CN104356099A - Homoserine lactone compounds as well as preparation methods and application thereof - Google Patents

Homoserine lactone compounds as well as preparation methods and application thereof Download PDF

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CN104356099A
CN104356099A CN201410662444.1A CN201410662444A CN104356099A CN 104356099 A CN104356099 A CN 104356099A CN 201410662444 A CN201410662444 A CN 201410662444A CN 104356099 A CN104356099 A CN 104356099A
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reaction
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homoserine lactone
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CN104356099B (en
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吴春丽
陈新丽
朱凯
蒋月明
梁永喜
赵峻洁
李杰明
吴冠连
任常忠
李攀
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Zhengzhou University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/32—Oxygen atoms
    • C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form

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  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract

The invention discloses homoserine lactone compounds as well as preparation methods and application thereof, relates to two series of compounds, i.e., N-acyl homoserine lactone and N-acetyl homoserine lactone, as well as preparation methods thereof, belonging to the chemical field of medicines, and in particular relates to a type of novel homoserine lactone compounds as shown in a chemical general formula described in the specification. According to the invention, mother nucleus of homoserine lactone is modified and an acyl side chain and a chalcone compound having large conjugated groups are introduced, thus improve quorum sensing inhibiting activity of the compound. The route preparation method is simple and easy to implement, and yield is high and reaches more than 70%.

Description

Homoserine lactone compounds, its preparation method and application thereof
Technical field
The present invention relates to medical compounds field, be specifically related to novel homoserine lactone compounds, its preparation method and application thereof.
Background technology
Traditional microbiotic be all disturb the synthesis of bacteria cell wall, the important vital process such as synthesis, the generation of protein, the synthesis of DNA of folic acid is target spot, by directly killing or suppressing microbial growth to realize anti-infectious object.Under the selection of this survival pressure, bacterium easily suddenlys change, the resistance of the raw element that can create antagonism.But, fungistat based on the development of bacterial population induction system can not disturb the normal physiological activity of bacterium, quorum sensing just by blocking its detrimental expression and anti-bacteria, thus make it lose pathogenecity, be therefore regarded as the new direction of antibacterials development.
Acyl homoserine lactones (AHL) compounds is the fungistat based on the development of bacterial population induction system; at present; activity research method for acyl homoserine lactones (AHL) compounds does not also have stdn, and the stdn strengthening activity rating contributes to having a better understanding the structure activity relationship of this compounds.Can more clearly understand quorum sensing regulation mechanism from the mode of action between Molecular level study this compounds and acceptor, be conducive to designing active better non-natural AHL analogue further.Although the synthesis and structure for this compounds modifies existing pertinent literature report, further further investigate because the shortcomings such as its complex synthetic route or required chiral raw material are difficult to obtain limit it.Therefore, new synthetic method and structural modification and will become the focus studied from now on from Molecular level study quorum sensing regulation mechanism, colony induction signaling path will become an effective drug target.
In a word, the research of quorum sensing inhibitor has very large potential value, is sensed as target spot and the antiseptic-germicide developed provides potential, development, a more wide medication space for people with bacterial population, is more of value to the health of people.
Summary of the invention
The object of the invention is to provide novel homoserine lactone types of populations to respond to inhibitor, its preparation method, for the screening of current quorum sensing inhibitor clinically provides possibility.
The general structure of homoserine lactone compounds provided by the invention is as follows:
R Wei – H;-Cl;-Br;-Ph;-3,5-dichloriol;-2-F, 4-Br;-3,4-dichlorilo;-3-OCH 3;-2-Cl;-4-F;-2-Br;-4-isopropyl;-4-tertiary butyl.
Be preferably as follows compound:
I type: (S, E)-2-((4-(3-(4-chloro-phenyl-) acryl) phenyl) amine)-N-(2-carbonyl tetrahydrofuran (THF)-3-base) ethanamide
(S, E)-2-((4-cinnyl phenyl) is amino)-N-(2-carbonyl tetrahydrofuran (THF)-3-base) ethanamide
(S, E)-2-((4-(3-(4-bromophenyl-hydrazine) acryl) phenyl) is amino)-N-(2-carbonyl tetrahydrofuran (THF)-3-base) ethanamide
(S, E)-2-((4-(3-([1,1'-biphenyl]-4-base) propionyl) phenyl) is amino)-N-(2-carbonyl tetrahydrofuran (THF)-3-base) ethanamide
(S, E)-2-((4-(3-(3,5-dichlorophenyl) acryl) phenyl) is amino)-N-(2-carbonyl tetrahydrofuran (THF)-3-base) ethanamide
(S, E)-2-((4-(3-(the bromo-2-fluorophenyl of 4-) acryl) phenyl) is amino)-N-(2-carbonyl tetrahydrofuran (THF)-3-base) ethanamide
(S, E)-2-((4-(3-(3,4-dichlorophenyl acryl) phenyl) is amino)-N-(2-carbonyl tetrahydrofuran (THF)-3-base) ethanamide
(S, E)-2-((4-(3-(3-p-methoxy-phenyl) acryl) phenyl) is amino)-N-(2-carbonyl tetrahydrofuran (THF)-3-base) ethanamide
(S, E)-2-((4-(3-(2-chloro-phenyl-) acryl) phenyl) is amino)-N-(2-carbonyl tetrahydrofuran (THF)-3-base) ethanamide
(S, E)-2-((4-(3-(4-fluorophenyl) acryl) phenyl) is amino)-N-(2-carbonyl tetrahydrofuran (THF)-3-base) ethanamide
(S, E)-2-((4-(3-(3-bromophenyl) acryl) phenyl) is amino)-N-(2-carbonyl tetrahydrofuran (THF)-3-base) ethanamide
(S, E)-2-((4-(3-(4-cumyl) acryl) phenyl) is amino)-N-(2-carbonyl tetrahydrofuran (THF)-3-base) ethanamide
(S, E)-2-((4-(3-(4-(tertiary butyl) phenyl) acryl) phenyl) is amino)-N-(2-carbonyl tetrahydrofuran (THF)-3-base) ethanamide
II type: (S, E)-N-(4-(3-(4-chloro-phenyl-) acryl phenyl)-2-((2-carbonyl tetrahydrofuran (THF)-3-base) is amino) ethanamide
(S, E)-N-(4-cinnyl phenyl)-2-((2-carbonyl tetrahydrofuran (THF)-3-base) is amino) ethanamide
(S, E)-N-(4-(3-(4-bromophenyl) acryl) phenyl)-2-((2-carbonyl tetrahydrofuran (THF)-3-base) is amino) ethanamide
(S, E)-N-(4-(3-([1,1'-biphenyl]-4-base) acryl) phenyl)-2-((2-carbonyl tetrahydrofuran (THF)-3-base) is amino) ethanamide
(S, E)-N-(4-(3-(3,5-dichlorophenyl) acryl) phenyl)-2-((2-carbonyl tetrahydrofuran (THF)-3-base) is amino) ethanamide
(S, E)-N-(4-(3-(the bromo-2-fluorophenyl of 4-) acryl) phenyl)-2-((2-carbonyl tetrahydrofuran (THF)-3-base) is amino) ethanamide
(S, E)-N-(4-(3-(3,4-dichlorophenyl) acryl) phenyl)-2-((2-carbonyl tetrahydrofuran (THF)-3-base) is amino) ethanamide
(S, E)-N-(4-(3-(3-p-methoxy-phenyl) acryl) phenyl)-2-((2-carbonyl tetrahydrofuran (THF)-3-base) is amino) ethanamide
(S, E)-N-(4-(3-(2-chloro-phenyl-) acryl) phenyl)-2-((2-carbonyl tetrahydrofuran (THF)-3-base) is amino) ethanamide
(S, E)-N-(4-(3-(4-fluorophenyl) acryl) phenyl)-2-((2-carbonyl tetrahydrofuran (THF)-3-base) is amino) ethanamide
(S, E)-N-(4-(3-(3-bromophenyl) acryl) phenyl)-2-((2-carbonyl tetrahydrofuran (THF)-3-base) is amino) ethanamide
(S, E)-N-(4-(3-(4-cumyl) acryl) phenyl)-2-((2-carbonyl tetrahydrofuran (THF)-3-base) is amino) ethanamide
(S, E)-N-(4-(3-(4-(tertiary butyl) phenyl) acryl) phenyl)-2-((2-carbonyl tetrahydrofuran (THF)-3-base) is amino) ethanamide
The invention provides the preparation method of above-claimed cpd, synthesized by following reaction scheme, general formula I reaction scheme is as follows:
R Wei – H;-Cl;-Br;-Ph;-3,5-dichloriol;-2-F, 4-Br;-3,4-dichlorilo;-3-OCH 3;-2-Cl;-4-F;-2-Br;-4-isopropyl;-4-tertiary butyl.
