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
MCF-7/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.