Currently, infections caused by drug-resistant bacteria have become a new challenge in anti-infective treatment, seriously endangering public health. In our continuous effort to develop new antimicrobials, a series of novel honokiol/magnolol amphiphiles were prepared by mimicking the chemical structures and antibacterial properties of cationic antimicrobial peptides. Among them, compound 5i showed excellent antibacterial activity against Gram-positive bacteria and clinical MRSA isolates (minimum inhibitory concentrations (MICs) = 0.5–2 μg/mL) with low hemolytic and cytotoxic activities and high membrane selectivity. Moreover, 5i exhibited rapid bactericidal properties, low resistance frequency, and good capabilities of disrupting bacterial biofilms. Mechanism studies revealed that 5i destroyed bacterial cell membranes, resulting in bacterial death. Additionally, 5i displayed high biosafety and potent in vivo anti-infective potency in a murine sepsis model. Our study indicates that these honokiol/magnolol amphiphiles shed light on developing novel antibacterial agents, and 5i is a potential antibacterial candidate for combating MRSA infections.

No abstract

To improve the insecticidal activity of (+)-nootkatone, a series of 42 (+)-nootkatone thioethers containing 1,3,4-oxadiazole/thiadiazole moieties were prepared to evaluate their insecticidal activities against Mythimna separata Walker, Myzus persicae Sulzer, and Plutella xylostella Linnaeus. Insecticidal evaluation revealed that most of the title derivatives exhibited more potent insecticidal activities than the precursor (+)-nootkatone after the introduction of 1,3,4-oxadiazole/thiadiazole on (+)-nootkatone. Among all of the (+)-nootkatone derivatives, compound 8c (1 mg/mL) exhibited the best growth inhibitory (GI) activity against M. separata with a final corrected mortality rate (CMR) of 71.4%, which was 1.54- and 1.43-fold that of (+)-nootkatone and toosendanin, respectively; 8c also displayed the most potent aphicidal activity against M. persicae with an LD50 value of 0.030 μg/larvae, which was closer to that of the commercial insecticidal etoxazole (0.026 μg/larvae); and 8s showed the best larvicidal activity against P. xylostella with an LC50 value of 0.27 mg/mL, which was 3.37-fold that of toosendanin and slightly higher than that of etoxazole (0.28 mg/mL). Furthermore, the control efficacy of 8s against P. xylostella in the pot experiments under greenhouse conditions was better than that of etoxazole. Structure–activity relationships (SARs) revealed that in most cases, the introduction of 1,3,4-oxadiazole/thiadiazole containing halophenyl groups at the C-13 position of (+)-nootkatone could obtain more active derivatives against M. separata, M. persicae, and P. xylostella than those containing other groups. In addition, toxicity assays indicated that these (+)-nootkatone derivatives had good selectivity to insects over nontarget organisms (normal mammalian NRK-52E cells and C. idella and N. denticulata fries) with relatively low toxicity. Therefore, the above results indicate that these (+)-nootkatone derivatives could be further explored as new lead compounds for the development of potential eco-friendly pesticides.

Persimmon (Diospyros kaki L.) leaves are commonly used in Asia as tea infusion and as an agent in traditional medicine. The present study aims to explore the antitumor and immunomodulatory effects of total flavonoids extract from persimmon leaves (PLF) in H22 liver tumor-bearing mice. We found that the PLF showed significant inhibition on the liver tumor growth in mice with a tumor inhibition rate of up to 49.35%. In contrast to the severe side effects of cyclophosphamide (CTX), the PLF exhibited anti-cachexia effect and showed no alternation in the body weight and food intake in mice. Moreover, compared with the vehicle control and CTX group, the PLF significantly enhanced the thymus and spleen indices, level of serum interleukin-18 (IL-18), monocyte/macrophage phagocytosis, level of serum hemolysin, and activity of natural killer (NK) cells. This study demonstrated that the PLF could effectively inhibit liver tumor growth in vivo via enhancement of the immune function in mice, and it displayed the potential to be a safe and effective anticancer agent or functional immune-enhancing agent.

