CN110313477A - The application of 4,5,6,7- tetrahydro benzo thiophenes - Google Patents

The application of 4,5,6,7- tetrahydro benzo thiophenes Download PDF

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CN110313477A
CN110313477A CN201910494705.6A CN201910494705A CN110313477A CN 110313477 A CN110313477 A CN 110313477A CN 201910494705 A CN201910494705 A CN 201910494705A CN 110313477 A CN110313477 A CN 110313477A
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alkyl
aryl
compound
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CN110313477B (en
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张莉
胡松
董雅雯
凌云
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China Agricultural University
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China Agricultural University
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    • 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
    • A01N43/02—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms
    • A01N43/04—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom
    • A01N43/06—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom five-membered rings
    • A01N43/10—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom five-membered rings with sulfur as the ring hetero atom
    • 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
    • A01N43/02—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms
    • A01N43/04—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom
    • A01N43/06—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom five-membered rings
    • A01N43/12—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom five-membered rings condensed with a carbocyclic ring
    • 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
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
    • 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
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
    • A01N43/42—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings condensed with carbocyclic rings
    • 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
    • A01N43/56—1,2-Diazoles; Hydrogenated 1,2-diazoles
    • 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
    • A01N43/60—1,4-Diazines; Hydrogenated 1,4-diazines
    • 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
    • A01N43/64—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with three nitrogen atoms as the only ring hetero atoms
    • A01N43/647—Triazoles; Hydrogenated triazoles
    • A01N43/653—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • 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
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/82—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with three ring hetero atoms
    • 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
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/84—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms six-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,4
    • 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
    • A01N47/08—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 one or more single bonds to nitrogen atoms
    • A01N47/10—Carbamic acid derivatives, i.e. containing the group —O—CO—N<; Thio analogues thereof
    • A01N47/18—Carbamic acid derivatives, i.e. containing the group —O—CO—N<; Thio analogues thereof containing a —O—CO—N< group, or a thio analogue thereof, directly attached to a heterocyclic or cycloaliphatic ring
    • G—PHYSICS
    • G06—COMPUTING; CALCULATING OR COUNTING
    • G06F—ELECTRIC DIGITAL DATA PROCESSING
    • G06F30/00—Computer-aided design [CAD]

Abstract

The present invention provides one kind 4,5,6, the application of 7- tetrahydro benzo thiophenes, more particularly to a kind of compound with formula (I) structure are preparing the application in β-N-acetylmuramic glycanchydrolase OfHex1 inhibitor, and the present invention is to provide the compounds of (I) structure to have good inhibiting effect to β-N-acetylmuramic glycanchydrolase OfHex1, it can be used in control of insect, and the raw materials of compound is easy to get, and synthesis difficulty is smaller, can be used for industrial development.

Description

The application of 4,5,6,7- tetrahydro benzo thiophenes
Technical field
The present invention relates to pesticide fields, more particularly to a kind of application of 4,5,6,7- tetrahydro benzo thiophenes.
Background technique
β-N-acetylmuramic glycanchydrolase OfHex1 is the important enzyme of the intracorporal one kind of agricultural pests Ostrinia furnacalis, belongs to sugar 20 family of glycosides hydrolase (GH20).The enzyme plays a major role in the degradation of Ostrinia furnacalis epidermis chitin, to Asia corn The growth and development of snout moth's larva is most important.Therefore, β-N-acetylmuramic glycanchydrolase OfHex1 is a kind of important action of agricultural chemicals target, suppression Preparation can be used as the potential drug of pest control.
In recent years, it has been found that a variety of OfHex1 micromolecular inhibitors with different chemical structures, wherein most It is inhibitor, such as DNJNAc, PUGNAc, NGT, TMG-chitotriomycin etc. based on sugar, they imitate the knot of substrate Syntype, catalytic transition state or reaction intermediate, some is then the inhibitor of non-carbohydrate.However, above-mentioned inhibitor Due to activity is poor or synthesis difficulty is larger etc., its follow-up developments is largely limited.Therefore, be badly in need of screening and It was found that a kind of skeleton is novel, is readily synthesized and the lesser high activity micromolecular inhibitor of economic cost.
