Discovery of Potent Inhibitors against P‑Glycoprotein-Mediated Multidrug Resistance Aided by Late-Stage Functionalization of a 2‑(4-(Pyridin-2-yl)phenoxy)pyridine Analogue

SIS3 is a specific inhibitor of Smad3 that inhibits the TGFβ1-induced phosphorylation of Smad3. In this article, a variety of SIS3 derivatives were designed and synthesized to discover potential inhibitors against P-glycoprotein-mediated multidrug resistance aided by late-stage functionalization of a 2-(4-(pyridin-2-yl)­phenoxy)­pyridine analogue. A novel class of potent P-gp reversal agents were investigated, and a lead compound 37 was identified as a potent P-gp reversal agent with strong bioactivity and outstanding affinity for P-gp.