ABSTRACT
1,5-Diaryl-3-Oxo-1,4-Pentadiene derivatives are intriguing organic compounds with a unique structure featuring a pentadiene core, aryl groups, and a ketone group. This study investigates the influence of fluorine atoms on the conformational features of these derivatives in deuterated chloroform (CDCl3) solution. Through nuclear magnetic resonance (NMR) spectroscopy and quantum chemical calculations, we discerned variations in interatomic distances and established predominant conformer proportions. The findings suggest that the non-fluorinated entity exhibits a uniform distribution across various conformer groups. The introduction of a fluorine atom induces substantial alterations, resulting in the predominance of a specific conformer group. This structural insight may hold the key to their diverse anticancer activities, previously reported in the literature.
Subject(s)
Alkadienes , Fluorine , Fluorine/chemistry , Molecular Conformation , Magnetic Resonance Spectroscopy/methodsABSTRACT
The present work analyzes the 1H NOESY MAS NMR spectra of three fenamates (mefenamic, tolfenamic, and flufenamic acids) localized in the lipid-water interface of phosphatidyloleoylphosphatidylcholine (POPC) membranes. The observed cross-peaks in the two-dimensional NMR spectra characterized intramolecular proximities between the hydrogen atoms of the fenamates as well as intermolecular interactions between the fenamates and POPC molecules. The peak amplitude normalization for an improved cross-relaxation (PANIC) approach, the isolated spin-pair approximation (ISPA) model, and the two-position exchange model were used to calculate the interproton distances indicative of specific conformations of the fenamates. The results showed that the proportions of the A+C and B+D conformer groups of mefenamic and tolfenamic acids in the presence of POPC were comparable within the experimental error and amounted to 47.8%/52.2% and 47.7%/52.3%, respectively. In contrast, these proportions for the flufenamic acid conformers differed and amounted to 56.6%/43.4%. This allowed us to conclude that when they bind to the POPC model lipid membrane, fenamate molecules change their conformational equilibria.
ABSTRACT
This study examines the influence of mefenamic acid on the physical and chemical properties of silica aerogels, as well as its effect on the sorption characteristics of the composite material. Solid state magic angle spinning nuclear magnetic resonance (MAS NMR) and high-pressure 13C NMR kinetic studies were conducted to identify the presence of mefenamic acid and measure the kinetic rates of CO2 sorption. Additionally, a high-pressure T1-T2 relaxation-relaxation correlation spectroscopy (RRCOSY) study was conducted to estimate the relative amount of mefenamic acid in the aerogel's pores, and a high-pressure nuclear Overhauser effect spectoscopy (NOESY) study was conducted to investigate the conformational preference of mefenamic acid released from the aerogel. The results indicate that mefenamic acid is affected by the chemical environment of the aerogel, altering the ratio of mefenamic acid conformers from 75% to 25% in its absence to 22% to 78% in the presence of aerogel.
Subject(s)
Mefenamic Acid , Silicon Dioxide , Kinetics , Magnetic Resonance Spectroscopy/methods , Magnetic Resonance ImagingABSTRACT
The experimental and theoretical study of influence of the conformational state and association on the chirality of the stereochemically nonrigid biologically active bis-camphorolidenpropylenediamine (CPDA) and its ability to induce the helical mesophase of alkoxycyanobiphenyls liquid-crystalline binary mixture was carried out. On the basis of quantum-chemical simulation of the CPDA structure, four relatively stable conformers were detected. A comparison of the calculated and experimental electronic circular dichroism (ECD) and 1H, 13C, 15N NMR spectra, as well as specific optical rotation and dipole moments, allowed to establish the most probable trans-gauche conformational state (tg) of dicamphorodiimine and CPDA dimer with a predominantly mutually parallel arrangement of molecular dipoles. The induction of helical phases in LC mixtures based on cyanobiphenyls and bis-camphorolidenpropylenediamine was studied by polarization microscopy. The clearance temperatures and the helix pitch of the mesophases were measured. The helical twisting power (HTP) was calculated. The decrease in HTP with increasing dopant concentration was shown to be connected with the CPDA association process in the LC phase. The effect of camphor-containing chiral dopants of various structures on nematic LCs was compared. The values of the permittivity and birefringence components of the CPDA solutions in CB-2 were measured experimentally. A strong effect of this dopant on the anisotropic physical properties of the induced chiral nematic was established. A significant decrease in the dielectric anisotropy was associated with the 3D compensation of the LC dipoles during the formation of the helix.
