CN102816067A - 4-hydroxybenzoylacrylic acid derivative, preparation method thereof and application - Google Patents
4-hydroxybenzoylacrylic acid derivative, preparation method thereof and application Download PDFInfo
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Abstract
本发明提供了一种4-羟基苯酰丙烯酸衍生物，其为具有式I所示结构的化合物：其中，R1为C1～C8烷基、被卤素或羟基取代的C1～C8烷基、C6～C8芳基、C1～C9烷酰基或C6～C9芳酰基；R2为C1～C8烷基、C6～C8芳基、C1～C8烷氨基或C6～C8芳氨基。本发明的优点在于，本发明的4-羟基苯酰丙烯酸衍生物具有对结核分枝杆菌蛋白激酶PknB的抑制活性，能够抑制结核分枝杆菌，包括多重耐药的结核分枝杆菌；还能够抑制耐甲氧西林金黄色葡萄球菌、耐甲氧西林表皮葡萄球菌、耐万古霉素肠球菌等多种耐药性革兰氏阳性菌，与已有的抗生素无交叉耐药性，具有良好的抗菌效果。The present invention provides a 4-hydroxybenzoylacrylic acid derivative, which is a compound having the structure shown in formula I:
Wherein, R 1 is C 1 -C 8 alkyl, C 1 -C 8 alkyl substituted by halogen or hydroxyl, C 6 -C 8 aryl, C 1 -C 9 alkanoyl or C 6 -C 9 aroyl ; R 2 is C 1 -C 8 alkyl, C 6 -C 8 aryl, C 1 -C 8 alkylamino or C 6 -C 8 arylamino. The advantage of the present invention is that the 4-hydroxybenzoylacrylic acid derivatives of the present invention have inhibitory activity to Mycobacterium tuberculosis protein kinase PknB, and can inhibit Mycobacterium tuberculosis, including multidrug-resistant Mycobacterium tuberculosis; Methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis, vancomycin-resistant Enterococcus and other drug-resistant Gram-positive bacteria, have no cross-resistance with existing antibiotics, and have good antibacterial Effect.
Description
Technical field
The present invention relates to a kind of 4-hydroxyl benzoyl acrylic acid derivative, its preparation method and application thereof with anti-microbial effect.Belong to field of medicaments.
Background technology
White plaque is the chronic infection property disease of a kind of serious harm human health of being caused by mycobacterium tuberculosis (Mycobacterium tuberculosis).For a long time, people use microbiotic to carry out chemotherapy to antituberculotic main means exactly, this treatment means once controlled effectively white plaque worldwide propagation and spread.Yet in recent years; Because the appearance of resistance (MDR) and super resistance (XDR) tubercule bacillus; The white plaque that originally has been effectively controlled has much the gesture of staging a comeback; The equal rebound significantly of its M & M has become the transmissible disease three big killers that also claim with AIDS, malaria, and World Health Organization's title white plaque in its report has become the No.1 fatal disease in the middle of the medicable infection.Therefore, seek and find that the novel antitubercular agent of new mechanism of action is most important.
The mycobacterium tuberculosis genome 11 kinds of STPKs that encode altogether.Pathogenic bacteria utilizes protein kinase and phosphatase catalytic some proteic phosphorylation and dephosphorylations; Not only can regulate and control the process of many cell intracellular metabolics; Also can disturb by the signal path of host cells infected simultaneously, play an important role aspect physiology and the toxicity.The serine/threonine protein kitase of mycobacterium tuberculosis and people's similar kinase whose homology very low (＜30%) therefore can be used as one type of new target spot of the new antituberculotic antibiotics of research and development.Comparative genomics and genome swivel base mutating experiment show PknA, PknB and PknG be mycobacterium tuberculosis in vivo or growth in vitro necessary, other most of STPKs then regulate and control some nonessential physiological processs of bacterium.PknB is a kind of transmembrane protein of acceptor class, and it has an extracellular signal pick-off and an intracellular kinases district, and it is absolutely necessary for the normal growth of mycobacterium, and bacterium division and growth are had certain regulating and controlling effect.The logarithmic phase of mycobacterium tuberculosis with and infect scavenger cell after, the pknB gene transcription can obviously improve, and when nutritive deficiency, its expression then can be reduced.In view of its important physical function in mycobacterium tuberculosis; And as the novelty of anti-infective with target spot; Protein kinase PknB can be used as a target of antitubercular agent screening, with solve the resistance mycobacterium tuberculosis and with the crossing drug resistant problem of using at present antitubercular agent clinically.
