CN104961735A - Pyrazoline derivative and application of pyrazoline derivative as tyrosinase inhibitor - Google Patents
Pyrazoline derivative and application of pyrazoline derivative as tyrosinase inhibitor Download PDFInfo
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- CN104961735A CN104961735A CN201510426524.1A CN201510426524A CN104961735A CN 104961735 A CN104961735 A CN 104961735A CN 201510426524 A CN201510426524 A CN 201510426524A CN 104961735 A CN104961735 A CN 104961735A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
- C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
- C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D319/18—Ethylenedioxybenzenes, not substituted on the hetero ring
Abstract
The invention discloses a series of pyrazoline derivatives. Claisen-schmidt condensation reaction is carried out on equivalent molar weights of ketone and aldehyde under alkaline condition, so that chalcone is synthesized; reaction is carried out on chalcone and thiosemicarbazide under the alkaline condition, so that the pyrazoline derivative is obtained; and the same reaction is carried out on chalcone and N-(4-chlorophenyl) semicarbazide under the alkaline condition, so that the pyrazoline derivative is synthesized. Biological activity determination on the series of compounds proves that the synthesized pyrazoline derivative has tyrosinase inhibitory effect and anti-tumour biological activity, is applicable to being taken as a tyrosinase inhibitor and a medicine used for preventing or treating a tumour disease and has a good potential application prospect.
Description
Technical field
The invention belongs to pharmaceutical technology sectors, be specifically related to a kind of pyrazoline derivative and uses thereof.
Background technology
Tyrosine oxidase is the key enzyme of organism synthesis of melanin.It deposits relevant with hyperpigmentation and pigment anomaly, is also the principal element causing fruits and vegetables generation Enzymatic browning, affects immunity and the growth of insect simultaneously.Because its exists extensively, in medical treatment, whitening, fresh-keeping, desinsection, all there is good application prospect.Tyrosine oxidase has single phenolase and bis-phenol enzyme activity, and single phenolase has the feature of hesitation in catalytic process, and enzyme concn, substrate, effector all can affect the length of lag time.
Tyrosine oxidase is the cupric oxydo-reductase of baroque many subunits, and it is first by tyrosine hydroxylase, produces ortho position dopa (L-3,4 dihydroxyphenylalanine), and then dopa oxidase is become DOPA quinone, and then generate a series of pigment thing causing brownization.In recent years, except carrying out except the fundamental research of structure function to this enzyme, due to generation and the treatment of hyperpigmentation, malignant melanoma, albinism and senile dementia, all directly related with tyrosine oxidase, medical aspect is mainly concentrated on to the research of this enzyme both at home and abroad.For the research of this enzyme inhibitors, studies in China is less and not deep enough, more mainly for the research of the conventional inhibitor of skin care and treatment.Abroad, professor Kubo of California, USA Berkeley university is to the research of tyrosinase inhibitor forward position the most.Professor Kubo has been extracted the inhibitor (being mainly flavonoid natural product) of this enzyme a series of from natural phant (anise, cashew nut etc.), determines their restraining effect to Mushroom Tyrosinase.But the research of associated tyrosine enzyme inhibition mechanism, all reports less both at home and abroad.
In tyrosinase inhibitor, carbonyl compound comprises cinnamophenone, and flavanone and pyrazole derivatives obtain to be paid close attention to widely, due to the interaction between itself and the hydrophobic protein pocket of tyrosine oxidase double-core copper activity location proximate.We illustrate a series of α at research, and beta-unsaturated carbonyl compound is as potential tyrosinase inhibitor.Analysis inhibiting mechanism shows, this compound being similar to thiosemicarbazone derivative and curcumine, has two complex copper ions at the reactive site of tyrosine oxidase.
