Propenone derivative of N-acetyl levofloxacin, and preparation method and application thereof
阅读说明：本技术 一种n-乙酰基左氧氟沙星的丙烯酮衍生物及其制备方法和应用 (Propenone derivative of N-acetyl levofloxacin, and preparation method and application thereof ) 是由 胡国强 仵钊锋 王爱丽 刘苏峰 张闯 于 2019-11-20 设计创作，主要内容包括：本发明公开了一种N-乙酰基左氧氟沙星的丙烯酮衍生物及其制备方法和应用,采用如下式Ⅰ化学结构通式：式I中,芳香环Ar为苯环或取代苯环或呋喃环或吡啶环。本发明的一种N-乙酰基左氧氟沙星的丙烯酮衍生物,实现了氟喹啉酮骨架与丙烯酮骨架的有效拼合,进而构筑了新的氟喹诺酮“类查尔酮”化合物,从而增加了新化合物的抗肿瘤活性及抗耐药性,并降低对正常细胞的毒副作用,可以作为抗肿瘤活性物质开发全新结构的抗肿瘤药物。(The invention discloses an acrylketone derivative of N-acetyl levofloxacin, a preparation method and application thereof, wherein the chemical structural general formula of the derivative is as follows:)
1. The propenone derivative of the N-acetyl levofloxacin is characterized by being a typical compound with the following structure:
2. the preparation method of the acrylketone derivative of N-acetyl levofloxacin according to claim 1, which comprises the following steps:
1) taking N-acetyl levofloxacin shown in a formula II as a raw material, reacting with Carbonyldiimidazole (CDI) to prepare an N-acetyl levofloxacin imidazole amide compound shown in a formula III, and then carrying out condensation reaction with monoethyl malonate potassium salt to prepare a C-3 formyl ethyl acetate compound of the N-acetyl levofloxacin shown in a formula IV; finally, the N-acetyl levofloxacin C-3 ethanone shown in the formula V is prepared by hydrolysis and decarboxylation of the formula IV:
2) the propenone derivative of N-acetyl levofloxacin as shown in claim 1 can be prepared by carrying out Claisen-Schmidt condensation reaction on N-acetyl levofloxacin C-3 ethanone shown in a formula V and aromatic aldehyde under the catalysis of alkali to form an propenone structure and carrying out post-treatment.
3. The preparation method of the acrylketone derivative of N-acetyl levofloxacin according to claim 2, characterized in that the molar ratio of N-acetyl levofloxacin represented by the formula II to CDI is 1: 1.0-2.0, the molar ratio of N-acetyl levofloxacin imidazole amide represented by the formula III to monoethyl malonate potassium salt is 1: 1.0-1.5, and the molar ratio of N-acetyl levofloxacin-3 ethanone represented by the formula V to aromatic aldehyde is 1: 1.0-2.0.
4. The use of the acrylketone derivative of N-acetyl levofloxacin according to claim 1 for the preparation of an anti-tumor medicament.
5. The use of the propenone derivative of N-acetyl levofloxacin according to claim 4 in the preparation of an anti-tumor medicament, wherein the anti-tumor medicament is a medicament for treating human non-small cell lung cancer, kidney cancer, liver cancer, stomach cancer, pancreatic cancer or leukemia.
Technical Field
The invention belongs to the technical field of innovative drug synthesis, and particularly relates to an acrylketone derivative of N-acetyl levofloxacin, a preparation method of the acrylketone derivative of N-acetyl levofloxacin, and application of the acrylketone derivative in antitumor drugs.
