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Discovery of novel coumarin-containing triazolo[1,5-a]pyrimidine derivatives as potent ABCB1 inhibitor for modulation of multidrug resistance
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DOI：10.1080/14756366.2026.2629074.png)
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Abstract
En 中文
ABCB1-mediated drug efflux is a key determinant of multidrug resistance (MDR) in cancer. To overcome this mechanism, a series of thiol-substituted aminocoumarin-derived, coumarin-containing triazolo[1,5-a]pyrimidine derivatives (5a-5s) was synthesised, and compound 5r (NYH-707) was identified as the most potent ABCB1 inhibitor. NYH-707 markedly restored paclitaxel sensitivity in SW620/Ad300 MDR cells, reducing the IC50 from 4.55 +/- 0.73 & micro;M to 0.011 +/- 0.002 & micro;M (reversal factor = 413.6). Molecular docking predicted strong binding (-9.7 kcal/mol) through hydrogen bonding with LYS-826 and SER-880 and pi-pi stacking with PHE-994. CETSA confirmed direct ABCB1 engagement, while drug-accumulation assays demonstrated inhibition of ABCB1-mediated efflux. In vivo, co-administration of NYH-707 and paclitaxel significantly suppressed SW620/Ad300 xenograft growth without detectable systemic toxicity. These findings indicate that NYH-707 acts as a potent and selective ABCB1 modulator capable of reversing MDR likely by modulating ABCB1 conformational dynamics, thereby enhancing chemotherapeutic efficacy in resistant tumours.
Keywords:
Multidrug resistance
ABCB1
ABCB1 inhibitors
aminocoumarin-derived coumarin
triazolo[1,5-a]pyrimidine
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