Under room temperature, METHIONINE 1 and methyl iodide react in the aqueous solution of methyl alcohol, and stirring is spent the night, generate methide 2, be then hydrolyzed in the aqueous solution of sodium bicarbonate, the pH value of the hierarchy of control is at 4-7, subsequently system is proceeded to oil bath and be heated to back flow reaction, TLC tracks to hydrolysis completely.By solution evaporate to dryness through recrystallization, obtain solid chemical compound 3.Compound 3 refluxes in aqueous hydrochloric acid, and TLC detection reaction is complete.System is cooled to room temperature, and through washing, decompression obtains crude product after steaming solvent, and crude product is through recrystallization, and the drying of suction filtration final vacuum obtains key intermediate---homoserine lactone hydrochloride 4.
Homoserine lactone hydrochloride 4 and chloroacetyl chloride are under Schotten-Baumann reaction conditions; namely methylene dichloride is adopted: water as solvent; sodium bicarbonate makes acid binding agent; drip chloroacetyl chloride under low temperature, system is reacted under room temperature, and TLC detection reaction is complete; divide and get dichloromethane layer; pressure reducing and steaming solvent after drying process, vacuum-drying, obtains acylate 5.
The phenyl aldehyde of para-aminoacetophenone and a series of replacement adopts ethanol to make reaction solvent, sodium hydrate solid is added under 0 DEG C of cold condition, stirred at ambient temperature reaction is spent the night, there is Claisen-Schmidt reaction, reaction solution is poured in mixture of ice and water and be stirred to precipitation solid, obtain a series of chalcone compounds 7a-7m.
Make reaction solvent with aprotic solvent DMF, add potassiumiodide and make catalyzer, compound 5 activates at 60 DEG C-70 DEG C, then adds 7a-7m chalcone compound respectively, is warming up to 120 DEG C-140 DEG C reactions subsequently, and nucleophilic substitution reaction occurs.Reaction solution is cooled to room temperature, and through extraction, DMF is removed in eccysis, and after removing ethyl acetate under reduced pressure, silica gel column chromatography is separated, and obtains a series of target compound 8a-8m.
General formula I I reaction scheme is as follows:
R Wei – H;-Cl;-Br;-Ph;-3,5-dichloriol;-2-F, 4-Br;-3,4-dichlorilo;-3-OCH 3;-2-Cl;-4-F;-2-Br;-4-isopropyl;-4-tertiary butyl.
Under room temperature, METHIONINE 1 and methyl iodide react in the aqueous solution of methyl alcohol, and stirring is spent the night, generate methide 2, be then hydrolyzed in the aqueous solution of sodium bicarbonate, the pH value of the hierarchy of control is at 4-7, subsequently system is proceeded to oil bath and be heated to back flow reaction, TLC tracks to hydrolysis completely.By solution evaporate to dryness, through recrystallization, obtain compound 3.Compound 3 refluxes in aqueous hydrochloric acid, and TLC detection reaction is complete.System is cooled to room temperature, and through washing, decompression obtains crude product after steaming solvent, and crude product is through recrystallization, and suction filtration final vacuum is dry, obtains key intermediate---homoserine lactone hydrochloride 4.
The phenyl aldehyde of para-aminoacetophenone and a series of replacement adopts ethanol to make reaction solvent, sodium hydrate solid is added under 0 DEG C of cold condition, stirred at ambient temperature reaction is spent the night, there is Claisen-Schmidt reaction, reaction solution is poured in mixture of ice and water and be stirred to precipitation solid, obtain a series of chalcone compounds 7a-7m.
With cinnamophenone series compound 7a-7m for raw material, acetone is solvent, and salt of wormwood makes catalyzer, chloroacetyl chloride is added under low temperature, after return stirring reaction, reaction solution is poured in mixture of ice and water and be stirred to precipitation solid, after suction filtration, drying treatment, obtain alpha-chloro acid amides chalcone derivative 9a-9m.
With homoserine lactone hydrochloride (4) for raw material, similar Williamson is adopted to synthesize the method for ether, react from different substrate alpha-chloro acid amides chalcone derivative (9a-9m) respectively, namely with acetonitrile as solvents, after stirring and dissolving, add acid binding agent K 2cO 3, catalyzer KI, is heated to back flow reaction about under oil bath.After completion of the reaction, suction filtration removing K 2cO 3, after removing acetonitrile under reduced pressure, silica gel column chromatography is separated, and obtains N-acetylhomoserine lactone derivatives 10a-10m.
Advantage of the present invention and innovative point are: 1, homoserine lactone parent nucleus and the activity of acyl side-chain to this compounds most important, meanwhile, the introducing of aromatic nucleus also can improve the quorum sensing inhibit activities of this compounds.Therefore; under the prerequisite remaining homoserine lactone parent nucleus; attempt to introduce at the acyl side-chain end of compound to have the chalcone compounds of large conjugation group, simultaneously also because cinnamophenone itself is a good active group, it has the biological activity such as antibacterial, antitumor widely.2, route preparation method is simple, can be that raw material is prepared into key intermediate with METHIONINE.And yield is high, reach more than 70%.
Embodiment
Below in conjunction with embodiment, the present invention is described further.
Embodiment 1:
(S, E)-2-((4-(3-(4-chloro-phenyl-) acryl) phenyl) amine)-N-(2-carbonyl tetrahydrofuran (THF)-3-base) ethanamide
10.12g (67.7mmol) METHIONINE is added in the mixing solutions of 200mL water and 30mL methyl alcohol, after mixing, start slowly to drip methyl iodide in confined conditions and be about 5.1mL (1.2eq), drip and finish, stirred at ambient temperature reaction is spent the night, until system becomes clear shape.After concentrating under reduced pressure, in system, drip NaHCO 3the aqueous solution (5.69g is dissolved in 80mL water), drips and finishes, system is proceeded to oil bath and be heated to back flow reaction about 6 hours, after TLC detection reaction is complete, remove solvent under reduced pressure, obtain jonquilleous oily matter, acetone and ethanol (V:V=1:9) recrystallization obtain a large amount of white solid.White solid is dissolved in 100mL hydrochloric acid (6molL -1) in solution, reflux is about 10h, and system is burgundy, and TLC detection reaction is complete.System is cooled to room temperature, use respectively ether and washed with dichloromethane closely colourless to water layer, decompression steams with second alcohol and water recrystallization after solvent, and suction filtration final vacuum is dry, obtains white solid homoserine lactone hydrochloride 6.89g, yield 74%.
1.40g (0.01mol) homoserine lactone hydrochloride is dissolved in 15mL water and 15mL methylene dichloride mixed solvent, adds 2.52g NaHCO 3(0.03mol) stirring and dissolving is clarified to system.Slowly chloroacetyl chloride 920 μ L (0.012mol) is dripped under room temperature, after reacting about 6h, TLC detection reaction is complete, divide and get dichloromethane layer, pressure reducing and steaming solvent after anhydrous sodium sulfate drying process, vacuum-drying, obtains the chloro-N-of white solid (S)-2-(2-carbonyl tetrahydrofuran (THF)-3-base) ethanamide 1.3g, yield 72%.
In 100mL round-bottomed flask, add 0.27g (2mmol) para-aminoacetophenone, be dissolved in 25mL ethanol, add 0.52g (2.02mmol) 4-chloro-benzaldehyde and 0.12g sodium hydroxide successively, room temperature for overnight.Next day, reaction solution is poured in mixture of ice and water to be stirred to and separate out a large amount of yellow solid i.e. (E)-1-(4-aminophenyl)-3-(4-chloro-phenyl-) third-2-alkene-1-ketone 0.38g, productive rate 74%.