Based on above-mentioned discovery, we infer have the phenyl aldehyde of replacement and ketone coupling product not only with the double-core copper activity site compound of tyrosine oxidase, also there is interaction with hydrophobic enzyme pocket, therefore improve the binding affinity of inhibitor-enzyme, strengthen the restraining effect to Mushroom Tyrosinase.Cinnamophenone is phenyl aldehyde and the product that is coupled of ketone, as intermediate in biosynthesizing flavone derivative.Cinnamophenone is because biological activity broad spectrum causes our very large interest, so we report potential pharmacology and the biological characteristics of cinnamophenone recently.The anticancer potentiality of cinnamophenone excite the interest that we find new anti-cancer drug thing based on cinnamophenone.Cytotoxic activity and the interference microtubule of cinnamophenone are formed and tubulin suppresses closely related, and this is very important in cell processes, as cellular replication, and tenuigenin and Organelle movement, the regulation and control of mitotic division and cell shape.
Cinnamophenone, as promising carcinostatic agent and tyrosinase inhibitor, impels us to assess the cinnamophenone of a series of synthesis and the pyrazoline restraining effect to human carcinoma cell line and Mushroom Tyrosinase o-diphenolase activity.
Summary of the invention
The object of the invention is to provide a series of pyrazoline derivative, and it has tyrosinase inhibitory action and anti-tumor biological, is suitable as the medicine of tyrosinase inhibitor and prevention or treatment tumor disease.
For achieving the above object, adopt technical scheme as follows:
Pyrazoline derivative, has following structural formula:
In structure above, R represents following group:
R
1, R
2, R
3, R
4, R
5respective is independently hydrogen atom, methoxyl group or dimethyl amine.
By such scheme, described pyrazoline derivative is:
1-(2,3-dihydro-benzo [Isosorbide-5-Nitrae] dioxine-6-base)-3-(4-dimethylamino-naphthalene-1-base)-acrylketone (4),
3-cumarone-2-base-5-(4-dimethylamino-naphthalene-1-base)-4,5-dihydro-pyrazol-1-carbothioic acid amide (1a),
3-cumarone-2-base-5-(4,7-dimethoxy-naphthalene-1-base)-4,5-dihydro-pyrazol-1-carbothioic acid amide (2a),
3-(2,3-dihydro-benzo [Isosorbide-5-Nitrae] dioxine-6-base)-5-(4-dimethylamino-naphthalene-1-base)-4,5-dihydro-pyrazol-1-carbothioic acid amide (4a),
3-cumarone-2-base-5-(4-dimethylamino-naphthalene-1-base)-4,5-dihydro-pyrazol-1-carboxylic acid (4-chloro-phenyl-)-acid amides (1b) or
3-(2,3-dihydro-benzo [Isosorbide-5-Nitrae] dioxine-6-base)-5-(4-dimethylamino-naphthalene-1-base)-4,5-pyrazoline-1-carboxylic acids (the chloro-phenyl of 4-)-acid amides (4b).
Above-mentioned pyrazoline derivative is as the application of tyrosinase inhibitor.
Above-mentioned pyrazoline derivative is as prevention or the application for the treatment of malignant tumor medicine.
It is as follows that the present invention has beneficial effect:
The present invention by cinnamophenone and thiosemicarbazide two compounds in conjunction with design and synthesis one class novel pyrazole quinoline derivant, and provide a kind of valuable method for the design of medicine and synthesis.
The biological activity of this series compound of First Determination, the compound of proved invention synthesis has tyrosinase inhibitory action and anti-tumor biological, be suitable as the medicine of tyrosinase inhibitor and prevention or treatment tumor disease, there is good potential application foreground.
Embodiment
Following examples explain technical scheme of the present invention further, but not as limiting the scope of the invention.
Pyrazoline derivative preparation process of the present invention is as follows:
The ketone of equal molar quantities and aldehyde are used Claisen-Schmidt condensation reaction synthesizing chalcone (1-6) in the basic conditions.
Cinnamophenone (1-6) and thiosemicarbazide are reacted in the basic conditions, obtains pyrazoline derivative (1a-6a).
With identical reaction, in the basic conditions by cinnamophenone (1-6) and the reaction of N-(4-chloro-phenyl-) Urea,amino-, synthesizing pyrazole quinoline derivant (1b-6b).
