Multi‐Drug‐Resistance‐Reverting Agents: 2‐Aryloxazole and 2‐Arylthiazole Derivatives as Potent BCRP or MRP1 Inhibitors

The 2‐aryloxazole and 2‐arylthiazole scaffolds were used for generating compounds that we characterized for their inhibitory activity toward ATP binding cassette transporters involved in multi‐drug resistance, such as BCRP and MRP1, by using tumor cell lines overexpressing each transporter. These SAR studies are a significant step toward improving the inhibitory potency against P‐glycoprotein, BCRP, and MRP1. magnified image 2‐Aryloxazole and 2‐arylthiazole derivatives were evaluated for their inhibitory activity toward P‐glycoprotein (P‐gp) as well as their selectivity toward other ABC transporters involved in multi‐drug resistance such as BCRP and MRP1. These derivatives have 6,7‐dimethoxytetrahydroisoquinoline or cyclohexylpiperazine moieties, which are the same basic nuclei of the potent P‐gp inhibitors MC70 (EC50=0.05 μM) and PB28 (EC50=0.55 μM), respectively. The results demonstrate that 2‐aryloxazole and 2‐arylthiazole derivatives, planned as cycloisosteres of MC70, were found to be less potent than the reference compound in inhibiting P‐gp. These compounds were evaluated for their BCRP and MRP1 inhibitory activities. In particular, 6,7‐dimethoxytetrahydroisoquinoline derivatives, unsubstituted, 3‐Br, 3‐Cl, and 3‐OCH3 2‐aryloxalzole derivatives showed the best BCRP inhibitory activity (EC50 range: 0.24–0.46 μM). In contrast, all cyclohexylpiperazine derivatives except one (EC50=0.56 μM), showed decreased BCRP inhibitory activity. All compounds tested were unable to inhibit the MRP1 pump, with the exception of the 2‐OCH3 and 4‐OCH3 derivatives of the 6,7‐dimethoxytetrahydroisoquinoline series, which displayed high MRP1 inhibitory activity (EC50=0.84 and 0.90 μM, respectively).