Search Results (28)

The control of crystal form in chiral active pharmaceutical ingredients (APIs) is a critical challenge in pharmaceutical development, as differences in solid-state structure can significantly influence physical properties and manufacturing performance. Troglitazone, a molecule with two chiral centers, exists as four stereoisomers (RR, SS, RS, SR) that crystallize as two enantiomeric pairs: RR/SS and RS/SR. This study aims to elucidate the relationship between solution-state molecular interactions and crystallization behavior of these diastereomeric pairs. Antisolvent crystallization experiments were conducted for both mixed solutions containing all four isomers and solutions of individual pairs. Crystallization kinetics were monitored by HPLC, and the resulting solids were characterized by PXRD, DSC, TG, and microscopic observation. Nucleation induction times were determined over a range of supersaturation levels. To probe intermolecular interactions in solution, NOESY and targeted NOE NMR experiments were performed, and the results were compared with crystallographic data. The RS/SR crystals(H-form) consistently exhibited shorter induction times and faster crystallization rates than the RR/SS crystals (L-form), even under conditions where RR/SS solutions were more supersaturated. In mixed solutions, H-form crystallized preferentially, with L-form either remaining in solution or being incorporated into H-form crystals as a solid solution. NOESY and NOE analyses revealed intermolecular proximities between protons that are distant in the molecular structure, indicating the presence of ordered aggregates in solution. These aggregates were more structurally compatible with the H-form than with the L-form crystal lattice, as supported by crystallographic distance analysis. The results demonstrate that differences in nucleation kinetics between troglitazone diastereomers are closely linked to solution-state molecular arrangements. Understanding these relationships provides a molecular-level basis for the rational design of selective crystallization processes for chiral APIs. Full article

This article explores the connection between habits and the performing arts, arguing that habits are not only fundamental to the practice and appreciation of these arts but also inherently performative in nature. Drawing on insights from various philosophical traditions (including cognitive science, pragmatism, and phenomenology), it examines how habits function within artistic processes as resources for creativity and adaptation. Engaging critically with Noë’s interpretation of the entanglement between art and life, this article highlights the dual nature of habits: as routine practices that scaffold artistic expression and as dynamic, transformative elements responsive to specific cultural and performative contexts. By focusing on key notions such as gesture, style, and rituality in the performing arts, this article discusses the role of habits in aesthetic experiences, highlighting how habits shape both artistic performances and audience engagement. This perspective challenges traditional views that oppose habits to creativity, defending instead the idea that habits are creatively operative in both the performing arts and their reception. Full article

Background and Objectives: A novel antitubercular cyclic peptide, Cyclo(1,6)-Ac-CLYHFC-NH₂, was designed to bind at the rifampicin (RIF) binding site on the RNA polymerase (RNAP) of Mycobacterium tuberculosis (MTB). This peptide inhibits RNA elongation in the MTB transcription initiation assay in the nanomolar range, which can halt the MTB transcription initiation complex, similar to RIF. Therefore, determining the solution conformation of this peptide is useful in improving the peptide’s binding affinity to the RNAP. Methods: Here, the solution structure of Cyclo(1,6)-Ac-CLYHFC-NH₂ was determined by two-dimensional (2D) NMR experiments and NMR-restrained molecular dynamic (MD) simulations. Results: All protons of Cyclo(1,6)-Ac-CLYHFC-NH₂ were assigned using TOCSY and NOE NMR spectroscopy. The NOE cross-peak intensities were used to calculate interproton distances within the peptide. The J_NH-HCα coupling constants were used to determine the possible Phi angles within the peptide. The interproton distances and calculated Phi angles from NMR were used in NMR-restrained MD simulations. The NOE spectra showed NH-to-NH cross-peaks at Leu2-to-Tyr3 and Tyr3-to-His4, indicating a βI-turn formation at the Cys1-Leu2-Tyr3-His4 sequence. Conclusions: The NMR-restrained MD simulations showed several low-energy conformations that were congruent with the NMR data. Finally, the conformation of this peptide will be used to design derivatives that can better inhibit RNAP activity. Full article

