Synthesis and evaluation of hydroxyazolopyrimidines as herbicides; the generation of amitrole <i>in planta</i>

Clough, James R.; Dale, Richard P.; Elsdon, Barry; Hawkes, Timothy R.; Hogg, Bridget; Howell, Anushka; Kloer, Daniel P.; Lecoq, K.; McLachlan, Matthew M. W.; Milnes, Phillip J.; O’Riordan, Timothy; Ranasinghe, Saranga; Shanahan, Stephen E.; Sumner, Karen D.; Tayab, Shanaaz

doi:10.1002/ps.4264

Cited by 6 publications

(5 citation statements)

References 26 publications

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“…The active site of At IspD comprises subpockets for the methylerythritol, phosphate, ribose, and cytosine moieties of the substrates 2 C -methyl- d -erythritol 4-phosphate (MEP) and CTP (Scheme A). The allosteric pocket, which opens up upon binding the previously reported allosteric inhibitors 1 – 3 ,, and the new phenylisoxazol ligand 4 (Figure ) is in close proximity, 6–8 Å away from the methylerithritol subpocket. This binding pocket is not developed in the ligand-free state, and conformational changes induced by its formation mediate the allosteric inhibition (see below).…”

Section: Resultsmentioning

confidence: 99%

Mechanism of Allosteric Inhibition of the Enzyme IspD by Three Different Classes of Ligands

et al. 2017

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Enzymes of the nonmevalonate pathway of isoprenoid biosynthesis are attractive targets for the development of herbicides and drugs against infectious diseases. While this pathway is essential for many pathogens and plants, mammals do not depend on it for the synthesis of isoprenoids. IspD, the third enzyme of the nonmevalonate pathway, is unique in that it has an allosteric regulatory site. We elucidated the binding mode of phenylisoxazoles, a new class of allosteric inhibitors. Allosteric inhibition is effected by large conformational changes of a loop region proximal to the active site. We investigated the different roles of residues in this loop by mutation studies and identified repulsive interactions with Asp291 and Asp292 to be responsible for inhibition. Crystallographic data and the response of mutant enzymes to three different classes of allosteric inhibitors provide an in-depth understanding of the allosteric mechanism. The obtained mutant enzymes show selective resistance to allosteric inhibitors and provide conceptually valuable information for future engineering of herbicide-resistant crops. We found that the isoprenoid precursors IPP and DMAPP are natural inhibitors of Arabidopsis thaliana IspD; however, they do not seem to bind to the allosteric site.

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Section: Resultsmentioning

confidence: 99%

Mechanism of Allosteric Inhibition of the Enzyme IspD by Three Different Classes of Ligands

et al. 2017

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“…However, 6‐phenoxy‐[1,2,4]‐triazolo[1,5‐ a ]pyrimidine‐5,7‐diol 37 (63 %) was synthesized using Na as a base and EtOH as the solvent in the reaction of 1,2,4‐triazol‐5‐amine with diethyl 2‐phenoxymalonate at reflux during 18 h (Scheme 21). [31] …”

Section: Triazolopyrimidine Synthesismentioning

confidence: 99%

“…However, 6-phenoxy-[1,2,4]-triazolo[1,5-a]pyrimidine-5,7diol 37 (63 %) was synthesized using Na as a base and EtOH as the solvent in the reaction of 1,2,4-triazol-5-amine with diethyl 2-phenoxymalonate at reflux during 18 h (Scheme 21). [31] The synthetic procedure of the steroidal D-ring substituted [1,2,4]-triazolo[1,5-a]pyrimidyl derivatives 38 (50-54 %) was performed by Fan et al [32] The Claisen condensation of Δ 1,4 -pregnadien-3,20-dione or 4-chloro-Δ 1,4 -pregnadien-3,20dione with dimethyl oxalate in dichloromethane led to the 21-methoxalyl derivative. Treating the latter with 3-amino-1,2,4-triazole in the reflux of acetic acid and KOAc resulted in the triazolopyrimidine derivative (Scheme 22).…”

