Overcoming Multidrug Resistance (MDR): Design, Biological Evaluation and Molecular Modelling Studies of 2,4‐Substituted Quinazoline Derivatives

Some 2,4‐disubstituted quinazolines were synthesized and studied as multidrug resistance (MDR) reversers. The new derivatives carried the quinazoline‐4‐amine scaffold found in modulators of the ABC transporters involved in MDR, as the TKIs gefitinib and erlotinib. Their behaviour on the three ABC transporters, P‐gp, MRP1 and BCRP, was investigated. Almost all compounds inhibited the P‐gp activity in MDCK‐MDR1 cells overexpressing P‐gp, showing EC(50) values in the nanomolar range (1 d, 1 e, 2 a, 2 c, 2 e). Some compounds were active also towards MRP1 and/or BCRP. Docking results obtained by in silico studies on the P‐gp crystal structure highlighted common features for the most potent compounds. The P‐gp selective compound 1 e was able to increase the doxorubicin uptake in HT29/DX cells and to restore its antineoplastic activity in resistant cancer cells in the same extent of sensitive cells. Compound 2 a displayed a dual inhibitory effect showing good activities towards both P‐gp and BCRP.