Because antibiotic a large amount of and irrational use has also caused the serious resistance problem of other bacterium except that the tuberculosis mycobacterium.At present, main resistant organism has ETEC (ESBL), multidrug resistant Pseudomonas aeruginosa (MDR-PA) of methicillin-resistant staphylococcus aureus (MRSA), penicillin resistant streptococcus pneumoniae (PRSP), vancomycin-resistant enterococcus (VRE), extended spectrum etc.The world is faced with and gets into the back microbiotic epoch, and till that time, in default of effective treatment means and sfgd., a lot of common infection will past medical help, and much human will be died from common infection.Therefore, seek and find new mechanism of action, do not have the novel anti bacterium of crossing drug resistant with existing microbiotic, comprise the medicine of drug-resistant bacteria, become one of research focus that this century, the whole world was paid close attention to.
The inventor is based on above-mentioned new target spot, after a large amount of experimental studies, filtered out the new active and active compound of antimicrobial agent of Killing Mycobacterium Tuberculosis that has.
Summary of the invention
The object of the present invention is to provide a kind of have Killing Mycobacterium Tuberculosis activity, the active 4-hydroxyl of antimicrobial agent benzoyl acrylic acid derivative.
Another object of the present invention is to provide the method for the above-mentioned 4-hydroxyl benzoyl acrylic acid derivative of preparation.
The present invention also aims to provide the application of above-mentioned 4-hydroxyl benzoyl acrylic acid derivative.
In order to realize the object of the invention, 4-hydroxyl benzoyl acrylic acid derivative of the present invention is the compound with structure shown in the following formula I:
Wherein, R
1Be C
1～C
8Alkyl, by halogen or the substituted C of hydroxyl
1～C
8Alkyl, C
6～C
8Aryl, C
1～C
9Alkyloyl or C
6～C
9Aroyl; R
2Be C
1～C
8Alkyl, C
6～C
8Aryl, C
1～C
8Alkylamino or C
6～C
8Virtue is amino.
Wherein, R
1Be preferably C
1～C
3Alkyl, C
6～C
8Aryl, C
1～C
3Alkyloyl or C
6～C
9Aroyl; R
2Be preferably C
1～C
3Alkyl, C
6～C
8Aryl, C
1～C
3Alkylamino or C
6～C
8Virtue amino.
More preferably, R
1Be methyl, cyclohexyl, phenyl, benzyl, ethanoyl, benzoyl group; R
2Be methyl, ethyl, normal-butyl amino.
The present invention also provides the method for the above-mentioned 4-hydroxyl benzoyl acrylic acid derivative of preparation, and it may further comprise the steps:
1) with 4-hydroxyl benzoyl acrylic acid, alkaline matter and R
1X
1Back flow reaction 4～8h makes intermediate product in organic solvent;
Wherein, R
1Like above-mentioned definition; X
1Be bromine, chlorine or iodine; Said alkaline matter is salt of wormwood or triethylamine; Said organic solvent is acetone or acetonitrile;
2) with above-mentioned intermediate product and R
2X
2Carry out esterification or amidate action, make purpose product 4-hydroxyl benzoyl acrylic acid derivative;
Wherein, R
2Like above-mentioned definition; X
2Be hydroxyl or amino.
In the above-mentioned preparation process, the hydroxyl of 4-described in step 1) benzoyl acrylic acid, alkaline matter and R
1X
1Mol ratio be 1: 1.2～1.5: 1.1～1.2, be preferably 1: 1.5: 1.2.
Step 2) esterification described in or amidate action get final product under the common reaction conditions in this area, for example in the presence of the vitriol oil, carry out esterification, perhaps in the presence of EDC/HOBt etc., carry out amidate action etc.
