Search Results (139)

Two new 2-N-phenylamino-5-nitropyridine—4-methyl (2PA5N4MP) and 2-N-phenylamino-5-nitropyridine-6-methyl (2PA5N6MP) isomers were synthesized and comprehensively characterized by single-crystal X-ray diffraction, IR/Raman spectroscopy, UV–Vis absorption, and photoluminescence measurements. DFT and TD-DFT calculations were also carried out to support the experimental results. The X-ray analysis revealed significant structural differences: 2PA5N6MP adopted an almost planar conformation (pyridine–phenyl dihedral ~3°), whereas 2PA5N4MP was markedly twisted (~45°), leading to distinct hydrogen-bonding motifs (N–H⋯N dimers vs. N–H⋯O interactions). These geometric disparities influenced their electronic properties: 2PA5N6MP exhibited a narrower HOMO–LUMO gap (≈2.45 eV) than 2PA5N4MP (≈3.77 eV), which was consistent with a pronounced bathochromic shift in absorption. Both isomers showed broad UV–Vis absorption (200–520 nm), but the 6-methyl derivative featured an additional low-energy charge–transfer band around 460 nm (with a maximum at ~500 nm) compared to ~355 nm in the 4-methyl isomer. Likewise, their photoluminescence spectra differed as follows: 2PA5N4MP emitted in the violet–blue region (bands at ~415 and 450 nm), whereas 2PA5N6MP had an extra orange band peaking at ~560 nm (in addition to a ~450 nm band). The red-shifted 560 nm emission of 2PA5N6MP was attributed to intersystem crossing into triplet states, in line with TD-DFT predictions. Furthermore, both isomers readily formed complexes with Eu³⁺ ions, and the Eu³⁺ chelates exhibited the characteristic red f–f emissions (⁵D₀ → ⁷F transitions ~590–700 nm), demonstrating efficient sensitization of Eu³⁺ luminescence. Overall, the position of the methyl substituent strongly modulates the compounds’ optical behavior, and these isomers show promise as tunable organic dyes and effective ligands for luminescent lanthanide complexes. Full article

Background: The golden era of antibiotics has long passed, and the clinical failures caused by emerging drug-resistant bacteria have intensified the demand for novel antimicrobial agents. Antimicrobial peptides have attracted significant attention as promising candidates for next-generation antibiotics. Methods: In this study, we identified a novel antimicrobial peptide, Caerin 1.1-LC, from the skin secretion of the Australian green tree frog, Litoria caerulea. Subsequent structure–activity relationship studies led us to design a series of analogues and revealed the critical role of the peptide’s intrinsic hinge structure in shaping its biological activity. Results: Incorporation of D-isomers at the valine residues within the hinge preserved overall helical content but altered the hinge conformation, resulting in an 8-fold increase in antibacterial activity against Gram-negative bacteria. Simultaneously, haemolytic activity was markedly reduced, leading to a 56-fold improvement in therapeutic index (from 0.47 to 26.6). Structural modulation of the hinge also switched the mechanism of action from classical membrane disruption with associated permeability changes to a non-membrane-permeabilising, ‘cell-penetrating-like’ behaviour, inducing membrane potential depolarisation and ATP disruption to trigger bacterial death. In vivo studies using infected larval models, along with in vitro LPS neutralisation assays, further demonstrated the therapeutic potential of the D-analogue as a novel antibacterial agent. Conclusions: This work highlights the pivotal role of hinge structures in Caerin-family/hinge-containing AMPs, offering a strategic avenue for optimising antibacterial efficacy. Full article

