charged aza[10]annulene periphery, centrally locked through a sp3 carbon. Magnetic anisotropic effects arising from electron delocalization through its curved π-surface were mapped through a specific set of chemical groups introduced through this sp3 carbon. The nucleus-independent chemical shift calculations revealed negative chemical shift values, indicating the aromatic nature of the aza[10] annulene rim. This is corroborated by a clockwise diatropic ring current, evident from anisotropy-induced current density analysis. Variations in the chemical shift of NMR signals in these systems were also computationally examined through isotropic chemical shielding surface analysis.

Synthesis and Spatial Structure of 3-Phenylacrylic Acid Octahydroquinolizin-1-Ylmethyl Ester and 2-(Octahydroquinolizin-1-Ylmethyl)Isoindole-1,3-Dione

The reactions of lupinine alkaloid and its chlorine derivative with cinnamoyl chloride and 2-K-isoindole-1,3-dione were investigated to obtain 3-phenylacrylic acid octahydroquinolizin-1-ylmethyl ester and 2-(octahydroquinolizin-1-ylmethyl)isoindole-1,3-dione, respectively. The optimal conditions for carrying out the aforementioned reactions were determined, taking into account the nature of the solvent and medium. It was established that acylation of the molecule in a benzene medium, in the presence of trimethylamine, resulted in the formation of 3-phenylacrylic acid octahydroquinolizin-1-ylmethyl ester, with an 82% yield. It was demonstrated that the interaction of chlorolupinine with 2-K-isoindole-1,3-dione under Gabriel reaction conditions resulted in the formation of 2-(octahydroquinolizin-1-ylmethyl)isoindole-1,3-dione. The conformer with an axial orientation of the isoindole-1,3-dione substituent was observed to exhibit greater stability than the conformer with an equatorial orientation. The structure of the synthesized compounds was investigated by IR, 1H, and 13C NMR spectroscopy. The use of two-dimensional spectra in COSY (1H-1H) and HMQC (1H-13C) formats enabled the establishment of homo- and heteronuclear interactions, thereby confirming the structure of the compounds under investigation. The values of chemical shifts, multiplet and integrated intensity of 1H and 13C signals in one-dimensional NMR spectra of the novel compounds were determined. The crystal structures of 3-phenylacrylic acid octahydroquinolizin-1-ylmethyl ester and 2-(octahydroquinolizin-1-ylmethyl)isoindole-1,3-dione were elucidated through X-ray analysis.

Understanding the Interactions of Nanoparticles and Dissolved Organic Matter at the Molecular Level by 1H 2D Multi-Exponential Transverse Relaxation NMR Spectroscopy.

The interaction between humic acid (HA) and engineered nanoparticles (NPs) is critical in environmental sciences, especially for understanding the behavior of NPs in natural waters. This study employs 1H 2D Multi-Exponential Transverse Relaxation (METR) NMR spectroscopy to examine the molecular-level interactions between Pahokee Peat humic acid (HA) and carboxyl-functionalized iron oxide nanoparticles (NPCOs). First, 1H 2D METR NMR spectroscopy allowed not only the identification of HA in terms of its chemical composition but also the separation of molecules with the same chemical shift values but different rates of molecular tumbling. Then, using solutions with varying NPCO concentrations (0, 10, 40, and 100 μM), we observed significant changes in the T2 relaxation times of HA components, indicating interactions between HA and NPCO. Analysis showed the biggest effect on two chemical shift regions, corresponding to lipids and carbohydrates, revealing that smaller molecules within these regions exhibit the most significant changes in T2 values upon the addition of NPCO. This suggests that these molecules are the initial sites of interaction, with the entire HA system being affected at higher NPCO concentrations. These findings highlight the utility of METR NMR spectroscopy in studying complex environmental mixtures and provide insights into the behavior of HA and NPs, essential for understanding the fate of NPs in the environment.

