Modulation of the binding affinity of naproxen to bovine serum albumin by conversion of the drug into amino acid ester salts

• Published in: Journal of molecular liquids Vol. 319; p. 114283
• Main Authors: Ossowicz, Paula, Janus, Ewa, Klebeko, Joanna, Światek, Ewelina, Kardaleva, Proletina, Taneva, Stefka, Krachmarova, Elena, Rangelov, Miroslav, Todorova, Nadezhda, Guncheva, Maya
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.12.2020
• Subjects: Albumin; Binding affinity; Ionic liquids; Isothermal titration calorimetry; Molecular docking; Naproxen derivatives; Ionic liquids; Albumin; Binding affinity; Isothermal titration calorimetry; Naproxen derivatives; Molecular docking
• ISSN: 0167-7322; 1873-3166
• DOI: 10.1016/j.molliq.2020.114283

Naproxen (NAP) is one of the most widely prescribed non-steroidal anti-inflammatory drugs. Novel formulations of NAP aiming at better water-solubility, dosage, and the onset of action or new routes of application in order to minimize or prevent side effects of NAP are in the current interest of the pharmaceutical industry. Here, we report the synthesis, chemical, spectral and physicochemical characterization of a series of salts containing cations amino acid alkyl esters (AAE) and NAP anion, which potentially can be used as novel drug formulation. The [l-AAE][NAP] were obtained in three steps: preparation of the AAE hydrochlorides, neutralization of the hydrochlorides to the corresponding AAE, and formation of the target organic salts. All NAP derivatives, tested at a concentration as high as 100 μM, exhibited no toxicity against murine macrophage cell line (RAW 264.7). The binding parameters and stoichiometry of [AAE][NAP]s to bovine serum albumin (BSA) are in the range of that estimated for the parent NAP. Only l-valine isopropyl ester naproxenate characterizes with about one order of magnitude lower binding affinity for BSA, which suggests a faster diffusion rate in the circulatory system than the parent NAP and other derivatives, and therefore faster reach to the target system. Using molecular modeling seven binding pockets of BSA were probed for their suitability to binds the cation and the anion and results are discussed in correlation with the obtained thermodynamic parameters for the binding of NAP derivatives to BSA. [Display omitted] •Five novel naproxen-based amino acid ester salts were synthesized and characterized.•They are not toxic to murine macrophages tested in concentrations up to 100 μM.•The binding constants to bovine albumin is in a range of 3.5 × 106 to 1.5 × 107 M−1.•Four binding sites in bovine albumin are suitable for the cation and the anion.