CN106317074A - Alpha, beta-unsaturated ketone derivatives of ofloxacin, and preparation method and applications thereof - Google Patents
Alpha, beta-unsaturated ketone derivatives of ofloxacin, and preparation method and applications thereof Download PDFInfo
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- CBHGTBLKJZIKNV-UHFFFAOYSA-N CC(COc1c(c(F)c2)N3CCN(C)CC3)N(C=C3C=O)c1c2C3=O Chemical compound CC(COc1c(c(F)c2)N3CCN(C)CC3)N(C=C3C=O)c1c2C3=O CBHGTBLKJZIKNV-UHFFFAOYSA-N 0.000 description 1
- NDLVIKCGPSOVDW-UHFFFAOYSA-N CC(COc1c(c(F)c2)N3CCN(C)CC3)N(CC3)c1c2C3=O Chemical compound CC(COc1c(c(F)c2)N3CCN(C)CC3)N(CC3)c1c2C3=O NDLVIKCGPSOVDW-UHFFFAOYSA-N 0.000 description 1
- VDBIOVXGJQTHEZ-HWKANZROSA-N CC1N(C=C(/C=C/C(c(cc2)cc3c2OCO3)=O)C(c2cc(F)c3N4CCN(C)CC4)=O)c2c3OC1 Chemical compound CC1N(C=C(/C=C/C(c(cc2)cc3c2OCO3)=O)C(c2cc(F)c3N4CCN(C)CC4)=O)c2c3OC1 VDBIOVXGJQTHEZ-HWKANZROSA-N 0.000 description 1
- DQNUNKQCJBGYFI-UHFFFAOYSA-N CC1N(CC(C=O)C(c2cc(F)c3N4CCN(C)CC4)=O)c2c3OC1 Chemical compound CC1N(CC(C=O)C(c2cc(F)c3N4CCN(C)CC4)=O)c2c3OC1 DQNUNKQCJBGYFI-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses alpha, beta-unsaturated ketone derivatives of ofloxacin, and a preparation method and applications thereof. The chemical structure formula of the derivatives is represented by a formula (I); in the formula (I), the aromatic ring Ar is a benzene ring, a substituted benzene ring, a furan ring, or a pyridine ring. According to the preparation method, a tricyclic fluoroquinolone skeleton and an alpha, beta-unsaturated ketone skeleton are effectively spliced so as to establish novel chiral fluoroquinolone chalcone liked compounds; the antitumor activity of novel compounds is enhanced, the toxic and side effect to normal cells is reduced at the same time; and the derivatives can be used as an antitumor active substance to develop antitumor drugs with a whole new structure.
Description
Technical field
The invention belongs to original new drug synthesis technical field, be specifically related to the α of a kind of ofloxacin, alpha, beta-unsaturated ketone derivant, with
Time further relate to the α of a kind of ofloxacin, the preparation method of alpha, beta-unsaturated ketone derivant, and its application in antitumor drug.
Background technology
New drug innovation originates from the discovery of primer, and rational drug MOLECULE DESIGN based on structure is to find the effective ways of primer.
In the pharmacophore of various structures, there is α, the chalcone compounds of alpha, beta-unsaturated ketone architectural feature as important natural effectively
Composition, is concerned because having multiple pharmacologically active.But, natural chalcone compounds mostly is the cyclosubstituted α of polyhydroxy benzenes,
Beta-unsaturated ketone compound, because its poor water solublity causes bioavailability relatively low, limits application clinically.It addition,
Also it is the important function target spot of antitumor drug in conjunction with the action target spot topoisomerase of antibacterial flouroquinolone drugs, can be resisted
Bacterium is active Transforming for anti-tumor activity, and find fluoroquinolone C-3 carboxyl be not pharmacophore necessary to anti-tumor activity, can
Replace by bioisostere to improve its anti-tumor activity.Based on this, for improving the water solublity of chalcones, improve it raw
Thing availability and activity, the present invention advantage pharmacophore piperazine of flouroquinolone drugs ofloxacin quinoline-4 (1H)-one skeleton
As α, the substituent group of alpha, beta-unsaturated ketone structure, and then devise the fluoroquinolones chalcone derivative of new structure.
