CN114403150A - Application of indoleamide compound as trehalose-6-phosphate synthase inhibitor - Google Patents
Application of indoleamide compound as trehalose-6-phosphate synthase inhibitor Download PDFInfo
- Publication number
- CN114403150A CN114403150A CN202210122745.XA CN202210122745A CN114403150A CN 114403150 A CN114403150 A CN 114403150A CN 202210122745 A CN202210122745 A CN 202210122745A CN 114403150 A CN114403150 A CN 114403150A
- Authority
- CN
- China
- Prior art keywords
- trehalose
- phosphate synthase
- compound
- indoleamide
- agent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Classifications
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
- A01N43/50—1,3-Diazoles; Hydrogenated 1,3-diazoles
Landscapes
- Life Sciences & Earth Sciences (AREA)
- Agronomy & Crop Science (AREA)
- Pest Control & Pesticides (AREA)
- Plant Pathology (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Dentistry (AREA)
- General Health & Medical Sciences (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Environmental Sciences (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Abstract
The invention discloses an application of indoleamide compound as trehalose-6-phosphate synthase inhibitor, wherein the indoleamide compound is a compound containing indoleamide skeleton or pharmaceutically acceptable salt thereof, the structural formula of the indoleamide compound is shown as a formula I,
Description
Technical Field
The invention belongs to the technical field of agricultural disease control, and particularly relates to an application of indoleamide compounds as trehalose-6-phosphate synthase inhibitors.
Background
The rice blast of rice is commonly occurred and is one of three fungal diseases of rice[1-2]. The rice blast can reduce the yield of rice by at least 10 to 20 percent in the current year[3]. The pathogenic bacterium of rice blast is Magnaporthe oryzae (Magnaporthe oryzae). At present, rice blast mainly takes chemical prevention and control as a main part, but the problems of drug resistance, pesticide residue and the like increasingly appear. Therefore, the research of pesticides based on targets and the development of environment-friendly green pesticides are needed for the development of modern green ecological pesticides.
Trehalose-6-phosphate synthase (TPS) is responsible for an important step in trehalose synthesis, catalyzing substrates UDP-glucose and glucose-6-phosphate to synthesize trehalose-6-phosphate. As TPS is not present in mammals, it is considered a potential target for designing pesticides to control diseases. TPS in the rice blast fungus is MoTps1, and a MoTps1 knockout strain cannot produce trehalose and can form attachment cells but has obviously reduced pathogenicity, namely MoTps1 is necessary for rice blast fungus pathogenicity[4-6]. The MoTps1 is an ideal target because of having important effect on rice blast fungus pathogenesis and ensuring safety[7]。
At present, research on trehalose-6-phosphate synthase inhibitors has also progressed. Xue et al virtually screened and optimized 40 ten thousand compounds in MLSMR library by using a method combining homologous modeling with virtual screening, and finally obtained Lead25 can be used as a Lead compound of MoTps1[7]. Researchers at the university of Duke carry out recombinant expression on TPS1 of Candida albicans and Aspergillus niger, and then screen out a plurality of small molecule inhibitors by a fluorescence polarization method, wherein closante has strong inhibition effect on cryptococcus in vitro at the concentration of 1mg/ml[8]. In addition, TPS has also been used in the study of pesticides. For example, Kern et al expressed and high throughput screened TPS from Drosophila and Cat fleas 11.5 millionThe compounds finally obtain a batch of insect TPS inhibitors, further optimize compounds such as 4-substitated-2, 6-diamino-3, 5-dicyano-4H-thiopyra and the like, have an inhibition constant from mM level to nM level on the insect TPS, and can be used as a lead compound for developing insecticides[9]。
Conventional methods for drug screening are high throughput screening and virtual screening. High-throughput screening is carried out on a large number of compounds through experiments such as biochemistry, and the like, so that the method is large in workload, long in time consumption, high in cost and limited to a certain extent. In recent years, virtual screening has been increasingly advantageous in finding a shoot-top compound. The virtual screening is based on a structural model of the protein, firstly, a compound library is virtually screened, then, a small amount of compounds with higher scores are verified by using experiments such as biochemistry and the like, the workload is greatly reduced, the research cost is reduced, and the method has important significance for finding a new compound framework to optimize a lead compound.
Disclosure of Invention
The object of the present invention is to provide a novel trehalose-6-phosphate synthase inhibitor which exhibits an excellent ability to inhibit the pathogenic bacteria of rice blast.
According to one aspect of the invention, the invention provides an application of an indoleamide compound as a trehalose-6-phosphate synthase inhibitor, wherein the indoleamide compound is a compound containing indoleamide skeleton or a pharmaceutically acceptable salt thereof, the structural formula of the indoleamide compound is shown in a formula I,
the trehalose-6-phosphate synthase is a trehalose-6-phosphate synthase from a pathogenic microorganism.
