A COMBINED HANSCH FREE-WILSON APPROACH AS PREDICTIVE TOOL IN QSAR STUDIES ON PROPAFENONE-TYPE MODULATORS OF MULTIDRUG-RESISTANCE/

A series of 48 propafenone-type modulators of multidrug resistance was synthesized and their P-glycoprotein inhibitory activity was measured using the daunomycin efflux assay. Both a Free Wilson and a combined Hansch/Free-Wilson analysis were performed using log P, partial log P and molar refraction values as Hansch descriptors. The results of the Free-Wilson analysis show that modifications on the central aromatic r ing generally influence pharmacological activity, whereby in almost al l cases a decrease in MDR-modulating potency is observed (Q(cv)(2) = 0 .66). The combined approach results in equations with remarkably highe r predictive power (Q(cv)(2) = 0.83), specifically molar refractivity shows : high significance in all equations derived. This indicates tha t polar interactions also contribute to protein binding.