Curcumol Derivatives Exhibit Ameliorating Effects on Lipopolysaccharide-Induced Acute Lung Injury: Synthesis, Biological Evaluation, Structure–activity Relationship and Action Mechanism

Acute lung injury (ALI) is an intricate clinical disease marked by high mortality and a sudden start. Currently, although there are no specific therapeutics for ALI, the administration of anti-inflammatory drugs is a promising treatment strategy. Curcumol, a terpenoid natural product, has demonstrated significant anti-inflammatory activity. Herein, we designed and synthesised 42 curcumol derivatives using curcumol as the core scaffold. These derivatives underwent in vitro screening for anti-inflammatory activity, and their structure–activity relationship was assessed. Among them, derivative 2 exhibited potent anti-inflammatory potential, inhibiting the expression of inflammatory markers at the nanomolar level. In addition, its water solubility was considerably improved, thereby laying the foundation for enhanced druggability. Derivative 2 also ameliorated lipopolysaccharide (LPS)-induced ALI and reduced pulmonary inflammation at a dose of 5 mg/kg. Proteomics analysis revealed that the anti-inflammatory effect of this compound primarily involved the mTOR signalling pathway. Furthermore, molecular docking and cellular thermal shift assays indicated that GSK3β is a critical target of action of derivative 2, as verified via western blotting. These findings suggest that derivative 2 can be a lead therapeutic compound for ALI, with GSK3β emerging as a promising novel target for the development of specific anti-ALI drugs.