Design, synthesis and 3D-QSAR analysis of novel thiopyranopyrimidine derivatives as potential antitumor agents inhibiting A549 and Hela cancer cells

Four series of thiopyranopyrimidine AZD9291 derivatives containing acrylamide structure were designed, synthesized and evaluated for their antiproliferative activity against A549 and Hela cancer cells. Most of the compounds exhibited excellent antiproliferative activity against A549 cells. Moreover, the compounds with indole ring fluorine substituted exhibited better antiproliferative activity against Hela cells. The most promising compound 23g exhibited excellent enzymatic inhibitory activity and selectivity for EGFR(L858R/T790M) double mutations. The IC50 value against EGFR(L858R/T790M) kinase was 16 nM. The compound 23g inhibits selectively against the mutated form of EGFR, with the selectivity more than 125-fold. Furthermore, compound 23g also inhibited A549 cells, Hela cells and H1975 cells proliferation at a low concentration, and the IC50 values were 0.057 mu M, 0.104 mu M and 0.916 mu M, respectively. To further investigate the QSAR5 of thiopyranopyrimidine derivatives, the CoMFA (q [2] = 0.765, r(2) = 0.965) and CoMSIA (q [2] = 0.875, r(2) = 0.956) models on Hela cancer cells were established. The generated 3D-QSAR model was validated to be reliable and can be used for further design and optimization of novel and selective EGFR inhibitors. (C) 2019 Elsevier Masson SAS. All rights reserved.