Novel Benzo Five-Membered Heterocycle Derivatives as P-Glycoprotein Inhibitors: Design, Synthesis, Molecular Docking, and Anti-Multidrug Resistance Activity

A proposed strategy to overcome multidrug resistance (MDR) of anticancer drugs in chemotherapy is to disable the efflux function of P-glycoprotein (P-gp). In this study, based on ring-merging and fragment-growing strategies, 105 novel benzo five-membered heterocycle derivatives were designed, synthesized, and screened. Exploration of the structure-activity relationship (SAR) led to the identification of d7 with low cytotoxicity and promising reversal activity to doxorubicin in MCF7/ADR cells. Furthermore, the mechanism studies revealed that the reversal activity of d7 stemmed from the inhibition of P-gp efflux. Molecular docking further clarified the observed trends in SAR with d7 displaying potent affinity to P-gp. Additionally, coadministration of d7 with doxorubicin achieved stronger antitumor activity in a xenograft model than doxorubicin alone. These results suggest that d7 is a potential MDR reveal agent acting as a P-gp inhibitor and provides guidelines for the future development of new P-gp inhibitors.

Automated summary

In this study, 105 novel benzo five-membered heterocycle derivatives were designed, synthesized, and screened. Compound d7 showed low cytotoxicity and promising reversal activity to doxorubicin. Mechanism studies revealed that d7 inhibited the efflux function of P-glycoprotein (P-gp), leading to its reversal activity. Molecular docking confirmed the strong affinity between d7 and P-gp. Combined administration of d7 with doxorubicin exhibited enhanced antitumor activity. These findings highlight the potential of d7 as a P-gp inhibitor in overcoming multidrug resistance.