The Spatial Structure of Macroheterocyclic Compounds, as a Key Factor Affecting the Course of the Macrocyclization Reaction

Belov, Konstantin V.; Eremeev, Ilya Е.; Sobornova, V.V.; Клочков, В. В.; Khodov, Ilya A.

doi:10.6060/mhc200388k

Cited by 8 publications

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“…Using the isolated spin-pair approximation (ISPA) model [ 39 , 77 , 78 ] (see Equation (4)), we obtained the values of the NH-H7 distances for the FFA system in DMSO-d 6 to be 2.75 ± 0.03 Å and 3.10 ± 0.07 Å for FFA in the SC-CO 2 medium with a small addition of DMSO-d 6 :

where r 0 is the reference distance obtained from experimental XRD analysis data, σ 0 is the cross-relaxation rate for the reference distance, σ exp is the cross-relaxation rate for the distance to be found, r exp is the internuclear distance obtained from the NOESY experiment.…”

Section: Resultsmentioning

confidence: 99%

Investigation of the Spatial Structure of Flufenamic Acid in Supercritical Carbon Dioxide Media via 2D NOESY

et al. 2023

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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.

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Section: Resultsmentioning

confidence: 99%

Investigation of the Spatial Structure of Flufenamic Acid in Supercritical Carbon Dioxide Media via 2D NOESY

et al. 2023

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“…where σ ij is the cross-relaxation rate between nuclei i and j, and r ij is the distance between them. Having known one fixed internuclear distance, we determined all other distance values using the ISPA model [29,54,62] (see Equation (4) below).…”

Section: An Analysis Of Structure Of Mfamentioning

confidence: 99%

The Role of Hidden Conformers in Determination of Conformational Preferences of Mefenamic Acid by NOESY Spectroscopy

et al. 2022

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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.

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Spatial structure and conformations of hydrazones derived from pyridoxal 5′-phosphate and 2-, 3-pyridinecarbohydrazide in the light of NMR study and quantum chemical calculations

Khodov

Belov

Pogonin

et al. 2021

Journal of Molecular Liquids

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The Spatial Structure of Macroheterocyclic Compounds, as a Key Factor Affecting the Course of the Macrocyclization Reaction

Cited by 8 publications

References 0 publications

Investigation of the Spatial Structure of Flufenamic Acid in Supercritical Carbon Dioxide Media via 2D NOESY

Investigation of the Spatial Structure of Flufenamic Acid in Supercritical Carbon Dioxide Media via 2D NOESY

The Role of Hidden Conformers in Determination of Conformational Preferences of Mefenamic Acid by NOESY Spectroscopy

Spatial structure and conformations of hydrazones derived from pyridoxal 5′-phosphate and 2-, 3-pyridinecarbohydrazide in the light of NMR study and quantum chemical calculations

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