The method of drug screening routine is high flux screening, is dived from a large amount of compound by the way that laboratory facilities discovery is new In lead compound, but this method heavy workload, time-consuming, costly, and blindness is bigger.In recent years, computer Aided drug design (computer-aided drug design, CADD) is quickly grown, and is sent out from original basic theory It transforms into as the subject of a comprehensive practical, is used by many medicament research and development companies, and achieve great success.CADD can not only The investment in drug development is enough substantially reduced, limited experimental resources are saved, reduces the waste of blindness, but also can contract significantly The period of short medicament research and development.Therefore, by the β-N- acetylhexosamine of Computer-Aided Drug Design method discovery novel framework Enzyme OfHex1 inhibitor lead compound, and it is optimized, β-N-acetylmuramic glycanchydrolase that discovery high activity is easily-synthesized OfHex1 inhibitor is of great significance.
Summary of the invention
In view of this, technical problem to be solved by the present invention lies in provide a kind of 4,5,6,7- tetrahydro benzo thiophene-baseds The application of object is closed, provided by the invention 4,5,6,7- tetrahydro benzo thiophenes are as β-N-acetylmuramic glycanchydrolase OfHex1 Inhibitor activity is high, and is easily-synthesized.
Compared with prior art, the present invention provides a kind of compound with formula (I) structure preparation β-N- acetyl oneself Application in osamine enzyme OfHex1 inhibitor is found through experiments that, the present invention is to provide the compounds of (I) structure to β-N- second Acyl hexosaminidase OfHex1 has good inhibiting effect, can be used in control of insect, and the raw materials of compound is easy to get, and synthesizes hardly possible Degree is smaller, can be used for industrial development.
Detailed description of the invention
Fig. 1 is 5 crystal complex overlapping figures；
Fig. 2 is Pharmacophore Model；
Fig. 3 is inhibiting effect result of the virtual screening compound VSI-1~VSI-28 to OfHex1；
Fig. 4 is optimization gained compound I-1~I-95；
Fig. 5 is the synthetic route of compound I-1~I-6；
Fig. 6 is the synthetic route of I-7~I-43, I-44 and I-87~I-95；
Inhibiting effect result of the compound I-1~I-95 obtained by Fig. 7 embodiment to OfHex1.
Specific embodiment
The present invention provides a kind of compounds with formula (I) structure or its pharmaceutically acceptable salt in preparation β-N- second Application in acyl hexosaminidase OfHex1 inhibitor,
Wherein, the R1For hydrogen, the alkyl or substituted or unsubstituted C6 of substituted or unsubstituted C1~C8 The aryl of~C15；
The R2For the straight chained alkyl of unsubstituted C3~C8, the straight chained alkyl, unsubstituted of substituted C1~C8 The branched alkyl of C3~C8, the branched alkyl of substituted C1~C8, substituted or unsubstituted C6~C30 aryl, The heteroaryl of substituted or unsubstituted C3~C8, substituted or unsubstituted C3~C10 naphthenic base or be substituted or Unsubstituted C3~C10 Heterocyclylalkyl；
The R3For hydrogen, cyano, R3-1CONHCH2Or R3-2OCO-, wherein the R3-1It is substituted or unsubstituted The straight chained alkyl of C3~C8, the branched alkyl of substituted or unsubstituted C3~C8, substituted or unsubstituted C6~C30 Aryl or substituted or unsubstituted C3~C8 heteroaryl；R3-1For the straight of substituted or unsubstituted C1~C8 The branched alkyl of alkyl group or substituted or unsubstituted C3~C8；
The L is ester group, amide groups, urea groups, substituted or unsubstituted C1~C5 alkylidene, is substituted or is not taken The sub- miscellaneous alkyl of the C1~C5 in generation.
According to the present invention, the R1In, the substituent group in the alkyl of substituted C1~C8 is preferably halogen or C6~C15 Aryl；Substituent group in the aryl of substituted C6~C15 is the alkoxy of halogen, nitro, the alkyl of C1~C5 or C1~C5, more Specifically, the R1Preferably hydrogen, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, n-pentyl, different Amyl, neopentyl, n-hexyl, phenyl, 4- aminomethyl phenyl, naphthalene or anthryl.
