Chalcones and their derivatives as inhibitors of key ABC transporters (ABCB1, ABCG2) to overcome tumor multidrug resistance.

Tumor multidrug resistance (MDR) remains a major cause of chemotherapy failure, primarily resulting from the overexpression of ATP-binding cassette (ABC) transporters, including ABCB1 and ABCG2, which play critical roles in drug resistance. In recent years, chalcones and their derivatives have attracted considerable research interest for reversing MDR due to their distinctive 1,3-diphenyl-2-propen-1-one scaffold, high structural modifiability, and multi-target activities. Numerous studies have demonstrated that chalcone-based compounds could reverse MDR through diverse mechanisms, including direct cytotoxicity against resistant tumor cells, inhibition of ABC transporter-mediated drug efflux, and modulation of transporter-associated ATPase activity. These mechanisms collectively increase intracellular drug accumulation and restore the efficacy of chemotherapeutic agents. Naturally occurring chalcones have shown promising MDR-reversal activity in both in vitro and in vivo studies, whereas derivatives obtained through structural optimization often display even greater potency. Furthermore, several novel chalcone derivatives have been identified that possess dual inhibitory activity against multiple MDR targets, thereby enhancing MDR-reversal efficacy. This review summarizes recent advances in chalcone-based MDR reversal agents, including both naturally derived compounds and synthetically optimized derivatives, and provides insights into the design of next-generation MDR modulators.