ABSTRACT
The search for new forms of already known drug compounds is an urgent problem of high relevance as more potent drugs with fewer side effects are needed. The trifluoromethyl group in flufenamic acid renders its chemical structure differently from other fenamates. This modification is responsible for a large number of conformational polymorphs. Therefore, flufenamic acid is a promising structural modification of well-known drug molecules. An effective approach in this field is micronization, employing "green" supercritical fluid technologies. This research raises some key questions to be answered on how to control polymorphic forms during the micronization of drug compounds. The results presented in this work demonstrate the ability of two-dimensional nuclear Overhauser effect spectroscopy to determine conformational preferences of small molecular weight drug compounds in solutions and fluids, which can be used to predict the polymorphic form during the micronization. Quantitative analysis was carried out to identify the conformational preferences of flufenamic acid molecules in dimethyl sulfoxide-d6 medium at 25 °C and 0.1 MPa, and in mixed solvent medium containing supercritical carbon dioxide at 45 °C and 9 MPa. The data presented allows predictions of the flufenamic acid conformational preferences of poorly soluble drug compounds to obtain new micronized forms.
ABSTRACT
Understanding of the nucleation process's fundamental principles in saturated solutions is an urgent task. To do this task, it is necessary to control the formation of polymorphic forms of biologically active compounds. In certain cases, a compound can exist in a single polymorphic form, but have several solvates which can appear in different crystal forms, depending on the medium and conditions of formation, and show different pharmaceutical activity. In the present paper, we report on the analysis of Arbidol conformational preferences in two solvents of different polarities-deuterated chloroform and dimethyl sulfoxide-at 25 °C, using the 2D NOESY method. The Arbidol molecule has various solvate forms depending on the molecular conformation. The method based on the nuclear Overhauser effect spectroscopy was shown to be efficient in the analysis of complex heterocyclic compounds possessing conformation-dependent pseudo-polymorphism. It is one of the types of polymorphism observed in compounds forming crystal solvates. Combined use of NMR methods and X-ray data allowed determining of conformer populations of Arbidol in CDCl3 and DMSO-d6 which were found to be 8/92% and 37/63%, respectively. The preferred conformation in solution is the same that appears in stable crystal solvates of Arbidol.
ABSTRACT
The study of supercritical carbon dioxide sorption processes is an important and urgent task in the field of "green" chemistry and for the selection of conditions for new polymer material formation. However, at the moment, the research of these processes is very limited, and it is necessary to select the methodology for each polymer material separately. In this paper, the principal possibility to study the powder sorption processes using 13C nuclear magnetic resonance spectroscopy, relaxation-relaxation correlation spectroscopy and molecular dynamic modeling methods will be demonstrated based on the example of polymethylmethacrylate and supercritical carbon dioxide. It was found that in the first nanoseconds and seconds during the sorption process, most of the carbon dioxide, about 75%, is sorbed into polymethylmethacrylate, while on the clock scale the remaining 25% is sorbed. The methodology presented in this paper makes it possible to select optimal conditions for technological processes associated with the production of new polymer materials based on supercritical fluids.
ABSTRACT
Mefenamic acid has been used as a non-steroidal anti-inflammatory drug for a long time. However, its practical use is quite limited due to a number of side effects on the intestinal organs. Conformational polymorphism provides mefenamic acid with unique properties regarding possible modifications obtained during the micronization process, which can improve pharmacokinetics and minimize side effects. Micronization can be performed by decompression of supercritical fluids; methods such as rapid expansion of the supercritical solution have proven their efficiency. However, this group of methods is poorly applicable for compounds with low solubility, and the modification of the method using a pharmaceutically suitable co-solvent may be useful. In our case, addition of only 2 mol% dimethyl sulfoxide increased the solubility remarkably. Information on the conformational state may be critically important for carrying out micronization. In this work, structural analysis and estimate of conformational preferences of mefenamic acid in dimethyl sulfoxide-d6 (at 25 °C and 0.1 MPa) and in a mixed solvent supercritical carbon dioxide + dimethyl sulfoxide-d6 (45 °C, 9 MPa) were performed based on nuclear Overhauser effect spectroscopy. Results show changes in the conformation fractions depending on the medium used. The importance of allowing for hidden conformers in estimating the conformational state was demonstrated in the analysis. Obtained results may be useful for improving micronization parameters.