To this end, it is an object of the invention to provide the α of a kind of ofloxacin, alpha, beta-unsaturated ketone derivant, have antineoplastic action and
Effect, provides the α of a kind of ofloxacin, the preparation method of alpha, beta-unsaturated ketone derivant simultaneously.
In order to realize object above, the technical solution adopted in the present invention is: the α of a kind of ofloxacin, alpha, beta-unsaturated ketone derivant,
Its chemical structural formula is as shown in logical formula (I):
Ar is phenyl ring or substituted benzene ring or furan nucleus or pyridine ring, and this compounds is the compound of following concrete structure:
The α of a kind of ofloxacin of the present invention, the preparation method of alpha, beta-unsaturated ketone derivant, is former with the ofloxacin shown in formula II
Material is prepared from;
Concrete preparation process is as follows:
1) compound shown in formula III is reacted to obtain with the ofloxacin shown in formula II through sodium borohydride reduction decarboxylation, then with formic acid
Ethyl ester condensation reaction prepares the compound shown in formula IV, and last formula IV and activated manganese dioxide aoxidize to obtain formula V ofloxacin aldehyde;
Step 1) Detailed operating procedures be referred to document (Kondo H, Sakamoto F, et al.Studies on prodrugs.7.
Synthesis and antimicrobial activity of 3-formylquinolone derivatives,J.Med.Chem.1988,31,
221~225.) the prodrug research synthesis of .7.3-formoxyl Carbostyril derivative and antimicrobial acivity) method prepare, detailed process
As follows:
2) ofloxacin aldehyde shown in formula V and aromatic radical ethyl ketone VI are carried out aldol condensation under the catalysis of alkali in dehydrated alcohol anti-
Should, after question response is complete, the treated target compound that obtains is as shown in formula I, and detailed process is as follows:
In formula I, Ar is phenyl ring or substituted benzene ring or furan nucleus or pyridine ring.
The general synthetically prepared operating procedure of target compound formula I is: take 1,8-(3,1-oxygen propyl group)-6-fluoro-7-(4-thyl-piperazin
-1-base)-quinoline-4 (1H)-one-3-formaldehyde formula V 1.1g (3.2mmol) is dissolved in 20mL dehydrated alcohol, adds aromatic radical ethyl ketone
VI (3.2mmol) and base catalyst piperidines (0.1mL).Mixed reactant back flow reaction 24h, places room temperature, and what filter collection produced consolidates
Body, dehydrated alcohol recrystallization, obtain pale yellow crystals thing formula I.
As further improving, the ofloxacin aldehyde shown in formula V is 1:1.0~1.2 with the mol ratio of aromatic radical ethyl ketone.
Described base catalyst is at least one in piperidines, pyridine, triethylamine, morpholine, potassium acetate and sodium acetate.
The α of described a kind of ofloxacin, the application in preparing antitumor drug of the alpha, beta-unsaturated ketone derivant.
Described antitumor drug is treatment hepatocarcinoma, cancer of pancreas or leukemia medicament.
The α of a kind of ofloxacin of the present invention, alpha, beta-unsaturated ketone derivant principle of hybridization based on pharmacophore, by fluoroquinolone skeleton
With α, alpha, beta-unsaturated ketone pharmacophore is effectively combined, and design has synthesized the α of ofloxacin, alpha, beta-unsaturated ketone derivant, it is achieved that
The complementation of different structure pharmacophore and the superposition of activity, thus reached the effect of potentiation toxicity reduction, can swell as the anti-of brand new
Tumor medicine is developed.
Detailed description of the invention
Embodiment 1
1,8-(3,1-oxygen propyl group) fluoro-7-of-6-(4-thyl-piperazin-1-base)-3-(2-benzoyl-ethylene-1-base)-quinoline-4 (1H)-one (I-1),
Its chemical structural formula is:
I.e. Ar in formula I is phenyl.
The preparation method of this compound is: substitute aromatic radical ethyl ketone VI with 1-Phenylethanone. (0.45g, 3.8mmol), according to above-mentioned mesh
The general preparative methods of mark thing formula I, obtains pale yellow crystals object (I-1), productivity 67.4%, m.p.135~137 DEG C.1H NMR
(400MHz,CD3Cl) δ: 1.44 (3H, d, CH3), 2.28 (3H, s, N-CH3), 3.15~3.46 (8H, m, piperazine-H),
4.57~4.68 (OCH2CHN), 7.53~8.05 (6H, m, Ph-H and 5-H), 8.23~8.76 (3H, m, 2-H, 1 '-H and
2’-H);MS (m/z): 448 [M+H]+;Calculate (C26H26FN3O3): 447.51.