In particular cases, the pathogenic microorganisms include, but are not limited to, Pyricularia oryzae, Fusarium graminearum, Botrytis cinerea, Ustilago virens.
According to another aspect of the present invention, there is provided a trehalose-6-phosphate synthase bacteriostatic agent, which comprises an active ingredient and an auxiliary agent, wherein the active ingredient is a compound containing an indoleamide skeleton represented by formula I or a pharmaceutically acceptable salt thereof.
In a specific case, the trehalose-6-phosphate synthase bacteriostatic agent is in a pharmaceutically acceptable dosage form; the formulation comprises at least one of missible oil, wettable powder, suspending agent, soluble powder, aqueous solution, water dispersible powder, smoke agent, granules and seed coating agent.
The compound VS-23 provided by the invention is used as a trehalose-6-phosphate synthase inhibitor, has the characteristics of strong specificity and high activity, and shows excellent rice blast fungus pathogenic inhibition capability.
Reference to the literature
[1] Zhxian, wangsing, wangzhaofang, Chinese tobacco diseases, Beijing: chinese agricultural press, 2002.
[2] Liu national right, Mengzhao river, Youyanjun, Li Chunguo, Liu Yongwei, Menglaucia, research progress and countermeasures for rice blast resistance, Chinese agronomy bulletin, 2004, 211-.
[3]Dean R.A.,Talbot N.J.,Ebbole D.J.,et al.The genome sequence of the rice blast fungus Magnaporthe grisea.Nature,2005,434:980-986.
[4]Foster A.J.,Jenkinson J.M.,and Talbot N.J.Trehalose synthesis and metabolism are required at different stages of plant infection by Magnaporthe grise.EMBO J,2003,22:225-235.
[5]Wilson R.A.,Jenkinson J.M.,Gibson R.P.,Littlechild J.A.,Wang Z.Y.,and Talbot N.J.Tps1 regulates the pentose phosphate pathway,nitrogen metabolism and fungal virulence.EMBO J,2007,26:3673-3685.
[6]Wilson R.A.,Gibson R.P.,Quispe C.F.,Littlechild J.A.,and Talbot N.J.An NADPH-dependent genetic switch regulates plant infection by the rice blast fungus.Proc Natl Acad Sci USA,2010,107:21902-21907.
[7]Xue Y,Shui G,Wenk M.R.TPS1 drug design for rice blast disease in Magnaporthe oryzae.SpringerPlus,2014,3:18.
[8]Perfect J.R.,Tenor J.L.,Miao Y.,and Brennan R.G.Trehalose pathway as an antifungal target.Virulence,2017,8:143-149.
[9]Kern C.,Wolf C.,Bender F.,Berger M.,Noack S.,Schmalz S.,and Ilg T.Trehalose-6-phosphate synthase from the cat flea Ctenocephalides felis and Drosophila melanogaster:gene identification,cloning,heterologous functional expression and identification of inhibitors by high throughput screening.Insect.Mol.Biol.2012,21:456-471.
[10]Wang S,Zhao Y,Yi L,Shen M,Wang C,Zhang X,Yang J,Peng YL,Wang D,Liu J.Crystal structures of Magnaporthe oryzae trehalose-6-phosphate synthase(MoTps1)suggest a model for catalytic process of Tps1.Biochemical J.2019,476:3227-3240.
Drawings
FIG. 1 shows the detection of the interaction of the compounds VS-23, UDP-glucose, glucose-6-phosphate with MoTps1 by surface plasmon resonance.
FIG. 2 is a graph of the glycosyltransferase kit to detect the effect of compound VS-23 on MoTps1 activity.
FIG. 3 is a graph showing the effect of compound VS-23 on the virulence of Pyricularia oryzae by in vitro inoculation.
Detailed Description
The invention takes the crystal structure of the compound of MoTps1 and a substrate as a receptor[10]The hit compound VS-23 (purchased from TopScience co., Ltd.) was finally screened by virtual screening through pharmacophore search, molecular docking and drug-like property screening. The structure of the compound is shown as a formula-I.
The surface plasmon resonance method has the characteristics of high sensitivity and good repeatability, and is an international universal method for detecting the interaction between small molecules and protein. Fixing MoTps1 protein on the surface of a chip by using an amino coupling method, flowing a series of concentration gradient VS-23 small molecules on the surface of the chip, detecting the change of a reaction signal, then fitting the change to a steady-state model preset by software, and calculating an equilibrium dissociation constant (K)DThe strength of reaction affinity), etc. (see fig. 1). This studyK for VS-23 and MoTps1 detectionDThe concentration was 41.4. mu.M. K of MoTps1 with its natural substrates UDP-glucose and glucose-6-phosphateD0.326mM and 8.38mM, respectively. It can be seen that the affinity of VS-23 to MoTps1 is much higher than that of MoTps1 to its natural substrates UDP-glucose and glucose-6-phosphate, reaching 7.8 times and 200 times respectively.