Background
New drug innovation stems from the discovery of leads, and rational drug molecular design based on structure or mechanism is an effective method for discovering leads. In the drug effect groups with various structures, the acrylketone structure is not only the characteristic structure of a chalcone compound which is a natural effective component, but also the characteristic drug effect group of a targeted antitumor drug sunitinib. Therefore, compounds constructed with acrylketone as a structural fragment and having various pharmacological activities have been attracting attention. However, most of natural chalcone compounds are multi-hydroxyl benzene ring substituted propenone compounds, and the poor water solubility of the compounds causes low bioavailability and limits clinical application. In addition, the topoisomerase which is an action target point of the antibacterial fluoroquinolone medicine is also an important action target point of the antitumor medicine, the antibacterial activity of the antibacterial fluoroquinolone medicine can be converted into the antitumor activity, and the fluoroquinolone C-3 carboxyl is not a pharmacophore required by the antitumor activity and can be replaced by a biological electron isostere to improve the antitumor activity of the fluoroquinolone medicine. However, the research on the replacement of the C-3 carboxyl group of fluoroquinolone with aryl acrylketone has not been reported. Based on the above, in order to improve the water solubility of chalcone, hydrophilic piperazinyl is introduced to increase the water solubility and improve the bioavailability and the biological activity of the chalcone, the invention uses the skeleton of the advantageous pharmacophore of the fluoroquinolone medicament N-acetyl levofloxacin, namely 1, 8-isopropoxy-6-fluoro-7- (4-acetyl piperazine-1-yl) -quinoline-4 (1H) -one, as a substituent of an aryl propenone structure, and further designs the novel fluoroquinolone chalcone derivatives.
Therefore, the invention aims to provide the acrylketone derivative of the N-acetyl levofloxacin, which has the anti-tumor effect and efficacy, and also provides a preparation method of the acrylketone derivative of the N-acetyl levofloxacin.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows: the acrylketone derivative of N-acetyl levofloxacin has a chemical structural formula shown as a general formula I:
in the formula I, Ar is a benzene ring or a substituted benzene ring or a furan ring or a pyridine ring, and the compound is a compound with the following specific structure:
the preparation method of the acrylketone derivative of N-acetyl levofloxacin takes commercially obtained N-acetyl levofloxacin shown in a formula II as a raw material to prepare the derivative;
the preparation method comprises the following specific steps:
1) the preparation method of the N-acetyl levofloxacin imidazole amide compound shown in the formula III is characterized in that commercially obtained N-acetyl levofloxacin shown in the formula II is used as a raw material and reacts with Carbonyldiimidazole (CDI), and the specific preparation method is as follows:
23.0g (60.0mmol) of S- (-) -1, 8-isopropoxy-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinolin-4 (1H) -one-3-carboxylic acid II was dissolved in 500mL of anhydrousTo acetonitrile, 15.2g (94.0mmol) of carbonyldiimidazole was added, and the mixture was stirred in a water bath and refluxed until the starting material II disappeared. Standing at room temperature, filtering and collecting generated solid, and recrystallizing with acetone to obtain N-acetyllevofloxacin imidazole amide light yellow crystal of formula III, wherein the yield is 76.3%, and the m.p.232-234 ℃.1H NMR(400MHz,CD3Cl)δ：1.65(3H,d,CH3),2.36(3H,s,COH3) 3.15 to 3.76(8H, m, piperazine-H), 4.46 to 4.87(3H, m, O-CH)2CH-N), 7.52-7.76 (2H, m, imidazole-H), 8.18(1H, s, imidazole-H), 8.96(1H, d, 5-H),9.16(1H, s, 2-H); MS (m/z): 440[ M + H ]]+Calculating (C)22H22FN5O4)：439.45。
As a further improvement, the molar ratio of the N-acetyl levofloxacin shown in the formula II to the carbonyldiimidazole is 1: 1.0-2.0, and the solvent can be at least one of acetonitrile, tetrahydrofuran, dioxane and dimethylformamide or a mixed solvent of the two.
