Development of heterocyclic derivatives as P-glycoprotein inhibitors against multidrug resistance: pharmacological activities, structure–activity relationship and target (2020–2024)

The overexpression of P-glycoprotein (P-gp) has been recognized as a pivotal factor contributing to the emergence of multidrug resistance (MDR), a phenomenon that frequently limits the efficacy of chemotherapy and profoundly impacts patient prognosis. Consequently, the inhibition of P-gp's efflux function has become a critical therapeutic strategy for overcoming drug resistance and enhancing chemotherapeutic efficacy. In recent years, the development of P-gp inhibitors has garnered significant attention, particularly with the frequent incorporation of heterocyclic derivatives, which exhibit exceptional biological activity and favorable chemical properties, into drug design. In this paper, we reviewed the latest research progress of pharmacological activities, structure-activity relationships and molecular targets of heterocyclic derivatives as P-gp inhibitors in the past five years (2020-2024). Through this comprehensive analysis, the potential of heterocyclic derivatives in modulating P-gp inhibition is highlighted, positioning them as promising candidates for the development of novel anti-resistance therapeutics. Meanwhile, the review offers a solid theoretical foundation and experimental guidance for the future design of more efficacious P-gp inhibitors.