The glycosyltransferase kit (R & D, cat # EA001) can be used to detect the relative enzyme activity of glycosyltransferases. VS-23 was detected to have inhibitory ability to the enzyme activity of MoTps1, the inhibition rate of VS-23 to the enzyme activity at the final concentration of 200. mu.M was about 50%, and the inhibition rate of VS-23 to the enzyme activity at the final concentration of 1mM was about 80% (see FIG. 2).
An in-vitro inoculation experiment based on rice leaf point grafting is a standard method for detecting the influence of a medicament on the pathogenicity of rice blast fungi (agricultural industry standard NY/T3257-2018 of the people's republic of China). The rice blast fungus spores mixed with 40 mug/ml VS-23 are spotted on rice leaves to form brown resistant disease spots, while the control group (the rice blast fungus spores with the same concentration and without adding agents) forms spindle-shaped disease spots characteristic to rice blast, which shows that VS-23 can inhibit the rice blast fungus spores from infecting the rice leaves, namely VS-23 can inhibit the occurrence of the rice blast (see figure 3). Meanwhile, the leaves of the phytotoxicity control group (40. mu.g/ml VS-23, no Magnaporthe grisea spores) had no necrotic spots, indicating that this concentration of the agent was not phytotoxic to plants (see FIG. 3).
Claims (4)
1. An application of indoleamide compound as trehalose-6-phosphate synthase inhibitor, the indoleamide compound is a compound containing indoleamide skeleton or pharmaceutically acceptable salt thereof, the structural formula is shown in formula I,
the trehalose-6-phosphate synthase is a trehalose-6-phosphate synthase from a pathogenic microorganism.
2. Use according to claim 1, said pathogenic microorganisms comprising Pyricularia oryzae, Fusarium graminearum, Botrytis cinerea, Ustilaginoidea virens.
3. A trehalose-6-phosphate synthase bacteriostatic agent, comprising an active ingredient and an auxiliary agent, wherein the active ingredient is the compound containing the indoleamide skeleton according to claim 1 or the pharmaceutically acceptable salt thereof.
4. The trehalose-6-phosphate synthase bacteriostatic agent according to claim 3, in a pharmaceutically acceptable dosage form; the formulation comprises at least one of missible oil, wettable powder, suspending agent, soluble powder, aqueous solution, water dispersible powder, smoke agent, granules and seed coating agent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210122745.XA CN114403150B (en) | 2022-02-09 | 2022-02-09 | Application of indoleamide compound as trehalose-6-phosphate synthase inhibitor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210122745.XA CN114403150B (en) | 2022-02-09 | 2022-02-09 | Application of indoleamide compound as trehalose-6-phosphate synthase inhibitor |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114403150A true CN114403150A (en) | 2022-04-29 |
| CN114403150B CN114403150B (en) | 2022-11-04 |
Family
ID=81279151
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210122745.XA Active CN114403150B (en) | 2022-02-09 | 2022-02-09 | Application of indoleamide compound as trehalose-6-phosphate synthase inhibitor |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114403150B (en) |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4619941A (en) * | 1984-11-19 | 1986-10-28 | American Cyanamid Company | N-[(1H-imidazol-1-yl)alkyl]-1H-indolecarboxamides useful as thromboxane synthetase inhibitors and antihypertensive agents |
| CN1639120A (en) * | 2002-03-06 | 2005-07-13 | 阿斯特拉曾尼卡有限公司 | Indolamid derivatives which possess glycogenphosphorylase inhibitory activity |
| CN106946761A (en) * | 2017-03-27 | 2017-07-14 | 沈阳药科大学 | Indole carboxamides class compound and its application |
| CN108101828A (en) * | 2018-01-15 | 2018-06-01 | 西华师范大学 | 3- indyl Carbox amides and preparation method thereof |
| CN108299276A (en) * | 2018-01-11 | 2018-07-20 | 中国农业科学院植物保护研究所 | A kind of Benzazole compounds and its application in prevention agricultural fungal evil |
| CN109896988A (en) * | 2019-03-20 | 2019-06-18 | 甘肃农业大学 | A kind of synthesis of indole amides analog derivative and its application as plant growth regulator |
-
2022
- 2022-02-09 CN CN202210122745.XA patent/CN114403150B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4619941A (en) * | 1984-11-19 | 1986-10-28 | American Cyanamid Company | N-[(1H-imidazol-1-yl)alkyl]-1H-indolecarboxamides useful as thromboxane synthetase inhibitors and antihypertensive agents |