The compound of all synthesis carrys out purifying by recrystallization technology or column chromatography.Successfully the new compound of synthesis is by mass spectrum,
13c-NMR,
1h-NMR and ultimate analysis confirm.
As substrate, tyrosinase inhibitory action detection is carried out to all compound L-DOPA of synthesis, makes positive control with kojic acid (5-hydroxyl-2-(methylol)-4 hydrogen-pyrans-4-ketone).Pyrazoline derivative and replacement cinnamophenone are summarized in Table 1 the IC50 value of tyrosine oxidase, and IC50 value is the mean values of three experiments.The results are shown in Table shown in 1.
Table 1
Result shows, most compounds demonstrates the effective restraining effect of Mushroom Tyrosinase, and each IC50 value changes within the scope of 4.72-87.24 μM.Compound 1b-6b has 4-chlorphenylamino urea to show inhibit activities more more effective than other compound.In addition, compound 1a, the inhibit activities that 4a, 1b and 4b display is stronger than positive reference substance kojic acid, 4b shows the most effective tyrosinase inhibitory activity, and IC50 value is 4.72 μMs.
Compared to cinnamophenone, pyrazoline derivative shows more effective inhibit activities.Most of cinnamophenone analogue demonstrates weak inhibit activities to tyrosine oxidase.In addition, this group thiosemicarbazide and 4-chlorphenylamino urea play an important role to tyrosinase inhibitory activity in raising.This may be relevant with tyrosine oxidase structure, has center and the coupling double-core copper activity site of 3 copper at catalytic core.The tyrosinase inhibitory action of compound 1a-6a depends on the sequestering power of sulphur atom and avtive spot double-core copper, and tyrosine oxidase will lose its catalytic capability after formation mixture.Observe and find that nitrogen-containing heterocgcies such as 4,4a and 4b has higher inhibit activities than 1,1a and 1b compound containing different rings system.
Embodiment 1
The synthesis of compound 1-(2,3-dihydro-benzo [Isosorbide-5-Nitrae] dioxine-6-base)-3-(4-dimethylamino-naphthalene-1-base)-acrylketone (4):
1-(2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxine-6-base) ethyl ketone (1.78g, 10mml) is joined in the ethanolic soln (15ml) of 4-dimethylamine-1-naphthaldehyde (1.99g, 10mml).Dropwise add the NaOH solution alkalize (PH=10) of 50% in the reactive mixture, reaction mixture stirs 8 hours at 27 DEG C.TLC monitors reaction and completes.Reaction solution is poured into (1ml concentrated hydrochloric acid) in the hydrochloric acid ice water mixture of 50ml.Extract by ethyl acetate (50ml), add water (150ml) washing, with anhydrous magnesium sulfate drying, Rotary Evaporators concentrates, obtain pale yellow powder 1-(2,3-dihydro-benzo [Isosorbide-5-Nitrae] dioxine-6-base)-3-(4-dimethylamino-naphthalene-1-base)-acrylketone (4) 1.76g, productive rate 49%.
1H NMR(500MHz,CDCl
3)δ:7.78(d,J＝8.5Hz,H),7.66(d,J＝7.0Hz,H),7.56(d,J＝7.3Hz,H),7.41(d,J＝6.0Hz,H),7.37-7.31(m,J＝8.0Hz,3H),7.15(s,H),7.12(d,J＝8.0Hz,H),6.82(d,J＝8.5Hz,H),6.61(d,J＝7.5Hz,H),5.12(m,J＝8.4Hz,4H),3.72(s,6H)；
13C NMR(DMSO-d
6)δ:32.2,32.8,82.2,82.6,111.3,118.2,119.6,123.5,124.3,126.3,127.2,128.2,128.8,129.1,129.5,132.4,133.4,137.3,146.5,148.8,152.4,154.6,190.2.Mass Spectrum(ESI)m/z:382.62[M+Na]+；Microanalysis Calculated for C
23H
21NO
3(359.42),C,76.86％；H,5.89％；N,3.90％.Found C:77.12％,H:5.98％,N:3.98％.
