Total Synthesis and Antibacterial Evaluation of Lupinifolin and Its Natural Analogues.

In this study, lupinifolin ( 1 ) and its natural analogues, mundulin ( 2 ), minimiorin ( 3 ), khonklonginol H ( 4 ), flemichin D ( 5 ), and eriosemaone A ( 27 ), were obtained by chemical synthesis for the first time. Key steps involved an electrocyclization to build the linear pyran rings and a Claisen/Cope rearrangement to install the 8-prenyl substituents. All compounds were assessed for their in vitro antimicrobial activities against clinically relevant human pathogens, including one Gram-negative bacterial strain ( E. coli ATCC 25922) and four Gram-positive bacterial strains ( S. aureus ATCC 29213, E. faecalis ATCC 29212, MRSA21-5, and VRE ATCC 51299). The result indicated that eriosemaone A ( 27 ) was the most potent one against Gram-positive bacteria, with minimum inhibitory concentrations in the range of 0.25-0.5 μg/mL. Mechanistic studies indicated that 27 has good membrane-targeting ability to bacterial inner membranes and can bind to phosphatidylglycerol and cardiolipin in bacterial membranes, thereby disrupting the bacterial cell membranes and causing bacterial death.