Design, synthesis and biological evaluation of novel N-(3-amino-4-methoxyphenyl)acrylamide derivatives as selective EGFRL858R/T790M kinase inhibitors

A series of novel N-(3-amino-4-methoxyphenyl)acrylamide derivatives were designed, synthesized and their antiproliferation activities against A549 and H1975 cell lines were evaluated. EGFR kinase inhibitory assay, acridine orange/ethidium bromide staining assay, cell apoptosis assay, cell cycle distribution assay, wound-healing assay and molecular docking assay were further performed. Compound 17i was demonstrated as a promising candidate and worth further study. [Display omitted] •A series of novel N-(3-amino-4-methoxyphenyl)acrylamide derivatives were designed, synthesized, and evaluated.•Compounds 17i exhibited comparable antitumor activities and selectivity ratio to osimertinib.•Compound 17i showed an IC50 value of 1.7 nM against EGFRL858R/T790M kinase.•Compound 17i could induce apoptosis process, G0/G1-phase arrestation and the inhibition of motility to H1975 cell line.•The action mode between compound 17i and EGFRL858R/T790M kinase was analyzed and discussed. On the basis of N-(3-amino-4-methoxyphenyl)acrylamide scaffold, a series of novel compounds containing 3-substitutional-1-methyl-1H-indole, 2-substitutional pyrrole or thiophene moieties were synthesized and their in vitro antiproliferation activities against A549 and H1975 cell lines were evaluated. The results indicated that most of the compounds showed moderate to excellent antitumor activities. Especially, compounds 9a (A549 IC50 = 1.96 μM, H1975 IC50 = 0.095 μM), 17i (A549 IC50 = 4.17 μM, H1975 IC50 = 0.052 μM), 17j (A549 IC50 = 1.67 μM, H1975 IC50 = 0.061 μM) exhibited comparable antitumor activities and selectivity ratios compared to the positive control osimertinib (A549 IC50 = 2.91 μM, H1975 IC50 = 0.064 μM). In vitro inhibitory activities against EGFR kinases containing different mutations were also tested. Compound 17i showed remarkable inhibitory activity (with IC50 value of 1.7 nM) to EGFRL858R/T790M kinase and selectivity (22-folds compared to EGFRWT kinase). Furthermore, acridine orange/ethidium bromide (AO/EB) staining assay, cell apoptosis assay, cell cycle distribution assay and wound-healing assay of the compounds 9a and 17i were performed on H1975 cell line. The results showed dose-dependent activities of the induction of apoptosis, G0/G1-phase arrestation and inhibition of migration, which were similar to the positive control osimertinib. Additionally, molecular docking analysis was performed to seek the possible binding mode between the selected compounds (9a, 17i-17j) and