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The efficacy of chemotherapy against malignant tumors is severely limited by multidrug resistance (MDR), of which the overexpression of P-glycoprotein (P-gp) is recognized as a key mechanism. Consequently, the development of potent, low-toxicity P-gp inhibitors represents a crucial direction in anticancer drug research. Based on our group's prior work on P-gp inhibitors and supported by molecular docking analysis, 21 novel tetrahydroisoquinoline derivatives were designed and synthesized in this study. Their ability to reverse MDR was assessed in the human esophageal carcinoma multidrug-resistant cell line Eca109/VCR. The most active compound 21 demonstrated a superior reversal fold (RF = 654) compared to the third-generation P-gp inhibitor TQ, as confirmed by colony formation and flow cytometry assays. Mechanistic investigations, including chemosensitization, intracellular fluorescent substrate accumulation, and molecular docking studies, verified that the MDR reversal effect of compound 21 is mediated through P-gp inhibition. This work provides a new strategic direction for developing tetrahydroisoquinoline-based sensitizers to overcome tumor drug resistance.