CN112824415A - Ofloxacin acrylketone derivative and preparation method and application thereof - Google Patents
Ofloxacin acrylketone derivative and preparation method and application thereof Download PDFInfo
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- CN112824415A CN112824415A CN201911139983.6A CN201911139983A CN112824415A CN 112824415 A CN112824415 A CN 112824415A CN 201911139983 A CN201911139983 A CN 201911139983A CN 112824415 A CN112824415 A CN 112824415A
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- ofloxacin
- formula
- acrylketone
- derivative
- preparation
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- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- -1 Ofloxacin acrylketone derivative Chemical class 0.000 title claims description 14
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- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 10
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- GSDSWSVVBLHKDQ-UHFFFAOYSA-N 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)COC3=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-UHFFFAOYSA-N 0.000 claims description 28
- 238000006243 chemical reaction Methods 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 10
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 7
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- 210000002966 serum Anatomy 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- OVYTZAASVAZITK-UHFFFAOYSA-M sodium;ethanol;hydroxide Chemical compound [OH-].[Na+].CCO OVYTZAASVAZITK-UHFFFAOYSA-M 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000012224 working solution Substances 0.000 description 1
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Abstract
The invention discloses an acrylketone derivative of ofloxacin and a preparation method and application thereof, which adopts the following chemical structural general formula I:
Description
Technical Field
The invention belongs to the technical field of innovative drug synthesis, and particularly relates to an acrylketone derivative of ofloxacin, a preparation method of the acrylketone derivative of ofloxacin, and application of the acrylketone derivative of ofloxacin 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, the hydrophilic piperazinyl is introduced to increase the water solubility and improve the bioavailability and the bioactivity of the chalcone, the invention uses the skeleton of the advantageous pharmacophore '1, 8-isopropoxy-6-fluoro-7- (4-methylpiperazin-1-yl) -quinolin-4 (1H) -one' of the fluoroquinolone drug ofloxacin as a substituent of an aryl propenone structure, and further designs the novel structure of the fluoroquinolone 'chalcone-like' derivative.
Therefore, the invention aims to provide the acrylketone derivative of the ofloxacin, which has the function and the effect of resisting tumors and simultaneously provides a preparation method of the acrylketone derivative of the ofloxacin.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows: an acrylketone derivative of ofloxacin, which 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 ofloxacin is prepared by taking the ofloxacin which is commercially obtained and is shown as a formula II as a raw material;
the preparation method comprises the following specific steps:
1) the ofloxacin imidazole amide compound shown as a formula III is prepared by taking ofloxacin shown as a formula II as a raw material and reacting with Carbonyldiimidazole (CDI), and the specific preparation method is as follows:
22.0g (60.0mmol) of 1, 8-isopropoxy-6-fluoro-7- (4-methylpiperazin-1-yl) -quinolin-4 (1H) -one-3-carboxylic acid II is dissolved in 500mL of anhydrous acetonitrile, 15.2g (94.0mmol) of carbonyldiimidazole is added, and the mixture is stirred in a water bath and refluxed until the raw material II disappears. Standing at room temperature, filtering to collect the generated solid, and recrystallizing with acetone to obtain the ofloxacin imidazole amide light yellow crystal shown as the formula III, wherein the yield is 82.7%, and the m.p.241-243 ℃.1H NMR(400MHz,CD3Cl)δ：1.57(3H,d,CH3),2.36(3H,s,N-CH3) 2.96 to 3.67(8H, m, piperazine-H), 4.34 to 4.86(3H, m, O-CH)2CH-N), 7.45-7.62 (2H, m, imidazole-H), 8.15(1H, s, imidazole-H), 8.95(1H, d, 5-H), 9.14(1H, s, 2-H); MS (m/z): 412[ M + H]+Calculating (C)21H22FN5O3)：411.44。
