Insertion of Small Flexible Linkers as a Useful Scaffold Hopping Tool in Agrochemistry

Lamberth, Clemens

doi:10.1021/acs.jafc.1c07971

Cited by 12 publications

(13 citation statements)

References 36 publications

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“…Also, other heterocyclic replacements of the original phenyl ring have been successfully applied in commercialized sulfonylurea herbicides 49 . A one‐atom spacer has been inserted between the phenyl ring and the sulfonyl group of some sulfonylurea herbicides, such as a CH 2 in bensulfuron‐methyl ( 62 ), a NH in orthosulfamuron and an O in ethoxysulfuron 50 . In addition, the terminal amino group of the sulfonylurea bridge may be part of a heterocyclic ring, such as in propoxycarbazone‐sodium ( 63 ), flucarbazone‐sodium and thiencarbazone‐methyl (Fig.…”

Section: Sulfonylureamentioning

confidence: 99%

Sulfur‐based functional groups in agrochemistry

Jeanguenat

Lamberth

2023

Pest Management Science

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The element sulfur has an outstanding role in the crop protection chemistry because it is used in its elemental form as a multisite fungicide, but is also part of agrochemicals in the form of aromatic or aliphatic sulfur‐containing rings or sulfur‐based functional groups. This review gives an exhaustive overview over the latter category. Several fundamental agrochemical compound classes are named after a sulfur‐based functionality, such as the dithiocarbamate fungicides and sulfonylurea herbicides. Altogether, 16 different sulfur‐based functional groups are presented with their typical synthesis approaches and most important representatives in crop protection. © 2023 Society of Chemical Industry.

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Section: Sulfonylureamentioning

confidence: 99%

Sulfur‐based functional groups in agrochemistry

Jeanguenat

Lamberth

2023

Pest Management Science

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“…Fenoxanil was obtained by reversing the amide functional group of the fungicide diclocymet, both having the same mode of action (Figure ). Lamberth listed many examples of amide reversal in his review, including the discovery of chlorantraniliprole, histone-deacetylase-inhibiting fungicides, γ-aminobutyric acid (GABA)-gated chloride-channel-modulating insecticides, etc …”

Section: Novel Bioisosteric Design Strategies For the Identification ...mentioning

confidence: 99%

Bioisosterism and Scaffold Hopping in Modern Nematicide Research

Cao

Yang

Liu

et al. 2022

J. Agric. Food Chem.

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The application of agrochemicals is critical to global food safety. Nowadays, environmentally friendly green agrochemicals are the trend in field crop protection. The research and development of nematicides absorbed more attention as a typical representation of agrochemicals. This review describes the origin of recently commercialized nematicides, the application of bioisosterism and scaffold hopping in the discovery and optimization of agrochemicals, especially nematicides, and novel bioisosteric design strategies for the identification of fluensulfone analogues. Pesticide repurposing, high-throughput screening, computer-aided drug design, and incorporation of known pharmacophoric fragments have been the most successful approach for the discovery of new nematicides. As outlined, the strategies of bioisosteric replacements and scaffold hopping have been very successful approaches in the search for new nematicides for sustainable crop protection. In the exploration of novel fluensulfone analogues with nematicidal activity, bioisosteric replacement of sulfone by amide, chain extension by insertion of a methylene group, and reversal of the amide group have proven to be successful approaches and yielded new and highly active fluensulfone analogues. These attempts might result in compounds with an optimal balance of steric, hydrophobic, electronic, and hydrogen-bonding properties and contribute to deal with the complex problem during the research and development of new nematicides. Further ideas are also put forward to provide new approaches for the molecular design of nematicides.

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“…Incorporation of two or more pharmacophores of bioactive scaffolds based on molecular hybridization has been one of the most successful strategies for the discovery of new pesticides and drugs. − For example, flubeneteram, a novel commercial SDHI fungicide approved recently (Figure ), was discovered through pharmacophore-linked fragment virtual screening (PFVS) by the Yang group, − which could be considered as a combination of pyrazole-4-carboxamide and diphenyl ether bioactive scaffolds based on the molecular hybridization strategy. Scaffold hopping, another widely exploited design approach, offers the opportunity to modify known lead compounds to afford novel structures with high potency, low toxicity, and enhanced physicochemical properties. − In this work, in search of novel SDHIs, flubeneteram was used as lead compounds, and we attempted to replace the diphenyl ether scaffold of flubeneteram with extended phenyl diether and aliphatic ether by scaffold hopping (Figure ). A series of novel pyrazole-4-carboxamide derivatives bearing an extended ether group were designed and synthesized by a simple synthetic method (Figure ).…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Antifungal Activities of Novel Pyrazole-4-carboxamide Derivatives Containing an Ether Group as Potential Succinate Dehydrogenase Inhibitors

Luo

Zhao

Zhang

et al. 2023

J. Agric. Food Chem.

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A series of novel pyrazole-4-carboxamides bearing an ether group were designed and synthesized on the basis of the structure of commercial succinate dehydrogenase inhibitor (SDHI) fungicide flubeneteram via scaffold hopping and evaluated for their antifungal activities against five fungi. The bioassay results showed that most of the target compounds exhibited excellent in vitro antifungal activity against Rhizoctonia solani and some compounds exerted remarkable antifungal activities against Sclerotinia sclerotiorum, Botrytis cinerea, Fusarium graminearum, and Alternaria alternate. Particularly, compounds 7d and 12b displayed outstanding antifungal activity against R. solani, with an EC 50 value of 0.046 μg/mL, far superior to that of boscalid (EC 50 = 0.741 μg/mL) and fluxapyroxad (EC 50 = 0.103 μg/mL). Meanwhile, compound 12b also presented a broader fungicidal spectrum than other compounds. Moreover, in vivo anti-R. solani results showed that compounds 7d and 12b could significantly inhibit the growth of R. solani in rice leaves with excellent protective and curative efficacies. In addition, the results of the succinate dehydrogenase (SDH) enzymatic inhibition assay showed that compound 7d generated significant SDH inhibition, with an IC 50 value of 3.293 μM, which was about 2 times better than that of boscalid (IC 50 = 7.507 μM) and fluxapyroxad (IC 50 = 5.991 μM). Furthermore, scanning electron microscopy (SEM) analysis indicated that compounds 7d and 12b significantly destroyed the typical structure and morphology of R. solani hyphae. The molecular docking study revealed that compounds 7d and 12b could embed into the binding pocket of SDH and form hydrogen bond interactions with TRP173 and TRY58 at the activity site of SDH, which was in line with fluxapyroxad, indicating that they had a similar mechanism of action. These results demonstrated that compounds 7d and 12b could be promising candidates of SDHI fungicides, which deserved further investigation.

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Insertion of Small Flexible Linkers as a Useful Scaffold Hopping Tool in Agrochemistry

Cited by 12 publications

References 36 publications

Sulfur‐based functional groups in agrochemistry

Sulfur‐based functional groups in agrochemistry

Bioisosterism and Scaffold Hopping in Modern Nematicide Research

Design, Synthesis, and Antifungal Activities of Novel Pyrazole-4-carboxamide Derivatives Containing an Ether Group as Potential Succinate Dehydrogenase Inhibitors

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