Exploring the therapeutic potential of ruthenium(II)-bis(benzimidazol-2-yl)pyridine complex on MDA-MB-231, HCT-116 and normal L6 cell lines

The in vitro anticancer efficacy and cytotoxicity of the [Ru(bbp)2]2+ complex (bbp = 2,6-bis(benzimidazol-2-yl) pyridine) on human breast cancerous MDA-MB-231, colorectal HCT-116, and normal cell lines were investigated by direct microscopic and MTT assay methods. The synthesised [Ru(bbp)2]2+ complex was characterised by UV–visible, FTIR, 1H NMR, and MALDI-TOF-MS spectroscopic techniques. The complex showed a metal-to-ligand charge transfer (MLCT) absorption peak at 481 nm. The FTIR spectrum of the complex showed absorption bands in the range of 3458–573 cm−1. The 1H NMR chemical shift values resembled those of the bbp ligand. The molecular ion peak (M+) of the [Ru(bbp)2]2+ complex was obtained at m/z 1013.48. The IC50 values of the complex on MDA-MB-231, HCT-116 and normal L6 cell lines were calculated from the percentage cellular viability and are found to be 28.71, 9.06 and 153.82 µM respectively. The morphological changes in the cell lines at various concentrations of the complex were attributed to the generation of reactive oxygen species (ROS). The obtained result revealed that the anticancer activity of the synthesised complex depends on the concentration of the complex. The complex reduced the proportion of viable cells in both malignant cell lines, causing apoptosis. The results suggeseted that the synthesised complex showed good anticancer activity on the MDA-MB-231 and HCT-116 cell lines with low cytotoxicity. Thus, the present investigation paved the way for the development of novel anticancer drugs.

Stabilization of the Compressed Planar Benzene Dianion in Inverse-Sandwich Rare Earth Metal Complexes.

For the first time, the capture of a planar antiaromatic benzene dianion in between two trivalent rare earth (RE) metal cations, each stabilized by two guanidinate ligands, is reported. The synthesized inverse-sandwich complexes [{(Me3Si)2NC(NiPr)2}2RE]2(µ-ƞ6:ƞ6-C6H6), (RE = Y (1), Dy (2), and Er (3)) feature a remarkably planar benzene dianion, previously not encountered for any metal ion prone to low or absent covalency. The -2 charge localization at the benzene ligand was deduced from the results obtained by single-crystal X-ray diffraction analyses, spectroscopy, magnetometry, and Density Functional Theory (DFT) calculations. In the 1H NMR spectrum of the diamagnetic Y complex 1, the equivalent proton resonance of the bridging benzene dianion ligand is drastically shifted to higher field in comparison to free benzene. This and the calculated highly positive Nucleus-Independent Chemical Shift (NICS) values are attributed to the antiaromatic character of the benzene dianion ligand. The crucial role of the ancillary guanidinate ligand scaffold in stabilizing the planar benzene dianion conformation was also elucidated by DFT calculations. Remarkably, the planarity of the benzene dianion originates from the stabilization of the π-type orbitals of the d-manifold and compression through its strong electrostatic interaction with the two REIII sites.

Stabilization of the Compressed Planar Benzene Dianion in Inverse‐Sandwich Rare Earth Metal Complexes

For the first time, the capture of a planar antiaromatic benzene dianion in between two trivalent rare earth (RE) metal cations, each stabilized by two guanidinate ligands, is reported. The synthesized inverse‐sandwich complexes [{(Me3Si)2NC(NiPr)2}2RE]2(µ–ƞ6:ƞ6–C6H6), (RE = Y (1), Dy (2), and Er (3)) feature a remarkably planar benzene dianion, previously not encountered for any metal ion prone to low or absent covalency. The ‐2 charge localization at the benzene ligand was deduced from the results obtained by single‐crystal X‐ray diffraction analyses, spectroscopy, magnetometry, and Density Functional Theory (DFT) calculations. In the 1H NMR spectrum of the diamagnetic Y complex 1, the equivalent proton resonance of the bridging benzene dianion ligand is drastically shifted to higher field in comparison to free benzene. This and the calculated highly positive Nucleus‐Independent Chemical Shift (NICS) values are attributed to the antiaromatic character of the benzene dianion ligand. The crucial role of the ancillary guanidinate ligand scaffold in stabilizing the planar benzene dianion conformation was also elucidated by DFT calculations. Remarkably, the planarity of the benzene dianion originates from the stabilization of the π‐type orbitals of the d‐manifold and compression through its strong electrostatic interaction with the two REIII sites.