Embodiment 2
1,8-(3,1-oxygen propyl group) fluoro-7-of-6-(4-thyl-piperazin-1-base)-3-[2-(4-methoxybenzoyl)-ethylene-1-base]-quinoline
-4 (1H)-one (I-2), its chemical structural formula is:
I.e. Ar in formula I is p-methoxyphenyl.
The preparation method of this compound is: substitute aromatic radical ethyl ketone VI with 4-methoxy-acetophenone (0.48g, 3.2mmol), according to
The general preparative methods of above-mentioned object formula I, obtains pale yellow crystals object (I-2), productivity 75.6%, m.p.138~140 DEG C.1H NMR(400MHz,CD3Cl) δ: 1.46 (3H, d, CH3), 2.31 (3H, s, N-CH3), 3.17~3.48 (8H, m,
Piperazine-H), 3.88 (3H, s, OCH3), 4.57~4.72 (OCH2CHN), 7.56~7.83 (5H, m, Ph-H and 5-H),
8.25~8.82 (3H, m, 2-H, 1 '-H and 2 '-H);MS (m/z): 478 [M+H]+;Calculate (C27H28FN3O4): 477.54.
Embodiment 3
1,8-(3,1-oxygen propyl group) fluoro-7-of-6-(4-thyl-piperazin-1-base)-3-[2-(3,4-dioxymethylene-benzoyl)-ethylene-1-base]-
Quinoline-4 (1H)-one (I-3), its chemical structural formula is:
I.e. Ar in formula I is 3,4-(dioxymethylene) phenyl.
The preparation method of this compound is: with 3, and 4-dioxymethylene-1-Phenylethanone. (0.52g, 3.2mmol) substitutes aryl methyl ketone VI, depends on
According to the general preparative methods of above-mentioned object formula I, obtain pale yellow crystals object thing (I-3), productivity 78.5%, m.p.
167~169 DEG C.1H NMR(400MHz,CD3Cl) δ: 1.48 (3H, d, CH3), 2.33 (3H, s, N-CH3), 3.18~3.52
(8H, m, piperazine-H), 4.61~4.74 (OCH2CHN), 6.26 (3H, s, OCH2O), 7.68~7.88 (4H, m, Ph-H
And 5-H), 8.26~8.85 (3H, m, 2-H, 1 '-H and 2 '-H);MS (m/z): 491 [M+H]+;Calculate (C27H26FN3O5):
491.52。
Embodiment 4
1,8-(3,1-oxygen propyl group) fluoro-7-of-6-(4-thyl-piperazin-1-base)-3-[2-(3,4,5-trimethoxy methyl-benzoyl)-ethylene-1-base]-
Quinoline-4 (1H)-one (I-4), its chemical structural formula is:
I.e. Ar in formula I is 3,4,5-2,4,5-trimethoxyphenyls.
The preparation method of this compound is: with 3, and 4,5-trimethoxies-1-Phenylethanone. (0.67g, 3.2mmol) substitutes aromatic radical ethyl ketone VI,
According to the general preparative methods of above-mentioned object formula I, obtain pale yellow crystals object thing (I-4), productivity 70.5%, m.p.
145~147 DEG C.1H NMR(400MHz,CD3Cl) δ: 1.52 (3H, d, CH3), 2.35 (3H, s, N-CH3), 3.24~3.55
(8H, m, piperazine-H), 4.61~4.74 (OCH2CHN), 3.86,3.88 (9H, 2s, 3 × OCH3), 7.74~8.13 (3H,
M, Ph-H and 5-H), 8.31~8.87 (3H, m, 2-H, 1 '-H and 2 '-H);MS (m/z): 538 [M+H]+;Calculate
(C29H32FN3O6): 537.59.
Embodiment 5
1,8-(3,1-oxygen propyl group) fluoro-7-of-6-(4-thyl-piperazin-1-base)-3-[2-(4-methyl-benzoyl)-ethylene-1-base]-quinoline-4 (1H)-
Ketone (I-5), its chemical structural formula is:
I.e. Ar in formula I is to methylphenyl.