To be the inventor screen and obtain through suppressing mycobacterium tuberculosis protein kinases PknB 4-hydroxyl benzoyl acrylic acid derivative of the present invention; Because PknB extensively exists in mycobacterium; Its analogue is also arranged in gram-positive microorganism, and therefore 4-hydroxyl benzoyl acrylic acid derivative of the present invention is to be that target spot is brought into play anti-microbial activity with PknB; But because the mechanism of action of medicine is very complicated, research, so 4-hydroxyl benzoyl acrylic acid derivative for a long time also possibly be many target drugs, and the PknB target spot possibly be merely one of its target spot.
In view of the above, the present invention also provides the application of above-mentioned 4-hydroxyl benzoyl acrylic acid derivative aspect inhibition mycobacterium tuberculosis protein kinases PknB.
In addition, the present invention also provides above-mentioned 4-hydroxyl benzoyl the acrylic acid derivative application in the preparation antibacterials, the particularly application in the medicine of preparation Killing Mycobacterium Tuberculosis and/or anti-drug resistance gram-positive microorganism.
Said resistance gram-positive microorganism is preferably the mycobacterium tuberculosis of methicillin-resistant staphylococcus aureus, methicillin-resistant staphylococcus epidermidis, vancomycin-resistant enterococcus, anti-Rifampin and vazadrine etc.
The invention has the advantages that 4-hydroxyl benzoyl acrylic acid derivative of the present invention has the inhibition of mycobacterium tuberculosis protein kinases PknB active, thereby can efficiently suppress mycobacterium tuberculosis, comprises multidrug resistant mycobacterium tuberculosis; Can also efficiently suppress methicillin-resistant gold Portugal bacterium (MRSA), methicillin-resistant staphylococcus epidermidis (MRSE), vancomycin-resistant enterococcus multiple resistance gram-positive microorganisms such as (VRE); And do not have cross resistance with existing microbiotic, have good antibacterial effect; In addition, 4-hydroxyl benzoyl acrylic acid derivative preparation method of the present invention is simple, easy and simple to handle, is suitable for suitability for industrialized production.
Embodiment
Below further specify the present invention through specific embodiment, but be not used for limiting scope of the present invention.
The preparation of embodiment 14-methoxyl group benzoyl methyl acrylate
(a) the acrylic acid preparation of 4-methoxyl group benzoyl
10g 4-hydroxyl benzoyl acrylic acid (52.04mmol), 10.77g salt of wormwood (78.06mmol) are added in the 100mL acetone; Stirring reaction is after 0.5 hour under 25 ℃ of temperature; Drip 8.86g methyl iodide (62.44mmol), after dripping reaction solution was warming up to 56 ℃ of back flow reaction 4 hours; After reaction was accomplished, vacuum rotary steam was removed acetone, in residual solution impouring 100mL frozen water, separates out white solid, and vacuum-drying gets 10.19g white powder solid, yield 95%.Detected result is following:
1H?NMR(400MHz，DMSO-d
6)δppm：3.81(3H，s)，6.99(1H，d，J＝15.2Hz)，7.09(2H，m)，8.05(2H，m)，8.21(1H，d，J＝15.2Hz)。
MS(ESI，m/z)：207.1(M
++1，100％)。
(b) preparation of 4-methoxyl group benzoyl methyl acrylate
The above-mentioned intermediate product of 8g (38.80mmol) is added in the 80mL methanol solution, drips the 1.94g vitriol oil (19.40mmol) down, reaction solution was warming up to 65 ℃ of back flow reaction 10 hours in room temperature (25 ℃); After reaction was accomplished, removal of solvent under reduced pressure was with saturated aqueous sodium carbonate adjust pH to 8; Resistates is used the 80mL acetic acid ethyl dissolution, washing, and organic layer is used anhydrous sodium sulfate drying; Suction filtration; The filtrate steaming removal solvent final vacuum is dry, obtains 8.5g off-white powder shape solid 4-methoxyl group benzoyl methyl acrylate, yield 88%.Detected result is following:
1H?NMR(400MHz，DMSO-d
6)δppm：3.76(3H，s)，3.83(3H，s)，6.58(1H，d，J＝15.2Hz)，7.09(2H，m)，8.05(2H，m)，8.20(1H，d，J＝15.2Hz)。
MS(ESI，m/z)：225.6(M
++1，100％)。
The preparation of embodiment 24-benzyloxy benzoyl acrylic acid ethyl ester
(a) preparation of 4-benzyloxy benzoyl acrylic acid
Replace methyl iodide with 10.68g bromobenzyl (62.44mmol),, make 14.1g off-white powder shape solid 4-benzyloxy benzoyl acrylic acid, yield 96% according to the method for embodiment 1 step (a).Detected result is following:
MS(ESI，m/z)：283.3(M
++1，100％)。
(b) preparation of 4-benzyloxy benzoyl acrylic acid ethyl ester
Replace methyl alcohol as solvent with 100mL ethanol; With the above-mentioned 10g 4-benzyloxy benzoyl acrylic acid (35.42mmol) that makes is raw material; According to the method for embodiment 1 step (b), make 9.89g off-white powder shape solid 4-benzyloxy benzoyl acrylic acid ethyl ester, yield 90%.
Detected result is following:
1H?NMR(400MHz，DMSO-d
6)δppm：1.32(3H，m)，4.19(2H，m)，5.22(2H，s)，6.58(1H，d，J＝15.2Hz)，7.10(2H，m)，7.34-7.47(5H，m)，8.09(2H，m)，8.20(1H，d，.J＝15.2Hz)
MS(ESI，m/z)：311.4(M
++1，100％)。
The preparation of embodiment 34-cyclohexyloxy benzoyl acrylic acid ethyl ester
(a) preparation of 4-cyclohexyloxy benzoyl acrylic acid
Replace methyl iodide with 7.41g chlorocyclohexane (62.44mmol),, obtain 13.28g off-white powder shape solid 4-cyclohexyloxy benzoyl acrylic acid, yield 93% according to the method for embodiment 1 step (a).Detected result is following:
MS(ESI，m/z)：275.3(M
++1，100％)。
(b) preparation of 4-cyclohexyloxy benzoyl acrylic acid ethyl ester
Replace methyl alcohol as solvent with 100mL ethanol; With the above-mentioned 10g 4-cyclohexyloxy benzoyl acrylic acid (36.46mmol) that makes is raw material; According to the method for embodiment 1 step (b), make 9.04g off-white powder shape solid 4-cyclohexyloxy benzoyl acrylic acid ethyl ester, yield 86%.
Detected result is following:
1H?NMR(400MHz，DMSO-d
6)δppm：1.43-1.95(10H，m)，3.60(1H，m)，3.82(3H，s)，6.56(1H，d，J＝15.2Hz)，7.10(2H，m)，8.09(2H，m)，8.17(1H，d，J＝15.2Hz)
MS(ESI，m/z)：289.4(M
++1，100％)。
The preparation of embodiment 4N-normal-butyl-4-phenoxy benzoyl acrylic amide
(a) preparation of 4-phenoxy benzoyl acrylic acid
Replace methyl iodide with 7.03g chlorinated benzene (62.44mmol),, make 12.84g off-white powder shape solid 4-phenoxy benzoyl acrylic acid, yield 92% according to the method for embodiment 1 step (a).Detected result is following:
MS(ESI，m/z)：269.2(M
++1，100％)。
(b) preparation of N-normal-butyl-4-phenoxy benzoyl acrylic amide
