ABCB1
and ABCG2 are the important ATP-binding cassette
(ABC) transporters
associated with multidrug resistance (MDR). Herein, we designed a
series of imidazo[1,2-a]pyridine derivatives as dual-target
inhibitors of ABCB1 and ABCG2 through the scaffold hopping strategy.
Compound Y22 displayed potential efflux function inhibitory
toward both ABCB1 and ABCG2 (reversal fold: ABCB1 = 8.35 and ABCG2
= 2.71) without obvious cytotoxicity. Y22 also enhanced
the potency of antiproliferative drugs in vitro. Mechanistic studies
demonstrated that Y22 slightly suppressed ATPase activity
but did not affect the protein expression of ABCB1 or ABCG2. Notably, Y22 exhibited negligible CYP3A4 inhibition and enhanced the
antiproliferative activity of adriamycin in vivo by restoring the
sensitivity of resistant cells. Thus, Y22 may be effective
clinically in combination with common chemotherapy agents. In summary, Y22 is a potential dual-target inhibitor that reverses MDR
by blocking the efflux function of ABCB1 and ABCG2.
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