1H NMR Chemical Shift Changes as a Result of Introduction of Carbonyl-Containing Protecting Groups Observed in Bornol and Isoborneol

Complete assignments of the 1H NMR chemical shifts for monoterpenes, borneol, and isoborneol, and their derivatives in which the secondary hydroxy group is protected with an acetyl group or a benzoyl group, have been made in CDCl3 and C6D6. Upon the protection of the hydroxy group with the carbonyl functional groups, or acetyl or benzoyl groups, many protons constituting the bicyclic ring exhibited downfield and upfield shifts in the chemical shift values, aiding in the unambiguous assignments of protons and carbons.

Synthesis, structure, and biological activity of sodium, zinc, and magnesium mono- and bis-1-alkoxy-4-(2′-naphthyl)-1,4-dioxo-2-buten-2-olates

The search for new biologically active compounds is a key area of chemical science. Therefore, the synthesis of compounds with a potentially bactericidal effect seems relevant. In order to extend the range of biologically active substances, the synthesis of sodium 4-(2’-naphthyl)-1,4-dioxo-1-ethoxy-2-buten-2-olate and sodium 1-butoxy-4-(2´-naphthyl)-1,4-dioxo-2-buten-2-olate was carried out by Claisen condensation of equimolar amounts of 2-acetonaphtone and dialkyloxalates in a non-polar medium in the presence of sodium as a condensing agent. Bidentate mononuclear metal chelates were obtained by the metal exchange reaction of sodium oxoenolates with Zn(II) and Mg(II) salts. The structure of the synthesized compounds was confirmed by infrared spectroscopy, (1Н, 13С) nuclear magnetic resonance spectroscopy, and mass spectrometry. The infrared spectra of solid samples of sodium oxoenolates and metal complexes contain bands of stretching vibrations of ester carbonyl groups, skeletal vibrations of aromatic rings, as well as “ether” bands due to vibrations of C–O–C bonds. The 1Н and 13С nuclear magnetic resonance spectra recorded in CDCl3 and Dimethyl sulfoxide-d6 are characterized by a complete set of all expected signals with chemical shift values that are well comparable with the reference data. In the mass spectra of the analyzed compounds, recorded in an acetonitrile solution in the electrospray mode, signals of [M+H]+ and [M+Na]+ protonated and cationized molecules are observed. The bactericidal action of the synthesized preparations was assessed using the agar well diffusion method in combination with the serial dilution method. The biological activity of sodium 4-(2’-naphthyl)-1,4-dioxo-1-ethoxy-2-buten-2-olate against Pseudomonas Aeruginosa and Staphylococcus Aureus, as well as sodium 1-butoxy-4-(2’-naphthyl)-1,4-dioxo-2-buten-2-olate against Pseudomonas Aeruginosa, was revealed. Pronounced resistance of Salmonella spp. to the studied compounds was established.

The impact of hetero-aromatic rings on optoelectronic and charge transport properties of fused polycyclic compounds

The structural, optoelectronic, and charge-transport properties of linearly fused polycyclic hydrocarbon molecules with heteroatoms (NH, O, S, and Se) in five-membered rings have been investigated using the DFT approach. The hybrid functional B3LYP in combination with the 6–311 + G (d,p) basis set is utilized in the Gaussian 16 W software package for all the calculations. The absorption and emission energies are investigated by using time-dependent density functional theory (TD-DFT) at the same level of theory. To investigate the stability of each molecule concerning its aromaticity, nucleus-independent chemical shift (NICS) values are computed. Electron affinity (EA), hole extraction potential (HEP), ionization potential (IP), and electron extraction potential (EEP) are also reported. The simulated hole (λ h) and electron (λ e) reorganization energies for the majority of the molecules are lower than the characteristics hole and electron-transporting materials. The reported fused polycyclic compounds may have potential applications in optoelectronic devices.

