The Unique Role of Halogen Substituents in the Design of Modern Crop Protection Compounds

Jeschke, Peter

doi:10.1002/9783527619580.ch35

Cited by 7 publications

(6 citation statements)

References 109 publications

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“…To investigate whether the enhanced potency of inhibitor 6 is due to fluorine induced interactions or better occupancy of the binding pocket, the 4- t -butylphenyl– group of inhibitor 12 was replaced by its isostere: a 4-heptafluoro- iso -propyl-phenyl group at R 1 of inhibitor 13 . 37 This compound is 20-fold more potent than inhibitor 6 , which indicates that the fluorine induced interactions in the left binding pocket are very strong (Table 2 ). These data suggest that the left side of the binding pocket is likely fluorophilic.…”

Section: Resultsmentioning

confidence: 95%

“…Thus, the potency of the inhibitor dropped when the size of the substituent at R 1 (Figure A) was increased from a 4- iso -propylphenyl group to a 4- tert -butylphenyl- group (inhibitors 11 and 12 ) (Table ). It is interesting that the inhibitor 6 , which has CF 3 – group in place of an iso -propyl– and tert -butyl– group, is more potent as an inhibitor when compared to inhibitors 11 and 12 . To investigate whether the enhanced potency of inhibitor 6 is due to fluorine induced interactions or better occupancy of the binding pocket, the 4- t -butylphenyl– group of inhibitor 12 was replaced by its isostere: a 4-heptafluoro- iso -propyl-phenyl group at R 1 of inhibitor 13 .…”

Section: Resultsmentioning

confidence: 99%

“…It is interesting that the inhibitor 6 , which has CF 3 – group in place of an iso -propyl– and tert -butyl– group, is more potent as an inhibitor when compared to inhibitors 11 and 12 . To investigate whether the enhanced potency of inhibitor 6 is due to fluorine induced interactions or better occupancy of the binding pocket, the 4- t -butylphenyl– group of inhibitor 12 was replaced by its isostere: a 4-heptafluoro- iso -propyl-phenyl group at R 1 of inhibitor 13 . This compound is 20-fold more potent than inhibitor 6 , which indicates that the fluorine induced interactions in the left binding pocket are very strong (Table ).…”

Section: Resultsmentioning

confidence: 99%

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Optimized Inhibitors of Soluble Epoxide Hydrolase Improve in Vitro Target Residence Time and in Vivo Efficacy

et al. 2014

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Diabetes is affecting the life of millions of people. A large proportion of diabetic patients suffer from severe complications such as neuropathic pain, and current treatments for these complications have deleterious side effects. Thus, alternate therapeutic strategies are needed. Recently, the elevation of epoxy-fatty acids through inhibition of soluble epoxide hydrolase (sEH) was shown to reduce diabetic neuropathic pain in rodents. In this report, we describe a series of newly synthesized sEH inhibitors with at least 5-fold higher potency and doubled residence time inside both the human and rodent sEH enzyme than previously reported inhibitors. These inhibitors also have better physical properties and optimized pharmacokinetic profiles. The optimized inhibitor selected from this new series displayed improved efficacy of almost 10-fold in relieving pain perception in diabetic neuropathic rats as compared to the approved drug, gabapentin, and previously published sEH inhibitors. Therefore, these new sEH inhibitors could be an attractive alternative to treat diabetic neuropathy in humans.