| CN1639120A (en) * | 2002-03-06 | 2005-07-13 | 阿斯特拉曾尼卡有限公司 | Indolamid derivatives which possess glycogenphosphorylase inhibitory activity |
| CN106946761A (en) * | 2017-03-27 | 2017-07-14 | 沈阳药科大学 | Indole carboxamides class compound and its application |
| CN108299276A (en) * | 2018-01-11 | 2018-07-20 | 中国农业科学院植物保护研究所 | A kind of Benzazole compounds and its application in prevention agricultural fungal evil |
| CN108101828A (en) * | 2018-01-15 | 2018-06-01 | 西华师范大学 | 3- indyl Carbox amides and preparation method thereof |
| CN109896988A (en) * | 2019-03-20 | 2019-06-18 | 甘肃农业大学 | A kind of synthesis of indole amides analog derivative and its application as plant growth regulator |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114403150B (en) | 2022-11-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Zhang et al. | A small molecule species specifically inhibits F usarium myosin I | |
| Jain et al. | The MAP kinase MpkA controls cell wall integrity, oxidative stress response, gliotoxin production and iron adaptation in Aspergillus fumigatus | |
| Allen et al. | Use of cDNA microarrays to monitor transcriptional responses of the chestnut blight fungus Cryphonectria parasitica to infection by virulence-attenuating hypoviruses | |
| Zwiers et al. | ABC transporters and azole susceptibility in laboratory strains of the wheat pathogen Mycosphaerella graminicola | |
| Zhang et al. | Identification and characterization of a pathogenicity-related gene VdCYP1 from Verticillium dahliae | |
| US20070265164A1 (en) | Active Substances for Increasing Pathogenic Defense in Plants and Methods for the Detection Thereof | |
| Yan et al. | The MET13 methylenetetrahydrofolate reductase gene is essential for infection-related morphogenesis in the rice blast fungus Magnaporthe oryzae | |
| Liang et al. | A thiadiazole reduces the virulence of Xanthomonas oryzae pv. oryzae by inhibiting the histidine utilization pathway and quorum sensing | |
| Liang et al. | Salicylic acid is required for broad-spectrum disease resistance in rice | |
| Zheng et al. | A Rho3 homolog is essential for appressorium development and pathogenicity of Magnaporthe grisea | |
| Zhang et al. | A Pmk1-interacting gene is involved in appressorium differentiation and plant infection in Magnaporthe oryzae | |
| Chen et al. | Genotypes and phenotypic characterization of field Fusarium asiaticum isolates resistant to carbendazim in Anhui Province of China | |
| Yang et al. | The deubiquitinating enzyme MoUbp8 is required for infection-related development, pathogenicity, and carbon catabolite repression in Magnaporthe oryzae | |
| Fouché et al. | Directed evolution predicts cytochrome b G37V target site modification as probable adaptive mechanism towards the QiI fungicide fenpicoxamid in Zymoseptoria tritici | |
| Xu et al. | The Colletotrichum gloeosporioides RhoB regulates cAMP and stress response pathways and is required for pathogenesis | |
| Song et al. | In vitro determination of sensitivity of Fusarium fujikuroi to fungicide azoxystrobin and investigation of resistance mechanism | |
| Xue et al. | Multiple mutations in SDHB and SDHC2 subunits confer resistance to the succinate dehydrogenase inhibitor cyclobutrifluram in Fusarium fujikuroi | |
| Gao et al. | Genome sequence and spore germination-associated transcriptome analysis of Corynespora cassiicola from cucumber | |
| Isidro‐Sánchez et al. | Genome‐wide association mapping of Fusarium langsethiae infection and mycotoxin accumulation in oat (Avena sativa L.) | |
| Nirmala et al. | Proteolysis of the barley receptor-like protein kinase RPG1 by a proteasome pathway is correlated with Rpg1-mediated stem rust resistance | |
| Liu et al. | Sensitivity and resistance risk assessment of Fusarium graminearum from wheat to prothioconazole | |
| Zhang et al. | FgRad50 regulates fungal development, pathogenicity, cell wall integrity and the DNA damage response in Fusarium graminearum | |
| Xiao et al. | Protein kinase Ime2 is associated with mycelial growth, conidiation, osmoregulation, and pathogenicity in Fusarium oxysporum | |
| Asai et al. | Differential biosynthesis and roles of two ferrichrome-type siderophores, ASP2397/AS2488053 and ferricrocin, in Acremonium persicinum | |
| CN114403150B (en) | Application of indoleamide compound as trehalose-6-phosphate synthase inhibitor |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |