REVERSAL OF MULTIDRUG RESISTANCE BY PHENOTHIAZINES AND STRUCTURALLY RELATED-COMPOUNDS

The multidrug-resistance (MDR)-reversal activity of 232 phenothiazines and structurally related compounds was tested in MDR P388 cells. Such activity was found among compounds exhibiting two ring structures (phenyl, cyclopentyl, cyclohexyl, thienyl or 5-norbornen-2-yl but not pyridinyl) linked by a variety of bridge types and possessing a secondary or tertiary amine group. Among 192 such compounds, 31.8% displayed good activity (MDR-reversal ratio, greater-than-or-equal-to 10) and 8.3%, outstanding activity (MDR-reversal ratio, greater-than-or-equal-to 30). In a subgroup comprising 56 compounds with a carbonyl residue, 4 with sulfuryl residue and 1 with thienyl residue, 42.7% showed good activity and 18%, outstanding activity. The contribution of these residues to the MDR-reversal activity was particularly evident among compounds containing a cyclic tertiary amine. Among 49 such compounds, 51% displayed good activity and 20.4%, outstanding activity, whereas among the 85 compounds lacking such groups, only 31.8% showed good activity and 4.7%, outstanding activity. Enhancement of this activity by the carbonyl group is also obtained when the latter is part of an amide bond of a tertiary amine. As compounds with a carbonyl group located on the rings, on the bridge to the amine group or beyond the amine are efficient MDR reversers, it seems that the exact molecular location of the carbonyl group is not critical for the elicitation of this activity