CN110313477B - Application of 4,5,6,7-tetrahydrobenzothiophene compounds - Google Patents
Application of 4,5,6,7-tetrahydrobenzothiophene compounds Download PDFInfo
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Abstract
The invention provides an application of a 4,5,6, 7-tetrahydrobenzothiophene compound, in particular to an application of a compound with a structure shown in a formula (I) in preparation of a beta-N-acetylhexosaminidase OfHex1 inhibitor, the compound with the structure (I) has a good inhibition effect on the beta-N-acetylhexosaminidase OfHex1, can be used for pest control, and the compound has easily available raw materials and low synthesis difficulty, and can be used for industrial development.
Description
Technical Field
The invention relates to the field of pesticides, and particularly relates to an application of a 4,5,6, 7-tetrahydrobenzothiophene compound.
Background
The beta-N-acetylhexosaminidase OfHex1 is an important enzyme in the body of the agricultural pest ostrinia nubilalis, belonging to the glycoside hydrolase 20 family (GH 20). The enzyme plays a main role in the degradation of epidermal chitin of the Asiatic corn borers and is important for the growth and development of the Asiatic corn borers. Therefore, the beta-N-acetylhexosaminidase OfHex1 is an important pesticide action target, and the inhibitor thereof can be used as a potential drug for controlling pests.
In recent years, a variety of small molecule inhibitors of OfHex1 have been discovered with diverse chemical structures, most of which are sugar-based inhibitors such as DNJNAc, punnac, NGT, TMG-chitotrimycin, etc., that mimic the binding mode of substrates, catalyze transition states or reaction intermediates, and some are non-sugar inhibitors. However, the subsequent development of the inhibitor is greatly limited due to poor activity or great synthesis difficulty and the like. Therefore, there is an urgent need to screen and find a highly active small molecule inhibitor with a novel framework, easy synthesis and low economic cost.
The conventional method for drug screening is high-throughput screening, and a new potential lead compound is found from a large amount of compounds through experimental means, but the method has the disadvantages of large workload, long time consumption, high cost and high blindness. In recent years, computer-aided drug design (CADD) has been developed rapidly, has been developed from the original basic theory to become a comprehensive and practical subject, and has been adopted by many drug research and development companies with great success. The CADD not only can greatly reduce the investment in drug development, save limited experimental resources and reduce blind waste, but also can greatly shorten the period of drug development. Therefore, the novel skeleton beta-N-acetylhexosaminidase OfHex1 inhibitor lead compound is discovered by means of a computer-aided drug design method, and is optimized, so that the novel skeleton beta-N-acetylhexosaminidase OfHex1 inhibitor lead compound has great significance for discovering a high-activity easily-synthesized beta-N-acetylhexosaminidase OfHex1 inhibitor.
Disclosure of Invention
In view of the above, the technical problem to be solved by the present invention is to provide an application of 4,5,6, 7-tetrahydrobenzothiophenes, wherein the 4,5,6, 7-tetrahydrobenzothiophenes provided by the present invention have high activity as β -N-acetylhexosaminidase OfHex1 inhibitor and are easy to synthesize.
Compared with the prior art, the invention provides the application of the compound with the structure shown in the formula (I) in the preparation of the beta-N-acetylhexosaminidase OfHex1 inhibitor, and experiments show that the compound with the structure shown in the formula (I) has a good inhibition effect on the beta-N-acetylhexosaminidase OfHex1, can be used for pest control, is easy to obtain raw materials, has low synthesis difficulty, and can be used for industrial development.
Drawings
FIG. 1 is a schematic overlay of 5 crystal composites;
FIG. 2 is a pharmacophore model;
FIG. 3 shows the results of virtual screening of compounds VSI-1 to VSI-28 for inhibition of OfHex 1;
FIG. 4 shows the optimized compounds I-1 to I-95;
FIG. 5 is a synthetic route for compounds I-1 to I-6;
FIG. 6 is a synthetic route of I-7 to I-43, I-44 and I-87 to I-95;
FIG. 7 shows the results of the inhibition of OfHex1 by the compounds I-1 to I-95 obtained in the example.
