Biological characterization of fenpicoxamid, a new fungicide with utility in cereals and other crops

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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

Section: Resultsmentioning

confidence: 90%

Section: Resultsmentioning

confidence: 99%

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

Owen

Meyer

Slanec

et al. 2019

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“…Recently, we described some of the biological characteristics of fenpicoxamid (Fig. ), a novel picolinamide fungicide discovered in collaboration with Meiji Seika Pharma Co. Ltd., which is currently under development by CAS . Fenpicoxamid is a derivative of the natural antifungal compound UK‐2A, originally isolated from actinomycete Streptomyces sp.…”

Section: Case Studiesmentioning

confidence: 99%

Natural products: a strategic lead generation approach in crop protection discovery

Lorsbach

Sparks

Cicchillo

et al. 2019

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With the anticipated population growth in the coming decades, the changing regulatory environment, and the continued emergence of resistance to commercial pesticides, there is a constant need to discover new lead chemistries with novel modes of action. We have established a portfolio of approaches to accelerate lead generation. One of these approaches capitalizes on the rich bioactivity of natural products (NPs), highlighted by the numerous examples of NP‐based crop protection compounds. Within Corteva Agriscience and the affiliated preceding companies, NPs have been a fruitful approach, for nearly three decades, to identifying and bringing to the market crop protection products inspired by or originating from NPs, . Included in these NP‐based crop protection products are the spinosyns family of insecticides, and those from more recent areas of NP‐based fungicidal chemistry, as highlighted in this perspective. © 2019 Society of Chemical Industry

“…Analysis of mutations conferring resistance in Saccharomyces cerevisiae and molecular docking studies have shown that UK‐2A inhibits at the same site as antimycin A . It strongly inhibited the in vitro growth of several ascomycete fungi, including the fungal pathogen Zymoseptoria tritici (formerly known as Mycosphaerella graminicola ) causing septoria blotch in wheat, Leptosphaeria nodorum in wheat and Pleomorphomonas oryzae in rice plants (Table ) …”

Section: Fungicidesmentioning

confidence: 99%

“…71 It strongly inhibited the in vitro growth of several ascomycete fungi, including the fungal pathogen Zymoseptoria tritici (formerly known as Mycosphaerella graminicola) causing septoria blotch in wheat, Leptosphaeria nodorum in wheat and Pleomorphomonas oryzae in rice plants (Table 4). 72 In Z. tritici, the pro-fungicide fenpicoxamid is converted in vivo to the natural metabolite UK-2A by cleavage of the O-3-(isobutyloxy)-methoxy residue, a 15-fold stronger inhibitor of Z. tritici growth (Fig. S11).…”

Section: Selected Chiral Development Candidate Fungicidesmentioning

confidence: 99%

Current status of chirality in agrochemicals

Jeschke

2018

137

The agrochemical industry is searching continuously for new pesticides to develop products that have optimal efficacy, lower application rates in the field, increased selectivity, favourable toxicological and environmental safety, enhanced user friendliness and better economic viability. One strategy by which to achieve these ambitious goals makes use of the unique properties of molecules containing asymmetric centres. In the past, many natural products and their congeners have been a source of inspiration in the design of new active ingredients, and the molecular structures of the resulting compounds have become increasingly complex; some 30% contain fragments with asymmetric centres. However, despite enormous progress in catalytic asymmetric processes over the past decade, few agrochemicals are produced in an enantiomerically pure or enriched form on an industrial scale. Since 2007, ∼ 43% of the 44 products launched (insecticides, acaricides, fungicides, nematicides and herbicides) contain one or more asymmetric centres in the molecule (∼ 47%) and most have been launched as racemic mixtures of enantiomers or diastereomers. This review provides an overview of the current status of chiral agrochemicals launched over the past 10 years and describes the inherently connected challenges of modern agricultural chemistry by managing important aspects resulting from the stereochemistry of these innovative products. © 2018 Society of Chemical Industry.