As a further improvement, the molar ratio of the ofloxacin 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 ofloxacin imidazole amide shown in a formula III and monoethyl malonate potassium salt are subjected to condensation reaction under the catalysis of triethylamine-magnesium chloride to prepare the C-3 formyl ethyl acetate compound of ofloxacin shown in a formula IV, and the specific preparation method is as follows:
1, 8-isopropoxy-6-fluoro-7- (4-methylpiperazin-1-yl) -3- (1H-imidazole-1-formyl) - [ quinolin-4 (1H) -one, 16.0g (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 mixture was stirred in a water bath and refluxed until the raw 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. And recovering dichloromethane at normal pressure, and recrystallizing the residue with absolute ethyl alcohol to obtain an off-white crystal shown as a formula IV, wherein the yield is 76.4%, and m.p.225-227 ℃.1H NMR(400MHz,CD3Cl)δ：1.28～1.62(6H，m，2×CH3)，2.38(3H,s,N-CH3) 2.93-3.65 (8H, m, piperazine-H), 3.42-4.87 (7H, m, COCH)2COOCH2And O-CH2CH-N)，8.92(1H，d，5-H)，9.15(1H，s,2-H)；MS(m/z)：432[M+H]+Calculating (C)22H26FN3O5)：431.47。
3) The C-3 ethyl formylacetate compound of the ofloxacin shown in the formula IV is subjected to hydrolysis decarboxylation reaction by using a sodium hydroxide aqueous solution with the mass fraction of 6 percent, so that the C-3 ethanone compound of the ofloxacin shown in the formula V can be conveniently prepared, and the specific preparation method is as follows:
taking 10g (23.0mmol) of 1, 8-isopropoxy-6-fluoro-7- (4-methylpiperazin-1-yl) -quinoline-4 (1H) -ketone-3-formylacetic acid ethyl ester formula IV and suspending the ethyl ester in 200mL of sodium hydroxide aqueous solution with the mass fraction of 6%, and stirring and refluxing the mixture in an oil bath until the raw material IV disappears. Standing at room temperature, collecting the generated solid by filtration, washing with water to be neutral, drying, and recrystallizing with absolute ethyl alcohol to obtain a light yellow crystal of formula V, wherein the yield is 87.6%, and m.p.236-238 ℃.1H NMR(400MHz,CD3Cl)δ：1.58(3H,d,CH3),2.36(3H,s,N-CH3)，2.42(3H，s，COCH3) 3.12 to 3.68(8H, m, piperazine-H), 4.36 to 4.87(3H, m, O-CH)2CH-N)，8.87(1H，d，5-H)，9.16(1H，s,2-H)；MS(m/z)：360[M+H]+Calculating (C)19H22FN3O3)：359.40。
4) C-3 ethanone of ofloxacin shown in 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 by treatment, wherein the target compound is shown in 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: 1.1g (3.0mmol) of 1, 8-isopropoxy-6-fluoro-7- (4-methylpiperazin-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 molar ratio of the ofloxacin 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 ofloxacin in preparing 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 ofloxacin is designed and synthesized by effectively combining a fluoroquinolone skeleton and an aryl acrylketone pharmacophore based on the split principle of the pharmacophores, realizes the complementation and activity superposition of the pharmacophores with different structures, achieves the effects of synergism, toxicity reduction and drug resistance, and can be developed as an anti-tumor drug with a brand new structure.
Detailed Description
Example 1
1, 8-isopropoxy-6-fluoro-7- (4-methylpiperazin-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: 1.1g (3.0mmol) of 1, 8-isopropoxy-6-fluoro-7- (4-methylpiperazin-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 as a base catalyst (0.1mL) 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 83.4%, and the m.p.238-240 ℃.1H NMR(400MHz,CD3Cl)δ：1.60(3H,d,CH3),2.38(3H,s,N-CH3) 3.16 to 3.67(8H, m, piperazine-H), 4.42 to 4.88: (3H，m，O-CH2CH-N), 7.58-8.65 (7H, m, Ph-H, 3 '-H and 2' -H), 8.92(1H, d, 5-H),9.15(1H, s, 2-H); MS (m/z): 448[ M + H ]]+Calculating (C)26H26FN3O3)：447.51。