Detailed Description
The invention provides an application of a compound with a structure shown in a formula (I) or a pharmaceutically acceptable salt thereof in preparing a beta-N-acetylhexosaminidase OfHex1 inhibitor,
wherein, R is1Is hydrogen, substituted or unsubstituted C1-C8 alkyl or substituted or unsubstituted C6-C15 aryl;
the R is2Is unsubstituted C3-C8 linear alkyl, substituted C1-C8 linear alkyl, unsubstituted C3-C8 branched alkyl, substituted C1-C8 branched alkyl, substituted or unsubstituted C6-C30 aryl, substituted or unsubstituted C3-C8 heteroaryl, substituted or unsubstituted C3-C10 cycloalkyl or substituted or unsubstituted C3-C10 heterocycloalkyl;
the R is3Is hydrogen, cyano, R3-1CONHCH2-or R3-2OCO-, wherein R is3-1Is a substituted or unsubstituted C3-C8 linear alkyl group, a substituted or unsubstituted C3-C8 branched alkyl group, a substituted or unsubstituted C6-C30 aryl group or a substituted or unsubstituted C3-C8 heteroaryl group; r3-1Is a substituted or unsubstituted C1-C8 straight chainAn alkyl group or a substituted or unsubstituted branched alkyl group of C3 to C8;
and L is an ester group, an amide group, a carbamido group, a substituted or unsubstituted C1-C5 alkylene group, and a substituted or unsubstituted C1-C5 heteroalkylene group.
According to the invention, said R1Among them, the substituent of the substituted C1-C8 alkyl group is preferably halogen or C6-C15 aryl; the substituent of the substituted C6-C15 aryl is halogen, nitro, C1-C5 alkyl or C1-C5 alkoxy, more specifically, the R is1Preferably hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, phenyl, 4-methylphenyl, naphthyl or anthracenyl.
According to the invention, said R2In the formula (I), the substituent of the linear alkyl substituted by C1-C8 is halogen, carboxyl, alkylamino of C1-C5, cycloalkyl of C3-C8, heterocycloalkyl of C3-C8, aryl of C6-C20 or heteroaryl of C5-C15; the substituent in the substituted C3-C8 branched alkyl is halogen, carboxyl, C1-C5 alkylamino, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C6-C20 aryl or C5-C15 heteroaryl; the substituent of the substituted C6-C30 aryl is halogen, carboxyl, nitro, C1-C6 alkoxy, C6-C15 aryl or C5-C10 heteroaryl; the substituent of the substituted C3-C8 heteroaryl is halogen, carboxyl, nitro, C1-C6 alkoxy, C6-C15 aryl or C5-C10 heteroaryl; the substituent of the substituted C3-C10 cycloalkyl is halogen, C3-C8 cycloalkyl, C6-C20 aryl or C5-C15 heteroaryl; the substituent of the substituted C3-C10 heterocyclic alkyl is halogen, C3-C8 cycloalkyl, C6-C20 aryl or C5-C15 heteroaryl; more specifically, said R2In particular the following groups:
wherein n is an integer of 2-8.
According to the invention, said R3Is hydrogen, cyano, R3-1CONHCH2-or R3-2OCO-, wherein R is3-1The aryl group is a substituted or unsubstituted C1-C8 linear alkyl group, a substituted or unsubstituted C3-C8 branched alkyl group, a substituted or unsubstituted C6-C30 aryl group or a substituted or unsubstituted C3-C8 heteroaryl group, wherein the substituent in the substituted C1-C8 linear alkyl group is halogen, carboxyl, alkylamino of C1-C5, cycloalkyl of C3-C8, heterocycloalkyl of C3-C8, aryl of C6-C20 or heteroaryl of C5-C15; the substituent in the substituted C3-C8 branched alkyl is halogen, carboxyl, C1-C5 alkylamino, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C6-C20 aryl or C5-C15 heteroaryl; the substituent of the substituted C6-C30 aryl is halogen, carboxyl, nitro, C1-C6 alkoxy, C6-C15 aryl or C5-C10 heteroaryl; the substituent of the substituted C3-C8 heteroaryl is halogen, carboxyl, nitro, C1-C6 alkoxy, C6-C15 aryl or C5-C10 heteroaryl; in particular, R3-1Is the following group:
R3-1the substituted or unsubstituted C1-C8 linear alkyl or substituted or unsubstituted C3-C8 branched alkyl, wherein the substituent of the substituted C1-C8 linear alkyl is halogen, carboxyl, alkylamino of C1-C5, cycloalkyl of C3-C8, heterocycloalkyl of C3-C8, aryl of C6-C20 or heteroaryl of C5-C15; the substituent in the substituted C3-C8 branched alkyl is halogen, carboxyl, C1-C5 alkylamino, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C6-C20 aryl or C5-C15 heteroaryl; in particular, R3-2Is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or n-pentyl.
