Shi Tang

Although α-quaternary amino acids often exhibit notable bioactivity, their synthesis has received comparatively less attention, primarily due to the considerable steric hindrance posed by the quaternary center.

Staphylococcus aureus is a major foodborne pathogen characterized by strong virulence and biofilm-forming ability, posing a persistent threat to food safety. Aquilaria sinensis (Lour.) Gilg, a medicinal and edible plant found in tropical regions such as Hainan, has rarely been investigated for its quorum-sensing inhibitory (QSI) potential. In this study, four types of A. sinensis essential oils were systematically evaluated for their ability to inhibit quorum sensing and related virulence in S. aureus . Among them, the Tong-Ti-Xiang type supercritical essential oil (TTC) exhibited the strongest activity. At a sub-inhibitory concentration of 125 μg/mL (1/4 MIC), TTC reduced biofilm formation by up to 78% without affecting bacterial growth. Confocal laser scanning Microscopy and scanning electron microscopy analyses further confirmed that TTC compromised the density and structural integrity of the biofilms. Moreover, TTC suppressed α-hemolysin activity and significantly downregulated quorum-sensing-regulated genes involved in biofilm formation and adhesion, including icaA , icaD , clfA , clfB , and agrA . Gas chromatography mass spectrometry analysis revealed that TTC is rich in chromone derivatives, among which 2-phenethyl-4H-chromen-4-one showed strong binding affinity toward the adhesion-associated IcaA protein and the QS-associated AgrA protein in molecular docking analysis, suggesting it as a key active compound responsible for the observed QSI effect. Overall, these findings highlight TTC as a promising natural anti-biofilm and anti-virulence agent for controlling foodborne pathogens.

An efficient metal-free methodology for the construction of rarely reported trifluoromethylated pyridazino[3,4-b]indole scaffolds has been developed. The protocol was conducted with an operationally safe and bench-stable trifluoromethyl N-tosylhydrazone reagent in the iodine-promoted oxidative annulation of indoles in only one step, providing rapid access to a variety of trifluoromethylated pyridazino[3,4-b]indoles in good yields with good functional group compatibility. The findings could be used as a synthetic toolbox for the preparation of polycyclic indole-pyridazine fused N-heteroarenes for practical applications.

The emergence of multidrug-resistant Chromobacterium violaceum, an opportunistic pathogen, poses a significant threat to human, animal, and environmental health, underscoring the urgent need for innovative strategies. Marine-derived natural compounds have gained attention as a promising source of quorum sensing inhibitors (QSIs) that can attenuate C. violaceum virulence without inducing resistance. This study reports, for the first time, the anti-quorum sensing (anti-QS) and anti-biofilm activities of oxirapentyn A, one marine natural compound, against C. violaceum. Results demonstrate oxirapentyn A (200 μg/mL) significantly inhibits biofilm formation, violacein production, and hemolysin synthesis by 48.8, 21.7, and 22.3%, respectively. Scanning electron microscopy (SEM) further corroborated the disruption of biofilm architecture. LC–MS analysis revealed a concentration-dependent reduction in the production of N-decanoyl-homoserine lactone (C₁₀-HSL), a key QS signaling molecule. Furthermore, RT-qPCR analysis indicated oxirapentyn A downregulated critical QS-related genes (cviI, cviR, vioA, chiA, and pykF) by 20.7, 36.6, 31.1, 66.6, and 30.7%, respectively. Notably, in vivo experiments demonstrated that oxirapentyn A significantly improved the survival of Galleria mellonella larvae infected with C. violaceum. Collectively, these findings highlight oxirapentyn A as a novel QSI with dual anti-QS and biofilm-disrupting activities, offering a promising strategy to combat drug-resistant bacterial infections.

The fascinating skeleton 3,2'-pyrrolidinyl spirooxindole exhibits diverse pharmacological activity. Despite advancements in the construction of this skeleton, the application rearrangement strategy for the synthesis of 3,2'-pyrrolidinyl spirooxindole remains underexplored. Herein, we reported an efficient method for the construction of 3,2'-pyrrolidinyl spirooxindole by the [2,3]-rearrangement reaction between 3-diazoindolin-2-one and arecoline under mild reaction conditions, which had a good functional group tolerance and high yield. This work not only facilitates the study of selective rearrangement of ammonium ylide but also contributes significantly to the synthesis of spiro compounds.

The complicated mechanism makes the regiodivergent rearrangement of ammonium ylide seem to be out of reach. Herein, we reported a regiodivergent rearrangement of gramine ammonium ylide well controlled by the substituents. Density functional theory studies reveal that the ammonium ylide with a more steric hindrance substituent 2-diazo-2-arylacetate goes through a stepwise mechanism to yield both a kinetically and thermodynamically preferred [1,2]-rearrangement product. In contrast, the ammonium ylide with a less steric hindrance ethyl diazoacetate goes through a concerted mechanism to generate the [2,3]-rearrangement product, which is kinetically favored as a result of the release of the ring strain in the transition state. This study would open up avenues to grasp the rearrangement of ammonium ylide, which will promote application in the skeletal editing and synthesis of complex natural products.

