CN104356099B - Homoserine lactone compounds, its preparation method and application thereof - Google Patents
Homoserine lactone compounds, its preparation method and application thereof Download PDFInfo
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- 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
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- C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
Abstract
The invention discloses homoserine lactone compounds, its preparation method and application thereof; relate to N-acyl homoserine lactones and two series compounds of N-acetyl group homoserine lactone and preparation method thereof; belong to pharmaceutical chemistry field, be specifically related to a class and have the novel homoserine lactone compounds of following chemical structure of general formula:
Description
Technical field
The present invention relates to medical compounds field, be specifically related to novel homoserine lactone compounds, its preparation methodAnd application.
Background technology
Traditional antibiotic is all the generation of disturbing synthetic, the protein of synthetic, the folic acid of bacteria cell wall, DNA'sThe important life process such as synthetic is target spot, by directly killing or suppressing microbial growth and realize anti-infectious object.Under the selection of this survival pressure, bacterium easily suddenlys change, and raw plain drug resistance can create antagonism. But, based on bacterial communityThe bacteriostatic agent of induction system development can not disturb the normal physiological activity of bacterium, just by its detrimental expression of blocking-upThe quorum sensing of anti-bacteria, thus make it lose pathogenecity, be therefore regarded as the new direction of antibacterials development.
Acyl homoserine lactones (AHL) compounds is the bacteriostatic agent based on the development of bacterial community induction system, at present,Activity research method for acyl homoserine lactones (AHL) compounds does not also have standardization, strengthens the mark of activity ratingStandardization contributes to the structure-activity relationship of this compounds to have a better understanding. From this compounds of Molecular level study and acceptorBetween the mode of action can more clearly understand quorum sensing regulation mechanism, be conducive to further to design activity better non-Natural A HL analog. Although modify existing pertinent literature report for the synthesis and structure of this compounds, because it is syntheticThe drawbacks limit such as the complicated or required chiral raw material of route is difficult to obtain its further further investigate. Therefore, new syntheticMethod and structure is modified and will be become the focus of research from now on, quorum sensing from Molecular level study quorum sensing regulation mechanismSignal 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 opens with bacterial communityThe antiseptic of sending out, for people provide potential, medication development, a more wide space, is more of value to people'sHealthy.
Summary of the invention
The object of the invention is to provide novel homoserine lactone types of populations induction inhibitor, its preparation method, at presentThe screening of quorum sensing inhibitor provides possibility clinically.
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-OCH3；-2-Cl；-4-F；-2-Br；-4-isopropyl；-4-tertiarybutyl。
Be preferably as follows compound:
I type: (S, E)-2-((4-(3-(4-chlorphenyl) acryloyl group) phenyl) amine)-N-(2-carbonyl oxolane-3-Base) acetamide
(S, E)-2-((4-cinnamoyl phenyl) amino)-N-(2-carbonyl oxolane-3-yl) acetamide
(S, E)-2-((4-(3-(4-bromophenyl-hydrazine) acryloyl group) phenyl) amino)-N-(2-carbonyl oxolane-3-yl)Acetamide