In the invention, L is an ester group, an amide group, a carbamido group, a substituted or unsubstituted C1-C5 alkylene group, a substituted or unsubstituted C1-C5 heteroalkylene group, wherein the substituent of the substituted C1-C5 alkyl group is preferably halogen or C6-C15 aryl; the substituent in the substituted C1-C5 heteroalkylene is halogen or aryl of C6-C15, and the heteroatom in the heteroalkylene is preferably one or more of oxygen, nitrogen and sulfur.
The compound with the structure of the formula (I) is:
the R is2-1Specifically, the following groups.
In the present invention, the compound having the structure of formula (I) is preferably obtained by screening according to the following method:
1) selecting qualified small molecular compounds in an SPECS database according to pesticide-like rules, and establishing a database 1;
2) acquiring a three-dimensional structure of OfHexI and ligand cocrystallization from a Protein Data Bank, analyzing an action mode, establishing a pharmacophore model, screening a database 1, and establishing a database 2;
3) adopting molecular docking to perform docking scoring on the compounds in the database 2, selecting the compounds with the scoring values closer to 10%, and establishing a database 3;
4) the software is used for calculating the binding free energy between the small molecule compound and the protein in the database 3, and the compound with the negative binding free energy is selected for target activity test, so that the beta-N-acetylhexosaminidase OfHex1 inhibitor with the structure of the formula (I) is obtained.
Specifically, the invention selects the micromolecule compound which meets the conditions in the SPECS database according to the pesticide-like property rule, and establishes a database 1; the method for establishing the small molecule database has no special requirement, and a person skilled in the art can select a proper database according to common general knowledge in the field; specifically, the weight (molecular weight), clog/water partition (coefficient), HBA (number of H-bond access indicators), HBD (number of H-bond access indicators), ROB (number of rotate bonds), and ARB (number of aromatic atoms) parameters of 20 ten thousand compounds in the SPECS library are calculated by using a Call descriptor module in the software MOE2016.08, and the parameters are selected according to the pesticide-like rules: 72720 micromolecule compounds with weight less than 435, ClogP less than 6, HBA less than 6, HBD less than 2, ROB less than 9 and ARB less than 17, and establishing a database 1;
in the invention, the three-dimensional structure of OfHexI and ligand cocrystallization is obtained from a Protein Data Bank, the action mode is analyzed, a pharmacophore model is established, a database 1 is screened, and a database 2 is established; wherein the three-dimensional structure of the co-crystal is a three-dimensional structure of PDB ID 3NSN, 3OZP, 3OZO, 3WMB and 3 WMC; in the model, the selected pharmacophore is characterized in that: a hydrogen bond donor site is defined at Glu328, and hydrophobic interactions are defined at Trp490, Trp524 and Trp 448; the data screening method comprises the following steps: a DOCK/virtual screening module in software MOE2016.08 is adopted, a newly-built database 1 is screened and scored by using a pharmacophore, score values S are sorted, the more negative the S values indicate that the matching degree of small molecular compounds and the pharmacophore is higher, 5329 compounds with the former S values are selected, and a database 2 is established.
In the invention, molecular docking is adopted to carry out docking scoring on the compounds in the database 2, and 10% of the compounds with the top scoring value are selected to establish a database 3; specifically, the method adopts a Dock module in MOE2016.08 to carry out molecular docking on the compound in the database 2, the selection method is Triangle Marcher, and the scoring function is London dG and GBVI/WSA dG; and sorting the scoring S values, wherein the more negative the S value is, the more stable the combination of the compound and the protein is, and selecting 250 compounds with the top S value to establish a database 3.
The software is used for calculating the binding free energy between the small molecule compound and the protein in the database 3, and the compound with the negative binding free energy is selected for target activity test, so that the beta-N-acetylhexosaminidase OfHex1 inhibitor with the structure of the formula (I) is obtained.
The invention provides application of a compound with a structure shown in a formula (I) in preparation of a beta-N-acetylhexosaminidase OfHex1 inhibitor, and experiments show that the compound with the structure shown in the formula (I) has a good inhibition effect on beta-N-acetylhexosaminidase OfHex1, can be used for pest control, is easy to obtain raw materials, has low synthesis difficulty and can be used for industrial development.