According to the present invention, the R2In, be substituted C1~C8 straight chained alkyl in substituent group be halogen, carboxyl, C1~ The alkyl amino of C5, the naphthenic base of C3~C8, the Heterocyclylalkyl of C3~C8, the aryl of C6~C20 or the heteroaryl of C5~C15； The substituent group in substituent group in the branched alkyl of substituted C3~C8 be halogen, carboxyl, the alkyl amino of C1~C5, C3~ The naphthenic base of C8, the Heterocyclylalkyl of C3~C8, the aryl of C6~C20 or the heteroaryl of C5~C15；Substituted C6~C30's Substituent group in aryl is the heteroaryl of halogen, carboxyl, nitro, the alkoxy of C1~C6, the aryl of C6~C15 or C5~C10； Substituent group in the heteroaryl of substituted C3~C8 is the aryl of halogen, carboxyl, nitro, the alkoxy of C1~C6, C6~C15 Or the heteroaryl of C5~C10；Substituent group in substituted C3~C10 naphthenic base be halogen, the naphthenic base of C3~C8, C6~ The aryl of C20 or the heteroaryl of C5~C15；Substituent group in substituted C3~C10 Heterocyclylalkyl is the ring of halogen, C3~C8 The heteroaryl of alkyl, the aryl of C6~C20 or C5~C15；More specifically, the R2Specially following group:
Wherein, the integer that n is 2~8.
According to the present invention, the R3For hydrogen, cyano, R3-1CONHCH2Or R3-2OCO-, wherein the R3-1For be substituted or The straight chained alkyl of unsubstituted C1~C8, substituted or unsubstituted C3~C8 branched alkyl, be substituted or do not taken The heteroaryl of the aryl of the C6~C30 in generation or substituted or unsubstituted C3~C8, wherein be substituted the straight chain of C1~C8 Substituent group in alkyl is halogen, carboxyl, the alkyl amino of C1~C5, the naphthenic base of C3~C8, the Heterocyclylalkyl of C3~C8, C6 The aryl of~C20 or the heteroaryl of C5~C15；The substituent group in substituent group in the branched alkyl of substituted C3~C8 is halogen Element, carboxyl, the alkyl amino of C1~C5, the naphthenic base of C3~C8, the Heterocyclylalkyl of C3~C8, the aryl of C6~C20 or C5~ The heteroaryl of C15；Substituent group in the aryl of substituted C6~C30 is halogen, carboxyl, nitro, the alkoxy of C1~C6, C6 The aryl of~C15 or the heteroaryl of C5~C10；Substituent group in the heteroaryl of substituted C3~C8 is halogen, carboxyl, nitre Base, the alkoxy of C1~C6, the aryl of C6~C15 or C5~C10 heteroaryl；Specifically, R3-1For following group:
R3-1For the straight chained alkyl or substituted or unsubstituted C3~C8 of substituted or unsubstituted C1~C8 Branched alkyl, wherein the substituent group being substituted in the straight chained alkyl of C1~C8 is halogen, carboxyl, the alkyl amino of C1~C5, C3 The naphthenic base of~C8, the Heterocyclylalkyl of C3~C8, the aryl of C6~C20 or the heteroaryl of C5~C15；Substituted C3~C8's The substituent group in substituent group in branched alkyl be halogen, carboxyl, the alkyl amino of C1~C5, the naphthenic base of C3~C8, C3~ The heteroaryl of the Heterocyclylalkyl of C8, the aryl of C6~C20 or C5~C15；Specifically, R3-2For methyl, ethyl, n-propyl, isopropyl Base, normal-butyl, isobutyl group or n-pentyl.
In the present invention, the L is ester group, amide groups, urea groups, substituted or unsubstituted C1~C5 alkylidene, is taken Generation or unsubstituted C1~C5 sub- miscellaneous alkyl, wherein the substituent group in the alkyl of substituted C1~C5 be preferably halogen or The aryl of C6~C15；Substituent group in the sub- miscellaneous alkyl of the substituted C1~C5 is halogen or the aryl of C6~C15, institute Stating the hetero atom in sub- miscellaneous alkyl is preferably one or more of oxygen, nitrogen and sulphur.
