Studies on propafenone-type modulators of multidrug resistance III: Variations on the nitrogen

Abstract

A series of piperazine- and piperidine-analogous propafenone derivatives was synthesized and tested for their ability to modulate PGP-mediated multidrug resistance. A good correlation between lipophilicity and activity was obtained for a set of 13 compounds. Nevertheless, 4-hydroxy-4-phenylpiperidines 4a-d generally showed higher activity than predicted. A QSAR equation for the complete set of compounds was obtained when using both lipophilicity and an indicator variable for compounds 4a-d (I = 1; else I = 0) or H-bond donor strength of the 4-hydroxy group (r2(cv) = 0.90; n = 17). Synthesis of aniline derivatives demonstrated that the propanolamine nitrogen interacts in protonated form. Studies on a series of diphenylalkylamines indicate, that steric factors also seem to play a role for the interaction of the nitrogen with PGP.