Semisynthesis, Structure Elucidation and Anti-Mycobacterium marinum Activity of a Series of Marine-Derived 14-Membered Resorcylic Acid Lactones with Interesting Ketal Groups.

The incidence of Mycobacterium marinum infection is on the rise; however, the existing drug treatment cycle is lengthy and often requires multi-drug combination. Therefore, there is a need to develop new and effective anti-M. marinum drugs. Cochliomycin A, a 14-membered resorcylic acid lactone with an acetonide group at C-5' and C-6', exhibits a wide range of antimicrobial, antimalarial, and antifouling activities. To further explore the effect of this structural change at C-5' and C-6' on this compound's activity, we synthesized a series of compounds with a structure similar to that of cochliomycin A, bearing ketal groups at C-5' and C-6'. The R/S configuration of the diastereoisomer at C-13' was further determined through an NOE correlation analysis of CH3 or CH2 at the derivative C-13' position and the H-5' and H-6' by means of a 1D NOE experiment. Further comparative 1H NMR analysis of diastereoisomers showed the difference in the chemical shift (δ) value of the diastereoisomers. The synthetic compounds were screened for their anti-microbial activities in vitro. Compounds 15-24 and 28-35 demonstrated promising activity against M. marinum, with MIC90 values ranging from 70 to 90 μM, closely approaching the MIC90 of isoniazid. The preliminary structure-activity relationships showed that the ketal groups with aromatic rings at C-5' and C-6' could enhance the inhibition of M. marinum. Further study demonstrated that compounds 23, 24, 29, and 30 had significant inhibitory effects on M. marinum and addictive effects with isoniazid and rifampicin. Its effective properties make it an important clue for future drug development toward combatting M. marinum resistance.

Synthesis, DFT investigation, antioxidant, molecular docking and ADME-T properties of N′-(1-benzylpiperidin-4-ylidene) furan-2-carbohydrazide derivatives against SARS-CoV-2 spike proteins

ABSTRACT A novel synthetic reaction was used to produce a piperidine derivative, specifically N′-(1-benzylpiperidin-4-ylidene)furan-2-carbohydrazide (BPFC). The structure of the synthesised compound was confirmed through FT-IR, 1H-NMR and 13C-NMR spectral analysis. DFT calculations were performed to optimise structural parameters and investigate Natural Bond Orbital (NBO) analysis, Frontier Molecular Orbitals (FMOs), Molecular Electrostatic Potentials, Mulliken Charge Analysis, and Non-linear Optical properties. The predicted chemical shift values align well with the expected results. The antioxidant properties of the newly synthesised compound were assessed using DPPH, ABTS, and H2O2 radical scavenging assays. Molecular docking studies were also carried out to explore the binding mechanism of the compound with COVID-19-related proteins, particularly 6WCF and 6LU7. Additionally, the synthesised compound was assessed for drug-likeness and ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) properties, revealing favourable pharmacokinetic profiles without any signs of toxicity.

1H, 13C, 15N NMR, and DFT Studies on Complex Formation of Zinc(II) Ion with Ethylenediamine in Ionic Liquid [C2mIm][TFSA