The compound of formula (I) structure are as follows:
The R2-1Specially following group.
In the present invention, preferably screening obtains the compound of formula (I) structure in accordance with the following methods:
1) qualified small molecule compound is selected in SPECS database according to class pesticide rule, establish data Library 1；
2) from Protein Data Bank obtain OfHexI and ligand cocrystallization three-dimensional structure, dissection mode, Pharmacophore Model is established, and database 1 is screened, establishes database 2；
3) molecular docking is used, docking marking is carried out to the compound in database 2, marking is selected to be worth forward 10% Compound establishes database 3；
4) Conjugated free energy between 3 small molecular compound of database and albumen is calculated using software, selection combines certainly Target active testing is carried out by the compound that can relatively bear, obtains the β-N-acetylmuramic glycanchydrolase OfHex1 suppression with formula (I) structure Preparation.
Specifically, the present invention selects qualified small molecule chemical combination according to class pesticide rule in SPECS database Object establishes database 1；Wherein, the present invention does not have particular/special requirement, those skilled in the art to the method for establishing small molecule database Suitable database can be selected according to general knowledge known in this field；Specifically, using in software MOE 2016.08 Calculate Descriptors module calculate the library SPECS in 200,000 compounds weight (molecular weight), ClogP(log octanol/water partition coefficient)、HBA(number of H-bond acceptor Atoms), HBD (number of H-bond donor atoms), ROB (number of rotatable bonds) and ARB (number of aromatic atoms) parameter selects eligible according to class pesticide rule: weight < 435, 72720 small molecule compounds of ClogP < 6, HBA < 6, HBD < 2, ROB < 9, ARB < 17, establish database 1；
In the present invention, the present invention obtains the three-dimensional structure of OfHexI and ligand cocrystallization from Protein Data Bank, Dissection mode is established Pharmacophore Model, and is screened to database 1, and database 2 is established；Wherein, the three-dimensional of cocrystallization Structure is the three-dimensional structure that PDB ID is 3NSN, 3OZP, 3OZO, 3WMB and 3WMC；In model, the pharmacophore feature of selection are as follows: A hydrogen bond donor site is defined at Glu328, defines hydrophobic effect at Trp490, Trp524 and Trp448；The side of data screening Method are as follows: using DOCK/virtualscreening module in software MOE2016.08, using pharmacophore to newly-built database 1 Screening marking is carried out, marking value S value is ranked up, S value is more negative, shows that the matching degree of small molecule compound and pharmacophore is got over Height, 5329 compounds for selecting S value forward, establishes database 2.
In the present invention, using molecular docking, docking marking is carried out to the compound in database 2, selects marking value forward 10% compound, establish database 3；Specifically, the present invention is using Dock module in MOE 2016.08 in database 2 Compound carry out molecular docking, the method selected be Triangle Marcher, and scoring functions are London dG and GBVI/ WSA dG；And be ranked up docking marking S value, S value is more negative, shows compound and protein bound more stable, and S value is selected to lean on 250 preceding compounds, establish database 3.
The Conjugated free energy between 3 small molecular compound of database and albumen is calculated using software, selection combines freely The compound that can relatively bear carries out target active testing, and β-N-acetylmuramic glycanchydrolase OfHex1 that obtaining has formula (I) structure inhibits Agent.
The present invention provides a kind of compounds with formula (I) structure to inhibit in preparation β-N-acetylmuramic glycanchydrolase OfHex1 Application in agent, is found through experiments that, the present invention is to provide the compounds of (I) structure to β-N-acetylmuramic glycanchydrolase OfHex1 There is good inhibiting effect, can be used in control of insect, and the raw materials of compound is easy to get, and synthesis difficulty is smaller, can be used for work Industry exploitation.
