Synthesis and biological activity of analogs of the antifungal antibiotic UK-2A. III. Impact of modifications to the macrocycle isobutyryl ester position.

BACKGROUND: Fenpicoxamid (Inatreq™ active), a new fungicide under development by Corteva Agriscience™, Agriculture Division of DowDuPont, is an isobutyryl acetal derivative of the antifungal antibiotic UK-2A. SAR studies around the picolinamide ring and benzyl substituents attached at positions 3 and 8, respectively, of the UK-2A bislactone macrocycle have recently been documented. This study focuses on replacement of the isobutyryl ester group in the 7 position. RESULTS: Thirty analogs, predominantly esters and ethers, were prepared and evaluated for inhibition of mitochondrial electron transport and in vitro growth of Zymoseptoria tritici, Leptosphaeria nodorum, Pyricularia oryzae and Ustilago maydis. Aliphatic substituents containing four to six carbon atoms deliver strong intrinsic activity, the pivaloate ester (IC50 1.44 nM) and the n-butyl, 1-Me-propyl, 3,3-diMe-propyl and 2-c-propyl propyl ethers (IC50 values = 1.08, 1.14, 1.15 & 1.32 nM, respectively) being the most active derivatives. QSAR modelling identified solvation energy (Esolv ) and critical packing parameters (vsurf_CP) as highly significant molecular descriptors for explaining relative intrinsic activity of analogs. Activity translation to fungal growth inhibition and disease control testing was significantly influenced by intrinsic activity and physical properties, the cyclopropanecarboxylate ester (log D 3.67, IC50 3.36 nM, Z. tritici EC50 12 µg L-1 ) showing the strongest Z. tritici activity in protectant tests. CONCLUSIONS: Substitution of the isobutyryl ester group of UK-2A generates analogs that retain strong antifungal activity against Z. tritici and other fungi. © 2019 Society of Chemical Industry.

Synthesis and biological activity of analogs of the antifungal antibiotic UK-2A. I. Impact of picolinamide ring replacement.

BACKGROUND: The antifungal antibiotic UK-2A strongly inhibits mitochondrial electron transport at the Qi site of the cytochrome bc1 complex. Previous reports have described semi-synthetic modifications of UK-2A to explore the structure-activity relationship (SAR), but efforts to replace the picolinic acid moiety have been limited. RESULTS: Nineteen UK-2A analogs were prepared and evaluated for Qi site (cytochrome c reductase) inhibition and antifungal activity. While the majority are weaker Qi site inhibitors than UK-2A (IC50 , 3.8 nM), compounds 2, 5, 13 and 16 are slightly more active (IC50 , 3.3, 2.02, 2.89 and 1.55 nM, respectively). Compared to UK-2A, compounds 13 and 16 also inhibit growth of Zymoseptoria tritici and Leptosphaeria nodorum more strongly, while 2 and 13 provide stronger control of Z. tritici and Puccinia triticina in glasshouse tests. The relative activities of compounds 1-19 are rationalized based on a homology model constructed for the Z. tritici Qi binding site. Physical properties of compounds 1-19 influence translation of intrinsic activity to antifungal growth inhibition and in planta disease control. CONCLUSIONS: The 3-hydroxy-4-methoxy picolinic acid moiety of UK-2A can be replaced by a variety of o-hydroxy-substituted arylcarboxylic acids that retain strong activity against Z. tritici and other agriculturally relevant fungi. © 2018 Society of Chemical Industry.

SAR studies directed toward the pyridine moiety of the sap-feeding insecticide sulfoxaflor (Isoclast™ active).

Sap-feeding insect pests constitute a major insect pest complex that includes a range of aphids, whiteflies, planthoppers and other insect species. Sulfoxaflor (Isoclast™ active), a new sulfoximine class insecticide, targets sap-feeding insect pests including those resistant to many other classes of insecticides. A structure activity relationship (SAR) investigation of the sulfoximine insecticides revealed the importance of a 3-pyridyl ring and a methyl substituent on the methylene bridge linking the pyridine and the sulfoximine moiety to achieving strong Myzus persicae activity. A more in depth QSAR investigation of pyridine ring substituents revealed a strong correlation with the calculated logoctanol/water partition coefficient (SlogP). Model development resulted in a highly predictive model for a set of 18 sulfoximines including sulfoxaflor. The model is consistent with and helps explain the highly optimized pyridine substitution pattern for sulfoxaflor.