Example 2
1, 8-isopropoxy-6-fluoro-7- (4-methylpiperazin-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: 1.1g (3.0mmol) of 1, 8-isopropoxy-6-fluoro-7- (4-methylpiperazin-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) 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-2, wherein the yield is 84.6%, and the m.p.241-243 ℃.1H NMR(400MHz,CD3Cl)δ：1.62(3H,d,CH3),2.41(3H,s,N-CH3) 3.18 to 3.72(8H, m, piperazine-H), 3.87(3H, s, OCH)3)，4.45～4.87(3H，m，O-CH2CH-N), 7.60-8.67 (6H, m, Ph-H, 3 '-H and 2' -H), 8.94(1H, d, 5-H),9.16(1H, s, 2-H); MS (m/z): 478[ M + H]+Calculating (C)27H28FN3O4)：477.54。
Example 3
1, 8-isopropoxy-6-fluoro-7- (4-methylpiperazin-1-yl) -3- (3, 4-dioxamethylenecinnamoyl) -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: 1.1g (3.0mmol) of 1, 8-isopropoxy-6-fluoro-7- (4-methylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of anhydrous ethanol, and 0.53g (3.5mmol) of 3, 4-dioxytolualdehyde 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 88.5%, and the m.p.244-246 ℃.1H NMR(400MHz,CD3Cl)δ：1.61(3H,d,CH3),2.42(3H,s,N-CH3) 3.15 to 3.76(8H, m, piperazine-H), 4.46 to 4.85(3H, m, O-CH)2CH-N)，6.22(2H，s，OCH2O), 7.62-8.75 (5H, m, Ph-H, 3 '-H and 2' -H), 8.90(1H, d, 5-H),9.13(1H, s, 2-H); MS (m/z): 492[ M + H]+Calculating (C)27H26FN3O5)：491.52。
Example 4
1, 8-isopropoxy-6-fluoro-7- (4-methylpiperazin-1-yl) -3- (3,4, 5-trimethoxycinnamoyl) -quinolin-4 (1H) -one (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: 1.1g (3.0mmol) of 1, 8-isopropoxy-6-fluoro-7- (4-methylpiperazin-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 78.2%, and the m.p.234-236 ℃.1H NMR(400MHz,CD3Cl)δ：1.58(3H,d,CH3),2.40(3H,s,N-CH3) 3.13 to 3.72(8H, m, piperazine-H), 3.87,3.92(9H, 2s,3 XOCH)3)，4.42～4.81(3H，m，O-CH2CH-N), 7.61-8.86 (4H, m, Ph-H, 3 '-H and 2' -H), 8.91(1H, d, 5-H),9.12(1H, s, 2-H); MS (m/z)：538[M+H]+Calculating (C)29H32FN3O6)：537.59。
Example 5
1, 8-isopropoxy-6-fluoro-7- (4-methylpiperazin-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: 1.1g (3.0mmol) of 1, 8-isopropoxy-6-fluoro-7- (4-methylpiperazin-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 68.6%, and the m.p.227-229 ℃.1H NMR(400MHz,CD3Cl)δ：1.57(3H,d,CH3),2.27(3H，s，Ph-CH3)，2.38(3H,s,N-CH3) 3.06 to 3.68(8H, m, piperazine-H), 4.36 to 4.78(3H, m, O-CH)2CH-N), 7.58-8.82 (6H, m, Ph-H, 3 '-H and 2' -H), 8.87(1H, d, 5-H),9.06(1H, s, 2-H); MS (m/z): 462[ M + H ]]+Calculating (C)27H28FN3O3)：461.54。
Example 6
1, 8-isopropoxy-6-fluoro-7- (4-methylpiperazin-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: 1.1g (3.0mmol) of 1, 8-isopropoxy-6-fluoro-7- (4-methylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone is dissolved in 20mL of anhydrous ethyl acetateTo the alcohol, 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 82.4%, and the m.p.243-245 ℃.1H NMR(400MHz,CD3Cl)δ：1.64(3H,d,CH3),2.43(3H,s,N-CH3) 3.23 to 3.76(8H, m, piperazine-H), 4.46 to 4.85(3H, m, O-CH)2CH-N), 7.64-8.84 (6H, m, Ph-H, 3 '-H and 2' -H), 8.96(1H, d, 5-H),9.18(1H, s, 2-H); MS (m/z): 466[ M + H]+Calculating (C)26H25F2N3O3)：465.50。
Example 7
1, 8-isopropoxy-6-fluoro-7- (4-methylpiperazin-1-yl) -3- (4-chlorocinnamoyl) -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: 1.1g (3.0mmol) of 1, 8-isopropoxy-6-fluoro-7- (4-methylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of anhydrous ethanol, and 0.45g (3.2mmol) of 4-chlorobenzaldehyde 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 78.7%, and m.p.235-237 ℃.1H NMR(400MHz,CD3Cl)δ：1.63(3H,d,CH3),2.42(3H,s,N-CH3) 3.18 to 3.77(8H, m, piperazine-H), 4.42 to 4.83(3H, m, O-CH)2CH-N), 7.63-8.86 (6H, m, Ph-H, 3 '-H and 2' -H), 8.95(1H, d, 5-H),9.16(1H, s, 2-H); MS (m/z): 482[ M + H ]]+Calculating (C)26H25FClN3O3)：481.96。
Example 8
