Discovery of Novel Pterostilbene-Based Derivatives as Potent and Orally Active NLRP3 Inflammasome Inhibitors with Inflammatory Activity for Colitis

Studies have shown that the abnormal
activation of the NLRP3 inflammasome
is involved in a variety of inflammatory-based diseases. In this study,
a high content screening model targeting the activation of inflammasome
was first established and pterostilbene was discovered as the active
scaffold. Based on this finding, total of 50 pterostilbene derivatives
were then designed and synthesized. Among them, compound 47 was found to be the best one for inhibiting cell pyroptosis [inhibitory
rate (IR) = 73.09% at 10 μM], showing low toxicity and high
efficiency [against interleukin-1β (IL-1β): half-maximal
inhibitory concentration (IC50) = 0.56 μM]. Further
studies showed that compound 47 affected the assembly
of the NLRP3 inflammasomes by targeting NLRP3. The in vivo biological activity showed that this compound significantly alleviated
dextran sodium sulfate (DSS)-induced colitis in mice. In general,
our study provided a novel lead compound directly targeting the NLRP3
protein, which is worthy of further research and structural optimization.