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CN108276473B - Insect kinin analogs and application thereof in pest control - Google Patents

Insect kinin analogs and application thereof in pest control Download PDF

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Publication number
CN108276473B
CN108276473B CN201810225612.9A CN201810225612A CN108276473B CN 108276473 B CN108276473 B CN 108276473B CN 201810225612 A CN201810225612 A CN 201810225612A CN 108276473 B CN108276473 B CN 108276473B
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fmoc
compound
insect
kinin
raa
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CN108276473A (en
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杨新玲
李欣潞
张喆
凌云
汪梅子
宋敦伦
陈梦婷
张怡萌
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China Agricultural University
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China Agricultural University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
    • 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
    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • A01N37/44—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing at least one carboxylic group or a thio analogue, or a derivative thereof, and a nitrogen atom attached to the same carbon skeleton by a single or double bond, this nitrogen atom not being a member of a derivative or of a thio analogue of a carboxylic group, e.g. amino-carboxylic acids
    • A01N37/46—N-acyl derivatives
    • 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
    • A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
    • A01N47/40—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having a double or triple bond to nitrogen, e.g. cyanates, cyanamides
    • A01N47/42—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having a double or triple bond to nitrogen, e.g. cyanates, cyanamides containing —N=CX2 groups, e.g. isothiourea
    • A01N47/44—Guanidine; Derivatives thereof

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  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Health & Medical Sciences (AREA)
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  • Pest Control & Pesticides (AREA)
  • Wood Science & Technology (AREA)
  • Dentistry (AREA)
  • Engineering & Computer Science (AREA)
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  • Organic Chemistry (AREA)
  • Agronomy & Crop Science (AREA)
  • Biophysics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Medicinal Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Peptides Or Proteins (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)

Abstract

The invention discloses insect kinin analogs and application thereof in pest control. The structural formula of the insect kinin analogue is shown as a formula I, wherein Raa is H or is derived from natural amino acid or unnatural amino acid. The invention adopts the strategy and method of mimic peptide science, and the transition point Phe of the active conformation VI type beta turn of the active kinin analog is2By substitution, i.e. at Phe2The side chain is substituted by an aromatic ring, and a piperidine ring, a saturated six-membered ring, a hydrophobic group and a hydrophilic group which have similar structures with a benzene ring are introduced for substitution modification, so that the novel insect kinin analogue with a novel structure is invented, the insecticidal activity of the novel compound is very obvious, the novel compound has a good control effect on aphids, and can be applied to control agricultural pests such as aphids.

Description

Insect kinin analogs and application thereof in pest control
Technical Field
The invention belongs to the technical field of pest control, and particularly relates to insect kinin analogs and application thereof in pest control.
Background
Insect kinins (Insect kinins) are a class of active peptides commonly found in invertebrates and have a variety of physiological functions. In 1984, 5 octapeptides having a hindgut contractile activity were first isolated from the brain extract of madra cockroach by Holman et al, and then 3 were extracted. The 8 peptides were designated as Leueokinin I-VIII, respectively, as isolated from the body of the McFaroach. The peptides are also isolated from cricket and locust, and then new insect kinins are sequentially isolated from different insects such as cotton bollworm, culex, aedes, american cockroach and the like by adopting a plurality of biological and pharmacological methods, 6 kinins of the family are also isolated from shellfish white shrimp by Nieto and the like, and the kinins of the family are also found in organisms such as spider, snail, pseudocoelomis pig roundworm and the like by using an immunological method. Cox et al cloned the neuropeptide-encoding receptor sequence GRLl04 in the central nervous system of Humifusus hydrostatic cone for the first time in 1997, thereby laying the foundation for further research on the action mechanism of insect kinins.
Insect kinins are conserved pentapeptide H-Phe1-Xaa2-Yaa3-Trp4-Gly5-NH2Is C-terminal, wherein Xaa can be Tyr, His, Ser, Phe, or Asn; yaa can be Ser, Pro or Ala, and the pentapeptide is the smallest fragment required to maintain biological activity, called the core pentapeptide. Over 40 different insect kinins have been isolated from 17 animals. Insect kinins are highly conserved high-activity small-molecule neuroactive substances, have various functions of promoting the contraction of hindgut of an insect, the writhing of a Mahalanobis tube and the secretion of prourine, regulating the haemolymph volume and the water-salt balance, depolarizing the transmembrane potential of the Mahalanobis tube, inhibiting the release of digestive enzymes in an insect body, increasing the weight of a larva and the like, and can be used as a potential medicament for regulating the physiological activities of the insect. However, natural insect kinins are easily degraded by proteases, and structural modification and structure-activity relationship studies have been carried out to develop more potent pseudopeptides and insect kinins with resistance to enzymatic hydrolysisA mimetic.
In recent years, with the growing concern of people on environmental ecology and food safety, development of new pesticides for the purpose of ecological friendliness has become an inevitable trend. Since insect kinins are polypeptide compounds consisting of a plurality of amino acids and have the characteristics of environmental friendliness and safety, development of novel pest control agents using insect kinins core pentapeptides as a lead has been attempted. Scholars at home and abroad introduce unnatural amino acid with steric hindrance effect into molecules in sequence, and structural modification and reformation are carried out on the unnatural amino acid to obtain the insect kinin analog with good enzymolysis resistance activity and good biological activity. However, the biological activity of the kinin analogs is still not very outstanding, the molecular weight is large, and the application of the kinin analogs as pesticide molecules in agricultural production still has certain limitations. Therefore, the development of highly active kinin analogues with novel and simple structures is necessary.
Disclosure of Invention
The present invention addresses the deficiencies of the prior art by providing a transition point Phe to the beta turn of active conformation VI of an active kinin analog2Is subjected to substitution modification by Phe2The side chain is substituted by aromatic ring, and simultaneously piperidine ring, saturated six-membered ring, hydrophobic group and hydrophilic group which have similar structures with benzene ring are introduced for development and modification and biological activity test, thereby providing an insect kinin analogue and application thereof in pest control, wherein the compound has good insecticidal activity.
The structural formula of the insect kinin analogues provided by the invention is shown as the formula I,
Figure BDA0001601253110000021
in the formula I, Raa is H or is derived from natural amino acid or unnatural amino acid.
beta-Ala is from beta-alanine;
trp is from tryptophan;
gly comes from glycine.
In the above insect kinin analog, the natural amino acid can be alanine, glycine, serine, aspartic acid, threonine, asparagine, glutamine, cysteine, leucine, glutamic acid, lysine, arginine, histidine, valine, isoleucine, or proline. The unnatural amino acid can be mono-or poly-substituted phenylalanine, phenylglycine, 2-amino-4-phenylbutyric acid, pyridylalanine, cyclohexylalanine, cyclohexylglycine, 2-aminobutyric acid, 2, 3-diaminopropionic acid, ornithine, citrulline, hydroxyproline, or the like.
Preferably, in formula i, the natural amino acid may be alanine, glycine, serine, aspartic acid, threonine, asparagine, glutamine, cysteine, leucine, glutamic acid, lysine, arginine, histidine, valine, isoleucine or proline. The unnatural amino acid may be 2-chlorophenylalanine, 3-chlorophenylalanine, 4-bromophenylalanine, 4-hydroxyphenylalanine, 4-aminophenylalanine, 4-formylaminophenylalanine, 4-methoxyphenylalanine, 4-methylphenylalanine, 4-nitrophenylalanine, 4-trifluoromethylphenylalanine, 1-naphthylalanine, phenylglycine, 2-amino-4-phenylbutyric acid, 4-pyridylalanine, cyclohexylalanine, cyclohexylglycine, 2-aminobutyric acid, 2, 3-diaminopropionic acid, ornithine, citrulline, hydroxyproline, or the like.
Particularly preferably, in formula I, the natural amino acid can be alanine, glycine, serine, aspartic acid, threonine, asparagine, glutamine, leucine, glutamic acid, lysine, arginine, histidine, valine, isoleucine, proline. The unnatural amino acid can be 2-chlorophenylalanine, 3-chlorophenylalanine, 4-hydroxyphenylalanine, 4-methoxyphenylalanine, 4-methylphenylalanine, 4-nitrophenylalanine, 4-trifluoromethylphenylalanine, 1-naphthylalanine, phenylglycine, 2-amino-4-phenylbutyric acid, 4-pyridylalanine, cyclohexylalanine, cyclohexylglycine, 2-aminobutyric acid, 2, 3-diaminopropionic acid, ornithine, citrulline, hydroxyproline, or the like.
The compounds represented by the formula I provided by the invention are prepared according to a polypeptide solid phase synthesis method in the literature (reference literature: Chan WG, White PD. Fmoc solid phase synthesis A Practical Approach, Oxford Ulersity Press, 2000; pp.9-74.).
The invention further provides the use of the insect kinin analogues described above in pest control. The pest may be aphids.
A medicament (e.g. an insecticide) comprising as an active ingredient an insect kinin analogue as described in any one of the preceding claims also within the scope of the present invention.
The insecticidal activity of the compounds of the invention against aphids was determined by the leaf soaking method (reference: Busvine, J.R., Recommended methods for measuring resistance to pests.1980); the bioassay results show that: the compound of the invention has very obvious poisoning activity on aphids and has value of further application and development as an aphid control agent.
The invention has the beneficial effects that: the invention adopts the strategy and method of mimic peptide science, and the transition point Phe of the active conformation VI type beta turn of the active kinin analog is2By substitution, i.e. at Phe2The side chain is substituted by an aromatic ring, and a piperidine ring, a saturated six-membered ring, a hydrophobic group and a hydrophilic group which have similar structures with a benzene ring are introduced for substitution modification, so that the novel insect kinin analogue with a novel structure is invented, the insecticidal activity of the novel compound is very obvious, the novel compound has a good control effect on aphids, and can be applied to control agricultural pests such as aphids.
Detailed Description
The experimental procedures used in the following examples are all conventional procedures unless otherwise specified.
Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
EXAMPLE 1 preparation of the Compound I-A-1 (Raa from 2-Chlorophenylalanine)
A polypeptide solid phase synthesis method is adopted to prepare a compound shown as I-A-1, and the specific steps are as follows:
after checking the air tightness of the polypeptide synthesizer, taking Rink Amide-Am resin (0.3mmol) and placing the Rink Amide-Am resin in 5mL DCM for activating for 2h, then washing the Rink Amide-Am resin for 5 times by DMF, and adding 5mL of 20% piperidine DMF solution for reacting for 20min to remove Fmoc protective groups on the resin; preparing 5mL DMF solution containing Fmoc-Gly-OH (1.2mmol), HBTU (1.2mmol), HOBt (1.2mmol) and DIEA (1.2mmol), activating for 5min, and reacting with resin at room temperature for 2h to obtain Fmoc-Gly with Rink Amide-amine resin. And continuously removing the Fmoc group, and sequentially accessing Fmoc-Trp (Boc) -OH, Fmoc-beta-Ala-OH, Fmoc-L-2-Cl-Phe-OH and cinnamic acid by the same method. Finally, trifluoroacetic acid is utilized: phenol: thioanisole: and (3) reacting the mixed solution of water and resin for 4 hours to obtain the target product, wherein the mixed solution is 90:5:2.5: 2.5. Filtering, removing TFA by nitrogen blowing, adding a proper amount of frozen ether for precipitation, centrifuging to remove supernatant, and freeze-drying the obtained solid to obtain a crude product. The crude product is separated by reversed phase C18 semi-preparative high performance liquid chromatography to obtain a pure product, and the chromatographic conditions are as follows: the mobile phase was 50% acetonitrile in water (containing 0.1% TFA), the flow rate was 10mL/min, the detection wavelength was 215nM, and the HPLC retention time was around 14 min. The structure identification data are shown in table 1, and the structure is correct after verification.
Example 2 preparation of the Compound I-A-2 (Raa from 3-Chlorophenylalanine)
The compound represented by I-A-2 was prepared according to the same procedure as in example 1 except that Fmoc-L-2-Cl-Phe-OH was replaced with Fmoc-L-3-Cl-Phe-OH. The structure identification data are shown in table 1, and the structure is correct after verification.
Example 3 preparation of a Compound I-A-3 (Raa from 4-Chlorophenylalanine)
The compound represented by I-A-3 was prepared according to the same procedure as in example 1 except that Fmoc-L-2-Cl-Phe-OH was replaced with Fmoc-L-4-Cl-Phe-OH. The structure identification data are shown in table 1, and the structure is correct after verification.
Example 4 preparation of a Compound I-A-4 (Raa from 4-Hydroxyphenylalanine)
The compound represented by I-A-4 was prepared according to the same procedure as in example 1 except that Fmoc-L-2-Cl-Phe-OH was replaced with Fmoc-L-4-OH-Phe-OH. The structure identification data are shown in table 1, and the structure is correct after verification.