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Section: Resultsmentioning

confidence: 95%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Optimized Inhibitors of Soluble Epoxide Hydrolase Improve in Vitro Target Residence Time and in Vivo Efficacy

et al. 2014

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“…23,24 Therefore, carboxylic acids and their derivatives have played significant roles in the development of herbicidal structures and deserve specific attention to their contribution to this significant and highly active research field (Figure 1b). 25,26 Herein, we provide an overview of the development of herbicidally active molecules containing carboxylic acidderived bioactive moieties in the last two decades. This review is divided into two major sections according to the sources of the acid-derived herbicidal molecules: (i) synthetic carboxylic acids and their derivatives for herbicidal applications; and (ii) naturally existing carboxylic acids and their derivatives for herbicidal applications.…”

Section: Introductionmentioning

confidence: 99%

Carboxylic Acid Derivatives in Herbicide Development

Cai

Gan

Jin

et al. 2023

J. Agric. Food Chem.

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Carboxylic acids and their derivatives are extensively found in natural and non-natural compounds with proven bioactivities. They have made great contributions to the development of herbicides and herbicidal lead structures in the past 70 years. Carboxylic acid-related herbicidal molecules have targeted a diversity of biosynthetic pathways, proteins, enzymes, energetic metabolism systems, and other reaction sites through different mechanisms. It is significant and helpful for us to know the herbicidal targets and mechanisms of the carboxylic acid-related herbicides as well as the basic rules for the design and development of herbicidal lead structures. We therefore summarize here the overall development of carboxyl group-containing herbicides and herbicidal molecules in the past 20 years based on their structural properties and herbicidal mechanisms.

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“…To obtain novel PPO inhibitors, a series of N -phenyl phthalimides were designed by molecular docking using the mt PPO as a target, and by using Flumioxazin as a lead (Figure 1) [22,23], after which they were synthesized and characterized by NMR and High resolution mass spectrometry (HR-MS). Their herbicidal activities were also evaluated against Brassica campestris ( B. campestris ), Amaranthus retroflexus ( A. retroflexus ) and Digitaria sanguinalis ( D. sanguinalis ) to verify our molecular design strategy.…”

Section: Introductionmentioning

confidence: 99%

Design and Synthesis of N-phenyl Phthalimides as Potent Protoporphyrinogen Oxidase Inhibitors

Wei

Ren

et al. 2019

Molecules

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Protoporphyrinogen oxidase (PPO) has been identified as one of the most promising targets for herbicide discovery. A series of novel phthalimide derivatives were designed by molecular docking studies targeting the crystal structure of mitochondrial PPO from tobacco (mtPPO, PDB: 1SEZ) by using Flumioxazin as a lead, after which the derivatives were synthesized and characterized, and their herbicidal activities were subsequently evaluated. The herbicidal bioassay results showed that compounds such as 3a (2-(4-bromo-2,6-difluorophenyl) isoindoline-1,3-dione), 3d (methyl 2-(4-chloro-1,3-dioxoisoindolin-2-yl)-5-fluorobenzoate), 3g (4-chloro-2-(5-methylisoxazol-3-yl) isoindoline-1,3-dione), 3j (4-chloro-2-(thiophen-2-ylmethyl) isoindoline-1,3-dione) and 3r (2-(4-bromo-2,6-difluorophenyl)-4-fluoroisoindoline-1,3-dione) had good herbicidal activities; among them, 3a showed excellent herbicidal efficacy against A. retroflexus and B. campestris via the small cup method and via pre-emergence and post-emergence spray treatments. The efficacy was comparable to that of the commercial herbicides Flumioxazin, Atrazine, and Chlortoluron. Further, the enzyme activity assay results suggest that the mode of action of compound 3a involves the inhibition of the PPO enzyme, and 3a showed better inhibitory activity against PPO than did Flumioxazin. These results indicate that our molecular design strategy contributes to the development of novel promising PPO inhibitors.

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The Unique Role of Halogen Substituents in the Design of Modern Crop Protection Compounds

Cited by 7 publications

References 109 publications

Optimized Inhibitors of Soluble Epoxide Hydrolase Improve in Vitro Target Residence Time and in Vivo Efficacy

Optimized Inhibitors of Soluble Epoxide Hydrolase Improve in Vitro Target Residence Time and in Vivo Efficacy

Carboxylic Acid Derivatives in Herbicide Development

Design and Synthesis of N-phenyl Phthalimides as Potent Protoporphyrinogen Oxidase Inhibitors

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