1, 8-isopropoxy-6-fluoro-7- (4-methylpiperazin-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: 1.1g (3.0mmol) of 1, 8-isopropoxy-6-fluoro-7- (4-methylpiperazin-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) carrying out reflux reaction on 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 m.p.238-240 ℃.1H NMR(400MHz,CD3Cl)δ：1.62(3H,d,CH3),2.44(3H,s,N-CH3) 3.16 to 3.78(8H, m, piperazine-H), 4.43 to 4.85(3H, m, O-CH)2CH-N), 7.65-8.87 (6H, m, Ph-H, 3 '-H and 2' -H), 8.93(1H, d, 5-H),9.15(1H, s, 2-H); MS (m/z): 526 and 528[ M + H ]]+(79Br and81br), calculating (C)26H25FBrN3O3)：526.41。
Example 9
1, 8-isopropoxy-6-fluoro-7- (4-methylpiperazin-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: 1.1g (3.0mmol) of 1, 8-isopropoxy-6-fluoro-7- (4-methylpiperazin-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 and collecting the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a yellow crystal, namely a formula I-9, wherein the yield is 83.6%, and the m.p.245-247 ℃.1H NMR(400MHz,CD3Cl)δ：1.68(3H,d,CH3),2.45(3H,s,N-CH3) 3.26 to 3.86(8H, m, piperazine-H), 4.47 to 4.88(3H, m, O-CH)2CH-N), 7.66-8.87 (6H, m, Ph-H, 3 '-H and 2' -H), 8.98(1H, d, 5-H),9.21(1H, s, 2-H); MS (m/z): 493[ M + H ]]+Calculating (C)26H25FN4O5)：492.51。
Example 10
1, 8-isopropoxy-6-fluoro-7- (4-methylpiperazin-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: 1.1g (3.0mmol) of 1, 8-isopropoxy-6-fluoro-7- (4-methylpiperazin-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. 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 yellow crystal, namely a formula I-10, wherein the yield is 75.6%, and the m.p.237-239 ℃.1H NMR(400MHz,CD3Cl)δ：1.60(3H,d,CH3),2.38(3H,s,N-CH3) 3.05 to 3.74(8H, m, piperazine-H), 4.41 to 4.85(3H, m, O-CH)2CH-N), 7.62-8.85 (6H, m, Ph-H, 3 '-H and 2' -H), 8.93(1H, d, 5-H),9.06(1H, s,2-H), 10.57(1H, s, OH); MS (m/z): 464, calculating (C)26H26FN3O4)：463.51。
Example 11
1, 8-isopropoxy-6-fluoro-7- (4-methylpiperazin-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: 1.1g (3.0mmol) of 1, 8-isopropoxy-6-fluoro-7- (4-methylpiperazin-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 85.3%, and the m.p.247-249 ℃.1H NMR(400MHz,CD3Cl)δ：1.73(3H,d,CH3),2.46(3H,s,N-CH3) 3.31 to 3.88(8H, m, piperazine-H), 4.46 to 4.93(3H, m, O-CH)2CH-N), 7.65(1H, d, 2 '-H), 8.87-9.12 (6H, 5-H, 3' -H and pyridine-H), 9.22(1H, s, 2-H); MS (m/z): 449, calculating (C)25H25FN4O3)：448.50。
Example 12
1, 8-isopropoxy-6-fluoro-7- (4-methylpiperazin-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: 1.1g (3.0mmol) of 1, 8-isopropoxy-6-fluoro-7- (4-methylpiperazin-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) carrying out reflux reaction on the mixed reactants for 18h, 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-12, wherein the yield is 75.4%, and the m.p.243-245 ℃.1H NMR(400MHz,CD3Cl)δ：1.63(3H,d,CH3),2.46(3H,s,N-CH3) 3.16 to 3.75(8H, m, piperazine-H), 4.43 to 4.86(3H, m, O-CH)2CH-N), 7.27-8.15 (5H, m, 2 '-H, 3' -H and furan-H), 8.95(1H, d, 5-H),9.13(1H, s, 2-H); MS (m/z): 438[ M + H]+Calculating (C)24H24FN3O3S)：437.47。
Test examples
One, embodiment 1-12 provides a determination of in vitro antitumor activity of acrylketone derivatives of ofloxacin
1. Test sample
Taking 15 OF the acrylic derivative OF ofloxacin 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 Ofloxacin (OF) as test samples, wherein HC, SN and OF are control experimental groups, and the samples OF examples 1-12 are test experimental groups;