The synthesis of embodiment 2. compound 3-cumarone-2-base-5-(4-dimethylamino-naphthalene-1-base)-4,5-dihydro-pyrazol-1-carbothioic acid amide (1a):
2-ethanoyl cumarone (1.60g, 10mml) is joined in the ethanolic soln (15ml) of 4-dimethylamine-1-naphthaldehyde (1.99g, 10mml).The NaOH solution dropwise adding 50% in the reactive mixture to alkalescence (PH=10), reaction mixture stirring reaction 8 hours at 27 DEG C.TLC monitors reaction and completes.Reaction solution is poured into (1ml concentrated hydrochloric acid) in the hydrochloric acid ice water mixture of 50ml.With ethyl acetate (50ml) extraction, add water (150ml) washing, and with anhydrous magnesium sulfate drying, Rotary Evaporators concentrates, and obtains cinnamophenone (1) 1.70g, productive rate 50%.
Thiosemicarbazide (0.55g, 6mmol) is joined in the ethanolic soln (15ml) of cinnamophenone (1) (1.70g, 5mmol).The NaOH solution dropwise adding 50% in the reactive mixture to alkalescence (PH=9), reaction mixture stirring reaction 10 hours at 30 DEG C.TLC monitors reaction and completes.Carry out purifying by recrystallization technology or column chromatography, obtain white powder pyrazoline (1a) 0.87g, productive rate 42%.
1H NMR(500MHz,CDCl
3)δ:8.80(s,D
2O exchangeable,2H,NH
2),7.78-7.30(m,J＝8.0Hz,10H),7.19(s,1H),5.52-5.47(dd,J＝12.0Hz,1H),4.21-4.13(dd,J＝12.0Hz,1H),3.87(s,6H),3.45-3.29(dd,J＝17.5Hz,1H)；Mass Spectrum(ESI)m/z:415.62[M+H]+；Microanalysis Calculated for C
24H
22N
4OS(414.52),C,69.54％；H,5.35％；N,13.52％；S,7.74％.Found C:69.63％,H:5.29％,N:13.61％,S:7.79％.
The synthesis of embodiment 3. compound 3-cumarone-2-base-5-(4,7-dimethoxy-naphthalene-1-base)-4,5-dihydro-pyrazol-1-carbothioic acid amide (2a):
Replace 4-dimethylamine-1-naphthaldehyde with 4,6-dimethoxy-1-naphthaldehyde, other are with embodiment 2, obtain white powder pyrazoline (2a), productive rate 39%.
1H NMR(500MHz,CDCl
3)δ:8.87(s,D
2O exchangeable,2H,NH
2),7.89-7.29(m,J＝8.0Hz, 8H),7.16(s,1H),6.92(d,J＝8.0Hz,1H),5.57-5.50(dd,J＝11.5Hz,1H),4.22-4.19(dd,J＝11.5Hz,1H),3.85(s,6H),3.47-3.34(dd,J＝17.5Hz,1H)；Mass Spectrum(ESI)m/z:432.52[M+H]+；Microanalysis Calculated for C
24H
21N
3O
3S(431.51),C,66.80％；H,4.91％；N,9.74％；S,7.43％.Found C:66.97％,H:4.98％,N:9.73％,S:7.41％.
The synthesis of embodiment 4. compound 3-(2,3-dihydro-benzo [Isosorbide-5-Nitrae] dioxine-6-base)-5-(4-dimethylamino-naphthalene-1-base)-4,5-dihydro-pyrazol-1-carbothioic acid amide (4a):
Replace 2-ethanoyl cumarone with 1-(2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxine-6-base) ethyl ketone, other are with embodiment 2, obtain yellow crystals pyrazoline (4a), productive rate 49%.