The preparation method of this compound is: substitute aromatic radical ethyl ketone VI with 4-methyl-acetophenone (0.51g, 3.8mmol), according to upper
The general preparative methods of the object formula I stated, obtains pale yellow crystals object thing (I-5), productivity 57.4%, m.p.130~132 DEG C.1H NMR(400MHz,CD3Cl) δ: 1.46 (3H, d, CH3), 2.25,2.32 (6H, 2s, Ph-CH3And N-CH3),
2.63~3.43 (8H, m, piperazine-H), 4.54~4.64 (OCH2CHN), 7.53~7.75 (5H, m, Ph-H and 5-H), 8.18~8.85
(3H, m, 2-H, 1 '-H and 2 '-H);MS (m/z): 462 [M+H]+;Calculate (C27H28FN3O3): 461.54.
Embodiment 6
1,8-(3,1-oxygen propyl group) fluoro-7-of-6-(4-thyl-piperazin-1-base)-3-[2-(the fluoro-benzoyl of 4-)-ethylene-1-base]-quinoline-4 (1H)-
Ketone (I-6), its chemical structural formula is:
I.e. Ar in formula I is to fluoro-phenyl.
The preparation method of this compound is: substitute aromatic radical ethyl ketone VI with the fluoro-1-Phenylethanone. of 4-(0.44g, 3.2mmol), according to above-mentioned
The general preparative methods of object formula I, obtain pale yellow crystals object thing (I-6), productivity 75.8%, m.p.156~158 DEG C.1H NMR(400MHz,CD3Cl) δ: 1.54 (3H, d, CH3), 2.35 (3H, s, N-CH3), 3.23~3.57 (8H, m,
Piperazine-H), 4.63~4.75 (OCH2CHN), 7.72~7.92 (5H, m, Ph-H and 5-H), 8.16~8.87 (3H, m, 2-H,
1 '-H and 2 '-H);MS (m/z): 466 [M+H]+, calculate (C26H25F2N3O3): 465.50.
Embodiment 7
1,8-(3,1-oxygen propyl group) fluoro-7-of-6-(4-thyl-piperazin-1-base)-3-[2-(4-nitro-benzoyl)-ethylene-1-base]-quinoline-4 (1H)-
Ketone (I-7), its chemical structural formula is:
I.e. Ar in formula I is p-nitrophenyl.
The preparation method of this compound is: substitute aromatic radical ethyl ketone VI with 4-nitro-acetophenone (0.53g, 3.2mmol), according to upper
The general preparative methods of the object formula I stated, obtains pale yellow crystals object thing (I-7), productivity 74.5%, m.p.168~170 DEG C.1H NMR(400MHz,CD3Cl) δ: 1.56 (3H, d, CH3), 2.37 (3H, s, N-CH3), 3.25~3.64 (8H, m,
Piperazine-H), 4.66~4.78 (OCH2CHN), 7.86~8.13 (5H, m, Ph-H and 5-H), 8.22~8.93 (3H, m, 2-H,
1 '-H and 2 '-H);MS (m/z): 493 [M+H]+, calculate (C26H25FN4O5): 492.51.
Embodiment 8
1,8-(3,1-oxygen propyl group) fluoro-7-of-6-(4-thyl-piperazin-1-base)-3-[2-(4-Hydroxy-benzoyIcarbamo)-ethylene-1-base]-quinoline-4 (1H)-
Ketone (I-8), its chemical structural formula is:
I.e. Ar in formula I is 4-hydroxy-pheny.
The preparation method of this compound is: substitute aromatic radical ethyl ketone VI with 4-hydroxy-acetophenone (0.45g, 3.3mmol), according to upper
The general preparative methods of the object formula I stated, obtains pale yellow crystals object thing (I-8), productivity 55.6%, m.p.151~153 DEG C.1H NMR(400MHz,CD3Cl) δ: 1.47 (3H, d, CH3), 2.33 (3H, s, N-CH3), 3.16~3.52 (8H, m,
Piperazine-H), 4.58~4.71 (OCH2CHN), 7.66~8.06 (5H, m, Ph-H and 5-H), 8.23~8.85 (3H, m, 2-H,
1 '-H and 2 '-H), 10.56 (1H, brs, OH);MS (m/z): 464 [M+H]+, calculate (C26H26FN3O4): 463.51.
