BACKGROUNDThe development of novel highly efficacious fungicides that lack cross‐resistance is extremely desirable. Fenpicoxamid (Inatreq™ active) possesses these characteristics and is a member of a novel picolinamide class of fungicides derived from the antifungal natural product UK‐2A.RESULTSFenpicoxamid strongly inhibited in vitro growth of several ascomycete fungi, including Zymoseptoria tritici (EC50, 0.051 mg L−1). Fenpicoxamid is converted by Z. tritici to UK‐2A, a 15‐fold stronger inhibitor of Z. tritici growth (EC50, 0.0033 mg L−1). Strong fungicidal activity of fenpicoxamid against driver cereal diseases was confirmed in greenhouse tests, where activity on Z. tritici and Puccinia triticina matched that of fluxapyroxad. Due to its novel target site (Qi site of the respiratory cyt bc1 complex) for the cereals market, fenpicoxamid is not cross‐resistant to Z. tritici isolates resistant to strobilurin and/or azole fungicides. Across multiple European field trials Z. tritici was strongly controlled (mean, 82%) by 100 g as ha−1 applications of fenpicoxamid, which demonstrated excellent residual activity.CONCLUSIONSThe novel chemistry and biochemical target site of fenpicoxamid as well as its lack of cross‐resistance and strong efficacy against Z. tritici and other pathogens highlight the importance of fenpicoxamid as a new tool for controlling plant pathogenic fungi. © 2017 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

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.

The present work demonstrated that the 3-phenyl-1,2,4-triazin-6-ones are a novel series of compounds with highly compelling levels of antifungal activity against agriculturally relevant plant-pathogenic fungi.

BACKGROUND Following the introduction of fenpicoxamid, a natural product‐based fungicide targeting the Qi site of mitochondrial cytochrome bc1 complex, a second generation fully synthetic picolinamide, florylpicoxamid, was discovered and its biological activity and attributes were characterized. RESULTS In vitro fungal growth inhibition assays and in planta glasshouse biological activity evaluations showed florylpicoxamid was active against 21 different plant pathogenic fungi within the phyla Ascomycota and Basidiomycota. Among the pathogens evaluated, florylpicoxamid was most potent against Zymoseptoria tritici, the causal organism of wheat leaf blotch, providing 80% growth inhibition in vitro at 0.0046 mg L−1 and 80% disease control in planta at 0.03 mg L−1 when applied as a preventative treatment. Florylpicoxamid was more efficacious than epoxiconazole, fluxapyroxad, and benzovindiflupyr versus a Z. tritici wild‐type isolate when applied as curative and preventative treatments, with superior 10‐day curative reachback activity. Analytical studies and in planta tests demonstrated that florylpicoxamid partitioned into plants quickly and showed good systemicity and translaminar activity on both monocot and dicot plants. No cross‐resistance was observed between florylpicoxamid and strobilurin or azole fungicides. Florylpicoxamid exerts its preventative effect by preventing spore germination on the leaf surface and curative activity by arresting mycelial growth and pycnidia development in leaf tissue. CONCLUSIONS With strong broad spectrum fungicidal activity, florylpicoxamid delivers an innovative solution for growers to sustain high productivity and quality of many crops, and also provides a new option for developing effective strategies for fungicide resistance management. © 2021 Society of Chemical Industry.

BACKGROUND: UK-2A is an antifungal antibiotic produced by Streptomyces sp. 517-02. Derivatization of its picolinamide OH to form the isobutyryl acetal led to the discovery of fenpicoxamid (InatreqTM active), which is currently under development as a fungicide by Dow AgroSciences LLC. This paper documents efforts to achieve additional efficacy enhancements through semi-synthetic modification of the benzyl substituent of the UK-2A macrocycle.RESULTS: Of 34 analogs prepared, the most active had mitochondrial electron transport IC 50 values 1.5-to 3.7-fold higher than UK-2A (IC 50 0.86 nM). The cyclohexyl analog (38, IC 50 1.23 nM) was the most intrinsically active derivative, and inhibited in vitro growth of Zymoseptoria tritici (EC 50 2.8 ppb) and Leptosphaeria nodorum (EC 50 6.2 ppb) more strongly than UK-2A (EC 50 5.3 and 11.3 ppb for Z. tritici and L. nodorum, respectively). Heterocyclic ring systems and polar linker functionalities resulted in substantial activity loss . Several analogs (20, 22, 23, 24, 36 and 38) translated Z. tritici in vitro growth inhibition activity to in planta disease control more effectively than did UK-2A, with log D being a key factor in this regard. CONCLUSIONS: UK-2A is amenable to further modification at the benzyl position on the macrocycle, which provides opportunities for manipulation of physical properties while retaining strong intrinsic and antifungal activity.

