Synthesis and antitumor activity of 4-aminoquinazoline derivatives containing morpholine moieties

Abstract

Eight 4-(morpholinyl arylamino)quinazoline-6-carbamoyl carboxylic acid methyl esters and four 4-(morpholinyl arylamino)quinazoline-6-carbamoyl hydroxamic acid derivatives were designed and synthesized by integrating morpholine moieties into the 4-aminoquinazoline scaffold, with additional modifications at the 6-position of quinazoline ring. The antitumor potential of these twelve derivatives was evaluated against human lung cancer A549 cells and breast cancer MDA-MB-231 cells using the Cell Counting Kit-8 (CCK-8) proliferation assays. The bioassay results indicated that most of the derivatives exhibited moderate to potent in vitro antiproliferative activity against both cancer cells. Particularly, compound 7bb demonstrated superior potency against MDA-MB-231 cells and A549 cells, with half maximal inhibitory concentration (IC₅₀) values of 4.286 and 4.720 μM, respectively, compared to the reference drug afatinib (IC₅₀ = 7.640 and 5.173 μM, respectively). This study provides valuable insights for the development of novel antitumor agents based on the 4-aminoquinazoline scaffold.