The above-mentioned 4-phenoxy benzoyl acrylic acid (29.82mmol) that makes of 8g, 6.04g I-hydroxybenzotriazole (44.74mmol), 8.58g 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (44.74mmol), 5.78g diisopropylethylamine (44.74mmol) and 3.27g n-Butyl Amine 99 (44.74mmol) are added in the 80mL N (DMF) room temperature reaction 12 hours; Use 6N hydrochloric acid adjust pH to 5 then, resistates is with 100mL ethyl acetate extraction after washing, and organic layer is used anhydrous sodium sulfate drying; Suction filtration; The filtrate steaming removal solvent final vacuum is dry, obtains 7.72g off-white powder shape solid N-normal-butyl-4-phenoxy benzoyl acrylic amide, yield 80%.Detected result is following:
1H?NMR(400MHz，DMSO-d
6)δppm：0.90(3H，m)，1.31(2H，m)，1.52(2H，m)，3.16(2H，m)，6.56(1H，d，J＝15.2Hz)，7.14-7.41(7H，m)，8.10(1H，d，J＝15.2Hz)，8.20(2H，m)
MS(ESI，m/z)：324.4(M
++1，100％)。
The preparation of embodiment 54-acetoxyl group benzoyl ethyl propenoate
(a) the acrylic acid preparation of 4-acetoxyl group benzoyl
10g 4-hydroxyl benzoyl acrylic acid (52.04mmol), 7.90g triethylamine (78.06mmol) are added in the 100mL acetonitrile; Then with mixed solution stirring reaction after 0.5 hour under 0 ℃ of temperature; Drip the 30mL acetonitrile solution of 4.90g Acetyl Chloride 98Min. (62.44mmol), reaction solution is warming up to 50 ℃ of reactions 8 hours; After reaction was accomplished, vacuum rotary steam was removed acetonitrile, and resistates is with 80mL acetic acid ethyl dissolution after washing; Organic layer is used anhydrous sodium sulfate drying, suction filtration, and the filtrate steaming removal solvent final vacuum is dry; Make 10.36g off-white powder shape solid 4-acetoxyl group benzoyl vinylformic acid, yield 85%.Detected result is following:
MS(ESI，m/z)：235.2(M
++1，100％)。
(b) preparation of 4-acetoxyl group benzoyl ethyl propenoate
Replace methyl alcohol as solvent with 100mL ethanol; With the above-mentioned 10g 4-acetoxyl group benzoyl vinylformic acid (42.70mmol) that makes is raw material; According to the method for embodiment 1 step (b), make 9.18g off-white powder shape solid 4-acetoxyl group benzoyl ethyl propenoate, yield 82%.
Detected result is following:
1H?NMR(400MHz，DMSO-d
6)δppm：1.36(3H，m)，2.28(3H，s)，4.20(2H，m)，6.57(1H，d，J＝15.2Hz)，7.46(2H，m)，8.19(2H，m)，8.20(1H，d，J＝15.2Hz)
MS(ESI，m/z)：263(M
++1，100％)。
The preparation of embodiment 64-benzoyloxy group benzoyl acrylic acid ethyl ester
(a) preparation of 4-benzoyloxy group benzoyl acrylic acid
With 8.78g Benzoyl chloride 99min. (62.44mmol) replacing acetyl chloride,, make 13.72g off-white powder shape solid 4-benzoyloxy group benzoyl acrylic acid, yield 89% according to the method for embodiment 5 steps (a).Detected result is following:
MS(ESI，m/z)：297.3(M
++1，100％)。
(b) preparation of 4-benzoyloxy group benzoyl acrylic acid ethyl ester
Replace methyl alcohol as solvent with 100mL ethanol; With the above-mentioned 10g4-benzoyloxy group benzoyl acrylic acid (33.75mmol) that makes is raw material; According to the method for embodiment 1 step (b), make 9.31g off-white powder shape solid 4-benzoyloxy group benzoyl acrylic acid ethyl ester, yield 85%.
Detected result is following:
1H?NMR(400MHz，DMSO-d
6)δppm：1.36(3H，m)，4.20(2H，m)，6.57(1H，d，J＝15.2Hz)，7.56-7.70(5H，m)，8.22-8.29(5H，m)
MS(ESI，m/z)：325.3(M
++1，100％)。
Embodiment 7 usefulness agar dilutions are measured the antibacterial activity in vitro of 4-hydroxyl benzoyl acrylic acid derivative
1, bacterial strain to be measured:
Streptococcus aureus as shown in table 1, staphylococcus epidermidis, enterococcus faecalis, M. smegmatics, Mycobacterium marinum and mycobacterium tuberculosis, and the persister of these bacterial strains.