Example 5 preparation of a Compound I-A-5 (Raa from 4-methoxyphenylalanine)
The compound represented by I-A-5 was prepared by following the same procedure as in example 1 except that Fmoc-L-2-Cl-Phe-OH was replaced with Fmoc-L-4-OCH3-Phe-OH. The structure identification data are shown in table 1, and the structure is correct after verification.
Preparation of the Compound shown in example 6, I-A-6 (Raa from 4-Methylphenylalanine)
The compound represented by I-A-6 was prepared according to the same procedure as in example 1 except that Fmoc-L-2-Cl-Phe-OH was replaced with Fmoc-L-4-CH3-Phe-OH. The structure identification data are shown in table 1, and the structure is correct after verification.
Preparation of the Compound shown in example 7, I-A-7 (Raa from 4-Nitrophenylalanine)
The compound represented by I-A-7 was prepared according to the same procedure as in example 1 except that Fmoc-L-2-Cl-Phe-OH was replaced with Fmoc-L-4-NO2-Phe-OH. The structure identification data are shown in table 1, and the structure is correct after verification.
Example 8 preparation of a Compound I-A-8 (Raa from 4-trifluoromethylphenylalanine)
The compound represented by I-A-8 was prepared according to the same procedure as in example 1 except that Fmoc-L-2-Cl-Phe-OH was replaced with Fmoc-L-4-CF3-Phe-OH. The structure identification data are shown in table 1, and the structure is correct after verification.
Example 9 preparation of a Compound shown in I-A-9 (Raa derived from 1-naphthylalanine)
The compound represented by I-A-9 was prepared according to the same procedure as in example 1 except that Fmoc-L-2-Cl-Phe-OH was replaced with Fmoc-Ala (1-Naphtyl) -OH. The structure identification data are shown in table 1, and the structure is correct after verification.
Preparation of the Compound shown in example 10, I-A-10 (Raa from phenylglycine)
The compound represented by I-A-10 was prepared according to the same procedure as in example 1 except that Fmoc-L-2-Cl-Phe-OH was replaced with Fmoc-Phg-OH. The structure identification data are shown in table 1, and the structure is correct after verification.
Example 11 preparation of a Compound I-A-11 (Raa from 2-amino-4-phenylbutyric acid)
The compound represented by I-A-11 was prepared according to the same procedure as in example 1 except that Fmoc-L-2-Cl-Phe-OH was replaced with Fmoc-HomopPhe-OH. The structure identification data are shown in table 1, and the structure is correct after verification.
EXAMPLE 12 preparation of the Compound shown in I-B-1 (Raa is Hydrogen)
A polypeptide solid phase synthesis method is adopted to prepare a compound shown as I-B-1, and the specific steps are as follows:
after checking the air tightness of the polypeptide synthesizer, taking Rink Amide-Am resin (0.3mmol) and placing the Rink Amide-Am resin in 5mL DCM for activating for 2h, then washing the Rink Amide-Am resin for 5 times by DMF, and adding 5mL of 20% piperidine DMF solution for reacting for 20min to remove Fmoc protective groups on the resin; preparing 5mL DMF solution containing Fmoc-Gly-OH (1.2mmol), HBTU (1.2mmol), HOBt (1.2mmol) and DIEA (1.2mmol), activating for 5min, and reacting with resin at room temperature for 2h to obtain Fmoc-Gly with Rink Amide-amine resin. The Fmoc group is removed continuously, and Fmoc-Trp (Boc) -OH, Fmoc-beta-Ala-OH and cinnamic acid are sequentially accessed in the same way. After each time of amino acid inoculation, Kaiser's reagent is needed to detect whether the reaction is complete, and if the indicator shows blue, the materials are fed again until the reaction is complete; if the indicator does not change color, the reaction is complete. Finally, trifluoroacetic acid is utilized: phenol: thioanisole: and (3) reacting the mixed solution of water and resin for 4 hours to obtain the target product, wherein the mixed solution is 90:5:2.5: 2.5. Filtering, removing TFA by nitrogen blowing, adding a proper amount of frozen ether for precipitation, centrifuging to remove supernatant, and freeze-drying the obtained solid to obtain a crude product. The crude product is separated by reversed phase C18 semi-preparative high performance liquid chromatography to obtain a pure product, and the chromatographic conditions are as follows: the mobile phase was 40% acetonitrile in water (containing 0.1% TFA), the flow rate was 10mL/min, the detection wavelength was 215nM, and the HPLC retention time was around 15 min. The structure identification data are shown in table 1, and the structure is correct after verification.