thiazole blue (MTT), HC, SN and OF 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 hepatoma cell strain Hep-3B, human gastric cancer cell strain HGC27, human pancreatic cancer cell strain Panc-1 and human in logarithmic growth phaseThe leukemia cell line HL60, the human renal clear cell carcinoma cell sunitinib drug-resistant strain 7SuR and the African green monkey kidney cell line VERO were inoculated on a 96-well plate with 6000 cells per well, then the working solution with 5 concentration gradients of the above 15 samples was added, 5 g.L.was added per well 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, performing linear regression on the cancer cell inhibition rate corresponding to each concentration by using the pair value of each concentration of the test sample to obtain a dose-effect equation, and calculating the half inhibition concentration (IC50) of the test sample to the experimental cancer cell from the obtained dose-effect equation; each data was measured in triplicate and averaged, the 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 ofloxacin, especially the growth inhibitory activity of some compounds on human non-small cell lung cancer cell line A549 is stronger than that of the control Hydroxycamptothecin (HC), the tyrosine kinase inhibitors Sunitinib (SN) and adriamycin (DOX), and the IC of the compounds is50The value is reached or close to nanomolar concentration, and the method has the value of new drug development. More significantly, the compounds provided in examples 1-12 were also resistant to sunitinib-resistant strain 7SuRShows extremely strong sensitivity, shows stronger drug resistance activity, simultaneously shows lower cytotoxicity to normal cells VERO and has the property of becoming drug property. 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.
Claims (5)
1. The acrylic derivative of ofloxacin is characterized by being a typical compound with the following structure:
2. the preparation method of the acrylketone derivative of ofloxacin as claimed in claim 1, which is characterized by comprising the following steps:
1) taking ofloxacin shown as a formula II as a raw material, reacting with Carbonyldiimidazole (CDI) to prepare an ofloxacin imidazole amide compound shown as 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 ofloxacin shown as a formula IV; finally, the ofloxacin C-3 ethanone shown in the formula V is prepared by the hydrolysis decarboxylation reaction of the formula IV:
2) the ofloxacin acrylketone derivative shown in the claim 1 can be prepared by carrying out Claisen-Schmidt condensation reaction on the ofloxacin C-3 ethanone shown in the formula V and aromatic aldehyde under the catalysis of alkali to form an acrylketone structure and carrying out post-treatment.
3. The preparation method of the acrylketone derivative of ofloxacin according to claim 2, wherein the molar ratio of ofloxacin represented by formula II to CDI is 1: 1.0-2.0, the molar ratio of ofloxacin imidazolamide represented by formula III to monoethyl malonate potassium salt is 1: 1.0-1.5, and the molar ratio of ofloxacin-3 ethanone represented by formula V to aromatic aldehyde is 1: 1.0-2.0.
4. The use of the acrylketone derivative of ofloxacin as defined in claim 1 in the preparation of antitumor drugs.
5. The use of the acrylketone derivative of ofloxacin as the claim 4, which is characterized in that the antitumor drug is a drug for treating human non-small cell lung cancer, kidney cancer, liver cancer, stomach cancer, pancreatic cancer or leukemia.
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| CN113801140A (en) * | 2021-10-26 | 2021-12-17 | 黄河水利职业技术学院 | Isoleucinine analogs, and preparation method and application of isoleucinine analogs from levofloxacin to isoleucinine analogs |
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| CN106317074A (en) * | 2015-06-26 | 2017-01-11 | 河南大学 | Alpha, beta-unsaturated ketone derivatives of ofloxacin, and preparation method and applications thereof |
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| CN113788828A (en) * | 2021-10-26 | 2021-12-14 | 黄河水利职业技术学院 | Isoleucinine analogue, preparation method and application of isoleucinine analogue from norfloxacin to isoleucinine analogue |
| CN113801140A (en) * | 2021-10-26 | 2021-12-17 | 黄河水利职业技术学院 | Isoleucinine analogs, and preparation method and application of isoleucinine analogs from levofloxacin to isoleucinine analogs |
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