Pseudomonas aeruginosa has already been stipulated as a “critical” pathogen, emphasizing the urgent need for researching and developing novel antibacterial agents due to multidrug resistance. Bacterial biofilm formation facilitates cystic fibrosis development and restricts the antibacterial potential of many current antibiotics. The capacity of P. aeruginosa to form biofilms and resist antibiotics is closely correlated with quorum sensing (QS). Bacterial QS is being contemplated as a promising target for developing novel antibacterial agents. QS inhibitors are a promising strategy for treating chronic infections. This study reported that the active compound PT22 (1H-pyrrole-2,5-dicarboxylic acid) isolated from Perenniporia tephropora FF2, one endophytic fungus from Areca catechu L., presents QS inhibitory activity against P. aeruginosa. Combined with gentamycin or piperacillin, PT22 functions as a novel antibiotic accelerant against P. aeruginosa. PT22 (0.50 mg/mL, 0.75 mg/mL, and 1.00 mg/mL) reduces the production of QS-related virulence factors, such as pyocyanin and rhamnolipid, and inhibits biofilm formation of P. aeruginosa PAO1 instead of affecting its growth. The architectural disruption of the biofilms was confirmed by visualization through scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM). Real-time quantitative PCR (RT-qPCR) indicated that PT22 significantly attenuated the expression of QS-related genes followed by docking analysis of molecules against QS activator proteins. PT22 dramatically increased the survival rate of Galleria mellonella. PT22 combined with gentamycin or piperacillin presents significant inhibition of biofilm formation and eradication of mature biofilm compared to monotherapy, which was also confirmed by visualization through SEM and CLSM. After being treated with PT22 combined with gentamycin or piperacillin, the survival rates of G. mellonella were significantly increased compared to those of monotherapy. PT22 significantly enhanced the susceptibility of gentamycin and piperacillin against P. aeruginosa PAO1. Our results suggest that PT22 from P. tephropora FF2 as a potent QS inhibitor is a candidate antibiotic accelerant to combat the antibiotic resistance of P. aeruginosa.

The formal cyclization strategy was generally used to construct azepino[4,5-b]indole. Herein, we reported a novel and expeditious protocol for the synthesis of quaternary carbon azepino[4,5-b]indole via ring expansion of ammonium ylide, which was formed by the reaction of tetrahydro-β-carbolines with the diazo compound. The easily available substrates, mild reaction conditions, and broad functional tolerance rendered this method a practical strategy that may significantly afford an efficient method of scaffold hopping in drug discovery.

Quorum sensing (QS) inhibition is recognized as a novel antimicrobial target for infections caused by drug-resistant pathogens and is an attractive strategy for antipathogenic agent development. We designed and synthesized three parts of 3-(2-isocyanobenzyl)-1H-indole derivatives and tested their activity as novel quorum sensing inhibitors (QSIs). 3-(2-Isocyanobenzyl)-1H-indole derivatives demonstrated promising QS, biofilms, and prodigiosin inhibitory activities against Serratia marcescens at subminimum inhibitory concentrations (sub-MICs). In particular, 3-(2-isocyano-6-methylbenzyl)-1H-indole (IMBI, 32) was identified as the best candidate based on several screening assays, including biofilm and prodigiosin inhibition. Further studies demonstrated that exposure to IMBI at 1.56 mu g/mL to S. marcescens NJ01 significantly inhibited the formation of biofilms by 42%. The IMBI treatment on S. marcescens NJ01 notably enhanced the susceptibility of the formed biofilms, destroying the architecture of the biofilms by up to 40%, as evidenced by scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM). For interference of virulence factors in S. marcescens NJ01, IMBI at 3.12 mu g/mL inhibited the activity of protease and extracellular polysaccharides (EPS) by 17% and 51%, respectively, which were higher than that of the positive control vanillic acid (VAN). Furthermore, IMBI downregulated the expression of QS- and biofilm-related genes fimA, bsmA, pigP, flhC, rssB, fimC, and rsmA by 1.02- to 2.74-fold. To confirm these findings, molecular docking was performed, which indicated that the binding of IMBI to SmaR, RhlI, RhlR, LasR, and CviR could antagonize the expression of QS-linked traits. In addition, molecular dynamic simulations (MD) and energy calculations indicated that the binding of receptors with IMBI was extremely stable. The biofilms of S. marcescens NJ01 were markedly reduced by 50% when IMBI (0.39 mu g/mL) was combined with kanamycin (0.15 mu g/mL). In conclusion, this study highlights the potency of IMBI in inhibiting the virulence factors of S. marcescens. IMBI has all the potential to be developed as an effective and efficient QS inhibitor and antibiofilm agent in order to restore or improve antimicrobial drug sensitivity.