Synthesis and Biological Evaluation of (Hetero)Arylmethyloxy- and Arylmethylamine-phenyl Derivatives as Potent P-glycoprotein Modulating Agents

Starting from lead compounds 12b and 28b, previously characterized as P-glycoprotein (P-gp) modulating agents, two series of new compounds were investigated. Compounds 14a,b and 15a,b displayed high P-gp modulating activity in the submicromolar range (EC50 values from 0.25 to 0.80 µM). Moreover, amino derivatives 23–27 showed EC50 values ranging from 0.085 to 0.90 µM. In the pyridyl series, the best result has been obtained for 4-pyridyl derivative 17b (EC50 = 0.85 µM). The best P-gp modulating agents 14a,b, 15a,b, and 23–27 also have been studied for determining their breast cancer resistance protein (BCRP) inhibition activity. The results demonstrated that only the amino derivatives 23–27 displayed moderate BCRP inhibition activity.