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. Full article

The study presents a thorough and detailed analysis of bicalutamide’s structural and conformational properties. Quantum chemical calculations were employed to explore the conformational properties of the molecule, identifying significant energy differences between conformers. Analysis revealed that hydrogen bonds stabilise the conformers, with notable variations in torsion angles. Conformers were classified into ‘closed’ and ‘open’ types based on the relative orientation of the cyclic fragments. NOE spectroscopy in different solvents (CDCl₃ and DMSO-d₆) was used to study the conformational preferences of the molecule. NOESY experiments provided the predominance of ‘closed’ conformers in non-polar solvents and a significant presence of ‘open’ conformers in polar solvents. The proportions of open conformers were 22.7 ± 3.7% in CDCl₃ and 59.8 ± 6.2% in DMSO-d₆, while closed conformers accounted for 77.3 ± 3.7% and 40.2 ± 6.2%, respectively. This comprehensive study underscores the solvent environment’s impact on its structural behaviour. The findings significantly contribute to a deeper understanding of conformational dynamics, stimulating further exploration in drug development. Full article

The design and synthesis of analogs of natural products can be a valuable source of medicinal preparations for the pharmaceutical industry. In the present study, the structural elucidation of eleven derivatives of 2,4-dihalogeno substituted synthetic analogues of the natural compound carvacrol was carried out by means of NMR experiments, and of another thirteen by DFT calculations. By selective NOE experiments and the irradiation of CH signals of the isopropyl group, individual conformers were assigned as syn and anti. By comparing GIAO/B3LYP/6-311++G(d,p)-calculated and experimentally measured vicinal ³J_CH spin-spin constants, this assignment was confirmed. An unusual relationship is reported for proton-carbon vicinal couplings: ³J_CH (180°) < ³J_CH (0°). The conformational mobility of carvacrols was studied by 2D EXSY spectra. The application of homonuclear decoupling technique (HOBS) to these spectra simplifies the spectra, improves resolution without reducing the sensitivity, and allows a systematic examination of the rotational barrier of all compounds via their CH signals of the isopropyl group in a wider temperature interval. The rate constants of the isopropyl rotation between syn and anti conformers were determined and the corresponding energy barriers (14–17 kcal/mol) were calculated. DFT calculations of the energy barriers in carvacrol derivatives allowed the determination of the steric origin of the restricted isopropyl rotation. The barrier height depends on the size of the 2- and 4-position substituents, and is independent of the derivatization of the OH group. Full article

Molecular structures, in chloroform and DMSO solution, of the free fatty acids (FFAs) caproleic acid, oleic acid, α-linolenic acid, eicosapentanoic acid (EPA) and docosahexaenoic acid (DHA) are reported with the combined use of NMR and DFT calculations. Variable temperature and concentration chemical shifts of the COOH protons, transient 1D NOE experiments and DFT calculations demonstrate the major contribution of low molecular weight aggregates of dimerized fatty acids through intermolecular hydrogen bond interactions of the carboxylic groups, with parallel and antiparallel interdigitated structures even at the low concentration of 20 mM in CDCl₃. For the dimeric DHA, a structural model of an intermolecular hydrogen bond through carboxylic groups and an intermolecular hydrogen bond between the carboxylic group of one molecule and the ω-3 double bond of a second molecule is shown to play a role. In DMSO-d₆ solution, NMR and DFT studies show that the carboxylic groups form strong intermolecular hydrogen bond interactions with a single discrete solvation molecule of DMSO. These solvation species form parallel and antiparallel interdigitated structures of low molecular weight, as in chloroform solution. This structural motif, therefore, is an intrinsic property of the FFAs, which is not strongly affected by the length and degree of unsaturation of the chain and the hydrogen bond ability of the solvent. Full article

Combined inoculation of legumes with rhizobia and plant growth-promoting rhizobacteria or endophytes is a known technique for increasing the efficiency of nitrogen-fixing symbiosis and plant productivity. The aim of this work was to expand knowledge about the synergistic effects between commercial rhizobia of pasture legumes and root nodule bacteria of relict legume species. Pot experiments were performed on common vetch (Vicia sativa L.) and red clover (Trifolium pratense L.) co-inoculated with the participation of the corresponding commercial rhizobial strains (R. leguminosarum bv. viciae RCAM0626 and R. leguminosarum bv. trifolii RCAM1365) and seven strains isolated from nodules of relict legumes inhabiting the Baikal Lake region and the Altai Republic: Oxytropis popoviana, Astragalus chorinensis, O. tragacanthoides and Vicia costata. The inoculation of plants with combinations of strains (commercial strain plus the isolate from relict legume) had a different effect on symbiosis depending on the plant species: the increase in the number of nodules was mainly observed on vetch, whereas increased acetylene reduction activity was evident on clover. It was shown that the relict isolates differ significantly in the set of genes related to different genetic systems that affect plant–microbe interactions. At the same time, they had additional genes that are involved in the formation of symbiosis and determine its effectiveness, but are absent in the used commercial strains: symbiotic genes fix, nif, nod, noe and nol, as well as genes associated with the hormonal status of the plant and the processes of symbiogenesis (acdRS, genes for gibberellins and auxins biosynthesis, genes of T3SS, T4SS and T6SS secretion systems). It can be expected that the accumulation of knowledge about microbial synergy on the example of the joint use of commercial and relict rhizobia will allow in the future the development of methods for the targeted selection of co-microsymbionts to increase the efficiency of agricultural legume–rhizobia systems. Full article