In bis(trifluoromethylsulfonyl)amide (TFSA-)-based ionic liquid (IL), 1-ethyl-3-methylimidazolium TFSA- ([C2mIm][TFSA]), the complex formation equilibria of zinc(II) ion (Zn2+) with ethylenediamine (EN) have been investigated. An EN molecule may coordinate with Zn2+ as a bidentate ligand. First, the formation of Zn2+-EN complexes in [C2mIm][TFSA] was confirmed from the difference of 1H and 13C NMR chemical shift values of EN molecules between [C2mIm][TFSA]-EN binary solvents and the 0.1 mol dm-3 Zn(TFSA)2/[C2mIm][TFSA]-EN solutions as a function of EN mole fraction xEN. Second, the stability constants of Zn2+-EN complexes formed in the IL were determined from the concentration ratio [EN]/[Zn2+] dependence of 15N NMR chemical shift values of the TFSA- N atom in the Zn2+/IL-EN solutions. In the IL, mono-, bis-, and tris-EN complexes are successively formed by 1:1 replacement of TFSA- anions coordinated with Zn2+ by EN molecules with increasing EN content. Third, 1H and 13C NMR measurements with the help of density functional theory (DFT) calculations were made on [C2mIm][TFSA]-EN binary solvents as a function of xEN to clarify key interactions to the mechanism of the complex formation. Fourth, the stability constants of Zn2+-EN complexes in the IL were compared with those in aqueous solutions. It was suggested that the hydrogen bonding of the EN molecule with the imidazolium ring H atoms and the TFSA- O atoms reduces the stability of the mono-EN complex in the IL. In contrast, the intracomplex hydrogen bonds between EN and TFSA- in the first coordination shell contribute to the higher stability of the bis-EN complex in the IL than that in aqueous solutions. The difference in the stability constants between the tris-EN complexes and hexaacetonitrile complexes, where acetonitrile (AN) molecules act as monodentate ligands, was interpreted in terms of the higher electron donicity of EN. Finally, to verify the present evaluation, the experimental 13C NMR chemical shift values of EN molecules in the solutions were compared with the theoretical values calculated by DFT using the stability constants determined.

Enhancing ketoprofen's solubility and anti-inflammatory efficacy with safe methyl-β-cyclodextrin complexation

Improved solubility and anti-inflammatory (AI) properties are imperative for enhancing the effectiveness of poorly water-soluble drugs, particularly non-steroidal anti-inflammatory drugs (NSAIDs). To address these critical issues, our focus is on obtaining NSAID materials in the form of inclusion complexes (IC) with methyl-beta-cyclodextrin (MCD). Ketoprofen (KTP) is selected as the NSAID for this study due to its potency in treating various types of pain, inflammation, and arthritis. Our objective is to tackle the solubility challenge followed by enhancing the AI activity. Confirmation of complexation is achieved through observing changes in the absorbance and fluorescence intensities of KTP upon the addition of MCD, indicating a 1:1 stoichiometric ratio. Phase solubility studies demonstrated improved dissolution rates after the formation of ICs. Further analysis of the optimized IC is conducted using FT-IR, NMR, FE-SEM, and TG/DTA techniques. Notable shifts in chemical shift values and morphological alterations on the surface of the ICs are observed compared to their free form. Most significantly, the IC exhibited superior AI and anti-arthritic (AA) activity compared to KTP alone. These findings highlight the potential of ICs in expanding the application of KTP, particularly in pharmaceuticals, where enhanced stability and efficacy of natural AIs and AAs are paramount.

Benzo[6,7]cyclohepta[1,2-d]pyrazolo[1,5-a]pyrimidines: Regioselective synthesis of a Novel Ring System, DFT-based NMR prediction, local reactivity indexes, and MEP analysis

Novel benzo[6,7]cyclohepta[1,2-d]pyrazolo[1,5-a]pyrimidines were prepared as a new ring system utilizing a regioselective protocol. A mixture of the appropriate 3,5-diamino-1H-pyrazoles and benzosuberone-based enones in ethanolic potassium hydroxide solution was heated at reflux for 5 h to produce the novel benzosuberone-fused pyrazolo[1,5-a]pyrimidines in 87–94 % yields. Both spectral data as well as elemental analyses were used to establish the structure of the novel products. Theoretical calculation of chemical shifts of NMR spectra is a powerful tool in analyzing experimental spectra for known substrates as well as elucidating the chemical structure for unknown ones. Using the DFT-GIAO approach under the B3LYP and mPW1PW91 functions, as well as a variety of basis sets, including 6–31G(d,p), 6–31+G(d), 6–311G(d), 6–311+G(d,p), 6–311++G-(d,p), and 6–311+G(2d,p), the chemical shifts of 1H- and 13C NMR in DMSO were calculated. The results that are most similar to the experimental observations are obtained from the computation of the chemical shift values under the 6–31G(d,p) or 6–31+G(d,p) basis sets and mPW1PW91 when using the multistranded approach. By identifying the preferred regions for electrophilic and nucleophilic attack, DFT-based FMO, global descriptors, local reactivity indexes, and MEP mapping were applied at the B3LYP function using the 6–31+G(d,p) basis set to provide additional insight into the regioselectivity in the desired reaction as well as the plausible mechanism for the formation of new products.