2, the preparation of testing sample and substratum:
(1) substratum uses Mueller-Hinton (MH) or 7H11 nutrient agar, prepares pH7.2～7.4 by this area ordinary method.
(2) cultivation of assay strain: 10 strain assay strains are in 37 ℃ of incubated overnight or to grow to OD600 be 1.5～2.0.
(3) the dull and stereotyped preparation of pastille: the compound that makes with embodiment 1-6 is a sample; With the antimicrobial drug Rifampin is reference substance; The sample and the reference substance of different concns (μ g/ml) are added (45～50 ℃) in MH agar or the 7H11 nutrient agar respectively, fully topple over the plate of respectively sterilizing behind the mixing.
(4) inoculum preparation and inoculation: preparation concentration is equivalent to the bacteria suspension of 0.5 Maxwell standard opacity tube, and dilution in 1: 10 is again drawn the bacterium liquid (about 1～2 μ l) for preparing with the multiple spot inoculator and is inoculated in each agar plate surface, and every some bacterium number is about 10
4CFU, forming diameter is the bacterial plaque of 5～8mm.Inoculation was hatched 16～48 hours for rearmounted 37 ℃, for mycobacterium tuberculosis, need put 37 ℃ after the inoculation and hatch 3-4 week.
(5) result judges: with growth control relatively, with the lowest drug concentration of complete bacteria growing inhibiting on the flat board as MIC.The result is as shown in table 1.
Table 1 antibacterial activity in vitro
Can find out that from table 1 4-hydroxyl benzoyl acrylic acid derivative of the present invention can suppress sensitive strain and the persister thereof of Gram-positive pathogenic bacteria common on mycobacterium tuberculosis reference culture and Resistant strain and other various clinical, and anti-microbial activity is high.
Embodiment 8 usefulness fluorescent methods detect 4-hydroxyl benzoyl acrylic acid derivative to suppressing the activity of mycobacterium tuberculosis PknB
1, the preparation of testing sample
The compound that respectively 1mg embodiment 1-6 is made dissolves in 1mL DMSO 99.8MIN. (DMSO), gets 1 μ L and acts on 50 μ L reaction systems, and making its final concentration is 20 μ g/mL.
2, sample is active detects
Prepare following reaction system (every hole reaction system TV is 50 μ l):
In reaction system, add component respectively by following three groupings:
Negative control group: add 1 μ L DMSO.
Positive controls: adding final concentration is the Staurosporine of 60 μ g/mL.
Sample experimental group: add 1 μ L testing sample.
Kinase
the Luminescent KinaseAssay test kit of Pomega company is adopted in determination of activity, comprises Kinase
damping fluid and Kinase
substrate in the test kit.Kinase
damping fluid is dissolved down at 37 ℃; With Kinase
substrate thorough mixing; Form green clear soln, promptly luciferase reaction liquid is subsequent use.
In same 96 orifice plate of adding behind above-mentioned each group reaction system difference mixing, place in the TriStarLB941 ELIASA of Berthold company, the unlatching temperature control is 37 ℃ and reacts.Take out every hole behind the reaction 180min and all add 50 μ L luciferase reaction liquid, place ELIASA to measure every hole fluorescent value.Time length 1s is measured in every hole, measures number of times 1 time.Calculate the inhibiting rate in each hole according to formula, PknB enzyme inhibiting rate alive is as shown in table 2.
Wherein:
Δ F
NBe the negative control hole fluorescent value,
Δ F
PBe positive control hole fluorescent value,
Δ F
SIt is sample experimental port fluorescent value.
The said compound of table 2 embodiment 1-6 is to PknB enzyme inhibiting rate alive
| Compound | Inhibiting rate |
| Embodiment 1 | 48.58％ |
| Embodiment 2 | 5123％ |
| Embodiment 3 | 56.55％ |
| Embodiment 4 | 50.67％ |
| Embodiment 5 | 43.76％ |
| Embodiment 6 | 42.27％ |
Can find out from table 2; 4-hydroxyl benzoyl acrylic acid derivative of the present invention demonstrates the inhibition of mycobacterium tuberculosis PknB active; Because PknB extensively exists in mycobacterium; Its analogue is also arranged, so 4-hydroxyl benzoyl acrylic acid derivative is brought into play anti-microbial activity with PknB as one of its target spot in gram-positive microorganism.