2) The preparation method comprises the following steps of carrying out condensation reaction on N-acetyl levofloxacin imidazole amide shown in a formula III and monoethyl malonate potassium salt under the catalysis of triethylamine-magnesium chloride to obtain a C-3 formyl ethyl acetate compound of N-acetyl levofloxacin shown in a formula IV, wherein the preparation method comprises the following steps:
s- (-) -1, 8-isopropoxy-6-fluoro-7- (4-acetylpiperazin-1-yl) -3- (1H-imidazole-1-formyl) - [ quinolin-4 (1H) -one, 17.0g (39.0mmol) of formula III, 6.6g (69.1mmol) of magnesium chloride and 8.3g (49.0mmol) of potassium monoethyl malonate were sequentially added to 600mL of anhydrous acetonitrile, 12.2g (12.0mmol) of triethylamine was added dropwise with stirring in an ice bath, and the reaction mixture was stirred in a water bath and refluxed until the starting material III disappeared. The solvent was evaporated under reduced pressure, 500mL of water was added, the mixture was extracted with methylene chloride (3X 150mL), the organic phases were combined, washed with water (3X 200mL), washed with saturated brine (2X 150mL), and dried over anhydrous sodium sulfate. Recovering dichloromethane at normal pressure, recrystallizing the residue with anhydrous ethanol to obtain white crystal of formula IVThe rate is 74.8 percent, and the m.p.226-228 ℃.1H NMR(400MHz,CD3Cl)δ：1.27～1.68(6H，m，2×CH3)，2.37(3H,s,COH3) 3.13 to 3.75(8H, m, piperazine-H), 3.46 to 4.82(7H, m, COCH)2COOCH2And O-CH2CH-N)，8.95(1H，d，5-H)，9.14(1H，s,2-H)；MS(m/z)：460[M+H]+Calculating (C)23H26FN3O6)：459.48。
3) The C-3 ethyl formylacetate compound of the N-acetyl levofloxacin shown in the formula IV is hydrolyzed and decarboxylated by using 6 percent of sodium hydroxide aqueous solution by mass fraction, so that the C-3 ethanone compound of the N-acetyl levofloxacin shown in the formula V can be conveniently prepared, and the specific preparation method is as follows:
taking 10g (22.0mmol) of S- (-) -1, 8-isopropoxy-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinolin-4 (1H) -one-3-formylacetic acid ethyl ester shown in the formula IV and suspending the solution in 200mL of 3% by mass sodium hydroxide aqueous solution, and stirring and refluxing the solution in an oil bath until the raw material IV disappears. Standing at room temperature, collecting the generated solid by filtration, washing with water to neutrality, drying, and recrystallizing with anhydrous ethanol to obtain light yellow crystal of formula V, with yield of 81.5%, m.p.230-232 deg.C.1H NMR(400MHz,CD3Cl)δ：1.67(3H,d,CH3),2.38,2.43(6H，2s，2×COCH3) 3.15 to 3.76(8H, m, piperazine-H), 4.46 to 4.83(3H, m, O-CH)2CH-N)，8.97(1H，d，5-H)，9.16(1H，s,2-H)；MS(m/z)：388[M+H]+Calculating (C)20H22FN3O4)：387.41。
4) C-3 ethanone of N-acetyl levofloxacin shown in a formula V and aromatic aldehyde are subjected to Claisen-Schmidt aldol condensation reaction in absolute ethyl alcohol under the catalysis of alkali, and after the reaction is completed, a target compound is obtained through treatment, wherein the target compound is shown in a formula I, and the specific process is as follows:
wherein Ar in the formula I is a benzene ring or a substituted benzene ring or a furan ring or a pyridine ring.
The general synthetic preparation procedure for the target compound of formula i is: 1.2g (3.0mmol) of S- (-) -1, 8-isopropoxy-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinolin-4 (1H) one-3-ethanone V was dissolved in 20mL of anhydrous ethanol, and an aromatic aldehyde (3.0mmol) and a base catalyst, piperidine (0.1mL) were added. And (3) refluxing and reacting the mixed reactants for 15-24 h, standing at room temperature, filtering and collecting the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a light yellow crystal shown in the formula I.
As a further improvement, the mol ratio of the N-acetyl levofloxacin C-3 ethanone shown in the formula V to the aromatic aldehyde is 1: 1.0-1.5.
The base catalyst is at least one of piperidine, pyridine, triethylamine, morpholine, potassium acetate, sodium hydroxide ethanol solution or potassium hydroxide ethanol solution.
The application of the acrylketone derivative of the N-acetyl levofloxacin in preparing the antitumor drugs.
The anti-tumor drug is a drug for treating human non-small cell lung cancer, kidney cancer, liver cancer, stomach cancer, pancreatic cancer or leukemia.