Embodiment 9
1,8-(3,1-oxygen propyl group) fluoro-7-of-6-(4-thyl-piperazin-1-base)-3-[2-(4-pyridine-formoxyl)-ethylene-1-base]-quinoline-4 (1H)-
Ketone (I-9), its chemical structural formula is:
I.e. Ar in formula I is 4-pyridine radicals.
The preparation method of this compound is: substitute aromatic radical ethyl ketone VI with 4-pyridine-ethyl ketone (0.39g, 3.2mmol), according to above-mentioned
The general preparative methods of object formula I, obtain pale yellow crystals object thing (I-9), productivity 63.8%, m.p.177~179 DEG C.1H NMR(400MHz,CD3Cl) δ: 1.54 (3H, d, CH3), 2.36 (3H, s, N-CH3), 3.27~3.58 (8H, m,
Piperazine-H), 4.62~4.74 (OCH2CHN), 7.83 (1H, d, 5-H), 8.27~8.87 (7H, m, 2-H, 1 '-H, 2 '-H
And Py-H);MS (m/z): 449 [M+H]+, calculate (C25H25FN4O3): 448.50.
Embodiment 10
1,8-(3,1-oxygen propyl group) fluoro-7-of-6-(4-thyl-piperazin-1-base)-3-[2-(4-furan-formyl)-ethylene-1-base]-quinoline-4 (1H)-
Ketone (I-10), its chemical structural formula is:
I.e. Ar in formula I is 2-furyl.
The preparation method of this compound is: substitute aromatic radical ethyl ketone VI with 2-furan-ethyl ketone (0.42g, 3.8mmol), according to above-mentioned
The general preparative methods of object formula I, obtain pale yellow crystals object thing (I-10), productivity 68.3%, m.p.162~164 DEG C.1H NMR(400MHz,CD3Cl) δ: 1.51 (3H, d, CH3), 2.34 (3H, s, N-CH3), 3.22~3.58 (8H, m,
Piperazine-H), 4.60~4.73 (OCH2CHN), 6.83~7.86 (4H, m, 5-H and furan-H), 8.16~8.83 (3H, m, 2-H,
1 '-H and 2 '-H);MS (m/z): 438 [M+H]+, calculate (C24H24FN3O4): 437.47.
Test example
One, the α of a kind of ofloxacin that embodiment 1-10 provides, the anti tumor activity in vitro of alpha, beta-unsaturated ketone derivant measures
1, test sample
With the α of a kind of ofloxacin that embodiment 1-10 provides, alpha, beta-unsaturated ketone derivant and classical antitumor TOPO inhibitor
10-hydroxycamptothecine (HC) and parent compound ofloxacin (OF) are test sample, and totally 12 kinds, wherein HC and OF is
Matched group, embodiment 1-10 sample is experimental group;
Experiment JEG-3 is people's hepatocarcinoma Hep-3B cell, human pancreas cancer Panc-1 cell and human leukemia HL60 cell respectively
Strain is all bought from Chinese Academy of Sciences's Shanghai cell bank.Normal cell uses VERO African green monkey kidney cell, buys and sends in upper Cacumen et folium clerodendri mandarinori (Clerodendron mandarinorum Diels)
Bio tech ltd.