For a family of 24-atom triazine macrocycles, a single intramolecular hydrogen bond (IMHB) network leads to a conserved, hinge-like motif in solution. Modifications to the backbone of these macrocycles preserve this motif. Modifications to peripheral sites lead to conformational isomers due to hindered bond rotation while conserving the hinge motif. Here, a competitive IMHB network is introduced by the addition of a hydrogen bond donor on the periphery. Cyclization remains quantitative, but multiple conformers result. Three conformers are derived from the hinge motif. Three others are attributed to a new motif that utilizes the new IMHB network. Crystallographic analysis confirms this hypothesis and establishes that this new motif differs significantly from the original with respect to overall shape and disposition of groups. Variable temperature ¹H NMR spectroscopy is used to partially assign the spectra because conformers adopting the hinge motif undergo dynamic motion on the NMR timescale, while the new motif appears static. QTAIM analysis corroborates the hydrogen bond designations in the new conformer and categorizes these interactions as moderate and strong. Full article

Spiropyran (SP)–Merocyanine (MC) systems represent versatile molecular switches, with their open–closed equilibrium can be finely tuned by their structural characteristics. In this study, we combined conformational sampling, DFT (Density Functional Theory) calculations to rationalize the distinct behaviors of two recently synthesized derivatives: SP1/MC1 and SP3/MC3. While SP1 primarily exists in the colorless, non-fluorescent SP form, MC3 remains stabilized in the colored, open MC state, displaying intense emission. Our results reveal that allyl and benzyl substituents impose conformational constraints that limit interconversion, while hydroxyl substitution and solvent polarity modulate the relative stability of the SP and MC isomers. Full article

The impact of counterion structure, especially variations in constitutional and stereochemical isomers, on the properties and performance of AABSs remains under-explored. This study investigates how structural variations, particularly the stereochemistry of diammonium cyclohexane (DACH) counterions, influence the self-assembly behavior of AABSs. Four AABSs: undecanoyl-glycine, -L-alanine, -L-valine, and -L-leucine, were paired with six DACH counterions representing cis/trans isomers of 1,2-, 1,3-, and 1,4-DACH. Critical micelle concentrations (CMCs) were determined via conductimetry, and micellar sizes were measured using dynamic light scattering. The degree of counterion binding (β) was calculated to probe micelle stability, while geometry-optimized structures of the DACH isomers were obtained using density functional theory. Lastly, pH measurements were taken to probe the protonation of DACH counterions at their natural pH, where both the DACH counterion and AABS headgroups intrinsically behave as buffers. Results indicate that while surfactant hydrophobicity primarily dictates CMC in other AABS/DACH combinations, trans-1,3-DACH leads to consistently higher CMCs. This deviation likely arises from its structural conformation, which positions the amine groups an intermediate distance of ~4.4–4.5 Å apart, allowing a small fraction of divalently charged counterions to form strong electrostatic bridging pockets at the micelle interface. These interactions dominate over headgroup effects, leading to elevated and surfactant-independent CMC values. Regarding size and other unusual trends in the systems, cis- isomers formed slightly larger micelles, and trans-1,4-DACH induces abnormal aggregation in undecanoyl-glycine leading to temperature dependent gel formation. These findings highlight the significant influence of counterion structure on AABS behavior and support counterion design as a strategy for enhancing surfactant performance in sustainable applications. Full article

Nerolidol (REL), a sesquiterpene with cis and trans isomers, exhibits diverse bioactive and sensory properties. In this study, we integrate single-crystal X-ray diffraction (SC-XRD), molecular docking, molecular dynamics (MD) simulations, and MM/GBSA binding free energy calculations to investigate its inclusion behavior in β-cyclodextrin (β-CD). Crystallization from a cis/trans mixture yielded a complex containing exclusively the trans isomer, forming a 2:1 host–guest assembly where a head-to-head β-CD dimer encapsulates one trans-REL molecule in an extended conformation. Computational models of cis-REL (bent c1 and extended c8 conformers) also stabilized within the β-CD cavity, with the extended conformer showing the most favorable dynamics. The computed binding affinities for all complexes differed by less than the estimated MM/GBSA uncertainty, indicating no statistically significant preference. Since cis/trans separation of nerolidol and related long-chain terpenoids is of considerable interest, our findings suggest that crystallization selectivity in β-CD inclusion complexes cannot be rationalized solely by binding affinity; instead, it likely arises from crystal packing forces and conformational preferences that govern the solid-state assembly. Full article