1H, 13C and 15N resonance assignments of a shark variable new antigen receptor against hyaluronan synthase.

Single domain antibody (sdAb) is only composed of a variable domain of the heavy-chain-only antibody, which is devoid of light chain and naturally occurring in camelids and cartilaginous fishes. Variable New Antigen Receptor (VNAR), a type of single domain antibody present in cartilaginous fishes such as sharks, is the smallest functional antigen-binding fragment found in nature. The unique features, including flexible paratope, high solubility and outstanding stability make VNAR a promising prospect in antibody drug development and structural biology research. However, VNAR's research has lagged behind camelid-derived sdAb, especially in the field of structural research. Here we report the 1H,15N,13C resonance assignments of a VNAR derived from the immune library of Chiloscyllium plagiosum, termed B2-3, which recognizes the hyaluronan synthase. Analysis of the backbone chemical shifts demonstrates that the secondary structure of VNAR is predominately composed of β-sheets corresponding to around 40% of the B2-3 backbone. The Cβ chemical shift values of cysteine residues, combined with mass spectrometry data, clearly shows that B2-3 contains two pairs of disulfide bonds, which is import for protein stability. The assignments will be essential for determining the high resolution solution structure of B2-3 by NMR spectroscopy.

Synthesis, QTAIM, anticancer activity analysis of pyrrole-imidazole/benzimidazole derivatives and investigation of their reactivity properties using DFT calculations and molecular docking

As part of our ongoing investigation into pyrrole derivatives, we here present the synthesis, spectroscopic characterization, QTAIM, reactivity, anticancer activity, and comparative experimental and computational analysis of pyrrole-imidazole ((3l), (3p)) and benzimidazole derivatives ((3h), (3i), (3j), (3k), (3m), (3n), (3o)). All synthesized compounds (3h-3p) have been well characterized by spectroscopic techniques (FT-IR, 1H and 13C NMR, Mass spectrometry). The experimental 1H and 13C NMR chemical shift values of synthesized pyrrole-imidazole (3l, 3p) and benzimidazole (3h-3o) derivatives have been well corroborated with computed chemical shifts. The vibrational analysis for four derivatives of pyrrole-benzimidazole (3m), (3n), (3o), and pyrrole-imidazole (3p) has the suitability for dimer formation in solid state by intermolecular heteronuclear hydrogen bonding (N–H···O) and the interaction energy of dimers are calculated to be 10.88, 11.70, 9.89 and 10.72 kcal/mol, using DFT. After basis-set superposition error (BSSE) correction, the interaction energies of dimers were found to be 11.12, 12.11, 10.13, and 11.52 kcal/mol. Estimated intermolecular H-bond in (3m-3n) compounds were found to be -13.38, -12.86, -11.02, and -11.28 kJ/mol using QTAIM. All the synthetic pyrrole-imidazole (3l, 3p) and benzimidazole (3h-3o) derivatives exhibit strong antileukemia activity in vitro against the proliferative cell line L1210 leukemia cells. A dataset of investigated compounds was subjected for molecular modelling simulation against three distinct proteins (SYK, PI3K, and BTK), which was found to be highly implicated in the favourable interaction between the compounds and their target proteins in every instance. The synthesized pyrrole-imidazole (3l, 3p) and benzimidazole (3h-3o) derivatives shown favourable interactions with their target proteins, with high activity and binding free energy values falling between 15.22 and 13.43 and -7.4 and -9.8 kcal/mol, respectively. The structure of pyrrole-imidazole (3l, 3p) and benzimidazole (3h-3o) derivatives is thoroughly examined, and several parameters are proposed here to improve their anticancer activity.