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.

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.

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.

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Infections caused by multidrug-resistant (MDR) bacteria are increasing worldwide, and with limited clinically available antibiotics, it is urgent to develop new antimicrobials to combat these MDR bacteria. Here, a class of novel amphiphilic xanthohumol derivatives were prepared using a building-block approach. Bioactivity assays showed that the molecule IV15 not only exhibited a remarkable antibacterial effect against clinical methicillin-resistant Staphylococcus aureus (MRSA) isolates (MICs: 1–2 μg/mL) but also had the advantages of rapid bactericidal properties, low toxicity, good plasma stability, and not readily inducing bacterial resistance. Mechanistic studies indicated that IV15 has good membrane-targeting ability and can bind to phosphatidylglycerol and cardiolipin in bacterial membranes, thus disrupting the bacterial cell membranes and causing increased intracellular reactive oxygen species and leakage of proteins and DNA, eventually resulting in bacterial death. Notably, IV15 exhibited remarkable in vivo anti-MRSA efficacy, superior to vancomycin, making it a potential candidate to combat MRSA infections.