In 25mL round-bottomed flask, add the chloro-N-of 96mg (0.54mmol) (S)-2-(2-carbonyl tetrahydrofuran (THF)-3-base) ethanamide and potassiumiodide 270mg, add 10mLDMF stirring and dissolving, under 60 DEG C of oil baths, react 2h.Then, 139mg (0.54mmol) (E)-1-(4-aminophenyl)-3-(4-chloro-phenyl-) third-2-alkene-1-ketone is added in reaction system, be heated to 120 DEG C and react about 6h, reaction solution is cooled to room temperature, extraction into ethyl acetate, washing removing DMF, after removing ethyl acetate under reduced pressure, silica gel column chromatography is separated (eluent: acetone/sherwood oil=2/3), obtains yellow solid and target compound 157mg, productive rate 73%.
Embodiment 2:
(S, E)-N-(4-(3-(4-chloro-phenyl-) acryl phenyl)-2-((2-carbonyl tetrahydrofuran (THF)-3-base) is amino) ethanamide
10.12g (67.7mmol) METHIONINE is added in the mixing solutions of 200mL water and 30mL methyl alcohol, after mixing, start slowly to drip methyl iodide in confined conditions and be about 5.1mL (1.2eq), drip and finish, stirred at ambient temperature reaction is spent the night, until system becomes clear shape.After concentrating under reduced pressure, in system, drip NaHCO 3the aqueous solution (5.69g is dissolved in 80mL water), drips and finishes, system is proceeded to oil bath and be heated to back flow reaction about 6 hours, after TLC detection reaction is complete, remove solvent under reduced pressure, obtain jonquilleous oily matter, acetone and ethanol (V:V=1:9) recrystallization obtain a large amount of white solid.White solid is dissolved in 100mL hydrochloric acid (6molL -1) in solution, reflux is about 10h, and system is burgundy, and TLC detection reaction is complete.System is cooled to room temperature, use respectively ether and washed with dichloromethane closely colourless to water layer, decompression steams with second alcohol and water recrystallization after solvent, and suction filtration final vacuum is dry, obtains white solid homoserine lactone hydrochloride 6.89g, yield 74%.
In 100mL round-bottomed flask, add 0.27g (2mmol) para-aminoacetophenone, be dissolved in 25mL ethanol, add 0.52g (2.02mmol) 4-chloro-benzaldehyde and 0.12g sodium hydroxide successively, room temperature for overnight.Next day, reaction solution is poured in mixture of ice and water to be stirred to and separate out a large amount of yellow solid i.e. (E)-1-(4-aminophenyl-3-(4-chloro-phenyl-) third-2-alkene-1-ketone 0.38g, productive rate 74%.
In 50ml round-bottomed flask, add 0.51g (E)-1-(4-aminophenyl)-3-(4-chloro-phenyl-) third-2-alkene-1-ketone, be dissolved in 25ml acetone, add 332mg K successively 2cO 3(1.2eq) He 180 μ l chloroacetyl chlorides (1.2eq); After r.t stirs 3h; reaction solution is poured in mixture of ice and water to be stirred to and separate out a large amount of solid; suction filtration; washing filter cake; vacuum-drying obtains the chloro-N-of 0.53g (E)-2-(4-(3-(4-chloro-phenyl-) acryl) phenyl) ethanamide solid, and productive rate is 70%.
The chloro-N-of 150mg (0.45mmol) (E)-2-(4-(3-(4-chloro-phenyl-) acryl) phenyl) ethanamide and 62mg (0.45mmol) homoserine lactone hydrochloride is added in 25mL round-bottomed flask; add 10mL acetonitrile stirring and dissolving, then add acid binding agent K 2cO 3187mg (1.35mmol), catalyzer KI 15mg (0.09mmol), be heated to back flow reaction under oil bath and be about 6h.It is complete that TLC follows the tracks of reaction, suction filtration removing K 2cO 3, after removing acetonitrile under reduced pressure, silica gel column chromatography is separated (eluent: acetone/sherwood oil=1/2), obtains yellow solid, i.e. target compound 118mg, productive rate 66%.
Chemical structure and the nuclear magnetic data of employing aforesaid method synthesis the compounds of this invention are as follows:
Compound 8a
1H NMR(DMSO-d 6,400MHz):δ8.61-8.59(d,J＝8.0Hz,1H,-CO- NH),8.02-8.00(d,J＝8.0Hz,2H,Ar-H),7.96-7.89(t,3H,-CO-HC＝ CH-and Ar-H),7.64-7.61(d,J＝12.0Hz,1H,-CO- HC＝CH-),7.52-7.50(d,J＝8.0Hz,2H,Ar-H),7.08-7.06(t,J＝4.0Hz,1H,Ar- NH),6.66-6.64(d,J＝8.0Hz,2H,Ar-H),4.66-4.59(dd,J＝20.0Hz,J＝8.0Hz,1H,-O-CH 2-),4.37-4.32(t,J＝8.0Hz,1H,- CH-NH),4.22-4.18(dd,J＝20.0Hz,J＝8.0Hz,1H,-O-CH 2-),3.85-3.84(d,J＝4.0Hz,2H,-HN- CH 2-),2.41-2.35(m,1H,-O-CH 2- CH 2-CH),2.24-2.14(m,1H,-O-CH 2- CH 2-CH)； 13C NMR(DMSO,101MHz)δ186.42,175.64,170.15,153.30,140.72,134.95,134.55,131.36,130.76,129.34,126.49,123.53,112.01,65.75,48.39,46.33,28.52.
Compound 8b
1H NMR(DMSO-d 6,400MHz):δ8.59-8.57(d,J＝8.0Hz,1H,-CO- NH),8.02-8.00(d,J＝8.0Hz,2H,Ar-H),7.93-7.89(d,J＝16.0Hz,1H,-CO-HC＝ CH-),7.87-7.85(m,2H,Ar-H),7.67-7.63(d,J＝16.0Hz,1H,-CO- HC＝CH-),7.47-7.43(m,3H,Ar-H),7.02(brs,1H,Ar- NH),6.67-6.65(d,J＝8.0Hz,2H,Ar-H),4.66-4.59(dd,J＝20.0Hz,J＝8.0Hz,1H,-O-CH 2-),4.35-4.33(t,J＝8.0Hz,1H,- CH-NH),4.22-4.19(dd,J＝20.0Hz,J＝8.0Hz,1H,-O-CH 2-),3.85(s,2H,-HN- CH 2-),2.41-2.36(m,1H,-O-CH 2- CH 2-CH),2.25-2.14(m,1H,-O-CH 2- CH 2-CH)； 13C NMR(DMSO,101MHz)δ186.56,175.59,170.13,153.22,142.15,135.56,131.27,130.51,129.31,129.02,126.60,122.77,112.01,65.74,48.39,46.37,31.15,28.54.
Compound 8c
1H NMR(DMSO-d 6,400MHz):δ8.61-8.59(d,J＝8.0Hz,1H,-CO- NH),8.02-8.00(d,J＝8.0Hz,1H,Ar-H),7.98-7.94(d,J＝16.0Hz,1H,-CO-HC＝ CH-),7.84-7.82(d,J＝8.0Hz,1H,Ar-H),7.75-7.73(d,J＝8.0Hz,1H,Ar-H),7.66-7.59(m,3H,Ar-H and-CO- HC＝CH-),7.07(brs,1H,Ar- NH),6.66-6.64(d,J＝8.0Hz,1H,Ar-H),6.60-6.58(d,J＝8.0Hz,1H,Ar-H),4.64-4.57(dd,J＝20.0Hz,J＝8.0Hz,1H,-O-CH 2-),4.36-4.32(t,J＝8.0Hz,1H,- CH-NH),4.22-4.18(dd,J＝20.0Hz,J＝8.0Hz,1H,-O-CH 2-),3.85-3.80(m,2H,-HN- CH 2-),2.39-2.35(m,1H,-O-CH 2- CH 2-CH),2.25-2.17(m,1H,-O-CH 2- CH 2-CH)； 13C NMR(DMSO,101MHz)δ195.72,186.40,175.63,170.20,170.13,153.32,153.00,140.80,134.90,132.26,131.36,130.99,130.74,126.48,126.09,123.79,123.60,112.00,111.72,65.74,48.38,46.34,28.52,26.43.