Artemisinin is known to bind to the main plasma protein carrier serum albumin (SA); however, there are no atomic level structural data regarding its binding mode with serum albumin. Herein, we employed a combined strategy of saturation transfer difference (STD), transfer nuclear Overhauser effect spectroscopy (TR-NOESY), STD–total correlation spectroscopy (STD-TOCSY), and Interligand Noes for PHArmacophore Mapping (INPHARMA) NMR methods and molecular docking calculations to investigate the structural basis of the interaction of artemisinin with human and bovine serum albumin (HSA/BSA). A significant number of inter-ligand NOEs between artemisinin and the drugs warfarin and ibuprofen as well as docking calculations were interpreted in terms of competitive binding modes of artemisinin in the warfarin (FA7) and ibuprofen (FA4) binding sites. STD NMR experiments demonstrate that artemisinin is the main analyte for the interaction of the A. annua extract with BSA. The combined strategy of NMR and docking calculations of the present work could be of general interest in the identification of the molecular basis of the interactions of natural products with their receptors even within a complex crude extract. Full article

The aqueous dissolution profile of the isomeric synthetic adamantane phenylalkylamine hydrochlorides I and II was probed. These adducts have shown significant antiproliferative/anticancer activity associated with an analgesic profile against neuropathic pain. They are both devoid of toxic effects and show appreciable enzymatic human plasma stability. The structures of these two compounds have been elucidated using 2D NMR experiments, which were used to study their predominant conformations. Compound II’s scaffold appeared more flexible, as shown by the NOE spatial interactions between the alkyl bridge chain, the aromatic rings, and the adamantane nucleus. Conversely, compound I appeared very rigid, as it did not share significant NOEs between the aforementioned structural segments. MD simulations confirmed the NOE results. The aqueous dissolution profile of both molecules fits well with their minimum energy conformers’ features, which stem from the NOE data; this was nicely demonstrated, especially in the case of compound II. Full article

A framework for the stochastic description of relaxation processes in flexible macromolecules including dissipative effects has been recently introduced, starting from an atomistic view, describing the joint relaxation of internal coordinates and global degrees of freedom, and depending on parameters recoverable from classic force fields (energetics) and medium modelling at the continuum level (friction tensors). The new approach provides a rational context for the interpretation of magnetic resonance relaxation experiments. In its simplest formulation, the semi-flexible Brownian (SFB) model has been until now shown to reproduce correctly correlation functions and spectral densities related to orientational properties obtained by direct molecular dynamics simulations of peptides. Here, for the first time, we applied directly the SFB approach to the practical evaluation of high-quality ¹³C nuclear magnetic resonance relaxation parameters, $T_1$ and $T_2$, and the heteronuclear NOE of several oligosaccharides, which were previously interpreted on the basis of refined ad hoc modelling. The calculated NMR relaxation parameters were in agreement with the experimental data, showing that this general approach can be applied to diverse classes of molecular systems, with the minimal usage of adjustable parameters. Full article

