Brusatol, a biologically active naturalproduct, was modified infour distinct positions through the covalent attachment of a furoxanmoiety, which acts as a nitric oxide (NO) donor. Forty derivativeswere synthesized and evaluated for their inhibitory effects on excessNO biosynthesis in activated macrophages. Among them, compound 75demonstrated inhibition (IC50= 0.067 μM)comparable to that of brusatol but were less cytotoxic. More importantly,even at very low doses (2 μmol/kg/day), compound 75also showed substantial inhibitory efficacy against chronic obstructivepulmonary disease (COPD)-like inflammation in the mouse model inducedby cigarette smoke (CS) and lipopolysaccharide (LPS). Particularly,this compound was over 100-fold less toxic (LD50> 3852μmol/kg) than brusatol and could be a promising lead for furtherstudies. Notably, the improved properties of this derivative are associatedwith its NO-releasing capability. [ABSTRACT FROM AUTHOR]