EXAMPLE 13 preparation of the Compound shown in I-B-2 (Raa from 4-pyridylalanine)
The compound represented by I-B-2 was prepared according to the same procedure as in example 12, except that after the grafting of Fmoc- β -Ala-OH and before the grafting of cinnamic acid, Fmoc-Ala (4-pyridoyl) -OH was grafted. The structure identification data are shown in table 1, and the structure is correct after verification.
Example 14 preparation of a Compound shown in I-B-3 (Raa from cyclohexylalanine)
The compound represented by I-B-3 was prepared according to the same procedure as in example 12, except that Fmoc- β -Ala-OH was grafted to Fmoc-L-Cha-OH after the grafting and before the grafting to cinnamic acid. The structure identification data are shown in table 1, and the structure is correct after verification.
Preparation of the Compound shown in example 15, I-B-4 (Raa from cyclohexylglycine)
The compound represented by I-B-4 was prepared according to the same procedure as in example 12, except that Fmoc- β -Ala-OH was inoculated, and Fmoc-L-Chg-OH was inoculated, only after the inoculation of Fmoc- β -Ala-OH, but before the inoculation of cinnamic acid. The structure identification data are shown in table 1, and the structure is correct after verification.
Example 16 preparation of a Compound shown in I-B-5 (Raa from alanine)
The compound represented by I-B-5 was prepared according to the same procedure as in example 12, except that after the grafting of Fmoc- β -Ala-OH and before the grafting of cinnamic acid, Fmoc-L-Ala-OH was grafted. The structure identification data are shown in table 1, and the structure is correct after verification.
EXAMPLE 17 preparation of the Compound shown in I-B-6 (Raa derived from 2-aminobutyric acid)
The compound represented by I-B-6 was prepared according to the same procedure as in example 12, except that after the grafting of Fmoc- β -Ala-OH and before the grafting of cinnamic acid, Fmoc-L-Abu-OH was grafted. The structure identification data are shown in table 1, and the structure is correct after verification.
Example 18 preparation of a Compound shown as I-B-7 (Raa from leucine)
The compound represented by I-B-7 was prepared according to the same procedure as in example 12, except that Fmoc- β -Ala-OH was grafted to Fmoc-L-Leu-OH after the grafting and before the grafting to cinnamic acid. The structure identification data are shown in table 1, and the structure is correct after verification.
EXAMPLE 19 preparation of the Compound shown in I-B-8 (Raa from Glycine)
The compound represented by I-B-8 was prepared according to the same procedure as in example 12, except that Fmoc- β -Ala-OH was grafted to Fmoc-Gly-OH after the grafting of Fmoc- β -Ala-OH and before the grafting of cinnamic acid. The structure identification data are shown in table 1, and the structure is correct after verification.
Example 20 preparation of a Compound I-B-9 (Raa from serine)
The compound represented by I-B-9 was prepared according to the same procedure as in example 12, except that after the grafting of Fmoc- β -Ala-OH and before the grafting of cinnamic acid, Fmoc-Ser-OH was grafted. The structure identification data are shown in table 1, and the structure is correct after verification.
Preparation of the Compound shown in example 21, I-B-10 (Raa from aspartic acid)
The compound represented by I-B-10 was prepared according to the same procedure as in example 12, except that Fmoc-Asp (Otbu) -OH was inoculated only after the inoculation of Fmoc- β -Ala-OH and before the inoculation of cinnamic acid. The structure identification data are shown in table 1, and the structure is correct after verification.
Example 22 preparation of the Compound I-B-11 (Raa from threonine)
The compound represented by I-B-11 was prepared according to the same procedure as in example 12, except that Fmoc-Thr (tbu) -OH was inoculated only after the inoculation of Fmoc- β -Ala-OH and before the inoculation of cinnamic acid. The structure identification data are shown in table 1, and the structure is correct after verification.