It is noted that
Wen Zhong, the carbon atom number being defined in substituted alkyl, substituted aryl etc. do not include the carbon on substituent group Atomicity, such as: the straight chained alkyl of substituted C1~C5 refers to that the number of the carbon on branched alkyl is 1~5, does not wrap Include the number of the carbon on substituent group.
Miscellaneous alkyl involved in text or the hetero atom in heteroaryl are one or more of oxygen, nitrogen and sulphur.
Wen Zhong does not indicate that group is the group replaced, thinks for the group not comprising substituent group.
It is clearly and completely described below in conjunction with the technical solution of the embodiment of the present invention, it is clear that described implementation Example is only a part of the embodiment of the present invention, instead of all the embodiments.Based on the embodiments of the present invention, this field is common Technical staff's every other embodiment obtained without making creative work belongs to the model that the present invention protects It encloses.
Embodiment 1
The screening of compound with formula (I) structure
(1) obtained from Protein Data Bank OfHex1 and ligand cocrystallization three-dimensional structure (PDB ID:3NSN, 3OZP, 3OZO, 3WMB and 3WMC), three-dimensional structure is compared using Align/Superpose module in MOE 2016.08 Analysis determines that active pocket, the result is shown in Figure 1, Fig. 1 are 5 crystal complex overlapping figures, wherein the ligand in 3NSN is yellow, 3OZP is cyan, and 3OZO is purple, and 3WMB is green, and 3WMC is blue；Colored region is ligand binding pocket.
(2) it is calculated 200,000 in the library SPECS using the Calculate Descriptors module in software MOE 2016.08 Weight (molecular weight), ClogP (the log octanol/water partition of a compound coefficient)、HBA(number of H-bond acceptor atoms)、HBD(number of H-bond donor Atoms), ROB (number of rotatable bonds) and ARB (number of aromatic atoms) parameter, according to According to class pesticide rule, select eligible: weight < 435, ClogP < 6, HBA < 6, HBD < 2, ROB < 9, ARB < 17 72720 small molecule compounds, establish database 1；
(3) using in five crystal complexes of Ligand interaction module analysis in software MOE 2016.08 Interaction between ligand and receptor, determines key amino acid, using Pharmacophore Editor in MOE 2016.08 Module establishes the Pharmacophore Model based on receptor, the pharmacophore feature of selection are as follows: a hydrogen bond donor position is defined at Glu328 Hydrophobic effect is defined at point, Trp490, Trp524 and Trp448, Pharmacophore Model is shown in that Fig. 2, Fig. 2 are Pharmacophore Model.
(4) using DOCK/virtual screening module in software MOE 2016.08, using pharmacophore to newly-built Database 1 carries out screening marking, marking value S value is ranked up, S value is more negative, shows of small molecule compound and pharmacophore 5329 compounds higher with degree, selecting S value forward, establish database 2.
(5) molecular docking, the side of selection are carried out to the compound in database 2 using Dock module in MOE 2016.08 Method is Triangle Matcher, and scoring functions are London dG and GBVI/WSA dG, docking marking S value is ranked up, S It is worth more negative, shows compound and protein bound more stable, 250 compounds for selecting S value forward establish database 3.
(6) using the MMGBSA module in Amber 12 to the small molecule compound in database 3 and between OfHex1 Conjugated free energy is calculated, and Conjugated free energy is more negative, shows that the combination between compound and OfHex1 is more stable, and selection combines Relatively negative preceding 28 compounds (being denoted as: VSI-1~VSI-28) of free energy, particular compound is as follows:
(7) above-mentioned 28 compounds are subjected to target active testing, testing procedure is as follows: using MU-GlcNAc as substrate, 20mM sodium chloride and 20mM sodium dihydrogen phosphate mixed liquor are buffer, set experimental group and control group (+), control group (-), every group If three repetitions.Experimental group: in standard reaction system, the OfHex1's and buffer of the certain density compound of 2 μ L and 88 μ L Premixed liquid, 30 DEG C are incubated for 10 minutes, add the substrate of 10 μ L, and 30 DEG C are incubated for 20 minutes, later, the carbon of 100 μ L 0.5M are added Sour sodium terminates reaction, and the MU of release detects its absorption value A, excitation wavelength 360nm by fluorescence detector, and launch wavelength is 460nm.Control group (+): the 2 certain density compounds of μ L are replaced with the DMSO of 2 μ L, remaining step is identical as experimental group.Control Group (-): replacing the substrate of 10 μ L with the buffer of 10 μ L, remaining step is identical as experimental group.Inhibiting rate carries out as follows It calculates.