The acrylketone derivative of N-acetyl levofloxacin disclosed by the invention is designed and synthesized by effectively combining a fluoroquinolone skeleton and an aryl acrylketone pharmacophore based on the splicing principle of the pharmacophores, and the complementation and activity superposition of the pharmacophores with different structures are realized, so that the effects of synergism, toxicity reduction and drug resistance are achieved, and the acrylketone derivative of N-acetyl levofloxacin can be developed as an anti-tumor drug with a brand new structure.
Detailed Description
Example 1
S- (-) -1, 8-isopropoxy-6-fluoro-7- (4-acetylpiperazin-1-yl) -3-cinnamoyl-quinolin-4 (1H) -one (I-1) having the chemical formula:
namely, Ar in the formula I is phenyl.
The preparation method of the compound comprises the following steps: 1.2g (3.0mmol) of S- (-) -1, 8-isopropoxy-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of anhydrous ethanol, and 0.40g (3.8mmol) of benzaldehyde and piperidine (0.1mL) as a base catalyst were added. And (3) refluxing and reacting the mixed reactants for 18h, standing at room temperature, filtering and collecting the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a light yellow crystal, namely a formula I-1, wherein the yield is 76.6%, and the m.p. is 233-235 ℃.1H NMR(400MHz,CD3Cl)δ：1.66(3H,d,CH3),2.37(3H，s，COCH3) 3.15 to 3.78(8H, m, piperazine-H), 4.46 to 4.86(3H, m, O-CH)2CH-N), 7.64-8.72 (7H, m, Ph-H, 3 '-H and 2' -H), 8.97(1H, d, 5-H),9.16(1H, s, 2-H); MS (m/z): 476[ M + H ]]+Calculating (C)27H26FN3O4)：475.52。
Example 2
S- (-) -1, 8-isopropoxy-6-fluoro-7- (4-acetylpiperazin-1-yl) -3- (4-methoxycinnamoyl) -quinolin-4 (1H) -one (I-2) having the chemical formula:
namely, Ar in the formula I is p-methoxyphenyl.
The preparation method of the compound comprises the following steps: 1.2g (3.0mmol) of S- (-) -1, 8-isopropoxy-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of anhydrous ethanol, and 0.57g (4.2mmol) of 4-methoxybenzaldehyde and piperidine (0.1mL) as a base catalyst were added. And (3) refluxing and reacting the mixed reactants for 20 hours, standing at room temperature, filtering and collecting the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a light yellow crystal, namely a formula I-2, wherein the yield is 78.4%, and the m.p.234-236 ℃.1H NMR(400MHz,CD3Cl)δ：1.67(3H,d,CH3),2.38(3H，s，COCH3) 3.17 to 3.77(8H, m, piperazine-H), 3.92(3H, s, OCH)3)，4.48～4.86(3H，m，O-CH2CH-N), 7.64-8.87 (6H, m, Ph-H, 3 '-H and 2' -H), 8.97(1H, d, 5-H),9.16(1H, s, 2-H); MS (m/z): 506[ M + H]+Calculating (C)28H28FN3O5)：505.55。
Example 3
S- (-) -1, 8-isopropoxy-6-fluoro-7- (4-acetylpiperazin-1-yl) -3- (3, 4-dioxocinnamoyl) -quinolin-4 (1H) -one (I-3) having the chemical formula:
namely, Ar in the formula I is 3,4- (dioxymethylene) phenyl.
The preparation method of the compound comprises the following steps: 1.2g (3.0mmol) of S- (-) -1, 8-isopropoxy-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of anhydrous ethanol, and 0.53g (3.5mmol) of 3, 4-dioxotolualdehyde and piperidine (0.1mL) as a base catalyst were added. And (3) carrying out reflux reaction on the mixed reactants for 20h, standing at room temperature, filtering to collect the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a light yellow crystal, namely a formula I-3, wherein the yield is 86.2%, and the m.p.236-238 ℃.1H NMR(400MHz,CD3Cl)δ：1.67(3H,d,CH3),2.37(3H，s，COCH3) 3.15 to 3.76(8H, m, piperazine-H), 4.47 to 4.86(3H, m, O-CH)2CH-N)，6.24(2H，s，OCH2O), 7.63-8.86 (5H, m, Ph-H, 3 '-H and 2' -H), 8.95(1H, d, 5-H),9.16(1H, s, 2-H); MS (m/z): 520[ M + H ]]+Calculating (C)28H26FN3O6)：519.53。
Example 4
S- (-) -1, 8-isopropoxy-6-fluoro-7- (4-acetylpiperazin-1-yl) -3- (3,4, 5-trimethoxycinnamoyl) -quinoline-4 (1H) -one-
Ketone (I-4) having the chemical formula:
namely, Ar in the formula I is 3,4, 5-trimethoxyphenyl.