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

Zymoseptoria tritici (wheat leaf blotch) can cause up to 50% yield losses in untreated wheat in Europe. Fungicide applications can significantly reduce yield losses, but fungicide resistance has been documented [1]. Hence, new fungicides are necessary for long-term management of this disease. Most fungicidally active molecules inhibit fungal spore germination and/or germ tube growth. The ability to visualize the impact of active molecules on fungal structures growing on wheat leaves would greatly facilitate the development of new fungicides. However, imaging fungal structures in situ is non-trivial due to the fixation, dehydration, and critical point drying required for conventional high-vacuum SEM. Development of an imaging method that requires less sample preparation but still allows visualization of fungal infections would improve our understanding of this disease and aid development of future treatments and disease management strategies.Environmental SEM (ESEM) allows the imaging of fully hydrated biological samples, thus facilitating the observation of fungal structures on plant surfaces in their native state. In order to acquire high-quality ESEM images of wheat leaves infected by Z. tritici, several factors were tested and optimized. We found that fungal spores freshly harvested from diseased leaves were much more regular in size and shape than those grown on potato dextrose agar. The density of spores applied to leaves was also a key variable, as the density should be high enough to be able to find spores easily in the microscope, but low enough that the spores don't aggregate together and obscure details. Wheat seedling leaves have a naturally ultrahydrophobic surface [2], so the inclusion of a surfactant was critical to allow the inoculum droplet to stick to, and spread on, the leaf surface. Several common surfactants were tested for compatibility with ESEM imaging, and although all of the surfactants tested appeared to work to some extent, we found that Tween™ 20 yielded the highest quality images (Figure 1).A lower-magnification light microscopic view of infected leaf surfaces gives a broader overview of the biology of the host/pathogen interaction. In order to find the relatively small (25 x 1.5 µm) spores on the leaf surface by light microscopy, it was necessary to use a GFP-expressing culture and fluorescence microscopy. Unfortunately, the large height variation between the ridges and valleys of a wheat leaf made it impossible to keep fine fungal structures in focus using widefield fluorescence microscopy. Because the optics of the confocal microscope physically exclude out-of-focus light from the sample, this instrument is ideal for collecting depth series images. A method was developed for using confocal microscopy directly of leaf surfaces without any mountant or coverslip (Figure 2A).Because this confocal microscopy imaging method is non-destructive, it was possible to image a leaf first by low-magnification confocal microscopy, then image the same region at higher magnification by ESEM, and d...

Maize, wheat, and rice are major cereal crops in the world, which provide more caloric energy than any other type of cereal class. In recent years, the yield of these cereal grains has stagnated due to a myriad of constraints, including infestation by pests and pathogens. Plant pathogens, especially agricultural phytopathogenic fungi, may be resistant to the available chemical fungicides which may have detrimental effects and are expensive. This study investigated whether natural products isolated from Linzia glabra Steetz of family Asteraceae could be used as alternative antifungals for control of cereal diseases caused by agricultural fungi. A single pure fraction was separated and identified from L. glabra methanolic flower crude extract using high performance liquid chromatography and high resolution mass spectrometry methods. The pure fraction isolated was tested for inhibition of spore germination in vitro against Fusarium graminearum, Fusarium oxysporum, Fusarium verticillioides, Zymoseptoria tritici, Ustilago maydis, and Pyricularia oryzae. The fraction was identified as a flavonol, 3-O-Methylquercetin using high resolution mass spectrometry. Among the fungi tested, spores of Z. tritici were the most susceptible to 3-O-Methylquercetin (44% spore inhibition), followed by F. oxysporum (33% inhibition) at 27 μg/mL. Azoxystrobin, a standard commercialized fungicide, gave a complete inhibition of 100% against Z. tritici and 58% inhibition against F. oxysporum at 5 μg/mL. L. glabra contains flavonols with antifungal activity, but the modest and weak antifungal activity of 3-O-Methylquercetin compared to a standard such as azoxystrobin demonstrates the challenge to produce highly potent natural product fungicides. There is need for continued search for antifungals with new modes of action as solutions to challenges in agricultural production.