Though, the present invention has been done detailed description in the preceding text with general explanation and specific embodiments, on basis of the present invention, can to some modifications of do or improvement, this will be apparent to those skilled in the art.Therefore, these modifications or the improvement on the basis of not departing from spirit of the present invention, made all belong to the scope that requirement of the present invention is protected.
Claims (8)
1. 4-hydroxyl benzoyl acrylic acid derivative is characterized in that it is the compound with structure shown in the formula I:
Wherein, R
1Be C
1～C
8Alkyl, by halogen or the substituted C of hydroxyl
1～C
8Alkyl, C
6～C
8Aryl, C
1～C
9Alkyloyl or C
6～C
9Aroyl; R
2Be C
1～C
8Alkyl, C
6～C
8Aryl, C
1～C
8Alkylamino or C
6～C
8Virtue is amino.
2. 4-hydroxyl benzoyl acrylic acid derivative as claimed in claim 1 is characterized in that R
1Be C
1～C
3Alkyl, C
6～C
8Aryl, C
1～C
3Alkyloyl or C
6～C
9Aroyl; R
2Be C
1～C
3Alkyl, C
6～C
8Aryl, C
1～C
3Alkylamino or C
6～C
8Virtue amino.
3. 4-hydroxyl benzoyl acrylic acid derivative as claimed in claim 2 is characterized in that R
1Be methyl, cyclohexyl, phenyl, benzyl, ethanoyl, benzoyl group; R
2Be methyl, ethyl, normal-butyl amino.
4. prepare the method for each said 4-hydroxyl benzoyl acrylic acid derivative of claim 1-3, it is characterized in that, may further comprise the steps:
1) with 4-hydroxyl benzoyl acrylic acid, alkaline matter and R
1X
1Back flow reaction 4～8h makes intermediate product in organic solvent;
Wherein, R
1Such as claim 1-3 each definition; X
1Be bromine, chlorine or iodine; Said alkaline matter is salt of wormwood or triethylamine; Said organic solvent is acetone or acetonitrile;
2) with above-mentioned intermediate product and R
2X
2Carry out esterification or amidate action, make purpose product 4-hydroxyl benzoyl acrylic acid derivative;
Wherein, R
2Such as claim 1-3 each definition; X
2Be hydroxyl or amino.
5. preparation method as claimed in claim 4 is characterized in that, the hydroxyl of 4-described in step 1) benzoyl acrylic acid, alkaline matter and R
1X
1Mol ratio be 1: 1.2～1.5: 1.1～1.2.
6. the application of each described 4-hydroxyl benzoyl acrylic acid derivative of claim 1-3 aspect inhibition mycobacterium tuberculosis protein kinases PknB.
7. the application of each said 4-hydroxyl benzoyl acrylic acid derivative of claim 1-3 in the preparation antibacterials.
8. application as claimed in claim 7 is characterized in that, said antibacterials are meant Killing Mycobacterium Tuberculosis medicine and/or anti-drug resistance gram-positive microorganism medicine.
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Cited By (2)
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|---|---|---|---|---|
| CN106316876A (en) * | 2015-06-29 | 2017-01-11 | 中国医学科学院医药生物技术研究所 | Beta-carbonyl acrylamide compounds, preparation method and applications thereof |
| CN108329225A (en) * | 2018-01-24 | 2018-07-27 | 北京大学 | It is a kind of to dibenzoyl dimer derivate and its synthetic method and application |
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| CN108329225A (en) * | 2018-01-24 | 2018-07-27 | 北京大学 | It is a kind of to dibenzoyl dimer derivate and its synthetic method and application |
| CN108329225B (en) * | 2018-01-24 | 2021-03-09 | 北京大学 | A kind of terephthaloyl dimer derivative and its synthesis method and application |
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