Conformational State of Fenamates at the Membrane Interface: A MAS NOESY Study

Abstract

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.

Conformational Analysis of 1,5-Diaryl-3-Oxo-1,4-Pentadiene Derivatives: A Nuclear Overhauser Effect Spectroscopy Investigation

“…Here, structural analysis is performed based on NMR results in CDCl 3 . Prior research [28,68,69] has emphasized that the conformation of active pharmaceutical ingredient (API) molecules can profoundly influence membrane structure and domain dynamics. Consequently, variations in API conformations may lead to distinct interactions with the cell membrane and result in differing pharmaceutical effects.…”

“…This knowledge is essential for the strategic development and execution of synthesizing novel chemicals and altering pre-existing ones. Furthermore, as elucidated in the article by Scheidt et al [28], the configuration of a molecule can have a crucial impact on its ability to attach to the target molecule, thereby influencing its biological functionality. Nevertheless, investigating 1,5-diaryl-3-oxo-1,4pentadiene derivatives necessitates a unique technique due to the molecule's inherent conformational instability, leading to numerous conformers.…”