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Graphical abstract Highlights • Twenty-eight pyridone–aminal derivatives were designed and synthesized. • 42i was a selective MNK1/2 inhibitor (MNK1 IC 50 = 7.0 nM; MNK2 IC 50 = 6.1 nM). • 42i decreased the level of p-eIF4E in CT-26 cell in a dose-dependent manner. • 42i inhibited the tumor growth of CT-26 allograft models. Abstract Excessive phosphorylation of eukaryotic translation initiation factor 4E (eIF4E) plays a major role in the dysregulation of mRNA translation and the activation of tumor cell signaling. eIF4E is exclusively phosphorylated by mitogen-activated protein kinase interacting kinases 1 and 2 (MNK1/2) on Ser209. So, MNK1/2 inhibitors could decrease the level of p-eIF4E and regulate tumor-associated signaling pathways. A series of pyridone–aminal derivatives were synthesized and evaluated as MNK1/2 inhibitors. Several compounds exhibited great inhibitory activity against MNK1/2 and selected compounds showed moderate to excellent anti-proliferative potency against hematologic cancer cell lines. In particular, compound 42i (MNK1 IC 50 = 7.0 nM; MNK2 IC 50 = 6.1 nM) proved to be the most potent compound against TMD-8 cell line with IC 50 value of 0.91 μM. Furthermore, 42i could block the phosphorylation level of eIF4E in CT-26 cell line, and 42i inhibited the tumor growth of CT-26 allograft model significantly. These results indicated that compound 42i was a promising MNK1/2 inhibitor for the potent treatment of colon cancer. [ABSTRACT FROM AUTHOR]