STUDIES ON PROPAFENONE-TYPE MODULATORS OF MULTIDRUG-RESISTANCE III - VARIATIONS ON THE NITROGEN

A series of piperazine- and piperidine-analogous propafenone derivativ es was synthesized and tested for their ability to modulate PGP-mediat ed multidrug resistance. A good correlation between lipophilicity and activity was obtained for a set of 13 compounds. Nevertheless, 4-hydro xy-4-phenylpiperidines 4a-d generally showed higher activity than pred icted. 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 ( r(cv)(2)=0.90; n=17). Synthesis of aniline derivatives demonstrated th at the propanolamine nitrogen interacts in protonated form. Studies on a series of diphenylalkylamines indicate, that steric factors also se em to play a role for the interaction of the nitrogen with PGP.