Herbicides have consistently contributed to yield increases in crop production for many decades however, those same herbicides are facing the loss of effectiveness because of the rapid spread of weed resistance. Since the first instance of herbicide resistance to triazine herbicides over 50 years ago, resistant biotypes have been observed to the major herbicides numbering more than 150 different weed species due to excessive use of single mode of action (MoA)treatments combined with limited crop rotation practices. In the US, the most well-known broad-spectrum herbicide used in major crops, glyphosate is facing huge challenges due to the appearance of many resistant weed species. The consequences of the loss of effectiveness of the current herbicide choices, coinciding with an increasing world population with improved living standards, is beginning to present a severe constraint on food security globally. Unfortunately, the agriculture industry has been unable to find any new mechanism in the last 30 years. The absence of choices of novel active ingredients along with the increased costs of developing new entities is forcing the industry to rely on older modes of action which, with limited application, means lower annual yields of the major crops as the number of resistant weed species increases. The Chemical Genomics group in FMC Agricultural Solutions Discovery has been building ‘Chemistry to Gene’ (C2G) capability to identify new MoAsby applying chemical genomics tools. We have recently discovered that compounds described in WO2017075559A1, are potent selective herbicides with novel action that control many grasses. As a result of knowledge of the mechanism of this area of chemistry, we have extended the work to include a ‘Gene to Chemistry’ (G2C) approach to provide new structural starting points for more synthesis projects.

Growing resistance to insecticides, especially pyrethroids, poses an increased risk for insect control world-wide. Thus, alternative compounds are urgently needed. Accordingly, my laboratory has been investigating synthetic materials, as well as natural products, which are an attractive source of new chemistries. We have examined the insecticidal and synergistic activity of new compounds using Drosophila melanogaster and the mosquitoes Aedes aegypti and Anopheles gambiae as model insects. In addition, we have also been investigating the modes of action of experimental molecules in various physiological preparations. Natural product research included thymol, which was toxic to Ae. aegypti adults at doses (3-50 μg/mg) similar to published toxicities for the cabbage looper larvae, Trichoplusia ni. On homomultimeric Anopheles gambiae GABA receptor-chloride channel complex expressed in Xenopus laevis oocytes, thymol acts as a positive allosteric modulator, increasing the potency and maximal effectiveness of applied GABA, consistent with the sluggish paralysis it elicits in exposed insects. Other studies investigated matrine; a bioactive component extracted from Sophora flavescens that is used as the main ingredient in Chinese bio-pesticidal products. Matrine caused flaccid paralysis in headless fourth instar larvae of Ae. aegypti (50% paralysis in 5 hours at 8 ppm) and was toxic to adult females by contact (topical LD50 = 258 ng/mg). Adult toxicity was increased about 2-fold by pretreatment with the mono-oxygenase inhibitor, piperonyl butoxide. Interestingly, this compound was much less effective on D. melanogaster in either glass contact or feeding bioassays. Adult mosquito knockdown was rapid, with little or no expression of hyperactivity or hyperexcitability. Matrine (ca. 1 mM) had effects similar to thymol on expressed An. gambiae GABA receptors, and reduced EPSP amplitude at the Musca domestica neuromuscular junction, without any evidence of neuroexcitation or membrane depolarization. These physiological actions are sufficient to explain the whole animal intoxication by matrine, but require relatively high concentrations to manifest themselves. Other studies tested a series of potassium channel blockers, including 1-((2-chlorophenyl)diphenylmethyl)-1H-pyrazole (TRAM-34), 11-dansylaminoundecanoic acid (DAUDA), and 5-hydroxydecanoic acid (5-HDC) as insecticides and synergists of pyrethroids. We also evaluated the action of these compounds in patch clamp recordings of engineered HEK cells expressing Anopheles gambiae Kv2.1 channels. Patch clamp studies revealed that fatty acid compounds without functional groups in the alkyl chain (e.g., decanoate, DAUDA) yielded a more potent blocking action on Kv2.1 currents than substituted fatty acids (e.g., 5-HDC). Also, in comparison to 2-methoxy-N-((1-phenylcyclopentyl)methyl)benzamide (2S-65465), a known Kv2 channel blocker (IC50 = 100 nM), decanoate and DAUDA were 6-fold and 12-fold less active, respectively, as blockers of potassium current. TRAM-34 was the least potent inhibitor tested in patch clamp studies (IC50 = 30 uM). When tested on D. melanogaster CNS, the compounds typically gave an initial increase in firing rate, followed by a decrease, both effects at micromolar concentrations. Various toxicity assays showed the same potency ranking as that obtained through patch-clamp recordings, indicating a possible connection between channel block and whole organism effects. In order to possibly improve the insecticidal activity of the fatty acids, we synthesized derivatized analogs (e.g., methyl esters) presumed to better penetrate the cuticular barrier, but activity did not improve. Finally, in contrast to a published patent, we found that fatty acids did not show much synergism with pyrethroids. The implications of this work for resistance management will be discussed.

