Structure-Based Discovery of Potential Fungicides as Succinate Ubiquinone Oxidoreductase Inhibitors

Li, Xiong; Li, Hua; Jiang, Leiming; Ge, Jingming; Yang, Wen‐Chao; Zhu, Xiao Lei; Yang, Guang‐Fu

doi:10.1021/acs.jafc.6b05134

Cited by 137 publications

(145 citation statements)

References 47 publications

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“…Furthermore, the recent studies on the structural modification of amide SDHI fungicides mainly focused on the substituents in aromatic ring and polar moiety. [7][8][9][10][11][12][13][14] Recently, several literatures reported the effect of changes in the amide bridge on fungicidal activity, such as ⊍-hydroxy and ⊍-carbonyl chiral amide ( Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

Studies on the novel pyridine sulfide containing SDH based heterocyclic amide fungicide

Hua

Liu

et al. 2020

Pest Management Science

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BACKGROUND: Succinate dehydrogenase (SDH) has been identified as one of the most significant targets for fungicide discovery. To date, 23 commercial SDH inhibitor (SDHI) fungicides have been approved for plant protection since the first launch of carboxin in 1966, and extensively applied to combat destructive plant fungi. RESULTS:In this project, 20 novel pyridine sulfide derivatives containing SDH-based heterocyclic amide fungicide were designed, synthesized, and characterized by proton nuclear magnetic resonance ( 1 H-NMR), carbon-13 ( 13 C)-NMR and highresolution mass spectrometry (HRMS). In vitro fungicidal activity experiment, the target compound I-1 displayed excellent inhibitory rates against the common agricultural pathogens with half maximal effective concentration (EC 50 ) values of 5.2 to 39.8 ∼g mL −1 . The in vivo fungicidal activities demonstrated that the compound I-1 could effectively prevent Botrytis cinerea from infecting tomato and cucumber leaves with the preventative rates of 67% and 50%. The mitochondrial membrane potential detection, SDH enzyme assay and the molecular docking simulation revealed that the mechanism of action of the compound I-1 and the relevant interactions with the target enzyme may be similar to those of the control fluopyram.CONCLUSION: The biological activity screening and validation of mechanism of action indicated that the compound I-1 could be identified as a potential SDH inhibitor for further study.

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Section: Introductionmentioning

confidence: 99%

Studies on the novel pyridine sulfide containing SDH based heterocyclic amide fungicide

Hua

Liu

et al. 2020

Pest Management Science

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“…For instance, the inhibitory activities of cytochrome bc 1 complex and succinate dehydrogenase inhibitors have been found to be in the picomolar and nanomolar ranges, respectively. [28][29][30] To improve the screening efficiency, we further developed a new web server based on the PFVS approach, the Auto Core Fragment in silico Screening (ACFIS) server. 31 To continue work on the discovery of antiresistance AHAS inhibitors with higher potency, we carried out a PFVS with pyrimidinyl-salicylic as the pharmacophore in wild-type AHAS and P197L mutant using the ACFIS server.…”

Section: Introductionmentioning

confidence: 99%

Fragment‐based discovery of flexible inhibitor targeting wild‐type acetohydroxyacid synthase and P197L mutant

Yang

Chen

et al. 2020

Pest Management Science

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BACKGROUND Intensifying weed resistance has challenged the use of existing acetohydroxyacid synthase (AHAS)‐inhibiting herbicides. Hence, there is currently an urgent requirement for the discovery of a new AHAS inhibitor to effectively control AHAS herbicide‐resistant weed species produced by target mutation. RESULTS To combat weed resistance caused by AHAS with P197L mutation, we built a structure library consisting of pyrimidinyl‐salicylic acid derivatives. Using the pharmacophore‐linked fragment virtual screening (PFVS) approach, hit compound 8 bearing 6‐phenoxymethyl substituent was identified as a potential AHAS inhibitor with antiresistance effect. Subsequently, derivatives of compound 8 were synthesized and evaluated for their inhibitory activities. The study of the enzyme‐based structure–activity relationship and structure−resistance relationship studies led to the discovery of a qualified candidate, 28. This compound not only significantly inhibited the activity of wild‐type Arabidopsis thaliana (At) AHAS and P197L mutant, but also exhibited good antiresistance properties (RF = 0.79). Notably, compared with bispyribac at 37.5–150 g of active ingredient per hectare (g a.i. ha–1), compound 27 exhibited higher growth inhibition against both sensitive and resistant Descurainia sophia, CONCLUSION The title compounds have great potential to be developed as new leads to effectively control herbicide‐resistant weeds comprising AHAS with P197L mutation. Also, our study provided a positive case for discovering novel, potent and antiresistance inhibitors using a fragment‐based drug design approach.

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“…An SAR study reported that the oxazolyl carbamate skeleton plays an important role in its activity profile, while a complex macrolide skeleton has little effect on it [70]. Instead of this complex and less important left chain in neopeltolide, simple biaryl moiety was inspired by other similar fungicide metominostrobin 36 , famoxadone 37 , or other biaryl ethers, as illustrated in Scheme 6 [71].…”

Section: Resultsmentioning

confidence: 99%

Design and Synthesis of Anti-Cancer Chimera Molecules Based on Marine Natural Products

Song

Chung

et al. 2019

Marine Drugs

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In this paper, the chemical conjugation of marine natural products with other bioactive molecules for developing an advanced anti-cancer agent is described. Structural complexity and the extraordinary biological features of marine natural products have led to tremendous research in isolation, structural elucidation, synthesis, and pharmacological evaluation. In addition, this basic scientific achievement has made it possible to hybridize two or more biologically important skeletons into a single compound. The hybridization strategy has been used to identify further opportunities to overcome certain limitations, such as structural complexity, scarcity problems, poor solubility, severe toxicity, and weak potency of marine natural products for advanced development in drug discovery. Further, well-designed marine chimera molecules can function as a platform for target discovery or degradation. In this review, the design, synthesis, and biological evaluation of recent marine chimera molecules are presented.

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Structure-Based Discovery of Potential Fungicides as Succinate Ubiquinone Oxidoreductase Inhibitors

Cited by 137 publications

References 47 publications

Studies on the novel pyridine sulfide containing SDH based heterocyclic amide fungicide

Studies on the novel pyridine sulfide containing SDH based heterocyclic amide fungicide

Fragment‐based discovery of flexible inhibitor targeting wild‐type acetohydroxyacid synthase and P197L mutant

Design and Synthesis of Anti-Cancer Chimera Molecules Based on Marine Natural Products

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