(8) test result is shown in Fig. 3, selects active preferable compound VS1-13 (Ki=10.9 μM) as lead compound Continue to optimize.The property for studying the amino acid around the binding pattern and active chamber of lead compound and OfHex1, optimizes guide Compound obtains I-1~I-95 series compound (particular compound is shown in that Fig. 4, Fig. 4 are optimization gained compound I-1~I-95), Wherein compound I-1~I-43 and I-87~I-95 carries out organic synthesis, compound according to Fig. 5~synthetic route shown in fig. 6 I-44~I-86 carries out the survey of target activity according to method described in step (7) as obtained by purchase, and by above-mentioned part of compounds Examination, test result is shown in Fig. 7, from test result as can be seen that the compound protected of the present invention is to β-N-acetylmuramic glycanchydrolase OfHex1 has preferable inhibitory activity, wherein it is I-93 (Ki=3.6 μM) that inhibitory activity is more outstanding.
(9) it was found that the compound of the present invention with Formulas I structure has β-N-acetylmuramic glycanchydrolase OfHex1 There is inhibiting effect, and inhibitory activity is high, and compound structure described herein is simple, synthesis difficulty is smaller, is suitble to industrialization Production.
Wherein, the R1For hydrogen, the alkyl or substituted or unsubstituted C6 of substituted or unsubstituted C1~C8 The aryl of~C15；
The R2For the straight chained alkyl of unsubstituted C3~C8, the straight chained alkyl, unsubstituted of substituted C1~C8 The branched alkyl of C3~C8, the branched alkyl of substituted C3~C8, substituted or unsubstituted C6~C30 aryl, The heteroaryl of substituted or unsubstituted C3~C8, substituted or unsubstituted C3~C10 naphthenic base or be substituted or Unsubstituted C3~C10 Heterocyclylalkyl；
The R3For hydrogen, cyano, R3-1CONHCH2Or R3-2OCO-, wherein the R3-1It is substituted or unsubstituted The straight chained alkyl of C1~C8, the branched alkyl of substituted or unsubstituted C2~C8, substituted or unsubstituted C6~C30 Aryl or substituted or unsubstituted C3~C8 heteroaryl；R3-2For the straight of substituted or unsubstituted C1~C8 The branched alkyl of alkyl group or substituted or unsubstituted C3~C8；
The L is ester group, amide groups, urea groups, substituted or unsubstituted C1~C5 alkylidene, is substituted or is not taken The sub- miscellaneous alkyl of the C1~C5 in generation.
The above description of the embodiment is only used to help understand the method for the present invention and its core ideas.It should be pointed out that pair For those skilled in the art, without departing from the principle of the present invention, the present invention can also be carried out Some improvements and modifications, these improvements and modifications also fall within the scope of protection of the claims of the present invention.

Claims (10)

1. compound or its pharmaceutically acceptable salt that one kind has formula (I) structure are in preparation β-N-acetylmuramic glycanchydrolase Application in OfHex1 inhibitor,
Wherein, the R1For hydrogen, the alkyl or substituted or unsubstituted C6~C15 of substituted or unsubstituted C1~C8 Aryl；
The R2For the straight chained alkyl of unsubstituted C3~C8, the straight chained alkyl of substituted C1~C8, unsubstituted C3~ The branched alkyl of C8, the branched alkyl of substituted C3~C8, substituted or unsubstituted C6~C30 aryl, be substituted Or it the heteroaryl of unsubstituted C3~C8, substituted or unsubstituted C3~C10 naphthenic base or is substituted or is not taken C3~C10 Heterocyclylalkyl in generation；
The R3For hydrogen, cyano, R3-1CONHCH2Or R3-2OCO-, wherein the R3-1For substituted or unsubstituted C1~ The straight chained alkyl of C8, the branched alkyl of substituted or unsubstituted C2~C8, substituted or unsubstituted C6~C30 virtue The heteroaryl of base or substituted or unsubstituted C3~C8；R3-2For the straight chain alkane of substituted or unsubstituted C1~C8 The branched alkyl of base or substituted or unsubstituted C3~C8；
The L is ester group, amide groups, urea groups, substituted or unsubstituted C1~C5 alkylidene, substituted or unsubstituted The sub- miscellaneous alkyl of C1~C5.
