Design, Synthesis, and Pharmacological Characterization of <i>N</i>‑(4-(2 (6,7-Dimethoxy-3,4-dihydroisoquinolin-2(1<i>H</i>)yl)ethyl)phenyl)quinazolin-4-amine Derivatives: Novel Inhibitors Reversing P‑Glycoprotein-Mediated Multidrug Resistance

P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) is a principal obstacle for successful cancer chemotherapy. A novel P-gp inhibitor with a quinazoline scaffold, <b>12k</b>, was considered to be the most promising for in-depth study. <b>12k</b> possessed high potency (EC₅₀ = 57.9 ± 3.5 nM), low cytotoxicity, and long duration of activity in reversing doxorubicin (DOX) resistance in K562/A02 cells. <b>12k</b> also boosted the potency of other MDR-related cytotoxic agents with different structures, increased accumulation of DOX, blocked P-gp-mediated Rh123 efflux, and suppressed P-gp ATPase activity in K562/A02 MDR cells. However, <b>12k</b> did not have any effects on CYP3A4 activity or P-gp expression. In particular, <b>12k</b> had a good half-life and oral bioavailability and displayed no influence on DOX metabolism to obviate the side effects closely related to increased plasma concentrations of cytotoxic agents in vivo