The preparation method of the compound comprises the following steps: 1.2g (3.0mmol) of S- (-) -1, 8-isopropoxy-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of anhydrous ethanol, and 0.63g (3.2mmol) of 3,4, 5-trioxybenzaldehyde and piperidine (0.1mL) as a base catalyst were added. And (3) refluxing and reacting the mixed reactants for 20 hours, standing at room temperature, filtering and collecting the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a light yellow crystal, namely a formula I-4, wherein the yield is 73.6%, and m.p.227-229 ℃.1H NMR(400MHz,CD3Cl)δ：1.66(3H,d,CH3),2.38(3H，s，COCH3) 3.15 to 3.82(8H, m, piperazine-H), 3.88,3.93(9H, 2s,3 XOCH)3)，4.46～4.86(3H，m，O-CH2CH-N), 7.62-8.87 (4H, m, Ph-H, 3 '-H and 2' -H), 8.97(1H, d, 5-H),9.15(1H, s, 2-H); MS (m/z): 566[ M + H]+Calculating (C)30H32FN3O7)：565.60。
Example 5
S- (-) -1, 8-isopropoxy-6-fluoro-7- (4-acetylpiperazin-1-yl) -3- (4-methylcinnamoyl) -quinolin-4 (1H) -one (I-5) having the chemical formula:
namely, Ar in the formula I is p-methyl-phenyl.
The preparation method of the compound comprises the following steps: 1.2g (3.0mmol) of S- (-) -1, 8-isopropoxy-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of anhydrous ethanol, and 0.58g (4.8mmol) of 4-methylbenzaldehyde and piperidine (0.1mL) as a base catalyst were added. And (3) carrying out reflux reaction on the mixed reactants for 15h, standing at room temperature, filtering to collect the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a light yellow crystal, namely a formula I-5, wherein the yield is 68.2%, and the m.p.226-228 ℃.1H NMR(400MHz,CD3Cl)δ：1.65(3H,d,CH3),2.26(3H，s，Ph-CH3)，2.37(3H，s，COCH3) 3.10 to 3.76(8H, m, piperazine-H), 4.45 to 4.82(3H, m, O-CH)2CH-N)，7.63～8.86(6H, m, Ph-H, 3 '-H and 2' -H), 8.96(1H, d, 5-H),9.11(1H, s, 2-H); MS (m/z): 490[ M + H [ ]]+Calculating (C)28H28FN3O4)：489.55。
Example 6
S- (-) -1, 8-isopropoxy-6-fluoro-7- (4-acetylpiperazin-1-yl) -3- (4-fluorocinnamoyl) -quinolin-4 (1H) -one (I-6) having the chemical formula:
namely, Ar in the formula I is p-fluoro-phenyl.
The preparation method of the compound comprises the following steps: 1.2g (3.0mmol) of S- (-) -1, 8-isopropoxy-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of anhydrous ethanol, and 0.48g (3.8mmol) of 4-fluorobenzaldehyde and piperidine (0.1mL) as a base catalyst were added. And (3) carrying out reflux reaction on the mixed reactants for 15h, standing at room temperature, filtering to collect the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a light yellow crystal, namely a formula I-6, wherein the yield is 80.7%, and the m.p.237-239 ℃.1H NMR(400MHz,CD3Cl)δ：1.68(3H,d,CH3),2.40(3H，s，COCH3) 3.23 to 3.87(8H, m, piperazine-H), 4.48 to 4.92(3H, m, O-CH)2CH-N), 7.67-8.93 (6H, m, Ph-H, 3 '-H and 2' -H), 9.05(1H, d, 5-H),9.17(1H, s, 2-H); MS (m/z): 494[ M + H]+Calculating (C)27H25F2N3O4)：493.51。
Example 7
S- (-) -1, 8-isopropoxy-6-fluoro-7- (4-acetylpiperazin-1-yl) -3- (4-chlorocinnamyl) -quinolin-4 (1H) -one (I-7) having the chemical formula:
namely, Ar in the formula I is p-chlorophenyl.
