STUDIES ON PROPAFENONE-TYPE MODULATORS OF MULTIDRUG-RESISTANCE-IV - SYNTHESIS AND PHARMACOLOGICAL ACTIVITY OF 5-HYDROXY AND 5-BENZYLOXY DERIVATIVES

A series of 5-hydroxy and 5-benzyloxy analogs of the antiarrhythmic an d multidrug resistance (MDR) modulating drug propafenone was synthesiz ed and the MDR-modulating activity of the compounds was evaluated usin g a daunomycin efflux assay system. The key step of the synthesis is t he selective reduction of the double bond in 1 without cleavage of the benzyl group thus leading to the phenol 3. Alkylation with epichloroh ydrine followed by nucleophilic epoxide ring opening gave the benzylat ed target compounds 5a-d. Subsequent cleavage of the benzyl group gave the 5-hydroxy analogs 6a-d. Structure activity relationship studies s howed, that the 5-hydroxy derivates 6a-d fit the log P/log potency cor relation line previously established for a series of propafenone analo gs. In contrast, all four 5-benzyloxy analogs 5a-d showed almost ident ical EC50 values, independent of their log P value.