1H NMR(500MHz,CDCl
3)δ:8.94(s,D
2O exchangeable,2H,NH
2),7.82-7.47(m,J＝6.5Hz,8H),7.12(s,1H),5.42-5.32(dd,J＝12.0Hz,1H),5.12(m,J＝8.0Hz,4H),4.22-4.15(dd,J＝12.0Hz,1H),3.80(s,6H),3.24-3.12(dd,J＝16.0Hz,1H)；Mass Spectrum(ESI)m/z:455.64[M+Na]+；Microanalysis Calculated for C
24H
24N
4O
2S(432.54),C,66.64％；H,5.59％；N,12.95％；S,7.41％.Found C:66.68％,H:5.56％,N:12.99％,S:7.43％.
The synthesis of embodiment 5. compound 3-cumarone-2-base-5-(4-dimethylamino-naphthalene-1-base)-4,5-dihydro-pyrazol-1-carboxylic acid (4-chloro-phenyl-)-acid amides (1b):
Replace thiosemicarbazide with 4-(4-chlorobenzene)-3-thiosemicarbazide, other are with embodiment 2, obtain white powder pyrazoline (1b), productive rate 42%.
1H NMR(500MHz,CDCl
3)δ:8.91(s,NH),7.75-7.17(m,J＝8.0Hz,14H),7.09(s,1H),5.42-5.34(dd,J＝12.0Hz,1H),4.18-4.12(dd,J＝12.0Hz,1H),3.82(s,6H),3.22-3.16(m,J＝17.5Hz,1H)；Mass Spectrum(ESI)m/z:510.13[M+H]+；Microanalysis Calculated for C
30H
25ClN
4O
2(509.00),C,70.79％；H,4.95％；N,11.01％.Found C:70.83％,H:4.98％,N:10.98％.
Embodiment 6. compound 3-(2,3-dihydro-benzo [1,4] dioxine-6-base) synthesis of-5-(4-dimethylamino-naphthalene-1-base)-4,5-pyrazoline-1-carboxylic acids (the chloro-phenyl of 4-)-acid amides (4b):
Replace 2-ethanoyl cumarone with 1-(2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxine-6-base) ethyl ketone, other are with embodiment 5, obtain yellow powder pyrazoline (4b), productive rate 42%.
1H NMR(500MHz,CDCl
3)δ:8.94(s,NH),7.80-7.27(m,J＝8.0Hz,12H),7.15(s,1H),5.36-5.27(dd,J＝12.5Hz,1H),5.11(m,J＝8.0Hz,4H),4.28-4.16(dd,J＝12.5Hz,1H),3.86(s,6H),3.33-3.19(dd,J＝16.0Hz,1H)；Mass Spectrum(ESI)m/z:528.05[M+H]+；Microanalysis Calculated for C
30H
27ClN
4O
3(527.01),C,68.37％；H,5.16％；N,10.63％.Found C:68.39％,H:5.14％,N:10.68％。
Claims (4)
1. pyrazole quinoline derivant, is characterized in that having following structural formula:
In structure above, R represents following group:
R
1, R
2, R
3, R
4, R
5respective is independently hydrogen atom, methoxyl group or dimethyl amine.
2. pyrazoline derivative as claimed in claim 1, is characterized in that described pyrazoline derivative is:
1-(2,3-dihydro-benzo [Isosorbide-5-Nitrae] dioxine-6-base)-3-(4-dimethylamino-naphthalene-1-base)-acrylketone,
3-cumarone-2-base-5-(4-dimethylamino-naphthalene-1-base)-4,5-dihydro-pyrazol-1-carbothioic acid amide,
3-cumarone-2-base-5-(4,7-dimethoxy-naphthalene-1-base)-4,5-dihydro-pyrazol-1-carbothioic acid amide,
3-(2,3-dihydro-benzo [Isosorbide-5-Nitrae] dioxine-6-base)-5-(4-dimethylamino-naphthalene-1-base)-4,5-dihydro-pyrazol-1-carbothioic acid amide,
3-cumarone-2-base-5-(4-dimethylamino-naphthalene-1-base)-4,5-dihydro-pyrazol-1-carboxylic acid (4-chloro-phenyl-)-acid amides or
3-(2,3-dihydro-benzo [Isosorbide-5-Nitrae] dioxine-6-base)-5-(4-dimethylamino-naphthalene-1-base)-4,5-pyrazoline-1-carboxylic acids (the chloro-phenyl of 4-)-acid amides.