The preparation method of the compound comprises the following steps: taking S- (-) -1, 8-isopropoxy-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V1.2 g (3.0mmol) was dissolved in 20mL of absolute ethanol, and 4-chlorobenzaldehyde 0.45g (3.2mmol) and piperidine (0.1mL) as a base catalyst were added. And (3) refluxing and reacting the mixed reactants for 20 hours, standing at room temperature, filtering and collecting the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a light yellow crystal, namely a formula I-7, wherein the yield is 76.4%, and the m.p.234-236 ℃.1H NMR(400MHz,CD3Cl)δ：1.67(3H,d,CH3),2.39(3H，s，COCH3) 3.18 to 3.85(8H, m, piperazine-H), 4.46 to 4.88(3H, m, O-CH)2CH-N), 7.66-8.90 (6H, m, Ph-H, 3 '-H and 2' -H), 9.03(1H, d, 5-H),9.17(1H, s, 2-H); MS (m/z): 510[ M + H]+Calculating (C)27H25FClN3O4)：509.97。
Example 8
S- (-) -1, 8-isopropoxy-6-fluoro-7- (4-acetylpiperazin-1-yl) -3- (4-bromocinnamoyl) -quinolin-4 (1H) -one (I-8) having the chemical formula:
namely, Ar in the formula I is p-bromophenyl.
The preparation method of the compound comprises the following steps: 1.2g (3.0mmol) of S- (-) -1, 8-isopropoxy-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of anhydrous ethanol, and 0.67g (3.6mmol) of 4-bromobenzaldehyde and piperidine (0.1mL) as a base catalyst were added. And (3) refluxing and reacting the mixed reactants for 24 hours, standing at room temperature, filtering and collecting the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a light yellow crystal, namely a formula I-8, wherein the yield is 78.2%, and the m.p.237-239 ℃.1H NMR(400MHz,CD3Cl)δ：1.68(3H,d,CH3),2.41(3H，s，COCH3) 3.19 to 3.85(8H, m, piperazine-H), 4.48 to 4.87(3H, m, O-CH)2CH-N), 7.66-8.92 (6H, m, Ph-H, 3 '-H and 2' -H), 9.03(1H, d, 5-H),9.16(1H, s, 2-H); MS (m/z): 554 and 556[ M + H]+(79Br and81br), calculating (C)27H25FBrN3O4)：554.42。
Example 9
S- (-) -1, 8-isopropoxy-6-fluoro-7- (4-acetylpiperazin-1-yl) -3- (4-nitrocinnamoyl) -quinolin-4 (1H) -one (I-9) having the chemical formula:
namely, Ar in the formula I is p-nitrophenyl.
The preparation method of the compound comprises the following steps: 1.2g (3.0mmol) of S- (-) -1, 8-isopropoxy-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of anhydrous ethanol, and 0.54g (3.6mmol) of 4-nitrobenzaldehyde and piperidine (0.1mL) as a base catalyst were added. And (3) carrying out reflux reaction on the mixed reactants for 24 hours, standing at room temperature, filtering to collect the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a yellow crystal, namely a formula I-9, wherein the yield is 73.2%, and the m.p.245-247 ℃.1H NMR(400MHz,CD3Cl)δ：1.72(3H,d,CH3),2.43(3H，s，COCH3) 3.27 to 3.87(8H, m, piperazine-H), 4.48 to 4.95(3H, m, O-CH)2CH-N), 7.68-9.06 (6H, m, Ph-H, 3 '-H and 2' -H), 9.12(1H, d, 5-H),9.23(1H, s, 2-H); MS (m/z): 521[ M + H]+Calculating (C)27H25FN4O6)：520.52。
Example 10
S- (-) -1, 8-isopropoxy-6-fluoro-7- (4-acetylpiperazin-1-yl) -3- (4-hydroxy-cinnamoyl) -quinolin-4 (1H) -one (I-10) having the chemical formula:
namely, Ar in the formula I is 4-hydroxy-phenyl.
