ABSTRACT
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.
Subject(s)
Anti-Bacterial Agents , Flavonoids , Gram-Positive Bacteria , Microbial Sensitivity Tests , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Molecular Structure , Gram-Positive Bacteria/drug effects , Gram-Negative Bacteria/drug effectsABSTRACT
Isoflavones are a class of natural products that exhibit a wide range of interesting biological properties, including antioxidant, hepatoprotective, antimicrobial, and anti-inflammatory activities. Scandenone (1), osajin (2), and 6,8-diprenylgenistein (3) are natural prenylated isoflavones that share the same polyphenol framework. In this research, the key intermediate 15 was used for the synthesis of the natural isoflavones 1-3, establishing a stereoselective synthetic method for both linear and angular pyran isoflavones. The antibacterial activities of 1-3 were also evaluated, and all of them displayed good antibacterial activity against Gram-positive bacteria. Among them, 2 was the most potent one against MRSA, with a MIC value of 2 µg/mL, and the SEM assay indicated that the bacterial cell membranes of both MRSA and E. faecalis could be disrupted by 2. These findings suggest that this type of isoflavone could serve as a lead for the development of novel antibacterial agents for the treatment of Gram-positive bacterial infections.
Subject(s)
Anti-Bacterial Agents , Isoflavones , Microbial Sensitivity Tests , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Isoflavones/pharmacology , Isoflavones/chemistry , Isoflavones/chemical synthesis , Molecular Structure , Methicillin-Resistant Staphylococcus aureus/drug effects , Gram-Positive Bacteria/drug effects , Biological Products/pharmacology , Biological Products/chemistry , Biological Products/chemical synthesis , Enterococcus faecalis/drug effectsABSTRACT
The total syntheses of the natural prenylated flavones cudraflavones A-C (1-3), artoheterophyllin D (28) and artelasticin (29) are reported, along with the evaluations of their antibacterial activities. The key steps of the synthesis involved a Baker-Venkataraman rearrangement and an intramolecular cyclization for the construction of the flavone core and the regioselective formation of the pyran and isopentenyl scaffolds. The tested natural flavones 1-3 and 27-29 exhibited potent activity against S. aureus ATCC 29213, S. epidermidis ATCC 14990, E. faecalis ATCC 29212 and B. subtilis ATCC 6633 with MIC values ranging from 0.125 µg/mL to 16 µg/mL. Compound 3 displayed the strongest potency, with MIC values in the range between 0.125 and 1 µg/mL, as a potential candidate to combat G+ bacterial infections. Preliminary mechanism of action studies suggested that this compound killed bacteria by disrupting bacterial membrane integrity.