In the current study, we investigated the inhibitory activity of water soluble β-glucan from oat (Avena sativa) against various digestive enzymes such as α-glucosidase, sucrase, maltase and glucoamylase. Inhibition of these enzymes involved in the absorption of disaccharide can significantly decrease the post-prandial increase of blood glucose level after a mixed carbohydrate diet. The β-glucan had the highest documented rate of small intestinal sucrase inhibitory activity (2.83 mg/mL, IC50) relevant for potentially managing post-prandial hyperglycemia. Furthermore, we evaluated the effects of β-glucan on the level of post-prandial blood glucose in animal model. The post-prandial blood glucose levels were tested two hours after sucrose/starch administration, with and without β- glucan (100, and 500 mg/kg-body weight). The maximum blood glucose levels (Cmax) of β-glucan administration group were decreased by about 23% (from 219.06±27.82 to 190.44±13.18, p<0.05) and 10% (from 182.44±13.77 to 165.64±10.59, p<0.01) in starch and sucrose loading test, respectively, when compared to control in pharmacodynamics study. The β -Glucan administration significantly lowered the mean, maximum, and minimum level of post-prandial blood glucose at 30 min after meal. In view of the foregoing, it is felt that our findings suggest that β-glucan from oat serves to reduce post-prandial blood glucose rise secondary to slower absorption of glucose in the small intestine, via carbohydrate hydrolyzing enzymes inhibition.

Insecticidal crystal toxins from the bacterium Bacillus thuringiensis (Bt) kill insects via a complex mode of action resulting in the creation of cytolytic pores in the membrane of midgut epithelial cells. These toxins are expressed in transgenic cotton and maize which have been adopted worldwide to control lepidopteran pests while reducing dependence on chemical insecticides. However, insect resistance to Bt toxins is increasing in certain key pest species. Beginning with Heliothis virescens, genetic studies in Bt-resistant Lepidoptera and Coleoptera have found mutations in ABC transporters. Cry1A, Cry1C, Cry2A, and Cry3B toxins each appear to target a different member of the ABC superfamily. These studies confirm the essential role of ABC proteins in Bt toxin mode of action. It is proposed that ABC proteins assist in the insertion of the toxin into the midgut epithelial membrane, a crucial step for which the mechanism has not been known in detail. Properties of ABC transporters suggest strategies to increase efficacy of Bt toxins and to delay the evolution of Bt toxin resistance in target insect pests.

The acetylcholinesterase (AChE) inhibition of 12 plant-derived insecticidal compounds (anethol, anisaldehyde, 3-carene, 1,8-cineol, ethyl-cinnamate, linalool, magnolol, ethyl-p-methoxycinnamate, p-methoxycinamic acid, safrol, terpinen-4-ol, and α-terpineol) towards adult mosquitoes were examined by using Ellman method. Result were compared with those of dichlorvos, a potent AChE inhibitor. 3-Carene strongly inhibited AChE (IC50, 5.78×10-4 M), although the inhibition of the compound was lower than dichlorvos (IC50, 1.45×10-4 M). These results indicate that 3-carene acts as an AChE inhibitor, although an involvement of other insecticidal mechanism(s) might not be ruled out.

배추좀나방의 발육단계별 indoxacarb의 살충활성, 침투이행성 및 잔효성을 조사하였고, esterase, acetylcholinesterase, glutathione S-transferase 등의 효소활성에 미치는 영향을 검토하였다. 배추좀나방 유충에 대해서 높은 살충효과를 나타내었으나, 알과 번데기에 대해서는 살충율이 이하이었다. 엽면침투이행성과 근부침투이행성의 효과는 없었으며, 잔효성은 10일째까지 의 살충효과를 유지하였다. Indoxacarb는 esterase와 glutathione S-transferase의 활성은 저해하지 않았지만 acetylcholinesterase의 활성을 저해하였다.