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.

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.

To discover novel natural-product-based insecticide candidates, herein, a variety of osthole-derived Nbenzoylthioureas were synthesized and assessed for their insecticidal activities against three insect pests. An insecticidal assay showed that most of the target osthole-derived N-benzoylthioureas displayed a more potent and broad-spectrum insecticidal effect than the parent osthole after the introduction of N-benzoylthioureas on the C-3′ position of osthole. Compound B24 displayed the most potent growth inhibitory (GI) effect on Mythimna separata Walker, with a final corrected mortality rate of 82.1% when treated with a concentration of 1 mg/mL, which was 1.64-and 1.53-fold higher in comparison to osthole and the botanical insecticide toosendanin, respectively. Compounds B22, B23, and B25 displayed a more promising aphicidal effect on Myzus persicae Sulzer, and their LD 50 values were 0.015, 0.017, and 0.019 μg/larvae, respectively, superior to the commercially available insecticide rotenone (0.024 μg/larvae). Derivatives B19, B20, B23, and B25 displayed more potent larvicidal activity against Plutella xylostella Linnaeus, with LC 50 values of 0.22, 0.26, 0.15, and 0.30 mg/mL, respectively, exceeding that of rotenone (0.37 mg/mL). Furthermore, both compounds B19 and B23 against P. xylostella were found to be more effective than rotenone in a control efficacy assay under greenhouse conditions. The structure−activity relationship (SAR) suggested that osthole-derived N-benzoylthioureas are more active in most cases when the R group is an electron-withdrawing group than when it is an electron-donating group, especially for halogenated groups. Additionally, the potent compounds B19 and B23 possessed good selectivity and were less toxic to non-target organisms. This study suggests that these osthole-derived N-benzoylthioureas could be further studied in depth as eco-friendly natural product pesticides in crop protection.

Many phytopathogenic fungi can easily infect crops, resulting in crop yield reductions. In continuation of our efforts to develop natural product (NP)-based antifungal agents, a series of N-phenylpyrazole sarisan hybrids 6a -v were prepared via I 2 -mediated oxidative cyclization, and their structures were determined by various spectral analyses including IR, 1 H-NMR and ESI-MS. Among all N-phenylpyrazole sarisan hybrids, compounds 6a, 6b, 6e, 6i, 6j and 6r exhibited more encouraging antifungal action against at least two phytopathogenic fungi than the reference fungicide hymexazol. Especially, 6a displayed really encouraging and broad-spectrum antifungal activity against F. graminearum, V. mali, and F. oxysporum f.sp.niveum with the EC 50 values of 12.6 � 0.9, 18.5 � 0.2, and 37.4 � 1.8 μg/mL, respectively. Moreover, the structure-activity relationships (SARs) were also observed. Additionally, compounds 6a and 6e also exhibited relative low toxicity on normal LO2 cells. This study indicates that these N-phenylpyrazole sarisan hybrids would shed light on developing novel NP-based antifungal agents.