Recently, an article was published in which a more accurate pre-screening method compared to MMFF for conformer distributions in flexible organic molecules was presented. However, experimental data on conformer distributions are almost completely lacking. Therefore, old experimental and computational work on the thermodynamic partition of DIPN isomers was revisited to compare the new method, corrected MMFF (cMMFF), with MMFF as a pre-screening tool. Next, the preliminary conformer distributions were used as input for higher-level QM calculations to yield more reliable conformer distributions. Generally, it was found that cMMFF yields smaller energy differences between DIPN isomers and conformers of a DIPN isomer than MMFF, in line with the results of DFT methods B3LYP and B3PW91, used in higher-level calculations. MP2 turned out to be a remarkable outlier, yielding even smaller energy differences both between DIPN isomers and conformers of a DIPN isomer. Preliminary conformer distributions of DIPN isomers obtained with MMFF and optimized with B3LYP and B3PW91 yielded excellent thermodynamic equilibrium partitions of DIPN isomers compared to the available experimental data. Preliminary conformer distributions of DIPN isomers obtained with cMMFF and optimized with B3LYP and B3PW91 performed less well. However, this seems due to a small effect on the energy (~4 kJ/mol) of the local geometry of the β-isopropyl group on naphthalene, which still strongly affects the thermodynamic equilibrium partitions. To obtain a more balanced judgement on the newly proposed method and the existing ones, more comparisons between experimental and computational data on small molecules with a higher degree of flexibility are needed. Full article

The ability of enzymes to access various conformational states is often essential for their catalytic activity. Lysine 5,6-aminomutase (5,6-LAM), a pyridoxal 5′-phosphate (PLP) and 5′-deoxyadenosylcobalamin (dAdoCbl)dependent enzyme, catalyzes 1,2-amino shift in lysine isomers by shuttling between an open conformational state and a closed conformational state. Nevertheless, suicide inactivation of 5,6-LAM is an obstacle to the realization of its potential as a biocatalyst. In this work, the fate of the reaction of 5-hydroxylysine, an analogue of lysine, is investigated using spectroscopic and computational methods. Although 5-hydroxylysine does not afford any product, results obtained from UV–visible and electron paramagnetic resonance (EPR) spectroscopies demonstrate that initial steps of the catalytic cycle are performed with it. Simulation of the weakly spin-coupled spectrum estimates an intermediate distance between the PLP substrate-based radical and Co(II) in comparison to the that in the open state and the closed state. This distinct conformational state, different from the open state and the closed state, is alluded to in its putative role in suicide inactivation and denoted as the suicidally-inactivated state. Our findings highlight the emergence of EPR spectroscopy as a powerful tool to uncover the hidden conformations in radical enzymes. These results provide new insights into the suicide inactivation of dAdoCbl-dependent enzymes. Full article

The creation of larger prebiotic molecules in astronomical regions may require aminoketene (NH₂CHCO) as an intermediate, and the two conformers of this molecule exhibit infrared vibrational frequencies with intensities larger even than the antisymmetric stretch in CO₂. While the present quantum chemically computed frequencies of these fundamentals of ∼4.7 μm are in the same spectroscopic region as features from functionalized polycyclic aromatic hydrocarbons, they provide clear markers for what James Webb Space Telescope IR observations may be able to distinguish. Additionally, the IR and radioastronomical spectral characterization of two additional 2-iminoacetaldehyde, HN=CHC(=O)H, conformers are also computed as are the same data for a new carbene isomer (NH₂CC(=O)H). All conformers of aminoketene and 2-iminoacetaldehyde exhibit dipole moments of more than 2.0 D, if not greater than 4.0 D, implying that they would be notable targets for radioastronomical searches. Additionally, the 2-iminoacetaldehyde conformers have a notable mid-IR C=O stretch around 1735 cm⁻¹ slightly below the same fundamental in formaldehyde. This quantum chemical study is providing a more complete set of reference data for the potential observation of these tautomers and conformers of NH₂CHCO in the laboratory or even in space. Full article