The preparation method of the compound comprises the following steps: 1.2g (3.0mmol) of S- (-) -1, 8-isopropoxy-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of anhydrous ethanol, and 0.49g (4.0mmol) of 4-hydroxy-benzaldehyde and piperidine (0.1mL) as a base catalyst were added. The mixed reactants are refluxed and reacted for 20 hours, and then putStanding at room temperature, filtering to collect the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a yellow crystal of formula I-10, wherein the yield is 74.6%, and m.p.235-237 ℃.1H NMR(400MHz,CD3Cl)δ：1.67(3H,d,CH3),2.40(3H，s，COCH3) 3.13 to 3.85(8H, m, piperazine-H), 4.47 to 4.86(3H, m, O-CH)2CH-N), 7.64-8.87 (6H, m, Ph-H, 3 '-H and 2' -H), 8.96(1H, d, 5-H),9.15(1H, s,2-H), 10.67(1H, s, OH); MS (m/z): 492, calculate (C)27H26FN3O5)：491.52。
Example 11
S- (-) -1, 8-isopropoxy-6-fluoro-7- (4-acetylpiperazin-1-yl) -3- [3- (pyridin-3-yl) acryloyl ] -quinolin-4 (1H) -one (I-11) having the chemical formula:
namely, Ar in the formula I is 3-pyridyl.
The preparation method of the compound comprises the following steps: 1.2g (3.0mmol) of S- (-) -1, 8-isopropoxy-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of anhydrous ethanol, and 0.37g (3.6mmol) of 3-pyridylaldehyde and piperidine (0.1mL) as a base catalyst were added. And (3) carrying out reflux reaction on the mixed reactants for 15h, standing at room temperature, filtering to collect the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a yellow crystal, namely a formula I-11, wherein the yield is 83.1%, and the m.p.248-250 ℃.1H NMR(400MHz,CD3Cl)δ：1.72(3H,d,CH3),2.44(3H，s，COCH3) 3.35 to 3.88(8H, m, piperazine-H), 4.48 to 4.97(3H, m, O-CH)2CH-N), 7.67(1H, d, 2 '-H), 8.87-9.18 (6H, 5-H, 3' -H and pyridine-H), 9.23(1H, s, 2-H); MS (m/z): 477 calculating (C)25H25FN4O4)：476.51。
Example 12
S- (-) -1, 8-isopropoxy-6-fluoro-7- (4-acetylpiperazin-1-yl) -3- [3- (furan-2-yl) acryloyl ] quinolin-4 (1H) -one (I-12) having the chemical formula:
namely, Ar in the formula I is 2-furyl.
The preparation method of the compound comprises the following steps: the preparation method of the compound comprises the following steps: 1.2g (3.0mmol) of S- (-) -1, 8-isopropoxy-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of anhydrous ethanol, and 0.38g (4.0mmol) of 2-furfural and piperidine (0.1mL) as a base catalyst were added. And (3) refluxing and reacting the mixed reactants for 18h, standing at room temperature, filtering and collecting the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a yellow crystal, namely a formula I-12, wherein the yield is 75.2%, and the m.p.243-245 ℃.1H NMR(400MHz,CD3Cl)δ：1.68(3H,d,CH3),2.42(3H，s，COCH3) 3.17 to 3.86(8H, m, piperazine-H), 4.48 to 4.90(3H, m, O-CH)2CH-N), 7.36-8.26 (5H, m, 2 '-H, 3' -H and furan-H), 8.98(1H, d, 5-H),9.15(1H, s, 2-H); MS (m/z): 466[ M + H]+Calculating (C)25H24FN3O5S)：465.49。
Test examples
Examples 1-12 measurement of antitumor Activity in vitro of acrylketone derivative of N-acetyllevofloxacin
1. Test sample
15 samples of the propenone derivative of N-acetyl levofloxacin provided in examples 1-12, the classical antitumor TOPO inhibitor 10-Hydroxycamptothecin (HC), the chalcone tyrosinase inhibitor Sunitinib (SN), the broad spectrum anticancer drug Doxorubicin (DOX) and the parent compound levofloxacin (ALOF) are used as test samples, wherein HC, SN and ALOF are used as control experiment groups, and examples 1-12 are used as test experiment groups;
thiazole blue (MTT), HC, SN and ALOF are all products of Sigma company; the RPMI-1640 culture solution is a product of GIBCO company; other used reagents are all domestic analytical pure reagents.
