Total Synthesis and Antibacterial Evaluation of Lupinifolin and Its Natural Analogues

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 Gramnegative bacterial strain (E. coli ATCC 25922) and four Grampositive 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 Grampositive 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.

Total Syntheses and Antibacterial Studies of Natural Isoflavones: Scandenone, Osajin, and 6,8-Diprenylgenistein

“…Aromatic Claisen rearrangement or cyclization in DMF afforded 20 as the main product (77%, entry 3), while in xylene, 19 was isolated as the main product in a yield of 55% (entry 4). We then found that the addition of KOH to xylene could effectively control the regioselectivity, and pure 19 was obtained in 93% yield (entry 5) [33,35], whereas the reported Claisen rearrangement/cyclization conditions of 15 only yielded a roughly 1:1 mixture of 19 and 20 under harsh conditions (entry 6) [23]. As shown in Table 2, the synthesis of scandenone (1) and osajin (2) commenced with the stereocontrolled preparations of tetracyclic isoflavens 19 and 20, which possessed a linear or angular pyran attached to the A-ring, respectively.…”

“…The MIC of natural compound 2 against S. aureus ATCC29213 was 2 The target compounds (1-3) were evaluated for their in vitro antibacterial activities against three Gram-positive (G+) bacterial strains (S. aureus ATCC29213, MRSA ATCC33591, and Enterococcus faecalis ATCC29212,) and one Gram-negative (G-) bacterial strain (E. coli ATCC25922) using minimum inhibitory concentration (MIC) values. Ampicillin and vancomycin were used as the positive controls [33].…”

“…Therefore, compound 2 displayed the most potent antibacterial activity due to its well-balanced lipophilicity [37]. To further confirm the antibacterial activity of Osajin (2), we subsequently performed a scanning electron microscopy (SEM) assay [32,33], to image both MRSA ATCC33591 and E. faecalis ATCC29212 after incubation with 2 for 2 h. As shown in Figure 3, the untreated control groups (Figure 3A,C) had an intact cell structure and surface morphology, while treatment of MRSA ATCC33591 and E. faecalis ATCC29212 with 2 at a concentration of 8 × its MIC resulted in a rough and wrinkled cell membrane surface (Figure 3B,D), indicating that the bacterial cell membrane was disrupted by 2. These findings suggested that Osajin (2) could inhibit bacterial growth by disrupting the integrity of the cell membrane.…”

“…After a few attempts, we found that the use of p -toluenesulfonic acid in CH 2 Cl 2 could generate 16 in 14% yield (entry 4). Finally, 16 could be obtained in a satisfactory isolated yield (72%) using acidic alumina as a catalyst and 1,2-dichloroethane (DCE) as a solvent (entry 5) [ 31 , 32 , 33 ]. Compound 16 was treated with newly prepared sodium dodecane-1-thiolate in reflux DMF to generate natural product 3 in 78% yield [ 19 ].…”

“…Aromatic Claisen rearrangement or cyclization in DMF afforded 20 as the main product (77%, entry 3), while in xylene, 19 was isolated as the main product in a yield of 55% (entry 4). We then found that the addition of KOH to xylene could effectively control the regioselectivity, and pure 19 was obtained in 93% yield (entry 5) [ 33 , 35 ], whereas the reported Claisen rearrangement/cyclization conditions of 15 only yielded a roughly 1:1 mixture of 19 and 20 under harsh conditions (entry 6) [ 23 ].…”