BackgroundST-246® is an antiviral, orally bioavailable small molecule in clinical development for treatment of orthopoxvirus infections. An intravenous (IV) formulation may be required for some hospitalized patients who are unable to take oral medication. An IV formulation has been evaluated in three species previously used in evaluation of both efficacy and toxicology of the oral formulation.Methodology/Principal FindingsThe pharmacokinetics of ST-246 after IV infusions in mice, rabbits and nonhuman primates (NHP) were compared to those obtained after oral administration. Ten minute IV infusions of ST-246 at doses of 3, 10, 30, and 75 mg/kg in mice produced peak plasma concentrations ranging from 16.9 to 238 µg/mL. Elimination appeared predominately first-order and exposure dose-proportional up to 30 mg/kg. Short IV infusions (5 to 15 minutes) in rabbits resulted in rapid distribution followed by slower elimination. Intravenous infusions in NHP were conducted at doses of 1 to 30 mg/kg. The length of single infusions in NHP ranged from 4 to 6 hours. The pharmacokinetics and tolerability for the two highest doses were evaluated when administered as two equivalent 4 hour infusions initiated 12 hours apart. Terminal elimination half-lives in all species for oral and IV infusions were similar. Dose-limiting central nervous system effects were identified in all three species and appeared related to high Cmax plasma concentrations. These effects were eliminated using slower IV infusions.Conclusions/SignificancePharmacokinetic profiles after IV infusion compared to those observed after oral administration demonstrated the necessity of longer IV infusions to (1) mimic the plasma exposure observed after oral administration and (2) avoid Cmax associated toxicity. Shorter infusions at higher doses in NHP resulted in decreased clearance, suggesting saturated distribution or elimination. Elimination half-lives in all species were similar between oral and IV administration. The administration of ST-246 was well tolerated as a slow IV infusion.

Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) continue to endanger public health. Here, we report the synthesis of neolignan isomagnolone (I) and its isomer II, and the preparation of a series of novel neolignan-antimicrobial peptide (AMP) mimic conjugates. Notably, conjugates III5 and III15 exhibit potent anti-MRSA activity in vitro and in vivo, comparable to that of vancomycin, a current effective treatment for MRSA. Moreover, III5 and III15 display not only fast-killing kinetics and low resistance frequency but also low toxicity as well as effects on bacterial biofilms. Mechanism studies reveal that III5 and III15 exhibit rapid bactericidal effects through binding to the phosphatidylglycerol (PG) and cardiolipin (CL) of the bacterial membrane, thereby disrupting the cell membranes and allowing increased reactive oxygen species (ROS) as well as protein and DNA leakage. The results indicate that these neolignan-AMP mimic conjugates could be promising antimicrobial candidates for combating MRSA infections.

Natural products are an abundant and environmentally friendly source for controlling plant pathogens and insect pests. Toward the development of new natural product-based pesticides, here, a series of osthole-based isoxazoline derivatives were prepared by [3 + 2] annulation and evaluated for their insecticidal activities and toxicities. The structures of all osthole-based isoxazoline derivatives were characterized by various spectral analyses, and derivative B13 was further confirmed by X-ray crystallography. Among all the osthole derivatives, B2 displayed the most promising growth inhibitory effect on Mythimna separata with a final corrected mortality rate of 96.4% ± 3.3, which was 1.80 times higher than those of both osthole and toosendanin. Derivative B13 displayed the most promising larvicidal activity against Plutella xylostella with an LC 50 value of 0.220 mg/mL, which was superior to rotenone. Furthermore, both B13 and B21 also exhibited better control efficacy against P. xylostella than rotenone in the pot experiments. Additionally, the toxicity evaluation suggested that these osthole-based isoxazoline derivatives showed relatively low toxicity toward nontarget organisms. Given these results, osthole derivatives B2, B13, and B21 could be deeply developed as natural insecticidal agents in agriculture.

An intelligent surgical knife (iKnife) coupled with rapid evaporative ionization mass spectrometry (REIMS) was employed for the lipidomic profiling of fresh and frozen−thawed beef muscle. The data were obtained by REIMS and then processed using multivariate statistical analysis methods including principal component analysis−linear discriminant analysis (PCA−LDA) and orthogonal partial least-squares discriminant analysis (OPLS-DA). The discrimination of fresh and frozen−thawed meat has been achieved, and the real-time identification accuracy was 92−100%. Changes in the composition and content of fatty acids and phospholipids were statistically analyzed by OPLS-DA, and the ions of m/z 279.2317, m/z 681.4830, and m/z 697.4882 were selected as differential compounds/metabolites. The developed method was also successfully applied in the discrimination of fresh and frozen−thawed meat samples. These results showed that REIMS as a high-throughput, rapid, and real-time mass spectrometry detection technology can be used for the identification of fresh and frozen−thawed meat samples.