1,4-Thiazine S,S-dioxide 1, the cis- and trans-isomers 2 and 3 of its precursor 2,6-diethoxy-1,4-oxathiane S,S-dioxide, and diethyl 2,3-dihydro-1,4-thiazine-3,5-dicarboxylate S,S-dioxide 4 have been fully characterised, both in solution by ¹H and ¹³C NMR and in the solid state by X-ray diffraction. Simulation has been used to model the unexpectedly complex ¹H NMR spectra and arrive at a full assignment of all chemical shifts and coupling constants. The crystal structures of both 1 and 4, which adopt, respectively, boat and half-chair conformations, are dominated by strong NH to O=S hydrogen bonding leading to chains of molecules. In the case of 4, the NMR data point to an equatorial position of the C(2)-ester group in solution, while in the crystal, this adopts an axial orientation. Compounds 2 and 3 adopt chair conformations both in solution and in the solid state with ring inversion on the NMR timescale leading to unexpected simplification of the spectra in the case of 3. Full article

Several carrier proteins are involved in nuclear translocation from the cytoplasm to the nucleus in eukaryotic cells. We have previously demonstrated the binding of several intact folded and disordered proteins to the human isoform importin α3 (Impα3); furthermore, disordered peptides, corresponding to their nuclear localization signals (NLSs), also interact with Impα3. These proteins and their isolated NLSs also bind to the truncated importin species ∆Impα3, which does not contain the N-terminal disordered importin binding domain (IBB). In this work, we added a further ‘layer’ of conformational disorder to our studies, testing whether the isolated D-enantiomers of NLSs of selected proteins, either folded or unfolded, were capable of binding to both Impα3 and ∆Impα3. The D-enantiomers, like their L-form counterparts, were monomeric and disordered in isolation, as shown by nuclear magnetic resonance (NMR). We measured the ability of such D-enantiomeric NLSs to interact with both importin species by using fluorescence, biolayer interferometry (BLI), isothermal titration calorimetry (ITC), and molecular simulations. In all cases, the binding affinities were within the same range as those measured for their L-isomer counterparts for either Impα3 or ∆Impα3, and the binding locations corresponded to the major NLS binding site of the protein. Thus, the stereoisomeric nature is not important in defining the binding of proteins to the main component of classical cellular translocation machinery, although the primary structure of the hot-spot site for NLS binding of importin is well defined. Full article

Background/Objective: Avapritinib is an orally bioavailable tyrosine kinase inhibitor and was approved by the FDA in 2020 for gastrointestinal stromal tumor treatments. Although avapritinib is known to be chiral, its stereochemistry was initially established randomly. This study aims to develop a definitive method for determining avapritinib’s absolute configuration and propose a universal methodology for stereochemical characterization of flexible chiral drugs. Methods: The absolute configuration of avapritinib was determined through an integrated approach combining chiral resolution, chiroptical spectroscopy and synthetic validation. Enantiomeric separation was achieved via chiral liquid chromatography, followed by comprehensive chiroptical characterization including electronic circular dichroism (ECD), specific optical rotation and optical rotatory dispersion. Conformational analysis and density functional theory (DFT) calculations correlated experimental spectra with theoretical predictions, facilitating definitive configurational assignment. The stereochemical determination were further verified through ECD derivatization and chemical synthesis. Finally, the enantiomers’ kinase inhibition profiles against c-KIT D816V were quantitatively assessed. Results: Two enantiomers of avapritinib were resolved via chiral HPLC and a Chiralpak IG column. Through combined experimental ECD spectra and time-dependent DFT calculations employing the core extraction method, the levo-isomer was unambiguously determined as S configuration. This stereochemical assignment was confirmed by p-cyanobenzaldehyde derivatization and de novo synthesis. Biological evaluation revealed (S)-(−)-avapritinib exhibited superior c-KIT D816V inhibitory activity compared to its (R)-(+)-counterpart, a finding corroborated by molecular docking studies elucidating their differential target interactions. Conclusions: This study advances avapritinib stereochemical understanding and establishes a definitive protocol for its absolute configuration assignment, serving as a paradigm for flexible chiral drug characterization. Full article