Example 23 preparation of a Compound shown in I-C-1 (Raa from glutamic acid)
A polypeptide solid phase synthesis method is adopted to prepare a compound shown as I-C-1, and the specific steps are as follows:
after checking the air tightness of the polypeptide synthesizer, taking Rink Amide-Am resin (0.3mmol) and placing the Rink Amide-Am resin in 5mL DCM for activating for 2h, then washing the Rink Amide-Am resin for 5 times by DMF, and adding 5mL of 20% piperidine DMF solution for reacting for 20min to remove Fmoc protective groups on the resin; preparing 5mL DMF solution containing Fmoc-Gly-OH (1.2mmol), HBTU (1.2mmol), HOBt (1.2mmol) and DIEA (1.2mmol), activating for 5min, and reacting with resin at room temperature for 2h to obtain Fmoc-Gly with Rink Amide-amine resin. Continuously removing the Fmoc group, and sequentially accessing Fmoc-Trp-OH, Fmoc-beta-Ala-OH, Fmoc-Glu-OH and cinnamic acid by the same method. After each time of amino acid inoculation, Kaiser's reagent is needed to detect whether the reaction is complete, and if the indicator shows blue, the materials are fed again until the reaction is complete; if the indicator does not change color, the reaction is complete. Finally, trifluoroacetic acid is utilized: thioanisole: and (3) reacting the mixed solution of water and the resin for 4 hours to obtain the target product. Filtering, removing TFA by nitrogen blowing, adding a proper amount of frozen ether for precipitation, centrifuging to remove supernatant, and freeze-drying the obtained solid to obtain a crude product. The crude product is separated by reversed phase C18 semi-preparative high performance liquid chromatography to obtain a pure product, and the chromatographic conditions are as follows: the mobile phase was 30% acetonitrile in water (containing 0.1% TFA), the flow rate was 10mL/min, the detection wavelength was 215nM, and the HPLC retention time was around 12 min. The structure identification data are shown in table 1, and the structure is correct after verification.
EXAMPLE 24 preparation of the compound shown in I-C-2 (Raa from asparagine)
The compound represented by I-C-2 was prepared according to the same procedure as in example 23 except that Fmoc-Glu-OH was replaced with Fmoc-Asn (trt) -OH. The structure identification data are shown in table 1, and the structure is correct after verification.
Example 25 preparation of a Compound I-C-3 (Raa from Glutamine)
The compound represented by I-C-3 was prepared according to the same procedure as in example 23 except that Fmoc-Glu-OH was replaced with Fmoc-Gln-OH. The structure identification data are shown in table 1, and the structure is correct after verification.
Example 26 preparation of a Compound I-C-4 (Raa from 2, 3-diaminopropionic acid)
The compound represented by I-C-4 was prepared according to the same procedure as in example 23 except that Fmoc-Glu-OH was replaced with Fmoc-dap (Boc) -OH. The structure identification data are shown in table 1, and the structure is correct after verification.
Example 27 preparation of a Compound I-C-5 (Raa from Ornithine)
The compound represented by I-C-5 was prepared according to the same procedure as in example 23 except that Fmoc-Glu-OH was replaced with Fmoc-Orn (Boc) -OH. The structure identification data are shown in table 1, and the structure is correct after verification.
Example 28 preparation of a Compound I-C-6 (Raa from lysine)
The compound represented by I-C-6 was prepared according to the same procedure as in example 23 except that Fmoc-Glu-OH was replaced with Fmoc-Lys (Boc) -OH. The structure identification data are shown in table 1, and the structure is correct after verification.
Example 29 preparation of a Compound I-C-7 (Raa from arginine)
The compound represented by I-C-7 was prepared according to the same procedure as in example 23 except that Fmoc-Glu-OH was replaced with Fmoc-Arg (mtr) -OH. The structure identification data are shown in table 1, and the structure is correct after verification.
Example 30 preparation of a Compound I-C-8 (Raa from citrulline)
The compound represented by I-C-8 was prepared by following the same procedure as in example 23 except that Fmoc-Glu-OH was replaced with Fmoc-Cit-OH. The structure identification data are shown in table 1, and the structure is correct after verification.
Example 31 preparation of a Compound I-C-9 (Raa from histidine)
The compound represented by I-C-9 was prepared according to the same procedure as in example 23 except that Fmoc-Glu-OH was replaced with Fmoc-His-OH. The structure identification data are shown in table 1, and the structure is correct after verification.
