Jun Ning

Design, synthesis and biological evaluation of organophosphorous-homodimers as dual binding site acetylcholinesterase inhibitors.

The cluster effect is an effective strategy to explore new lead compounds, and has been successfully applied in rational drug design and screening. A series of novel organophosphorous-homodimers were designed and synthesized based on the dual-site structure characteristics of acetylcholinesterase (AChE). The compounds were evaluated in vitro for their inhibitory activity to AChE extracted from Drosophila melanogaster and Musca domestic. Compound 4H showed an excellent inhibitor activity to both Drosophila melanogaster and Musca domestic with the corresponding IC(50) values of 23 and 168 nM, respectively. Meanwhile, its activities against Drosophila melanogaster and Musca domestic AChE were more than 10,00,000 and 100,000-fold higher compared with the parent compound (MH), and was up to 245 and 107-fold higher than those of the positive control omethoate. The molecular docking study revealed that 4H possessed an optimal spacer length and can perfectly fit into the central pocket, active gorge, and peripheral site of DmAChE, and consequently exhibited highly improved inhibitor potency to DmAChE. The bioassay tests showed that 4 series compounds showed prominent insecticidal activities against both Lipaphser erysimi and Tetranychus cinnbarinus at a concentration of 200mg/L. The insecticide activity of compound 4H was particularly significant that can cause 96% mortality to Tetranychus cinnbarinus after 24h of treatment.

Synthesis and insecticidal activity of novel carbamate derivatives as potential dual-binding site acetylcholinesterase inhibitors.

In biological systems, bivalent ligands often possess increased functional affinity for their receptors compared with monovalent ligands. On the basis of the structure of acetylcholinesterase (AChE), a series of novel carbamate heterodimetic derivatives were designed and synthesized with the aim of increasing the potency toward AChE inhibition. The AChE inhibitory ability of all the novel compounds was tested using AChE obtained from the brain of the housefly. The bioassay results showed that compounds 6j, 6k, 6m, 6n, 6p, and 6q had increased inhibitory activities in comparison with parent phenyl N-methylcarbamate (MH) at the concentration of 100 mg/L. Among them, the most potent AChE inhibitor of these compounds was 6q (IC(50) = 12 μM), which showed 62-fold greater AChE inhibitory activity than that of MH and 12-fold greater activity than metolcarb (MT), which suggested that the 3-nitrophenoxy moiety of compound 6q was able to interact with the aromatic amino acid residues lining the gorge and the phenyl N-methylcarbamate moiety was able to interact with the catalytic sites of AChE, simultaneously. The insecticidal activities of compounds 6j, 6k, 6m, 6n, 6p, and 6q were further evaluated. Consistent with the result in vitro bioassay, those compounds demonstrated better activities against Lipaphis erysimi than parent compound MH at the concentration of 300 mg/L, and compound 6q showed the best insecticidal activity, causing 98% mortality after 24 h of treatment.

Synthesis and herbicidal activity of novel N-(2,2,2)-trifluoroethylpyrazole derivatives.

A series of novel N-(2,2,2)-trifluoroethylpyrazole derivatives were synthesized, and their structures were characterized by IR, mass spectroscopy, (1)H NMR, and elementary analysis. The herbicidal activities of target compounds 10a-c and 11a-c were assessed. The bioassay results showed that these pyrazole derivatives exhibited good herbicidal activity. Compound 11a showed the best pre-emergence herbicidal effects against both dicotyledonous and monocotyledonous weeds with good safety to maize and rape at the dosage of 150 g a.i. ha(-1) in greenhouse. Field trials indicated that compound 11a exhibited better herbicidal activity by soil application than the commercial herbicide, metolachlor. Moreover, compound 11a showed the same level of safety to maize as metolachlor.

Design, synthesis and bioactivity of novel phthalimide derivatives as acetylcholinesterase inhibitors

A series of novel phthalimide derivatives related to benzylpiperazine were synthesized and evaluated as cholinesterase inhibitors. The results showed that all compounds were able to inhibit acetylcholinesterase (AChE), with two of them dramatically inhibiting butyrylcholinesterase (BuChE). Most compounds exhibited potent anti-AChE activity in the range of nM concentrations. In particular, compounds 7aIII and 10a showed the most potent activity with the IC50 values of 18.44 nM and 13.58 nM, respectively. To understand the excellent activity of these compounds, the structure-activity relationship was further examined. The protein-ligand docking study demonstrated that the target compounds have special binding modes and these results are in agreement with the kinetic study.

Homo- and hetero-dimers of inactive organophosphorous group binding at dual sites of AChE.

Homo- and hetero-dimers of inactive organophosphorous group(s) dramatically enhanced the acetylcholinesterase (AChE; EC 3.1.1.7) inhibiting potency, with the highest potency observed at a tether length of 6 methylene groups (6d) for the homodimers, and 7 methylene groups (8e) for the heterodimers. The docking model of Drosophila melanogaster AChE suggested that 6d and 8e bound at the catalytic and peripheral sites of AChE, in which two organophosphorous groups of 6d individually oriented towards TRP83 of catalytic sites and TRP321 of peripheral sites, and phthalicimide group of 8e was appropriately arranged for a π-π interaction with the phenyl ring of TYR330, furthermore, the organophosphorous group introduced hydrophobic interaction with TRP83. The compounds prepared in this work demonstrated high insecticidal activity to Lipaphis erysimi and Tetranychus cinnbarinus at the concentration 300mg/L.

Attraction of Coffee Bean Weevil, Araecerus fasciculatus, to Volatiles from the Industrial Yeast Kluyveromyces lactis

The coffee bean weevil (CBW), Araecerus fasciculatus (De Geer, 1775) (Coleoptera: Anthribidae) is an important pest of stored products such as grains, coffee beans, cassava, and traditional Chinese medicine materials. In China, CBW causes large losses of Daqu, a traditional Chinese liquor fermentation starter, and, unfortunately, the use of conventional insecticides against CBW is not suitable in Daqu storage. We found CBW to be highly attracted to fermenting yeast cultures, such as Kluyveromyces lactis. Eight volatile compounds, produced by fermenting cultures and not by sterile samples, were identified by gas chromatography coupled with mass spectrometry. Five of these substances elicited significant responses in Y-tube behavioral bioassays. Field trapping experiments revealed 2-phenylethanol and 2-phenylethyl acetate to be crucial for attraction of CBW. Results show that yeast volatiles play an important role in host location, and that 2-phenylethanol and 2-phenylethyl acetate could be utilized as potential attractants in monitoring and control systems against this important pest.

Assessment of genotoxic effects of flumorph by the comet assay in mice organs

The present study investigated the genotoxic effects of flumorph in various organs (brain, liver, spleen, kidney and sperm) of mice. The DNA damage, measured as comet tail length (µm), was determined using the alkaline comet assay. The comet assay is a sensitive assay for the detection of genotoxicity caused by flumorph using mice as a model. Statistically significant increases in comet assay for both dose-dependent and duration-dependent DNA damage were observed in all the organs assessed. The organs exhibited the maximum DNA damage in 96 h at 54 mg/kg body weight. Brain showed maximum DNA damage followed by spleen > kidney > liver > sperm. Our data demonstrated that flumorph had induced systemic genotoxicity in mammals as it caused DNA damage in all tested vital organs, especially in brain and spleen.

Sex pheromone of the alfalfa plant bug, Adelphocoris lineolatus

In northern China, due to the large‐scale adoption of transgenic Bacillus thuringiensis Berliner (Bt) cotton, the number of Adelphocoris lineolatus (Goeze) (Hemiptera: Miridae) has increased quickly, causing significant loss in cotton and alfalfa production. One of the environmentally safe strategies without use of pesticides is the application of insect pheromone for mating disruption. In our study, we aim to identify the active components in sexually mature virgin female A. lineolatus, and activity and optimal ratio of these components. By using gas chromatography–mass spectrometry (GC‐MS) and gas chromatography–electroantennographic detection (GC‐EAD), we identified three active compounds: hexyl butyrate (HB), (E)‐2‐hexenyl butyrate (E2HB), and (E)‐4‐oxo‐2‐hexenal (4‐OHE). We examined the release rate of septum and tube dispensers in a wind tunnel. In a field experiment, deletion of 4‐OHE or E2HB resulted in significant suppression of male trap catches, indicating that E2HB or 4‐OHE may be the active pheromone components. Traps baited with a blend of 4‐OHE and E2HB at 2:5, 3:4, and 4:3 caught significantly more males, suggesting that the optimal ratio of 4‐OHE and E2HB could be in the range of 1:1 to 1:2. The addition of a large amount of HB could strongly reduce the attractive activity of both virgin females and artificial lures. We also compared the attractiveness of septum lures and tube lures in field experiments. The septum lures attracted males in the first 3 days. The tube lures caught more males after 3 days and the attractive effects existed up to 5 weeks, suggesting them as a tool for long‐term monitoring and control of plant bugs.

Synthesis and biological activity of novel benzimidazole derivatives as potential antifungal agents

In the present study, a series of novel benzimidazole derivatives containing chrysanthemum acid moieties was designed and synthesized. Preliminary investigation of biological activity indicated that all of the compounds exhibited lower activity than that of beta-cypermethrin against Plutella xylostella and Lipaphis erysimi; meanwhile, they showed good inhibitory activity against Botrytis cinerea and Sclerotinia sclerotiorum in vitro. The fungicidal activity of compound 8a against B. cinerea was approximately equal to that of thiabendazole and was twice as active against S. sclerotiorum as was thiabendazole. In addition, compound 9e displayed the most potent inhibitory activity against both fungi and was almost twice as potent as thiabendazole.

Leucocytes DNA damage in mice exposed to JS-118 by the comet assay

JS-118 is an extensively used insecticide in China. The present study investigated the genotoxic effect of JS-118 on whole blood at 24, 48, 72 and 96 h by using alkaline comet assay. Male Kunming mice were given 6.25, 12.5, 25, 50 and 100 mg/kg BW of JS-118 intraperitoneally. A statistically significant increase in all comet parameters indicating DNA damage was observed at 24 h post-treatment (p < 0.05). A clear concentration-dependent increase of DNA damage was revealed as evident by the OTM (arbitrary units), tail length (µm) and tail DNA (%). From 48 h post-treatment, a gradual decrease in mean comet parameters was noted. By 96 h of post-treatment, the mean comet tail length reached control levels indicating repair of damaged DNA. This study on mice showed different DNA damage depending on the concentration of JS-118 and the period of treatment. The present study provided further information of the potential risk of the genetic damage caused by JS-118.