Section: Synthesis Of Triazolopyrimidines Derivatives From Aminotriazolementioning

confidence: 99%

Different Synthetic Methods for the Preparation of Triazolopyrimidines and their Biological Profile

et al. 2023

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One or more nitrogen‐containing molecules constitute an important class of heterocyclic compounds in organic synthesis, due to their reactivity and their presence in many molecules of natural, human or plant origin. These nitrogenous heterocycles play an essential role in various scientific domains, whether they are chemical, biological or pharmacological. N‐heterocycles are the privileged source of many research topics developed by several groups of researchers. Thus, different methods have been developed to access these heterocyclic compounds with nitrogenous rings, such as triazolopyrimidines. In this review, a bibliographic study summarizing the pharmacological importance of the triazolo[1,5‐a]pyrimidine ring, the different synthesis routes of these derivatives as well as their reactivity was reported.

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“…4 Knowledge of a herbicide's enzymatic target, the site of action (SoA), is of high importance to avoid repeated use of herbicides with the same target resulting in the selection of target site resistant weeds. For most herbicides, the enzymatic target is known or has recently been identified, like for aclonifen, 5 amitrole 6 and cinmethylin. 7 However, there are still several, especially older herbicides, for which the target enzyme has not been identified yet (HRAC class 0).…”

Section: Introductionmentioning

confidence: 99%

“…Effect of cinmethylin (A) and methiozolin (B) on the metabolite levels in Lemna plants. Boxes indicate accumulation (red) or depletion (blue) for three different timepoints (6, 24) and 48 h after treatment and two herbicide rates (10 and 100 μ m for cinmethylin, 100 and 500 μ m for methiozolin). Shown are only data for metabolites with significant effects (Welch‐test, P < 0.05) compared to mock treated control plants grown, harvested and analyzed in parallel.…”

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confidence: 99%

Inhibition of acyl‐ACP thioesterase as site of action of the commercial herbicides cumyluron, oxaziclomefone, bromobutide, methyldymron and tebutam

Johnen¹,

Zimmermann²,

Betz

et al. 2022

Pest Management Science

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BACKGROUND: Understanding the mode and site of action of a herbicide is key for its efficient development, the evaluation of its toxicological risk, efficient weed control and resistance management. Recently, the mode of action (MoA) of the herbicide cinmethylin was identified in lipid biosynthesis with acyl-ACP thioesterase (FAT) as the site of action (SoA). Cinmethylin was registered for selective use in cereal crops for the control of grass weeds in 2020.RESULTS: Here, we present a high-resolution co-crystal structure of FAT in complex with cumyluron identified by a high throughput crystallization screen. We show binding to and inhibition of FAT by cumyluron. Furthermore, in an array of experiments consisting of FAT binding assays, FAT inhibition assays, physiological and metabolic profiling, we tested compounds that are structurally related to cumyluron and identified the commercial herbicides oxaziclomefone, methyldymron, tebutam and bromobutide, with so far unknown sites of action, as FAT inhibitors. Additionally, we show that the previously described FAT inhibitors cinmethylin and methiozolin bind to FAT in a nanomolar range, inhibit FAT enzymatic activity and lead to similar metabolic changes.CONCLUSION: Based on presented data, we corroborate cinmethylin and methiozolin as potent FAT inhibitors and identify FAT as the SoA of the herbicides cumyluron, oxaziclomefone, bromobutide, methyldymron and tebutam.

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Synthesis and evaluation of hydroxyazolopyrimidines as herbicides; the generation of amitrole in planta

Cited by 6 publications

References 26 publications

Mechanism of Allosteric Inhibition of the Enzyme IspD by Three Different Classes of Ligands

Mechanism of Allosteric Inhibition of the Enzyme IspD by Three Different Classes of Ligands

Different Synthetic Methods for the Preparation of Triazolopyrimidines and their Biological Profile

Inhibition of acyl‐ACP thioesterase as site of action of the commercial herbicides cumyluron, oxaziclomefone, bromobutide, methyldymron and tebutam

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