Example 32 preparation of a Compound I-C-10 (Raa from hydroxyproline)
The compound represented by I-C-10 was prepared according to the same procedure as in example 23 except that Fmoc-Glu-OH was replaced with Fmoc-Hyp-OH. The structure identification data are shown in table 1, and the structure is correct after verification.
Example 33 preparation of a Compound shown in I-C-11 (Raa from valine)
The compound represented by I-C-11 was prepared according to the same procedure as in example 23 except that Fmoc-Glu-OH was replaced with Fmoc-Val-OH. The structure identification data are shown in table 1, and the structure is correct after verification.
Example 34 preparation of a Compound shown in I-C-12 (Raa from isoleucine)
The compound represented by I-C-12 was prepared according to the same procedure as in example 23 except that Fmoc-Glu-OH was replaced with Fmoc-Ile-OH. The structure identification data are shown in table 1, and the structure is correct after verification.
Example 35 preparation of a Compound I-C-13 (Raa from proline)
The compound represented by I-C-13 was prepared according to the same procedure as in example 23 except that Fmoc-Glu-OH was replaced with Fmoc-Pro-OH. The structure identification data are shown in table 1, and the structure is correct after verification.
Table 1 Structure, high resolution Mass Spectrometry, purity data for Compounds of formula I
Figure BDA0001601253110000091
Figure BDA0001601253110000101
Figure BDA0001601253110000111
Example 37 biological Activity of Compounds of the invention against aphids
The insecticidal activity of the compound on aphids is measured by a leaf-dipping method (leaf-dipping method), and the biological activity of the compound on Aphis glycines (Aphis glycines) is measured. Samples were prepared in different concentration gradients using aqueous solutions containing 0.05% triton X-100. And (3) cultivating the soybean leaves which are not contacted with any medicament and insect indoors, punching the leaves with proper size by using a puncher with the diameter of 15mm, respectively soaking the leaves into the diluted liquid medicine, taking out the leaves after 15 seconds, airing the leaves, and putting the leaves into a bioassay plate. The back of the leaf faces upwards, 1% agar is added at the bottom for moisturizing, and 20 +/-3 heads of soybean aphids are inoculated into each hole. And (4) placing the aphid in a climatic chamber, and checking the death number of the aphid after 48 hours at the temperature of 25 +/-1 ℃. The death judgment criteria were: the parasites were palpated and considered dead by only 1 foot or no movement. Pymetrozine was used as a control and an aqueous solution containing 0.05% Triton X-100 was used as a blank control. The experiment was repeated 3 times and the average was taken. The concentration of the primary screen was set at 200 mg/L. Corrected mortality was calculated as follows: corrected mortality (%) — (sample mortality-placebo mortality)/(1-placebo mortality) × 100%.
The results of the aphid-killing activity test are shown in Table 2.
TABLE 2 insecticidal Activity of Compounds of formula I on Aphis fabae
Figure BDA0001601253110000112
Figure BDA0001601253110000121
Remarking:nt denotes IC without test Compound50The value is obtained.
The results of biological activity tests in table 2 show that the compounds of the present invention all have killing activity on aphids, wherein the insecticidal rate of a plurality of compounds on soybean aphids is higher than 85%. The compounds I-A-8, I-A-9, I-A-11, I-B-3, I-B-4, I-B-11 and I-C-13 have more outstanding activity, and the insecticidal rate (all over 95%) of the compounds to soybean aphids is higher than that of a contrast agent pymetrozine. Of particular note are: LC of compound I-A-8, I-A-9, I-B-3, I-B-4 to soybean aphid50The value is far lower than that of a commercial medicament pymetrozine, and further shows that the compounds have excellent aphidicidal activity and have further development value as aphid control agents.

Claims (4)

1. A compound of the formula I,
Figure FDA0002730772790000011
in the formula I, Raa is from threonine, 4-trifluoromethylphenylalanine, 1-naphthylalanine, 2-amino-4-phenylbutyric acid, cyclohexylalanine or cyclohexylglycine.
2. The compound of claim 1, wherein: the compound is prepared by a polypeptide solid phase synthesis method.
3. Use of a compound of claim 1 for pest control;
the pests are aphids.
4. A medicament, characterized by: the active ingredient of which is a compound according to claim 1.
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