Compound 8d
1H NMR(DMSO-d 6,400MHz):δ8.60-8.58(d,J＝8.0Hz,1H,-CO- NH),8.04-8.02(d,J＝8.0Hz,2H,Ar-H),7.98-7.95(t,3H,-CO-HC＝ CH-and Ar-H),7.77-7.74(m,4H,Ar-H),7.71-7.67(d,1H,J＝16.0Hz,-CO- HC＝CH-),7.52-7.48(t,J＝8.0Hz,2H,Ar-H),7.42-7.40(d,J＝8.0Hz,1H,Ar-H),7.06-7.03(t,1H,Ar- NH),6.67-6.65(d,J＝8.0Hz,2H,Ar-H),4.67-4.60(dd,J＝20.0Hz,J＝8.0Hz,1H,-O-CH 2-),4.37-4.33(t,J＝8.0Hz,1H,- CH-NH),4.25-4.19(dd,J＝20.0Hz,J＝8.0Hz,1H,-O-CH 2-),3.86-3.85(d,J＝4.0Hz,2H,-HN- CH 2-),2.41-2.36(m,1H,-O-CH 2- CH 2-CH),2.22-2.17(m,1H,-O-CH 2- CH 2-CH)； 13C NMR(DMSO,101MHz)δ186.53,175.64,170.17,153.24,142.01,141.72,139.77,134.73,131.32,129.74,129.51,127.50,127.17,126.65,122.70,112.01,65.75,48.40,46.36,28.53.
Compound 8e
1H NMR(DMSO-d 6,400MHz):δ8.60-8.58(d,J＝8.0Hz,1H,-CO- NH),8.09-8.02(m,5H,-CO-HC＝ CH-and Ar-H),7.93(s,1H,Ar-H),7.56-7.55(d,1H,Ar-H),7.60-7.56(d,J＝16.0Hz,1H,-CO- HC＝CH-),7.11-7.08(t,1H,Ar- NH),6.66-6.64(d,J＝8.0Hz,2H,Ar-H),4.66-4.59(dd,J＝20.0Hz,J＝8.0Hz,1H,-O-CH 2-),4.37-4.33(t,J＝8.0Hz,1H,- CH-NH),4.23-4.18(dd,J＝20.0Hz,J＝8.0Hz,1H,-O-CH 2-),3.86-3.85(d,J＝4.0Hz,2H,-HN- CH 2-),2.42-2.35(m,1H,-O-CH 2- CH 2-CH),2.24-2.14(m,1H,-O-CH 2- CH 2-CH)； 13CNMR(DMSO,101MHz)δ186.17,175.60,170.09,153.47,139.41,139.06,135.03,131.56,129.33,127.45,126.34,125.81,112.01,65.74,48.40,46.32,28.54.
Compound 8f
1H NMR(DMSO-d 6,400MHz):δ8.59-8.57(d,J＝8.0Hz,1H,-CO- NH),8.10-8.08(d,J＝8.0Hz,1H,Ar-H),8.01-7.97(3H,CO-HC＝ CH-and Ar-H),7.70-7.66(2H,CO-HC＝ CH-and Ar-H),7.53-7.51(d,J＝8.0Hz,1H,Ar-H),7.10-7.07(brs,1H,Ar- NH),6.67-6.65(d,J＝8.0Hz,2H,Ar-H),4.66-4.59(dd,J＝20.0Hz,J＝8.0Hz,1H,-O-CH 2-),4.37-4.32(t,J＝8.0Hz,1H,- CH-NH),4.25-4.19(dd,J＝20.0Hz,J＝8.0Hz,1H,-O-CH 2-),3.86-3.85(d,J＝4.0Hz,2H,-HN- CH 2-),2.42-2.36(m,1H,-O-CH 2- CH 2-CH),2.22-2.17(m,1H,-O-CH 2- CH 2-CH)； 13C NMR(DMSO,101MHz)δ186.10,175.61,170.09,159.62,153.46,132.22,131.43,130.70,128.59,126.25,125.55,124.06,123.96,122.76,122.65,120.02,119.77,112.07,65.75,48.40,46.32,28.54,22.81.
Compound 8g
1H NMR(DMSO-d 6,400MHz):δ8.59-8.57(d,J＝8.0Hz,1H,-CO- NH),8.26(s,1H,Ar-H),8.04-8.00(d,3H,CO-HC＝ CH-and Ar-H),7.86-7.84(d,J＝8.0Hz,1H,Ar-H),7.71-6.99(d,J＝8.0Hz,1H,Ar-H),7.62-7.58(d,J＝16.0Hz,1H,-CO- HC＝CH-),7.07(brs,1H,Ar- NH),6.66-6.64(d,J＝8.0Hz,2H,Ar-H),4.66-4.59(dd,J＝20.0Hz,J＝8.0Hz,1H,-O-CH 2-),4.37-4.33(t,J＝8.0Hz,1H,- CH-NH),4.25-4.18(dd,J＝20.0Hz,J＝8.0Hz,1H,-O-CH 2-),3.86-3.85(d,J＝4.0Hz,2H,-HN- CH 2-),2.42-2.36(m,1H,-O-CH 2- CH 2-CH),2.22-2.17(m,1H,-O-CH 2- CH 2-CH)； 13C NMR(DMSO,101MHz)δ186.23,175.61,170.10,162.78,153.41,139.40,136.53,132.57,132.22,131.48,131.37,130.32,129.37,126.39,124.93,112.00,65.74,65.70,48.39,48.35,46.32,36.25,31.23,28.76,28.54,22.82.
Compound 8h
1H NMR(DMSO-d 6,400MHz):δ8.59-8.57(d,J＝8.0Hz,1H,-CO- NH),8.03-8.01(d,J＝8.0Hz,2H,Ar-H),7.93-7.89(d,J＝16.0Hz,1H,-CO-HC＝ CH-),7.63-7.59(d,J＝16.0Hz,1H,-CO- HC＝CH-),7.45(s,1H,Ar-H),7.41-7.33(m,2H,Ar-H),7.01-6.99(d,J＝8.0Hz,1H,Ar- NH),6.66-6.64(d,J＝8.0Hz,2H,Ar-H),4.66-4.59(dd,J＝20.0Hz,J＝8.0Hz,1H,-O-CH 2-),4.37-4.33(t,J＝8.0Hz,1H,- CH-NH),4.25-4.18(dd,J＝20.0Hz,J＝8.0Hz,1H,-O-CH 2-),3.84(s,2H,-HN- CH 2-),3.83(s,3H,-O CH 3-),2.42-2.35(m,1H,-O-CH 2- CH 2-CH),2.25-2.14(m,1H,-O-CH 2- CH 2-CH)； 13CNMR(DMSO,101MHz)δ186.57,175.61,170.15,160.10,153.24,142.18,136.99,131.33,130.33,126.59,123.03,121.84,116.62,113.65,112.00,65.75,55.75,48.39,46.37,28.54.
Compound 8i
1H NMR(DMSO-d 6,400MHz):δ8.60-8.58(d,J＝8.0Hz,1H,-CO- NH),8.21-8.19(d,1H,-CO-HC＝ CH-),8.03-8.01(d,J＝8.0Hz,2H,Ar-H),7.96(s,2H,Ar-H),7.56-7.55(d,1H,Ar-H),7.46-7.44(d,2H,-CO- HC＝CH-),7.09(brs,1H,Ar- NH),6.67-6.65(d,J＝8.0Hz,2H,Ar-H),6.66-6.64(d,J＝8.0Hz,2H,Ar-H),4.66-4.59(dd,J＝20.0Hz,J＝8.0Hz,1H,-O-CH 2-),4.37-4.33(t,J＝8.0Hz,1H,- CH-NH),4.25-4.18(dd,J＝20.0Hz,J＝8.0Hz,1H,-O-CH 2-),3.85(s,2H,-HN- CH 2-),2.42-2.35(m,1H,-O-CH 2- CH 2-CH),2.25-2.14(m,1H,-O-CH 2- CH 2-CH)； 13C NMR(DMSO,101MHz)δ186.23,175.62,170.09,153.45,136.83,134.52,133.18,131.48,130.42,128.88,128.10,126.29,125.58,112.05,65.75,48.40,46.32,31.17,28.54.
Compound 8j
1H NMR(DMSO-d 6,400MHz):δ8.60-8.58(d,J＝8.0Hz,1H,-CO- NH),8.02-8.00(d,J＝8.0Hz,2H,Ar-H),7.96-7.92(d,J＝8.0Hz,2H,Ar-H),7.90-7.86(d,J＝16.0Hz,1H,-CO-HC＝ CH-),7.66-7.62(d,J＝16.0Hz,1H,-CO- HC＝CH-),7.31-7.26(t,J＝8.0Hz,2H,Ar-H),7.04(brs,1H,Ar- NH),6.66-6.64(d,J＝8.0Hz,2H,Ar-H),4.66-4.59(dd,J＝20.0Hz,J＝8.0Hz,1H,-O-CH 2-),4.37-4.32(t,J＝8.0Hz,1H,- CH-NH),4.25-4.18(dd,J＝20.0Hz,J＝8.0Hz,1H,-O-CH 2-),3.85(s,2H,-HN- CH 2-),2.42-2.35(m,1H,-O-CH 2- CH 2-CH),2.25-2.14(m,1H,-O-CH 2- CH 2-CH)； 13C NMR(DMSO,101MHz)δ186.51,175.63,170.17,164.79,162.32,153.23,140.95,132.25,132.22,131.36,131.30,131.28,126.57,122.67,116.40,116.19,112.00,65.76,48.40,46.36,31.16,28.52.
Compound 8k
1H NMR(DMSO-d 6,400MHz):δ8.60-8.58(d,J＝8.0Hz,1H,-CO- NH),8.20(s,1H,Ar-H),8.05-8.03(d,J＝8.0Hz,2H,Ar-H),8.02-7.98(d,J＝16.0Hz,1H,-CO-HC＝ CH-),7.84-7.82(d,J＝8.0Hz,1H,Ar-H),7.62-7.58(m,2H,Ar-H and-CO- HC＝CH-),7.42-7.38(t,J＝8.0Hz,1H,Ar-H),7.09-7.07(t,J＝4.0Hz,1H,Ar- NH),6.66-6.64(d,J＝8.0Hz,2H,Ar-H),4.66-4.59(dd,J＝20.0Hz,J＝8.0Hz,1H,-O-CH 2-),4.37-4.33(t,J＝8.0Hz,1H,- CH-NH),4.23-4.18(dd,J＝20.0Hz,J＝8.0Hz,1H,-O-CH 2-),3.86-3.84(d,J＝8.0Hz,2H,-HN- CH 2-),2.42-2.35(m,1H,-O-CH 2- CH 2-CH),2.24-2.14(m,1H,-O-CH 2- CH 2-CH)； 13C NMR(DMSO,101MHz)δ186.33,175.63,170.12,153.36,140.45,138.13,132.98,131.46,131.36,130.97,128.49,126.44,124.30,122.85,111.99,65.74,48.39,46.33,28.53.
Compound 8l
1H NMR(DMSO-d 6,400MHz):δ8.59-8.57(d,J＝8.0Hz,1H,-CO- NH),8.01-7.99(d,J＝8.0Hz,2H,Ar-H),7.87-7.83(d,J＝16.0Hz,1H,-CO-HC＝ CH-),7.78-7.76(d,J＝8.0Hz,2H,Ar-H),7.64-7.61(d,J＝16.0Hz,1H,-CO- HC＝CH-),7.33-7.31(d,J＝8.0Hz,2H,Ar-H),7.02(s,1H,Ar- NH),6.67-6.65(d,J＝8.0Hz,2H,Ar-H),4.67-4.60(dd,J＝20.0Hz,J＝8.0Hz,1H,-O-CH 2-),4.37-4.33(t,J＝8.0Hz,1H,- CH-NH),4.25-4.19(dd,J＝20.0Hz,J＝8.0Hz,1H,-O-CH 2-),3.85-3.84(d,J＝4.0Hz,2H,-HN- CH 2-),2.42-2.36(m,1H,-O-CH 2- CH 2-CH),2.25-2.15(m,1H,-O-CH 2- CH 2-CH),1.3(s,1H,- CH(CH 3) 2),1.23-1.21(d,J＝8.0Hz,6H,-CH (CH 3 ) 2)； 13C NMR(DMSO,101MHz)δ186.61,175.62,170.18,153.16,151.26,142.23,133.27,131.22,129.16,127.30,126.71,121.81,112.01,65.74,48.39,46.39,33.86,31.40,31.15,28.54,24.12.
Compound 8m
1H NMR(DMSO-d 6,400MHz):δ8.59-8.57(d,J＝8.0Hz,1H,-CO- NH),8.01-7.99(d,J＝8.0Hz,2H,Ar-H),7.87-7.83(d,J＝16.0Hz,1H,-CO-HC＝ CH-),7.78-7.76(d,J＝8.0Hz,2H,Ar-H),7.64-7.60(d,J＝16.0Hz,1H,-CO- HC＝CH-),7.47-7.45(d,J＝8.0Hz,1H,Ar-H),7.33-7.31(d,J＝8.0Hz,1H,Ar-H),7.04-7.01(t,J＝4.0Hz,1H,Ar- NH),6.67-6.64(d,J＝12.0Hz,2H,Ar-H),4.67-4.60(dd,J＝20.0Hz,J＝8.0Hz,1H,-O-CH 2-),4.37-4.33(t,J＝8.0Hz,1H,- CH-NH),4.23-4.18(dd,J＝20.0Hz,J＝8.0Hz,1H,-O-CH 2-),3.85-3.84(d,J＝4.0Hz,2H,-HN- CH 2-),2.42-2.35(m,1H,-O-CH 2- CH 2-CH),2.25-2.14(m,1H,-O-CH 2- CH 2-CH),1.30(s,4H,-C (CH 3 ) 3),1.23-1.21(d,J＝8.0Hz,5H,-C (CH 3 ) 3)； 13C NMR(DMSO,101MHz)δ186.63,175.62,170.18,153.16,151.27,142.24,133.26,132.86,131.22,129.16,128.88,127.30,126.71,126.13,121.81,112.01,65.75,48.39,46.39,35.06,33.86,31.40,28.54,24.12.
Compound 10a
1H NMR(DMSO-d 6,400MHz):δ10.31(s,1H,Ar-NH),8.19-8.17(d,J＝8.0Hz,2H,Ar-H),8.01-7.97(d,J＝16.0Hz,1H,-HC＝CH-),7.95-7.93(d,J＝8.0Hz,2H,Ar-H),7.85-7.82(d,J＝12.0Hz,2H,Ar-H),7.74-7.70(d,J＝16.0Hz,1H,-HC＝CH-),7.54-7.52(d,J＝8.0Hz,2H,Ar-H),4.37-4.32(td,1H,-O-CH 2-),4.21-4.16(td,1H,-O-CH 2-),3.71-3.66(t,1H,- CH-NH),3.53(s,2H,-HN- CH 2-),2.96(brs,1H,- NH-CH 2),2.48-2.43(m,1H,-O-CH 2- CH 2-CH),2.10-2.00(m,1H,-O-CH 2- CH 2-CH)； 13C NMR(DMSO-d 6,101MHz)δ187.88,177.97,171.08,143.67,142.36,135.43,134.23,132.73,130.97,130.45,129.40,123.71,119.00,66.04,56.98,50.94,29.97.
Compound 10b
1H NMR(CDCl 3,400MHz):δ9.54(s,1H,Ar-NH),8.05-8.03(d,J＝8.0Hz,2H,Ar-H),7.83-7.77(m,3H,- HC＝CH-and Ar-H),7.67-7.65(d,J＝8.0Hz,2H,Ar-H),7.57-7.53(d,J＝16.0Hz,1H,-HC＝CH-),7.44-7.42(m,3H,Ar-H),4.47-4.42(td,1H,-O-CH 2-),4.27-4.20(td,1H,-O-CH 2-),3.68-3.58(m,3H,- CH-NH and-HN- CH 2-),2.66-2.59(m,1H,-O-CH 2- CH 2-CH),2.38(brs,1H,- NH-CH 2),2.18-2.13(m,1H,-O-CH 2- CH 2-CH)； 13C NMR(CDCl 3,101MHz)δ189.01,176.96,169.64,144.56,141.68,134.91,133.88,130.53,129.98,128.98,128.47,121.76,118.98,119.00,65.52,57.18,51.74,30.20.
Compound 10c
1H NMR(CDCl 3,400MHz):δ9.54(s,1H,Ar-NH),8.05-8.03(d,J＝8.0Hz,2H,Ar-H),7.83-7.77(m,3H,- HC＝CH-and Ar-H),7.67-7.65(d,J＝8.0Hz,2H,Ar-H),7.57-7.53(d,J＝16.0Hz,1H,-HC＝CH-),7.44-7.42(m,3H,Ar-H),4.47-4.42(td,1H,-O-CH 2-),4.27-4.20(td,1H,-O-CH 2-),3.68-3.58(m,3H,- CH-NH and-HN- CH 2-),2.66-2.59(m,1H,-O-CH 2- CH 2-CH),2.38(brs,1H,- NH-CH 2),2.18-2.13(m,1H,-O-CH 2- CH 2-CH)； 13C NMR(CDCl 3,101MHz)δ189.01,176.96,169.64,144.56,141.68,134.91,133.88,130.53,129.98,128.98,128.47,121.76,118.98,119.00,65.52,57.18,51.74,30.20.
Compound 10d
1H NMR(CDCl 3,400MHz):δ9.53(s,1H,Ar-NH),8.09-8.07(d,J＝8.0Hz,2H,Ar-H),7.90-7.78(d,J＝16.0Hz,1H,- HC＝CH),7.82-7.80(d,J＝8.0Hz,2H,Ar-H),7.76-7.74(d,J＝8.0Hz,2H,Ar-H),7.69-7.65(m,4H,Ar),7.62-7.58(d,J＝16.0Hz,1H,- HC＝CH),7.51-7.47(t,J＝8.0Hz,2H,Ar-H),7.42-7.41(d,J＝8.0Hz,1H,Ar-H),4.49-4.45(td,1H,-O-CH 2-),4.29-4.22(td,1H,-O-CH 2-),3.72-3.58(m,3H,- CH-NH and-HN- CH 2-),2.68-2.62(m,1H,-O-CH 2- CH 2-CH),2.63(brs,1H,- NH-CH 2),2.18-2.12(m,1H,-O-CH 2- CH 2-CH)； 13C NMR(CDCl 3,101MHz)δ188.01,172.16,143.53,143.35,142.43,139.71,134.42,132.96,130.26,129.99,129.51,129.36,129.31,128.46,127.54,127.21,127.02,126.88,122.39,119.40,62.49.
Compound 10e
1H NMR(CDCl 3,400MHz):δ9.57(s,1H,Ar-NH),8.20-8.16(d,J＝16.0Hz,1H,-HC＝CH-),8.04-8.02(d,J＝8.0Hz,2H,Ar-H),7.80-7.78(d,J＝8.0Hz,2H,Ar-H),7.52-7.48(d,J＝16.0Hz,1H,-HC＝CH-),7.46-7.43(m,1H,Ar-H),7.35-7.32(m,2H,Ar-H),4.47-4.43(td,1H,-O-CH 2-),4.26-4.21(td,1H,-O-CH 2-),3.70-3.49(3H,- CH-NH and-HN- CH 2-),2.67-2.20(brs,1H,- NH-CH 2),2.19-2.18(m,2H,-O-CH 2- CH 2-CH)； 13C NMR(CDCl 3,101MHz)δ188.85,177.00,169.68,141.83,140.28,135.45,133.57,133.25,131.19,130.29,130.11,127.81,127.13,124.47,118.98,65.54,57.20,51.74,30.20.
Compound 10f
1H NMR(CDCl 3,400MHz):δ9.56(s,1H,Ar-NH),8.05-8.02(d,J＝12.0Hz,2H,Ar-H),7.84-7.78(3H,- HC＝CH-and Ar-H),7.66-7.63(d,J＝12.0Hz,2H,-HC＝CH-),7.55-7.51(t,J＝8.0Hz,1H,Ar-H),7.37-7.33(t,J＝8.0Hz,2H,Ar-H),4.48-4.44(td,1H,-O-CH 2-),4.28-4.22(td,1H,-O-CH 2-),3.71-3.54(m,3H,- CH-NH and-HN- CH 2-),2.68-2.61(m,1H,-O-CH 2- CH 2-CH),2.36(brs,1H,- NH-CH 2),2.19-2.13(m,1H,-O-CH 2- CH 2-CH)； 13C NMR(CDCl 3,101MHz)δ188.57,176.92,169.59,162.55,159.98,141.87,135.98,133.51,130.61,130.58,130.07,128.05,128.01,124.69,124.61,124.49,122.27,122.15,120.14,119.89,118.99,65.50,57.23,51.78,30.23.
Compound 10g
1H NMR(DMSO-d 6,400MHz):δ10.42(s,1H,Ar-NH),8.29(1H,Ar-H),8.21-8.19(d,J＝8.0Hz,2H,Ar-H),8.09-8.05(d,J＝16.0Hz,1H,- HC＝CH),7.89-7.84(3H,Ar-H),7.73-7.71(d,J＝8.0Hz,1H,Ar-H),7.71-7.67(d,J＝16.0Hz,1H,-HC＝CH-),4.34-4.32(td,1H,-O-CH 2-),4.21-4.14(td,1H,-O-CH 2-),3.70-3.66(t,J＝8.0Hz,1H,- CH-NH),3.53(s,2H,-HN- CH 2-),2.96(brs,1H,- NH-CH 2),2.48-2.45(m,1H,-O-CH 2- CH 2-CH),2.10-2.02(m,1H,-O-CH 2- CH 2-CH)； 13C NMR(CDCl 3,101MHz)δ187.75,177.95,171.14,143.87,141.01,136.18,133.04,132.55,132.28,131.44,130.55,129.58,124.52,118.99,66.04,55.94,50.94,29.99.
Compound 10h
1H NMR(CDCl 3,400MHz):δ9.58(s,1H,Ar-NH),8.29(1H,Ar-H),8.02-8.00(d,J＝8.0Hz,2H,Ar-H),7.78-7.73(3H,- HC＝CH and Ar-H),7.53-7.49(d,J＝16.0Hz,1H,- HC＝CH),7.35-7.28(1H,Ar-H),7.24-7.22(d,J＝8.0Hz,1H,Ar-H)7.15(1H,Ar-H),6.97-6.94(dd,J＝8Hz,J＝4Hz,1H,Ar-H),4.43-4.39(td,1H,-O-CH 2-),4.24-4.18(td,1H,-O-CH 2-),3.85(s,3H,-OCH 3),3.66-3.56(m,3H,- CH-NH and-HN- CH 2-),2.63-2.57(m,1H,-O-CH 2- CH 2-CH),2.29(brs,1H,- NH-CH 2),2.14-2.08(m,1H,-O-CH 2- CH 2-CH)； 13C NMR(CDCl 3,101MHz)δ189.00,177.12,169.81,159.92,144.45,141.79,136.26,133.75,129.96,122.03,121.10,118.99,116.29,113.45,65.58,57.11,55.37,51.65,30.14.
Compound 10i
1H NMR(CDCl 3,400MHz):δ9.58(s,1H,Ar-NH),8.05-8.03(d,J＝8.0Hz,2H,Ar-H),7.81-7.78(d,J＝12.0Hz,2H,Ar-H),7.68-7.64(d,J＝12.0Hz,1H,-HC＝CH-),7.56-7.51(3H,-HC＝CH-and Ar-H),7.39(1H,Ar-H),4.49-4.44(td,1H,-O-CH 2-),4.28-4.22(td,1H,-O-CH 2-),3.71-3.66(m,1H,- CH-NH)3.50(s,2H,-HN- CH 2-),2.68-2.61(m,1H,-O-CH 2- CH 2-CH),2.34(brs,1H,- NH-CH 2),2.17-2.14(m,1H,-O-CH 2- CH 2-CH)； 13C NMR(CDCl 3,101MHz)δ188.07,176.96,169.66,142.03,141.22,137.94,135.59,133.30,130.09,129.94,126.51,124.04,119.03,65.52,57.23,51.77,50.85,30.23
Compound 10j
1H NMR(DMSO-d 6,400MHz):δ10.34(s,1H,Ar-NH),8.18-8.16(d,J＝8.0Hz,2H,Ar-H),8.00-7.96(dd,J＝8.0Hz,J＝4.0Hz,2H,Ar-H),7.95-7.91(d,J＝16.0Hz,1H,- HC＝CH-),7.85-7.83(d,J＝8.0Hz,2H,Ar-H),7.75-7.71(d,J＝16.0Hz,1H,-HC＝CH-),7.33-7.29(t,J＝8.0Hz,2H,Ar-H),4.34-4.32(td,1H,-O-CH 2-),4.21-4.15(td,1H,-O-CH 2-),3.71-3.64(m,1H,- CH-NH),3.53(s,2H,-HN- CH 2-),2.96(brs,1H,- NH-CH 2),2.49-2.43(m,1H,-O-CH 2- CH 2-CH),2.08-2.00(m,1H,-O-CH 2- CH 2-CH)； 13C NMR(DMSO-d 6,101MHz)δ187.91,177.96,171.09,165.05,162.58,143.64,142.60,132.80,131.97,131.93,131.67,131.59,130.40,122.34,118.99,116.49,116.28,66.04,55.96,50.94,29.98.