2, assay method
Concretely comprising the following steps of assay method:
1) first above-mentioned 12 kinds of test samples are dissolved with dimethyl sulfoxide (DMSO) respectively, be configured to 1.0 × 10-2mol·L-1
The storing solution of concentration, dilutes storing solution with the RPMI-1640 culture fluid of the calf serum that mass percent concentration is 10% afterwards
Become there are 5 Concentraton gradient (0.1,1.0,5.0,10.0,50.0 μm ol L-1) working solution;
2) take the logarithm people's hepatocarcinoma Hep-3B cell of trophophase, human pancreas cancer Panc-1 cell and human leukemia HL60 cell and
VERO cell strain, is inoculated in 96 orifice plates with 6000, every hole cell, and be separately added into above-mentioned 12 kinds of samples subsequently has 5
The working solution of Concentraton gradient, after 48 hours, every hole adds 5g L–1MTT (tetrazolium bromide) solution 10 μ L, continues to be further cultured for 4 hours
Add sodium lauryl sulphate (SDS) solution that 100 μ L mass percent concentrations are 10% afterwards.Cultivate 24 hours, then
At 570nm wavelength, absorbance (OD) value is measured by microplate reader;
3) test sample of the variable concentrations suppression ratio to cancerous cell is calculated by following shown formula,
Inhibition of cancer cell rate=[(1-experimental group OD value)/matched group OD value] × 100%;
Then with the logarithm value of each concentration of test sample, the inhibition of cancer cell rate that each concentration is corresponding is made linear regression, obtain docs-effect
Equation, goes out the test sample half-inhibition concentration (IC to experiment cancerous cell from gained docs-effect Equation for Calculating50);Each data
Parallel assay three times, seeks its meansigma methods, the results are shown in Table shown in 1.
Anti-tumor activity (the IC of each test sample of table 150)
As it can be seen from table 1 the compound that embodiment 1-10 provides is significantly stronger than parent to the inhibitory activity of 3 kinds of cancerous cell of experiment
It is right that the growth inhibitory activity of human pancreas cancer Panc-1 cell is better than by the activity of compound ofloxacin, especially majority of compounds
According to the activity of hydroxycamptothecin, its IC50Value is at or below micro-molar concentration.More meaningful, embodiment 1-10 provides
Compound demonstrates relatively low toxicity to VERO cell, has the potentiality of druggability.Therefore, according to the general way of drug development
Footpath is the antitumor in-vitro screening first carrying out routine, studies the most targetedly, so the compound of the present invention has strong
Anti-tumor activity and relatively low toxicity, can be become salt by acid acceptable with human body or be mixed with antitumor drug with pharmaceutical carrier.
Claims (6)
1. a α for ofloxacin, alpha, beta-unsaturated ketone derivant, it is characterised in that there is the general structure of following formula I:
Wherein aromatic rings Ar is phenyl ring or substituted benzene ring or furan nucleus or pyridine ring.
The α of a kind of ofloxacin the most according to claim 1, alpha, beta-unsaturated ketone analog derivative, it is typically characterized by with following
The typical compound of structure:
The α of a kind of ofloxacin the most according to claim 1 and 2, the preparation method of alpha, beta-unsaturated ketone derivant, its feature exists
In, concrete preparation process includes:
1) with the ofloxacin shown in formula II as raw material, the compound shown in formula III is reacted to obtain through sodium borohydride reduction decarboxylation, so
The compound shown in formula III is prepared afterwards with Ethyl formate condensation reaction;Last formula IV and activated manganese dioxide aoxidize to obtain formula V oxygen fluorine sand
Star aldehyde:
2) ofloxacin aldehyde shown in formula V and aromatic radical ethyl ketone are formed under the catalysis of alkali α, alpha, beta-unsaturated ketone structure, through after place
Reason can obtain the α of a kind of ofloxacin shown in formula I, alpha, beta-unsaturated ketone derivant:
Wherein the aromatic radical Ar in formula I is phenyl ring or substituted benzene ring or furan nucleus or pyridine ring.
The α of a kind of ofloxacin the most according to claim 3, the preparation method of alpha, beta-unsaturated ketone derivant, it is characterised in that
Ofloxacin aldehyde shown in described formula V is 1:1.0~1.2 with the mol ratio of aromatic radical ethyl ketone.
5. as right is required the α of a kind of ofloxacin as described in 1 or 2, and alpha, beta-unsaturated ketone derivant is in preparing antitumor drug
Application.
The α of a kind of ofloxacin the most according to claim 5, the application in preparing antitumor drug of the alpha, beta-unsaturated ketone derivant,
It is characterized in that, described antitumor drug is treatment hepatocarcinoma, cancer of pancreas or leukemic medicine.
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CN108191889A (en) * | 2018-01-11 | 2018-06-22 | 河南大学 | Fluoro- 7- piperazines nalidixic acid compounds of 1- (N- Ofloxacins amide groups) -6- and its preparation method and application |
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CN111647004B (en) * | 2019-11-20 | 2021-08-17 | 河南大学 | Propenone derivative for removing N-methylofloxacin and preparation method and application thereof |
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