A comprehensive theoretical investigation of the C₃H₂O potential energy surface (PES) was conducted, revealing 30 equilibrium structures (EQs), 128 transition state structures (TSs), and 35 direct dissociation channels (DCs), establishing a global reaction network comprising 101 isomerization pathways and dissociation channels. Particular focus was placed on the five most stable isomers, H₂CCCO (EQ3), OC(H)CCH (EQ7), H-c-CC(O)C-H (EQ0), HCC(H)CO (EQ1), and HO-c-CCC-H (EQ12), and their reactions with water molecules. Multicomponent artificial force-induced reaction (MC-AFIR) calculations were employed to study bimolecular collisions between H₂O and these stable isomers. The product distributions revealed isomer-specific reactivity patterns: EQ3 and EQ7 predominantly formed neutral species at high collision energies, EQ0 produced both ionic and neutral species, while EQ1 and EQ12 exhibited more accessible reaction pathways at lower collision energies with a propensity for spontaneous isomerization. Born–Oppenheimer Molecular Dynamics (BOMD) simulations complemented these findings, suggesting several viable products emerge from reactions with water molecules, including HCCC(OH)₂H (EQ7 + H₂O), OCCHCH₂OH (EQ1 + H₂O), and HO-c-CC(H)C(OH)-H (EQ12 + H₂O). This investigation elucidates the intrinsic relationships between isomers and their potential products, formed through biomolecular collisions with water molecules, establishing a fundamental framework for future conformational and reactivity studies of the C₃H₂O family. Full article

The synthetic availability and wide range of biological activity of hydrazides and hydrazones make them attractive subjects for investigation. In this study, we focused on synthesis of 2-methyl-5-nitro-6-phenylnicotinohydrazide-based hydrazones derived from the corresponding substituted aldehydes. The structure of the obtained compounds was studied using NMR spectroscopy and DFT calculations. After repeated recrystallization, all the synthesized compounds remained as mixtures of isomers. As a result of a detailed analysis, we found that the duplication and bifurcation of signals in the ¹H NMR spectra for some atoms is a consequence of the existence of four isomers, namely Z-I, Z-II, E-I and E-II. Duplicate proton signals with a chemical shift difference of 0.1–0.2 ppm and in a ratio of about 2:1 were noticed in the experimental data. By modeling the structures of individual configurations and conformations, Gibbs free energy values were obtained, which allowed us to estimate the approximate content of rotamers for the E-isomer equal to 3:2, which coincided with experimental data. We also tested the antibacterial and antifungal activity of the synthesized compounds. Full article

O-Methyldehydroserine, ΔSer(Me), is a non-standard α,β-dehydroamino acid, which occurs naturally in Cyrmenins with potential pharmaceutical application. The C-terminal part and the side chain of the ΔSer(Me) residue constitute the β-methoxyacrylate unit, responsible for antifungal activity of Cyrmenins. The short model, Ac-ΔSer(Me)-OMe, was analyzed considering the geometrical isomer Z (1) and E (2). The Ramachandran diagrams were created for both isomers, using quantum chemical calculations, to show possible conformations for isolated molecules (in vacuo), in weakly polar (chloroform) and polar (water) environments. The Ac-(Z)-ΔSer(Me)-OMe (1) was synthesized and the single-crystal X-ray diffraction analysis together with FT-IR spectra were performed. The detailed analysis of the conformations of the (Z)-ΔSer(Me) residue is presented considering the intra- and intermolecular interactions as well as their influence on the β-methoxyacrylate part. It is concluded that the β-methoxyacrylate structural motif is able to maintain a planar geometry, crucial for biological activity, regardless of the conformation adopted by O-methyldehydroserine. Full article