Efforts to use traditional native tissue strategies and reduce the use of meshes have been made in several countries. Combining native tissue repair with sufficient mesh applied apical repair might provide a means of effective treatment. The study group did perform and publish a randomized trial focusing on the combination of traditional native tissue repair with pectopexy or sacrocolpopexy and observed no severe or hitherto unknown risks for patients (Noé G.K. J Endourol 2015;29(2):210–215). The short-term follow-up of this international multicenter study carried out now is presented in this article. Material and Methods: Eleven clinics and 13 surgeons in four European counties participated in the trial. In order to ensure a standardized approach and obtain comparable data, all surgeons were obliged to follow a standardized approach for pectopexy, focusing on the area of fixation and the use of a prefabricated mesh (PVDF PRP 3 × 15 Dynamesh). The mesh was solely used for apical repair. All other clinically relevant defects were treated with native tissue repair. Colposuspension or TVT were used for the treatment of incontinence. Data were collected independently for 14 months on a secured server; 501 surgeries were registered and evaluated. Two hundred and sixty-four patients out of 479 (55.1%) returned for the physical examination and interview after 12–18 months. Main Outcome and Results: The mean duration of follow-up was 15 months. The overall success of apical repair was rated positively by 96.9%, and the satisfaction score was rated positively by 95.5%. A positive general recommendation was expressed by 95.1% of patients. Pelvic pressure was reduced in 95.2%, pain in 98.0%, and urgency in 86.0% of patients. No major complications, mesh exposure, or mesh complication occurred during the follow-up period. Conclusion: In clinical routine, pectopexy and concomitant surgery, mainly using native tissue approaches, resulted in high satisfaction rates and favorable clinical findings. The procedure may also be recommended for use by general urogynecological practitioners with experience in laparoscopy. Full article

How sequences of intrinsically disordered proteins (IDPs) code for their conformational dynamics is poorly understood. Here, we combined NMR spectroscopy, small-angle X-ray scattering (SAXS), and molecular dynamics (MD) simulations to characterize the conformations and dynamics of ChiZ1-64. MD simulations, first validated by SAXS and secondary chemical shift data, found scant α-helices or β-strands but a considerable propensity for polyproline II (PPII) torsion angles. Importantly, several blocks of residues (e.g., 11–29) emerge as “correlated segments”, identified by their frequent formation of PPII stretches, salt bridges, cation-π interactions, and sidechain-backbone hydrogen bonds. NMR relaxation experiments showed non-uniform transverse relaxation rates (R₂s) and nuclear Overhauser enhancements (NOEs) along the sequence (e.g., high R₂s and NOEs for residues 11–14 and 23–28). MD simulations further revealed that the extent of segmental correlation is sequence-dependent; segments where internal interactions are more prevalent manifest elevated “collective” motions on the 5–10 ns timescale and suppressed local motions on the sub-ns timescale. Amide proton exchange rates provides corroboration, with residues in the most correlated segment exhibiting the highest protection factors. We propose the correlated segment as a defining feature for the conformations and dynamics of IDPs. Full article

The asymmetric synthesis of a compound with the cyclopentan[c]pyran core of iridoid natural products in four steps and 40% overall yield is reported. Our methodology includes a one-pot tandem domino reaction which provides a trisubstituted cyclopentane with five new completely determined stereocenters, which were determined through 2D homo and heteronuclear NMR and n.O.e. experiments on different compounds specially designed for this purpose, such as a dioxane obtained from a diol. Due to their pharmaceutical properties, including sedative, analgesic, anti-inflammatory, CNS depressor or anti-conceptive effects, this methodology to produce the abovementioned iridoid derivatives, is an interesting strategy in terms of new drug discovery as well as pharmaceutical development. Full article

A series of disubstituted 1H-pyrazoles with methyl (1), amino (2), and nitro (3) groups, as well as ester (a) or amide (b) groups in positions 3 and 5 was synthesized, and annular tautomerism was investigated using X-ray, theoretical calculations, NMR, and FT-IR methods. The X-ray experiment in the crystal state showed for the compounds with methyl (1a, 1b) and amino (2b) groups the tautomer with ester or amide groups at position 3 (tautomer 3), but for those with a nitro group (3b, 4), tautomer 5. Similar results were obtained in solution by NMR NOE experiments in CDCl₃, DMSO-d₆, and CD₃OD solvents. However, tautomer equilibrium was observed for 2b in DMSO. The FT-IR spectra in chloroform and acetonitrile showed equilibria, which can be ascribed to conformational changes of the cis/trans arrangement of the ester/amide group and pyrazole ring. Theoretical analysis using the M06-2X/6-311++G(d,p) method (in vacuo, chloroform, acetonitrile, and water) and measurement of aromaticity (NICS) showed dependence on internal hydrogen bonds, the influence of the environment, and the effect of the substituent. These factors, pyrazole aromaticity and intra- and inter-molecular interactions, seem to have a considerable influence on the choice of tautomer. Full article