Oseltamivir-Based Organic Salts and Ionic Liquids: Physicochemical Properties, Cytotoxicity, and Neuraminidase Inhibition

Background: Neuraminidase (NA) inhibitors are widely used for the treatment of influenza, but the emergence of resistance and limitations in drug formulation can compromise their therapeutic performance. This study investigated whether counterion exchange can modulate the physicochemical properties, cytotoxicity, and NA-inhibitory activity of oseltamivir (OS) while preserving its covalent structure. Methods: Five OS-based ionic formulations, [OS][C1SO3], [OS][C3SO3], [OS][C6SO3], [OS][TolSO3], and [OS][CSA], were synthesized and characterized by NMR and ATR-FTIR spectroscopy, with isolated yields ranging from 84 to 88%. Spectroscopic data confirmed the formation of the desired 1:1 salts and showed that the OS ethyl ester remained chemically intact. The formulations were evaluated for aqueous solubility, octanol/water partitioning, cytotoxicity toward MDCK-SIAT1 cells, and NA-inhibitory activity using a MUNANA-based assay against NAs from A(H1N1)pdm09, its H275Y oseltamivir-resistant variant, A(H3N2), and type B influenza viruses. Results: All formulations exhibited low cytotoxicity, with CC50 values above 1200 µM. All OS ionic formulations showed lower IC50 values than oseltamivir phosphate against all four influenza viruses, with improvements ranging from approximately 2.5- to 393-fold. [OS][TolSO3] showed the highest potency, reducing the IC50 by approximately 336-fold against H275Y virus NA and 393-fold against influenza B virus NA. IC90 values showed the same overall potency ranking, although improvements at 50% inhibition were not always proportionally maintained at 90% inhibition. Conclusions: Overall, counterion selection substantially influenced both the physicochemical and biological profiles of OS. [OS][TolSO3] provided the highest NA-inhibitory potency, whereas [OS][CSA] exhibited the most balanced overall profile, supporting counterion engineering as a potential approach to optimize oseltamivir-based ionic formulations.