Integrative lipophilicity assessment and pharmacokinetic correlation of pyrimidine precursors and artesunate-pyrimidine hybrids: development of QSAR models for anticancer activity and interaction with -glycoprotein.

[AIMS] To evaluate chromatographic lipophilicity of novel artesunate-pyrimidine hybrids and precursors using reversed-phase thin-layer chromatography (RP-TLC) and assess plasma protein binding (PPB). The impact of measured and predicted lipophilicity on pharmacokinetic descriptors was evaluated. Principal component analysis (PCA) explored relationships among lipophilicity, PPB, and physicochemical descriptors. Quantitative structure-activity relationship (QSAR) and partial least squares (PLS) models linked molecular descriptors to cytotoxicity and resistance modulation in nonsmall cell lung cancer (NSCLC) cells.

[MATERIALS AND METHODS] Lipophilicity was measured by RP-TLC. PPB was determined using human serum albumin (HSA)-modified high-performance liquid chromatography (HPLC). PCA characterized physicochemical-pharmacokinetic correlations. Cytotoxicity in sensitive NCI-H460 and multidrug-resistant (MDR) NCI-H460/R cells was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. QSAR and PLS models identified key descriptors.

[RESULTS] Lipophilicity strongly influenced adsorption, distribution, and protein binding. Highly lipophilic hybrids showed near-complete HSA binding. Compound 2k lost cytotoxicity in the presence of albumin, whereas 4k retained potency. Models indicated steric and electronic features, alongside lipophilicity, dictate efficacy and -glycoprotein (-gp) interactions, particularly in resistant cells.

[CONCLUSIONS] Lipophilicity and steric/electronic descriptors govern distribution, protein binding, and anticancer activity. Integrating these features enables design of hybrids overcoming -gp-mediated multidrug resistance, with hybrid 4k emerging as a promising candidate.