Discovery of Imidazo[2,1-b][1,3,4]thiadiazole-Based MNK Inhibitors with Anti-inflammatory Efficacy via Dual Suppression of eIF4E Phosphorylation and NF-κB Signaling.

Mitogen-activated protein kinase-interacting kinase (MNK), a pivotal kinase downstream of MAPK signaling, is currently the only enzyme reported to be capable of phosphorylating eIF4E. This study first confirmed that MNK silencing in LPS-stimulated macrophages inhibits eIF4E phosphorylation, inflammatory polarization, and cytokine release. Based on the prior discovery that the imidazo[2,1-b][1,3,4]thiadiazole skeleton can effectively inhibit the MNK kinases, this study further designed and synthesized a series of imidazo[2,1-b][1,3,4]thiadiazole derivatives modified with sulfonyl or phosphoryl groups. Among these derivatives, compound 13 potently and selectively inhibited MNK1/2 (IC50 = 10.84/12.81 nM), exerted dose-dependent anti-inflammatory effects in LPS-induced RAW 264.7 cells, and alleviated kidney and spleen damage in the mouse model of LPS-induced inflammation. Mechanistically, 13 suppressed eIF4E phosphorylation, NF-κB signaling, and macrophage polarization, thereby reducing pro-inflammatory cytokines and oxidative stress. These results suggest that MNK inhibition is a promising strategy for treating inflammatory diseases by targeting both inflammation and oxidative stress.