Self-Healing of Core-Shell Magnetic Polystyrene Nanocomposites.

High heat generation is reported in core-shell magnetic nanoparticle polystyrene (PS) nanocomposites (3.5, 10 wt %) when they are placed in a high-frequency ac magnetic field. These magnetic nanoparticles with cobalt iron oxide core and manganese iron oxide shell were synthesized and characterized by wide-angle X-ray scattering (WAX), thermal gravimetric analysis (TGA), transmission electron microscopy (TEM), and ac field gradient magnetometery. When placed in a high-frequency ac magnetic field, the thermal energy generated in the magnetic polystyrene nanocomposites resulted in a surface temperature increase. The heat generation is attributed to the contribution of Néel relaxation and hysteresis of the core-shell magnetic nanoparticles in the solid state. The maximum surface temperature increased with increasing nanoparticle content and resulted in melting of the magnetic polystyrene nanocomposite.

Transparent large-strain thermoplastic polyurethane magnetoactive nanocomposites.

Organically modified superparamagnetic MnFe(2)O(4)/thermoplastic polyurethane elastomer (TPU) nanocomposites (0.1-8 wt %) were prepared by solvent mixing followed by solution casting. Linear aliphatic alkyl chain modification of spherical MnFe(2)O(4) provided compatibility with the TPU containing a butanediol extended polyester polyol-MDI. All MnFe(2)O(4)/TPU nanocomposite films were superparamagnetic and their saturation magnetization, σ(s), increased with increasing MnFe(2)O(4) content. All nanocomposite films exhibited large deformations (>10 mm) under a magneto-static field. This is the first report of large actuation of magnetic nanoparticle nanocomposites at low-loading levels of 0.1 wt % (0.025 vol %). The maximum actuation deformation of the MnFe(2)O(4)/TPU nanocomposite films increased exponentially with increasing nanoparticle concentration. An empirical correlation between the maximum displacement, saturation magnetization, and magnetic nanoparticle loading is proposed. The cyclic deformation actuation of a 6 wt % surface modified MnFe(2)O(4)/TPU, in a low magnetic field 151 < B(y) < 303 Oe, exhibited excellent reproducibility and controllability. MnFe(2)O(4)/TPU nanocomposite films (0.1-2 wt %) were transparent and semitransparent over the wavelengths from 350 to 700 nm.

Biological characterization of sulfoxaflor, a novel insecticide.

BACKGROUND: The commercialization of new insecticides is important for ensuring that multiple effective product choices are available. In particular, new insecticides that exhibit high potency and lack insecticidal cross-resistance are particularly useful in insecticide resistance management (IRM) programs. Sulfoxaflor possesses these characteristics and is the first compound under development from the novel sulfoxamine class of insecticides. RESULTS: In the laboratory, sulfoxaflor demonstrated high levels of insecticidal potency against a broad range of sap-feeding insect species. The potency of sulfoxaflor was comparable with that of commercial products, including neonicotinoids, for the control of a wide range of aphids, whiteflies (Homoptera) and true bugs (Heteroptera). Sulfoxaflor performed equally well in the laboratory against both insecticide-susceptible and insecticide-resistant populations of sweetpotato whitefly, Bemisia tabaci Gennadius, and brown planthopper, Nilaparvata lugens (Stål), including populations resistant to the neonicotinoid insecticide imidacloprid. These laboratory efficacy trends were confirmed in field trials from multiple geographies and crops, and in populations of insects with histories of repeated exposure to insecticides. In particular, a sulfoxaflor use rate of 25 g ha(-1) against cotton aphid (Aphis gossypii Glover) outperformed acetamiprid (25 g ha(-1) ) and dicrotophos (560 g ha(-1) ). Sulfoxaflor (50 g ha(-1) ) provided a control of sweetpotato whitefly equivalent to that of acetamiprid (75 g ha(-1) ) and imidacloprid (50 g ha(-1) ) and better than that of thiamethoxam (50 g ha(-1) ). CONCLUSION: The novel chemistry of sulfoxaflor, its unique biological spectrum of activity and its lack of cross-resistance highlight the potential of sulfoxaflor as an important new tool for the control of sap-feeding insect pests.

