Chromatographic Retention of Naproxen-Based Thiourea Derivatives in a Micellar System as a Predictor of Passive Gastrointestinal Absorption

Experimental assessment of passive gastrointestinal absorption is essential in early drug profiling. Biopartitioning micellar chromatography (BMC), a modified micellar liquid chromatography technique employing nonionic surfactants above the critical micellar concentration, enables indirect assessment of passive permeability by reflecting solute distribution among the stationary, aqueous, and micellar phases. BMC was employed to investigate the retention behavior and biorelevant properties of seven newly synthesized naproxen-based thiourea derivatives under biomimetic conditions mimicking biological membranes. Chromatographic experiments were performed using Brij 35 as a nonionic surfactant. To further elucidate structure-retention relationships, quantitative structure-retention relationship (QSRR) analysis was conducted using multiple linear regression. The results demonstrated pronounced differences in retention behavior among the tested compounds, primarily governed by their structural features. Derivatives containing esterified aromatic amino acids exhibited the highest retention factors, suggesting enhanced passive gastrointestinal absorption, whereas the p-aminoacetophenone derivative showed the lowest retention and absorption potential. A statistically significant model was obtained with the Mor20u descriptor, achieving high correlation (R = 0.977) between the experimental retention factor (k) values and those predicted by the MLR model. The selected 3D-MoRSE descriptor effectively captured the influence of molecular polarizability and aromaticity on retention behavior. However, these findings should be interpreted with caution given that the analysis was based on a limited dataset comprising only seven compounds. Overall, the combined BMC and QSRR approach provides valuable insights into the biopharmaceutical properties of naproxen-based thiourea derivatives and identified structural features associated with favorable passive gastrointestinal absorption.