Compound 10k
1H NMR(CDCl 3,400MHz):δ9.54(s,1H,Ar-NH),8.06-8.03(dd,J＝8.0Hz,2H,Ar-H),7.80-7.71(m,4H,- HC＝CH-and Ar-H),7.57-7.52(m,3H,Ar-H and- HC＝CH-),7.33-7.28(t,J＝8.0Hz,1H,Ar-H),4.48-4.44(td,1H,-O-CH 2-),4.28-4.22(td,1H,-O-CH 2-),3.71-3.55(m,3H,- CH-NH and-HN- CH 2-),2.68-2.61(m,1H,-O-CH 2- CH 2-CH),2.36(brs,1H,- NH-CH 2),2.22-2.14(m,1H,-O-CH 2- CH 2-CH)； 13C NMR(CDCl 3,101MHz)δ188.46,176.87,169.56,142.65,141.84,137.08,133.60,133.19,132.20,130.85,130.48,130.04,129.81,127.24,123.08,122.96,118.99,65.48,57.23,51.79,30.23.
Compound 10l
1H NMR(CDCl 3,400MHz):δ9.52(s,1H,Ar-NH),8.06-8.03(d,J＝12.0Hz,2H,Ar-H),7.83-7.77(m,3H,- HC＝CH-and Ar-H),7.61-7.59(d,J＝8.0Hz,2H,Ar-H),7.54-7.50(d,J＝16.0Hz,1H,-HC＝CH-),7.31-7.29(d,J＝8.0Hz,2H,Ar-H),4.47-4.43(td,1H,-O-CH 2-),4.25-4.21(td,1H,-O-CH 2-),3.70-3.58(m,3H,- CH-NH and-HN- CH 2-),2.99-2.93(m,1H,-O-CH 2- CH 2-CH),2.66-2.60(m,1H,- CH(CH 3) 2),2.37(brs,1H,- NH-CH 2),2.22-2.07(m,1H,-O-CH 2- CH 2-CH),1.30-1.28(d,J＝8.0Hz,6H,-CH( CH 3) 2)； 13C NMR(CDCl 3,101MHz)δ189.13,176.90,169.56,151.96,144.68,141.54,134.07,132.57,129.94,128.62,127.11,120.86,118.95,65.50,57.20,51.76,34.14,30.22,23.79.
Compound 10m
1H NMR(CDCl 3,400MHz):δ9.56(s,1H,Ar-NH),8.04-8.02(d,J＝8.0Hz,2H,Ar-H),7.82-7.77(m,3H,- HC＝CH-and Ar-H),7.61-7.59(d,J＝8.0Hz,2H,Ar-H),7.54-7.50(d,J＝16.0Hz,1H,-HC＝CH-),7.46-7.44(m,2H,Ar-H),4.45-4.41(td,1H,-O-CH 2-),4.23-4.19(td,1H,-O-CH 2-),3.69-3.49(m,3H,- CH-NH and-HN- CH 2-),2.64-2.58(m,1H,-O-CH 2- CH 2-CH),2.31(brs,1H,- NH-CH 2),2.20-2.12(m,1H,-O-CH 2- CH 2-CH),1.35(s,9H,-C(CH 3) 3)； 13C NMR(CDCl 3,101MHz)δ189.16,177.02,169.69,154.20,144.57,141.63,134.02,132.16,129.92,128.36,125.96,120.99,118.98,65.54,57.14,51.71,34.95,31.16,30.17.
Embodiment 3:
The target compound of the present invention's synthesis has carried out activity experiment to human liver cancer cell HePG2 and human esophagus cancer cell EC-109 two kinds of tumor cell lines, and experimental result display derivative has certain anti-tumor activity.
1, experimental technique:
(1) preparation of RPMI-1640: aseptically, gets appropriate serum-free RPMI 1640 substratum, is added to after in the foetal calf serum of 10% and rocks evenly; And then rock after adding dual anti-(Streptomycin sulphate 100 μ g/mL and penicillin 100 μ g/mL) evenly.Place in refrigerator and keep for subsequent use at 4 DEG C.
(2) preparation of PBS buffering salt: take 1.56g Na2HPO4,0.2g KH2PO4,0.2g KCl, 8.0g NaCl, be dissolved in 950mL ultrapure water after taking, by clean glass stick stirring and dissolving, and then add ultrapure water constant volume until 1000mL.Be positioned in clean infusion bottle, bottle stopper inserts syringe needle, cool after sterilizing 20min under 121 DEG C of High Temperature High Pressure, be positioned over maintenance 4 DEG C in refrigerator for subsequent use.
(3) bed board: by RPMI-1640, pancreatin and PBS preheating in 37 DEG C of water-baths.The nutrient solution covered with in the culturing bottle of cell discards, and with PBS cleaning twice, adds 1mL pancreatin, jiggles mixing, put into incubator 2min.Cell dissociation is complete adds 2mL nutrient solution in time afterwards, with suction pipe, cell is broken into suspension, is transferred to centrifuge tube centrifugal, discard centrifugal after supernatant liquor, add the mixing of 1mL RPMI-1640, continue to add to 2mL, fully mix.The cell suspension that takes a morsel counts to tally, obtains total cellular score.The plate number of the cell count spread needed for every hole and bed board calculates the volume of required cell quantity and cell suspension.Obtained cell suspension, joins in 96 orifice plates, and every hole 100 μ L, rocks gently after adding and cell is mixed, and puts into incubator and cultivates 24h, make cell attachment.
(4) dosing: medicine DMSO to be measured is mixed with 10mg/mL original liquid, the original liquid getting 10mg/mL during dosing is made into 3 concentration gradients, and be respectively 50,10,5 μ g/mL, concentration from high to low, every Kong Jun adds 100 μ L, and each concentration establishes four multiple holes; Negative control group need add 100 μ L substratum, put into incubator after adding medicine and cultivate 48h, add 5mg/ml MTT afterwards, 20 μ L/ holes, discard the supernatant in orifice plate after continuing to cultivate 4h-6h, add DMSO, 150 μ L/ holes, jolting 10min in shaking table, enzyme-linked immunosorbent assay instrument is surveyed absorbance during 490nm, calculates inhibiting rate.
(5) screen further: get the sample that inhibiting rate is greater than 50% and carry out half inhibiting rate (IC 50)
Experiment.Joined in 96 orifice plates with 64 μ g/mL, 32 μ g/mL, 16 μ g/mL, 8 μ g/mL, 4 μ g/mL, 2 μ g/mL, 1 μ g/mL concentration by testing sample, method is the same, measures absorbance during 490nm, calculates IC by SPSS statistical software 50value.(2) experimental data and result
The antitumor activity of compound data of the present invention's synthesis are in table 1
Table 1 list of target compound is to the pharmacologically active (IC of two kinds of tumour cells 50)
Note: a is human liver cancer cell; B is human esophagus cancer cell
(3) conclusion
Above-mentioned experimental result shows that compound of the present invention does not have inhibit activities or activity very little to human liver cancer cell HePG2, and has good anti tumor activity in vitro to human esophagus cancer cell EC-109, has potential using value.
Embodiment 4:
The target compound of the present invention's synthesis carries out detection to bacterium minimal inhibitory concentration MIC and and utilizes Pseudomonas aeruginosa las system liquid screening model PAO MWI (QSIS-lasI) (being pz1 again) to measure its IC 50value, experimental result display section derivative has certain quorum sensing inhibit activities.
2, experimental technique:
1. compound is to the detection of bacterium minimal inhibitory concentration MIC
(1) picking bacterial colony is in fresh MH substratum, in 37 DEG C, 150rpm shaking table is cultured to growth logarithmic phase.
(2) use LB liquid nutrient medium that bacterium liquid is diluted to OD 600≈ 0.05, is divided into 11 groups, and often group three is parallel, compound is added respectively to different final concentration (312.5 μ Μ, 0.625mM, 1.25mM by doubling dilution, 2.5mM, 5mM, 10mM, 20mM, 40mM, 80mM, 160mM), one group that does not add sample is set to positive controls, by bacterium liquid in 37 DEG C, quiescent culture 20h, and detects its OD 600.