Discovery and characterization of sulfoxaflor, a novel insecticide targeting sap-feeding pests.

The discovery of sulfoxaflor [N-[methyloxido[1-[6-(trifluoromethyl)-3-pyridinyl]ethyl]-λ(4)-sulfanylidene] cyanamide] resulted from an investigation of the sulfoximine functional group as a novel bioactive scaffold for insecticidal activity and a subsequent extensive structure-activity relationship study. Sulfoxaflor, the first product from this new class (the sulfoximines) of insect control agents, exhibits broad-spectrum efficacy against many sap-feeding insect pests, including aphids, whiteflies, hoppers, and Lygus, with levels of activity that are comparable to those of other classes of insecticides targeting sap-feeding insects, including the neonicotinoids. However, no cross-resistance has been observed between sulfoxaflor and neonicotinoids such as imidacloprid, apparently the result of differences in susceptibility to oxidative metabolism. Available data are consistent with sulfoxaflor acting via the insect nicotinic receptor in a complex manner. These observations reflect the unique structure of the sulfoximines compared with neonicotinoids.

Crystallography of ordered colloids using optical microscopy. 2. Divergent-beam technique.

A technique has been developed to extract quantitative crystallographic data from randomly oriented colloidal crystals using a divergent-beam approach. This technique was tested on a series of diverse experimental images of colloidal crystals formed from monodisperse suspensions of sterically stabilized poly-(methyl methacrylate) spheres suspended in organic index-matching solvents. Complete sets of reciprocal lattice basis vectors were extracted in all but one case. When data extraction was successful, results appeared to be accurate to about 1% for lattice parameters and to within approximately 2 degrees for orientation. This approach is easier to implement than a previously developed parallel-beam approach with the drawback that the divergent-beam approach is not as robust in certain situations with random hexagonal close-packed crystals. The two techniques are therefore complimentary to each other, and between them it should be possible to extract quantitative crystallographic data with a conventional optical microscope from any closely index-matched colloidal crystal whose lattice parameters are compatible with visible wavelengths.

Crystallography of ordered colloids using optical microscopy. 1. Parallel-beam technique.

A technique is described for determining the reciprocal lattice basis vectors of randomly oriented colloidal crystals from optical Fourier transform images using a parallel incident beam. This approach is demonstrated by comparing information gathered using this technique with results from real-space images for a single colloidal crystal grain with a random hexagonal close-packed structure. The reciprocal space and available real-space results agreed to within experimental error. The complete set of reciprocal lattice basis vectors was determined using the proposed technique in contrast to the partial lattice information available from real-space images. This technique appears to be generally capable of measuring lattice parameters to within 1% and orientation to better than 1 degrees .

An autonomous phase-boundary detection technique for colloidal hard sphere suspension experiments.

Colloidal suspensions of monodisperse spheres are used as physical models of thermodynamic phase transitions and as precursors to photonic band gap materials. Current techniques for identifying the phase boundaries involve manually identifying the phase transitions, which is very tedious and time-consuming. In addition, current image analysis techniques are not able to distinguish between densely packed phases within conventional microscope images, which are mainly characterized by degrees of randomness or order with similar grayscale value properties. We have developed an intelligent machine vision technique that automatically identifies colloidal phase boundaries. The technique utilizes intelligent image processing algorithms that accurately identify and track phase changes vertically or horizontally for a sequence of colloidal hard sphere suspension images. This technique is readily adaptable to any imaging application wherein regions of interest are distinguished from the background by differing patterns of motion over time.