Potentiometric and spectroscopic studies on the solution molecular structures of copper(II)-[S]-2-[N-(2′-hydroxybenzyl)aminomethyl]pyrrolidine complexes, potential non-steroidal anti-inflammatory agents (NSAIDs)

The purpose of this study was to investigate the complexes formed by copper(II) with potential non-steroidal anti-inflammatory agents (NSAIDs) under physiological conditions. A former study suggested that 2-benzylaminomethylpyrrolidine ligands could be good candidates as potential OIL (OH-inactivating ligand) when complexed to copper(II). In order to assess the chemical behavior as OIL, [S]-2-[N-(2′-hydroxybenzyl)aminomethyl]pyrrolidine (OHbamp) was synthesized and bound to copper(II). Physico-chemical properties were determined at 37 °C in 0.15 M NaCl using glass electrode potentiometry, UV–Vis and circular dichroism spectroscopies, before and after copper(II) complexation. [Cu(OHbamp)(H2O)3]+ was the main complex found at both physiological and inflammatory pH values, showing appreciable stability at pathological pH compared to copper(II) complexes of histidine, the predominant low-molar-mass ligand of copper(II) in blood plasma. However, neutral species such as [Cu(OHbamp)2(H2O)2] and [Cu(OHbamp)(OH)(H2O)3] are predominant only above pH 8, preventing a significant amount of drug from diffusing through membranes at inflammatory pH. In conclusion, copper(II)-OHbamp system does not meet all the requirements to be an OIL. Nevertheless, these results allow us to better identify the chemical features needed for a good OIL candidate.

Graphical abstractA former study has suggested that 2-benzylaminomethylpyrrolidine ligands, when complexed to copper(II), could act as potential non-steroidal anti-inflammatory agents (NSAIDs). In order to assess the chemical behavior as potential OIL (OH-inactivating ligand), [S]-2-[N-(2′-hydroxybenzyl)-aminomethyl]pyrrolidine (OHbamp) was synthesized and bound to copper(II). Potentiometry, UV–Vis and circular dichroism spectroscopies allow to identify the solution molecular structures of its copper(II) complexes. [Cu(OHbamp)(H2O)3]+ was the main complex found at both physiological and inflammatory pH values, whereas neutral species, such as [Cu(OHbamp)2(H2O)2] and [Cu(OHbamp)(OH)(H2O)3], were predominant only above pH 8.Figure optionsDownload full-size imageDownload as PowerPoint slide