Synthesis and antifungal activity of 3-aryl-1,2,4-triazin-6-one derivatives

Owen, W. J.; Sullenberger, Michael T; Meyer, Kevin G.; Slanec, Thomas

doi:10.1002/ps.3765

Cited by 16 publications

(20 citation statements)

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“…Fenpicoxamid and UK‐2A were additionally tested against the oomycete pathogen Phytophthora infestans . The 96‐well microtiter plate based growth inhibition assays employed for Z. tritici , L. nodorum , P. oryzae and U. maydis were essentially as described previously by Owen et al ., with minor modifications. The growth medium used for P. infestans assays was a synthetic medium consisting of 0.5 g NaNO 3 , 0.36 g MgCl 2 .6H 2 O, 0.2 g KH 2 PO 4 , 0.2 g CaCl 2 , 50.0 mg (NH 4 ) 2 SO 4 , 13.2 mg ferric‐sodium ethylenediaminetetraacetic acid (FeNa‐EDTA), 0.4 g α‐ketoglutarate, 0.2 g succinic acid, 10.0 g dextrose, 4.0 g casamino acids and 0.2 mg thiamine L −1 , adjusted to pH 5.5.…”

Section: Methodsmentioning

confidence: 99%

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

Owen¹,

Yao²,

Myung³

et al. 2017

Pest Management Science

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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.

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Section: Methodsmentioning

confidence: 99%

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

Owen¹,

Yao²,

Myung³

et al. 2017

Pest Management Science

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“…Although 1,2,4‐triazin‐6(1 H )‐one derivatives have been synthesized on solid phase and tested for antifungal, antihypertensive , and anxiolytic properties, herein a solid‐supported synthesis of LCAP derivatives with triazinone moiety in the terminal fragment as mixed 5‐HT 7/1A receptor ligands is reported for the first time.…”

Section: Resultsmentioning

confidence: 99%

Solid‐Supported Synthesis and 5‐HT₇/5‐HT_1A Receptor Affinity of Arylpiperazinylbutyl Derivatives of 4,5‐dihydro‐1,2,4‐triazine‐6‐(1H)‐one

et al. 2015

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A series of arylpiperazinylbutyl derivatives of 4,5-dihydro-1,2,4-triazine-6(1H)-ones was designed and synthesized according to the new solid-supported methodology. In this approach, triazinone scaffold was constructed from the Fmoc-protected glycine. The library representatives showed different levels of affinity for 5-HT7 and 5-HT1A receptors; compounds 13, 14 and 18-20 were classified as dual 5-HT7 /5-HT1A receptors ligands. The structure-affinity relationship analysis revealed that the receptor affinity and selectivity of the tested compounds depended on the kind of substituent in position 3 of triazinone fragment as well as substitution pattern of the phenylpiperazine moiety.

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“…Derivatization of the C‐8 alcohol can also be achieved using diol 4 , which was prepared in one step from UK‐2A (Scheme ). Selective etherification of the macrocyclic hydroxyl was achieved using neutral Pd‐catalyzed conditions . The allyl ethyl carbonates were prepared from ethyl chloroformate and the corresponding allylic alcohol.…”

Section: Methodsmentioning

confidence: 99%

“…Synthesized compounds were evaluated for antifungal activity against the four plant pathogens Z. tritici , L. nodorum, P. oryzae and Ustilago maydis using 96 well microtiter plate‐based growth inhibition assays and conditions and inoculum densities as previously described . A 3‐fold dilution series of test compounds was prepared using stock solutions in DMSO and 2 μL aliquots added to the wells to deliver a total of 10 test concentrations ranging from 0.000102 mg L −1 to 2 mg L −1 .…”

Section: Methodsmentioning

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

Pest Management Science

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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

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Synthesis and antifungal activity of 3-aryl-1,2,4-triazin-6-one derivatives

Abstract: 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.

Cited by 16 publications

References 16 publications

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

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

Solid‐Supported Synthesis and 5‐HT₇/5‐HT_1A Receptor Affinity of Arylpiperazinylbutyl Derivatives of 4,5‐dihydro‐1,2,4‐triazine‐6‐(1H)‐one

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

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Synthesis and antifungal activity of 3-aryl-1,2,4-triazin-6-one derivatives

Abstract: 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.

Cited by 16 publications

References 16 publications

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

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

Solid‐Supported Synthesis and 5‐HT7/5‐HT1A Receptor Affinity of Arylpiperazinylbutyl Derivatives of 4,5‐dihydro‐1,2,4‐triazine‐6‐(1H)‐one

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

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Product

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Solid‐Supported Synthesis and 5‐HT₇/5‐HT_1A Receptor Affinity of Arylpiperazinylbutyl Derivatives of 4,5‐dihydro‐1,2,4‐triazine‐6‐(1H)‐one