It should be noted that:
as used herein, the number of carbon atoms defined in a substituted alkyl group, a substituted aryl group, etc. does not include the number of carbon atoms in the substituent, for example: the substituted C1-C5 straight-chain alkyl group means that the number of carbons on the branched-chain alkyl group is 1-5, excluding the number of carbons on the substituent.
The heteroatom in the heteroalkyl or heteroaryl group referred to herein is one or more of oxygen, nitrogen and sulfur.
In the present specification, an unspecified group is a substituted group, and is considered to be a group containing no substituent.
The following will clearly and completely describe the technical solutions of the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
Screening of Compounds having the Structure of formula (I)
(1) Obtaining a three-dimensional structure (PDB ID: 3NSN, 3OZP, 3OZO, 3WMB and 3WMC) of OfHex1 and ligand cocrystallization from a Protein Data Bank, comparing and analyzing the three-dimensional structure by adopting an Align/Superpos module in MOE2016.08 to determine an active pocket, and obtaining a result shown in figure 1, wherein the figure 1 is an overlay of 5 crystal compounds, the ligand in 3NSN is yellow, the ligand 3OZP is cyan, the ligand 3OZO is purple, the ligand 3WMB is green, and the ligand 3WMC is blue; the colored region is the ligand binding pocket.
(2) Calculating the weight (molecular weight), the clog/water partition coefficient, the HBA (number of H-bond indicators), the HBD (number of H-bond detectors), the ROB (number of rotate binders), and the ARB (number of aromatic atoms) parameters of 20 ten thousand compounds in the SPECS library by using a Call Descriptors module in the software MOE2016.08, and selecting the parameters according to the pesticide-like rules: 72720 micromolecule compounds with weight less than 435, ClogP less than 6, HBA less than 6, HBD less than 2, ROB less than 9 and ARB less than 17, and establishing a database 1;
(3) analyzing the interaction between ligands and receptors in five crystal compounds by using a Ligand interaction module in software MOE2016.08 to determine key amino acids, establishing a Pharmacophore model based on the receptors by using a Pharmacophore Editor module in MOE2016.08, wherein the selected Pharmacophore is characterized in that: a hydrogen bond donor site is defined at Glu328, and hydrophobic interactions are defined at Trp490, Trp524 and Trp448, and the pharmacophore model is shown in fig. 2, and fig. 2 is the pharmacophore model.
(4) A DOCK/virtual screening module in the software MOE2016.08 is adopted, the newly-built database 1 is screened and scored by using the pharmacophore, the score values S are sorted, the more negative the S value is, the higher the matching degree of the micromolecule compound and the pharmacophore is, 5329 compounds with the former S values are selected, and the database 2 is established.
(5) And (3) performing molecular docking on the compounds in the database 2 by using a Dock module in MOE2016.08, wherein the selection method is Triangle Matcher, the scoring functions are London dG and GBVI/WSA dG, the docking scoring S values are ranked, the more negative the S value is, the more stable the compound and the protein are combined is, and 250 compounds with the top S values are selected to establish the database 3.
(6) The free energy of binding between the small molecule compound and OfHex1 in database 3 was calculated using the MMGBSA module in Amber 12, the more negative the free energy of binding, indicating that the more stable the binding between the compound and OfHex1, the first 28 compounds with more negative free energy of binding (denoted as: VSI-1 to VSI-28) were selected, with the following specific compounds:
(7) the 28 compounds were tested for target activity by the following procedure: an experimental group, a control group (+), and a control group (-), each of which was composed of three replicates, were prepared using MU-GlcNAc as a substrate and a mixture of 20mM sodium chloride and 20mM sodium dihydrogen phosphate as a buffer. Experimental groups: in a standard reaction system, 2 MU L of a compound with a certain concentration and 88 MU L of a premixed solution of OfHex1 and a buffer solution are incubated for 10 minutes at 30 ℃, 10 MU L of a substrate is added, incubation is carried out for 20 minutes at 30 ℃, then 100 MU L of 0.5M sodium carbonate is added to stop the reaction, the released MU is detected by a fluorescence detector to obtain an absorption value A, the excitation wavelength is 360nm, and the emission wavelength is 460 nm. Control group (+): mu.L of DMSO was used instead of 2. mu.L of the compound at a given concentration, and the procedure was the same as in the experimental group. Control group (-): mu.L of the substrate was replaced with 10. mu.L of the buffer, and the rest of the procedure was the same as in the experimental group. The inhibition ratio was calculated as follows.