2. application according to claim 1, which is characterized in that the R1In, the substituent group in the alkyl of substituted C1~C8 For halogen or the aryl of C6~C15；
Substituent group in the aryl of substituted C6~C15 is the alkoxy of halogen, nitro, the alkyl of C1~C5 or C1~C5.
3. application according to claim 1, which is characterized in that the R1For hydrogen, methyl, ethyl, n-propyl, isopropyl, just Butyl, isobutyl group, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, phenyl, 4- aminomethyl phenyl, naphthalene or anthryl.
4. application according to claim 1, which is characterized in that the R2In, it is substituted taking in the straight chained alkyl of C1~C8 Dai Jiwei halogen, carboxyl, the alkyl amino of C1~C5, the naphthenic base of C3~C8, the Heterocyclylalkyl of C3~C8, C6~C20 virtue The heteroaryl of base or C5~C15；
Substituent group in the branched alkyl of substituted C3~C8 is the ring of halogen, carboxyl, the alkyl amino of C1~C5, C3~C8 Alkyl, the Heterocyclylalkyl of C3~C8, the aryl of C6~C20 or C5~C15 heteroaryl；
Substituent group in the aryl of substituted C6~C30 is halogen, carboxyl, nitro, the alkoxy of C1~C6, C6~C15 The heteroaryl of aryl or C5~C10；
Substituent group in the heteroaryl of substituted C3~C8 is halogen, carboxyl, nitro, the alkoxy of C1~C6, C6~C15 The heteroaryl of aryl or C5~C10；
Substituent group in substituted C3~C10 naphthenic base be halogen, the naphthenic base of C3~C8, the aryl of C6~C20 or C5~ The heteroaryl of C15；
Substituent group in substituted C3~C10 Heterocyclylalkyl is the aryl or C5 of halogen, the naphthenic base of C3~C8, C6~C20 The heteroaryl of~C15.
5. application according to claim 1, which is characterized in that the R2Specially following group:
Wherein, the integer that n is 2~8.
6. application according to claim 1, which is characterized in that the R3In R3-1For following group:
The R3In R3-2For methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group or n-pentyl.
7. application according to claim 1, which is characterized in that the compound of formula (I) structure are as follows:
The R2-1Specially following group.
。
8. application according to claim 1, which is characterized in that the compound of formula (I) structure sieves in accordance with the following methods Choosing obtains:
1) qualified small molecule compound is selected in SPECS database according to class pesticide rule, establish database 1；
2) three-dimensional structure of OfHexI and ligand cocrystallization are obtained from Protein Data Bank, dissection mode is established Pharmacophore Model, and database 1 is screened, establish database 2；
3) molecular docking is used, docking marking is carried out to the compound in database 2, marking is selected to be worth 10% forward chemical combination Object establishes database 3；
4) Conjugated free energy between 3 small molecular compound of database and albumen is calculated using software, selects Conjugated free energy Relatively negative compound carries out target active testing, obtains the β-N-acetylmuramic glycanchydrolase OfHex1 inhibitor with formula (I) structure.
9. application according to claim 8, which is characterized in that the three-dimensional structure of cocrystallization is PDB ID in the step 2) For the three-dimensional structure of 3NSN, 3OZP, 3OZO, 3WMB and 3WMC.
10. application according to claim 1, which is characterized in that the method for the docking marking specifically: Triangle Matcher, scoring functions are London dG and GBVI/WSA dG, docking marking S value are ranked up, S value is more negative, showing Object and protein bound more stable is closed, 250 compounds for selecting S value forward establish database 3.
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