The experimental cancer cell strains are respectively a human non-small cell lung cancer cell strain A549, a human kidney cancer cell strain 769-P, a human hepatoma cell strain Hep-3B, a human gastric cancer cell strain HGC27, a human pancreatic cancer cell strain Panc-1 and a human leukemia cell strain HL60, which are purchased from Shanghai cell banks of Chinese academy of sciences. The human renal clear cell carcinoma cell sunitinib-resistant strain 7SuR was purchased from shanghai zel biotechnology limited, and the normal cell was obtained from african green monkey kidney cell line VERO and purchased from shanghai tong biology limited.
2. Measurement method
The determination method comprises the following specific steps:
1) firstly, the 15 samples were dissolved in dimethyl sulfoxide (DMSO) to prepare 1.0X 10- 4mol·L-1Stock solution of concentration, then diluting the stock solution with 10% calf serum RPMI-1640 culture solution to have 5 concentration gradients (0.1, 1.0, 5.0, 10.0, 50.0 μmol. L)-1) The working fluid of (1);
2) taking non-small cell lung cancer cell strain A549, human kidney cancer cell strain 769-P, human liver cancer cell strain Hep-3B, human gastric cancer cell strain HGC27, human pancreatic cancer cell strain Panc-1, human leukemia cell strain HL60, human renal clear cell cancer cell sunitinib drug-resistant strain 7SuR and African green monkey kidney cell strain VERO in logarithmic growth phase, inoculating 6000 cells in each hole to a 96-hole plate, then respectively adding working solution with 5 concentration gradients of the 15 samples, and adding 5 g.L.in each hole after 48 hours–1mu.L of MTT (thiazole blue) solution was added, and after further culturing for 4 hours, 100. mu.L of a 10% by mass Sodium Dodecyl Sulfate (SDS) solution was added. Culturing for 24 hours, and then measuring an absorbance (OD) value at a wavelength of 570nm by using a microplate reader;
3) the inhibition rate of the test samples with different concentrations on the cancer cells is calculated according to the following formula:
cancer cell inhibition rate ═ [ (1-experimental OD value)/control OD value ] × 100%;
then, linear regression is carried out on the cancer cell inhibition rate corresponding to each concentration by the pair value of each concentration of the test sample to obtain a dose-effect equation, and the half Inhibition Concentration (IC) of the test sample to the experimental cancer cell is calculated from the obtained dose-effect equation50) (ii) a Each data was measured in triplicate and averagedThe values and results are shown in Table 1.
TABLE 1 antitumor Activity (IC) of the test samples50)
As can be seen from Table 1, the inhibitory activity of the compounds provided in examples 1-12 on 7 cancer cells of experiment is significantly stronger than that of the parent compound N-acetyl levofloxacin, especially the growth inhibitory activity of some compounds on human non-small cell lung cancer cell strain A549 is stronger than that of the control Hydroxycamptothecin (HC), tyrosine kinase inhibitors Sunitinib (SN) and adriamycin (DOX), and the IC of the compounds is IC of the compounds50The value is close to nanomolar concentration, and the method has the value of new drug development. More significantly, the compounds provided in examples 1 to 12 also show extremely strong sensitivity to sunitinib-resistant strain 7SuR, show strong drug-resistant activity, and simultaneously show low cytotoxicity to normal cells VERO, and have the property of becoming drug-resistant. Therefore, according to the general approach of drug development, the conventional antitumor in vitro screening is carried out, and then the targeted research is carried out, so that the compound has strong antitumor activity, drug resistance activity and lower cytotoxicity, and can be used for preparing antitumor drugs by salifying with acid acceptable for human bodies or mixing with medicinal carriers.