3. pyrazoline derivative described in claim 1 or 2 is as the application of tyrosinase inhibitor.
4. pyrazoline derivative described in claim 1 or 2 is as prevention or the application for the treatment of malignant tumor medicine.
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| CN107235917A (en) * | 2016-12-31 | 2017-10-10 | 陕西科技大学 | The licochalcone A Dihydropyrimidines and its synthetic method of one class tool antitumor activity |
| CN107235916A (en) * | 2016-12-31 | 2017-10-10 | 陕西科技大学 | A kind of licochalcone A deracil analog derivative and its synthetic method for having antitumor activity |
| CN107235902A (en) * | 2016-12-31 | 2017-10-10 | 陕西科技大学 | The licochalcone A pyrazoline analog derivative and its synthetic method of one class tool antitumor activity |
| CN107311937A (en) * | 2016-12-31 | 2017-11-03 | 陕西科技大学 | The licochalcone A dihydro amino-metadiazine compound and its synthetic method of one class tool antitumor activity |
| CN107311936A (en) * | 2017-02-24 | 2017-11-03 | 陕西科技大学 | A kind of licochalcone A with antitumor activity and insoral cyclized derivative and its synthetic method |
| CN107382864A (en) * | 2016-12-31 | 2017-11-24 | 陕西科技大学 | A kind of licochalcone A pyrazoline Carbox amide and its synthetic method for having antitumor activity |
| CN108929271A (en) * | 2018-06-29 | 2018-12-04 | 中国药科大学 | Tyrosinase inhibitor and preparation method thereof and purposes |
| CN109180587A (en) * | 2018-09-20 | 2019-01-11 | 五邑大学 | A kind of new application of pyrazole analogs |
| CN110467605A (en) * | 2018-05-11 | 2019-11-19 | 南京大学 | The preparation method of a kind of novel triarylpyrazoline derivative and its application in anticancer drug |
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| CN107235917A (en) * | 2016-12-31 | 2017-10-10 | 陕西科技大学 | The licochalcone A Dihydropyrimidines and its synthetic method of one class tool antitumor activity |
| CN107235916A (en) * | 2016-12-31 | 2017-10-10 | 陕西科技大学 | A kind of licochalcone A deracil analog derivative and its synthetic method for having antitumor activity |
| CN107235902A (en) * | 2016-12-31 | 2017-10-10 | 陕西科技大学 | The licochalcone A pyrazoline analog derivative and its synthetic method of one class tool antitumor activity |
| CN107311937A (en) * | 2016-12-31 | 2017-11-03 | 陕西科技大学 | The licochalcone A dihydro amino-metadiazine compound and its synthetic method of one class tool antitumor activity |
| CN107382864A (en) * | 2016-12-31 | 2017-11-24 | 陕西科技大学 | A kind of licochalcone A pyrazoline Carbox amide and its synthetic method for having antitumor activity |
| CN107311936A (en) * | 2017-02-24 | 2017-11-03 | 陕西科技大学 | A kind of licochalcone A with antitumor activity and insoral cyclized derivative and its synthetic method |
| CN110467605A (en) * | 2018-05-11 | 2019-11-19 | 南京大学 | The preparation method of a kind of novel triarylpyrazoline derivative and its application in anticancer drug |
| CN110467605B (en) * | 2018-05-11 | 2022-07-29 | 南京大学 | Preparation method of novel triarylpyrazoline derivatives and application of novel triarylpyrazoline derivatives in anticancer drugs |
| CN108929271A (en) * | 2018-06-29 | 2018-12-04 | 中国药科大学 | Tyrosinase inhibitor and preparation method thereof and purposes |
| CN108929271B (en) * | 2018-06-29 | 2021-08-31 | 中国药科大学 | Tyrosinase inhibitor and preparation method and application thereof |
| CN109180587A (en) * | 2018-09-20 | 2019-01-11 | 五邑大学 | A kind of new application of pyrazole analogs |
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