(3) interpretation of result: the lowest concentration of drug that bacterial strain can be suppressed to occur rising appreciably is minimal inhibitory concentration MIC.
2. compound is to the Activity determination (IC of Pseudomonas aeruginosa las system 50)
(1) picking Pseudomonas aeruginosa QSIS2 mono-clonal is in LB liquid nutrient medium, in 37 DEG C.150rpm is cultured to logarithmic phase.
(2) OD is diluted to fresh aseptic ABT substratum 600=0.1, get 96 orifice plates, the LB substratum that every hole adds the above-mentioned bacterium liquid of 50 μ l, 50 μ l contain sucrose (56mg/ml), final concentration is gentamicin and 3-oxygen dodecanoyl homoserine lactone 3-oxo-C12-HSL (20nM) of 80 μ g/ml.In addition respectively by testing sample with 1 μM, 2 μMs, 4 μMs, 8 μMs, 16 μMs, 32 μMs, 64 μMs, 128 μMs, 256 μMs of concentration join in 96 orifice plates.Furanone C30 is positive control, and methyl alcohol is negative control.
(3) cultivate 9h at 37 DEG C, add TTC dyeing, then under 600nm wavelength, survey absorbancy.All compounds establish 12 multiple holes in each test, in triplicate.IC is calculated by SPSS statistical software 50value.
(2) experimental data and result
The determination data of the compound minimal inhibitory concentration of the present invention's synthesis is in table 2
The minimum inhibitory concentration MIC (mM) of table 2 target compound
Note: a is wild-type P. aeruginosa bacterial strain; B for be the two disappearance (PAO MWI) of rhlI and lasI, Pseudomonas aeruginosa mutant strain that pqs system is complete
The compounds of this invention to the Activity determination data of Pseudomonas aeruginosa las system in table 3
Table 3 target compound is to the activity (IC of Pseudomonas aeruginosa las system 50)
Note: a. data are expressed as: mean value ± standard deviation (n=3); B.NS shows do not have remarkable inhibiting activity; C. furanone C30 is as positive control, and methyl alcohol is as negative control
(3) conclusion
Above-mentioned experimental result shows that all derivatives of serial II (10a-10m) of the present invention all do not have obvious inhibit activities to intervention school-based.And serial I (8a-8m) has good quorum sensing inhibit activities, using this serial invention compound as quorum-quenching medicine, there is potential using value.

Claims (6)

1.N-acyl homoserine lactones compounds, is characterized in that, has structure shown in formula I:
Wherein R Wei – H;-Cl;-Br;-Ph;-3,5-dichloriol;-2-F, 4-Br;-3,4-dichlorilo;
-3-OCH 3；-2-Cl；-4-F；-2-Br；-4-isopropyl；-4-tertiary butyl。
2.N-acetylhomoserine lactone compound, is characterized in that, has structure shown in general formula I I:
Wherein R Wei – H;-Cl;-Br;-Ph;-3,5-dichloriol;-2-F, 4-Br;-3,4-dichlorilo;
-3-OCH 3；-2-Cl；-4-F；-2-Br；-4-isopropyl；-4-tertiary butyl。
3. prepare the method for compound as claimed in claim 1, it is characterized in that, it comprises the following steps:
R Wei – H;-Cl;-Br;-Ph;-3,5-dichloriol;-2-F, 4-Br;-3,4-dichlorilo;
-3-OCH 3；-2-Cl；-4-F；-2-Br；-4-isopropyl；-4-tertiary butyl；
Under room temperature, METHIONINE 1 and methyl iodide react in the aqueous solution of methyl alcohol, and stirring is spent the night, generate methide 2, be then hydrolyzed in the aqueous solution of sodium bicarbonate, the pH value of the hierarchy of control is at 4-7, subsequently system is proceeded to oil bath and be heated to back flow reaction, TLC tracks to hydrolysis completely; By solution evaporate to dryness through recrystallization, obtain solid chemical compound 3; Compound 3 refluxes in aqueous hydrochloric acid, and TLC detection reaction is complete; System is cooled to room temperature, and through washing, decompression obtains crude product after steaming solvent, and crude product is through recrystallization, and the drying of suction filtration final vacuum obtains key intermediate---homoserine lactone hydrochloride 4;
Homoserine lactone hydrochloride 4 and chloroacetyl chloride are under Schotten-Baumann reaction conditions, namely methylene dichloride is adopted: water as solvent, sodium bicarbonate makes acid binding agent, drip chloroacetyl chloride under low temperature, system is reacted under room temperature, and TLC detection reaction is complete, divide and get dichloromethane layer, pressure reducing and steaming solvent after drying process, vacuum-drying, obtains acylate 5;
The phenyl aldehyde of para-aminoacetophenone and a series of replacement adopts ethanol to make reaction solvent, sodium hydrate solid is added under 0 DEG C of cold condition, stirred at ambient temperature reaction is spent the night, there is Claisen-Schmidt reaction, reaction solution is poured in mixture of ice and water and be stirred to precipitation solid, obtain a series of chalcone compounds 7a-7m;
Make reaction solvent with aprotic solvent DMF, add potassiumiodide and make catalyzer, compound 5 activates at 60 DEG C-70 DEG C, then adds 7a-7m chalcone compound respectively, is warming up to 120 DEG C-140 DEG C reactions subsequently; Reaction solution is cooled to room temperature, and through extraction, DMF is removed in eccysis, and after removing ethyl acetate under reduced pressure, silica gel column chromatography is separated, and obtains a series of target compound 8a-8m.
4. prepare the method for compound as claimed in claim 2, it is characterized in that, it comprises the following steps:
R Wei – H;-Cl;-Br;-Ph;-3,5-dichloriol;-2-F, 4-Br;-3,4-dichlorilo;
-3-OCH 3；-2-Cl；-4-F；-2-Br；-4-isopropyl；-4-tertiary butyl；
Under room temperature, METHIONINE 1 and methyl iodide react in the aqueous solution of methyl alcohol, and stirring is spent the night, generate methide 2, be then hydrolyzed in the aqueous solution of sodium bicarbonate, the pH value of the hierarchy of control is at 4-7, subsequently system is proceeded to oil bath and be heated to back flow reaction, TLC tracks to hydrolysis completely; By solution evaporate to dryness, through recrystallization, obtain compound 3; Compound 3 refluxes in aqueous hydrochloric acid, and TLC detection reaction is complete; System is cooled to room temperature, and through washing, decompression obtains crude product after steaming solvent, and crude product is through recrystallization, and suction filtration final vacuum is dry, obtains key intermediate---homoserine lactone hydrochloride 4;
The phenyl aldehyde of para-aminoacetophenone and a series of replacement adopts ethanol to make reaction solvent, sodium hydrate solid is added under 0 DEG C of cold condition, stirred at ambient temperature reaction is spent the night, there is Claisen-Schmidt reaction, reaction solution is poured in mixture of ice and water and be stirred to precipitation solid, obtain a series of chalcone compounds 7a-7m;
With cinnamophenone series compound 7a-7m for raw material, acetone is solvent, and salt of wormwood makes catalyzer, chloroacetyl chloride is added under low temperature, after return stirring reaction, reaction solution is poured in mixture of ice and water and be stirred to precipitation solid, after suction filtration, drying treatment, obtain alpha-chloro acid amides chalcone derivative 9a-9m;
With homoserine lactone hydrochloride 4 for raw material, adopt similar Williamson to synthesize the method for ether, react from different substrate alpha-chloro acid amides chalcone derivative (9a-9m) respectively, namely with acetonitrile as solvents, after stirring and dissolving, add acid binding agent K 2cO 3, catalyzer KI, is heated to back flow reaction under oil bath; After completion of the reaction, suction filtration removing K 2cO 3, after removing acetonitrile under reduced pressure, silica gel column chromatography is separated, and obtains N-acetylhomoserine lactone derivatives 10a-10m.
5. N-acyl homoserine lactones compounds as claimed in claim 1 or 2 is preparing the application in medicine, it is characterized in that, uses it for and prepare anti esophageal cancer medicine.
6. N-acetylhomoserine lactone compound as claimed in claim 1 is preparing the application in medicine, it is characterized in that, uses it for preparation antibacterium quorum sensing and suppresses medicine.
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