Structure-activity relationship and target identification of marine anthranilamides as anti-inflammatory agents

Pro-inflammatory cytokines mediate intestinal inflammation and tissue lesions, making their inhibition a promising therapeutic approach for inflammatory bowel disease (IBD). In this work, a series of anthranilamide derivatives were rationally designed and synthesized via multi-site structural optimization based on marine natural product (MNP) 3. Among all the derivatives, compound 17 displayed potent inhibitory activity against pro-inflammatory cytokines at 10 μM in vitro, with inhibition rates of 104% for interleukin-6 (IL-6) and 93% for interleukin-1β (IL-1β). Mechanistic studies revealed that compound 17 acts as a selective histone deacetylase (HDAC) inhibitor with IC₅₀ values of 395 nM and 6.7 μM against HDAC6 and HDAC1, respectively. Molecular docking simulations were conducted to predict its detailed binding mode with HDAC6. Notably, compound 17 exerted remarkable therapeutic efficacy in a dextran sulfate sodium (DSS)-induced colitis mouse model, effectively ameliorating colonic pathological damage. Collectively, these results establish compound 17 as a selective HDAC6 inhibitor with favorable anti-IBD activity, supporting its further development as a promising lead candidate.