(8) The results of the tests are shown in fig. 3, and the optimization is continued by selecting the compound VS1-13 with better activity (Ki ═ 10.9 μ M) as the lead compound. Studying the combination mode of the lead compound and OfHex1 and the properties of amino acids around the active cavity, optimizing the lead compound to obtain I-1-I-95 series compounds (see figure 4 for specific compounds, figure 4 is for optimizing the obtained compounds I-1-I-95), wherein the compounds I-1 to I-43 and I-87 to I-95 are synthesized organically according to the synthetic routes shown in FIGS. 5 to 6, the compounds I-44 to I-86 are obtained by purchasing, and the target activity of the partial compounds is tested according to the method in the step (7), the test results are shown in fig. 7, and the test results show that the compounds protected by the invention have better inhibitory activity on beta-N-acetylhexosaminidase OfHex1, wherein the inhibitory activity is more prominent I-93(Ki is 3.6 mu M).
(9) We find that the compound with the structure of the formula I has an inhibiting effect on beta-N-acetylhexosaminidase OfHex1, has high inhibiting activity, and is simple in structure, low in synthesis difficulty and suitable for industrial production.
Wherein, R is1Is hydrogen, substituted or unsubstituted C1-C8 alkyl or substituted or unsubstituted C6-C15 aryl;
the R is2Is unsubstituted C3-C8 linear alkyl, substituted C1-C8 linear alkyl, unsubstituted C3-C8 branched alkyl, substituted C3-C8 branched alkyl, substituted or unsubstituted C6-C30 aryl, substituted or unsubstituted C3-C8 heteroaryl, substituted or unsubstituted C3-C10 cycloalkyl or substituted or unsubstituted C3-C10 heterocycloalkyl;
the R is3Is hydrogen, cyano, R3-1CONHCH2-or R3-2OCO-, wherein R is3-1Is a substituted or unsubstituted C1-C8 linear alkyl group, a substituted or unsubstituted C2-C8 branched alkyl group, a substituted or unsubstituted C6-C30 aryl group or a substituted or unsubstituted C3-C8 heteroaryl group; r3-2Is a substituted or unsubstituted C1-C8 linear alkyl or a substituted or unsubstituted C3-C8 branched alkyl;
and L is an ester group, an amide group, a carbamido group, a substituted or unsubstituted C1-C5 alkylene group, and a substituted or unsubstituted C1-C5 heteroalkylene group.
The above description of the embodiments is only intended to facilitate the understanding of the method of the invention and its core idea. It should be noted that, for those skilled in the art, it is possible to make various improvements and modifications to the present invention without departing from the principle of the present invention, and those improvements and modifications also fall within the scope of the claims of the present invention.
Claims (4)
1. Preparation of beta-N-acetylhexosaminidase from compound with structure of formula (I) or pharmaceutically acceptable salt thereofOfThe application of the Hex1 inhibitor in the preparation of the drug,
the compound with the structure of the formula (I) is:
2. the use according to claim 1, wherein the compound of formula (I) is selected according to the following method:
1) selecting qualified small molecular compounds in an SPECS database according to pesticide-like rules, and establishing a database 1;
2) obtaining from Protein Data BankOfAnalyzing an action mode of a three-dimensional structure of HexI and ligand cocrystallization, establishing a pharmacophore model, screening a database 1, and establishing a database 2;
3) adopting molecular docking to perform docking scoring on the compounds in the database 2, selecting the compounds with the scoring values closer to 10%, and establishing a database 3;
4) calculating the free energy of the small molecular compound and the protein in the database 3 by using software, selecting the compound with the negative free energy of the combination to perform a target activity test to obtain a lead compound, optimizing the lead compound, and performing the target activity test to obtain the beta-N-acetylhexosaminidase with the structure of the formula (I)OfHex1 inhibitors.
3. The use of claim 2, wherein the three-dimensional structure co-crystallized in step 2) is a three-dimensional structure with PDB ID of 3NSN, 3OZP, 3OZO, 3WMB and 3 WMC.
4. The application according to claim 2, wherein the method of docking and scoring is specifically: triangle Matcher, scoring function London dG and GBVI/WSA dG, will grade the S value of the score, the more negative S value, show the compound and protein combination more stable, select S value front 250 compounds, establish database 3.
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