(S, E)-2-((4-(3-([1,1'-biphenyl]-4-yl) propiono) phenyl) amino)-N-(2-carbonyl oxolane-3-yl) acetamide
(S, E)-2-((4-(3-(3,5-dichlorophenyl) acryloyl group) phenyl) amino)-N-(2-carbonyl oxolane-3-Base) acetamide
(S, E)-2-((4-(3-(the bromo-2-fluorophenyl of 4-) acryloyl group) phenyl) amino)-N-(2-carbonyl oxolane-3-yl) acetamide
(S, E)-2-((4-(3-(3,4-dichlorophenyl acryloyl group) phenyl) amino)-N-(2-carbonyl oxolane-3-Base) acetamide
(S, E)-2-((4-(3-(3-methoxyphenyl) acryloyl group) phenyl) amino)-N-(2-carbonyl oxolane-3-Base) acetamide
(S, E)-2-((4-(3-(2-chlorphenyl) acryloyl group) phenyl) amino)-N-(2-carbonyl oxolane-3-yl)Acetamide
(S, E)-2-((4-(3-(4-fluorophenyl) acryloyl group) phenyl) amino)-N-(2-carbonyl oxolane-3-yl)Acetamide
(S, E)-2-((4-(3-(3-bromophenyl) acryloyl group) phenyl) amino)-N-(2-carbonyl oxolane-3-yl)Acetamide
(S, E)-2-((4-(3-(4-cumenyl) acryloyl group) phenyl) amino)-N-(2-carbonyl oxolane-3-Base) acetamide
(S, E)-2-((4-(3-(4-(tert-butyl group) phenyl) acryloyl group) phenyl) amino)-N-(2-carbonyl oxolane-3-yl) acetamide
II type: (S, E)-N-(4-(3-(4-chlorphenyl) acryloyl group phenyl)-2-((2-carbonyl oxolane-3-yl) ammoniaBase) acetamide
(S, E)-N-(4-cinnamoyl phenyl)-2-((2-carbonyl oxolane-3-yl) amino) acetamide
(S, E)-N-(4-(3-(4-bromophenyl) acryloyl group) phenyl)-2-((2-carbonyl oxolane-3-yl) amino)Acetamide
(S, E)-N-(4-(3-([1,1'-biphenyl]-4-yl) acryloyl group) phenyl)-2-((2-carbonyl oxolane-3-Base) amino) acetamide
(S, E)-N-(4-(3-(3,5-dichlorophenyl) acryloyl group) phenyl)-2-((2-carbonyl oxolane-3-yl) ammoniaBase) acetamide
(S, E)-N-(4-(3-(the bromo-2-fluorophenyl of 4-) acryloyl group) phenyl)-2-((2-carbonyl oxolane-3-yl)Amino) acetamide
(S, E)-N-(4-(3-(3,4-dichlorophenyl) acryloyl group) phenyl)-2-((2-carbonyl oxolane-3-yl) ammoniaBase) acetamide
(S, E)-N-(4-(3-(3-methoxyphenyl) acryloyl group) phenyl)-2-((2-carbonyl oxolane-3-yl) ammoniaBase) acetamide
(S, E)-N-(4-(3-(2-chlorphenyl) acryloyl group) phenyl)-2-((2-carbonyl oxolane-3-yl) amino)Acetamide
(S, E)-N-(4-(3-(4-fluorophenyl) acryloyl group) phenyl)-2-((2-carbonyl oxolane-3-yl) amino)Acetamide
(S, E)-N-(4-(3-(3-bromophenyl) acryloyl group) phenyl)-2-((2-carbonyl oxolane-3-yl) amino)Acetamide
(S, E)-N-(4-(3-(4-cumenyl) acryloyl group) phenyl)-2-((2-carbonyl oxolane-3-yl) ammoniaBase) acetamide
(S, E)-N-(4-(3-(4-(tert-butyl group) phenyl) acryloyl group) phenyl)-2-((2-carbonyl oxolane-3-yl)Amino) acetamide
The invention provides the preparation method of above-claimed cpd, synthetic by following reaction scheme, general formula I reaction scheme asUnder:
R Wei – H;-Cl;-Br;-Ph;-3,5-dichloriol;-2-F, 4-Br;-3,4-dichlorilo;-3-OCH3；-2-Cl；-4-F；-2-Br；-4-isopropyl；-4-tertiarybutyl。
Under room temperature, METHIONINE 1 reacts in the aqueous solution of methyl alcohol with iodomethane, and stirring is spent the night, and generates methide2, then in the aqueous solution of sodium acid carbonate, be hydrolyzed, the pH value of the hierarchy of control, at 4-7, proceeds to oil bath by system subsequently and is heated to backStream reaction, TLC tracks to hydrolysis completely. Solution evaporate to dryness, through recrystallization, is obtained to solid chemical compound 3. Compound 3 is water-soluble at hydrochloric acidIn liquid, reflux, TLC detection reaction is complete. System is cooled to room temperature, and through washing, decompression obtains crude product, crude product warp after steaming solventRecrystallization, dry key intermediate---the homoserine lactone hydrochloride 4 that obtains of suction filtration final vacuum.
Homoserine lactone hydrochloride 4 under Schotten-Baumann reaction condition, adopts dichloro with chloracetyl chlorideMethane: water as solvent, sodium acid carbonate is made acid binding agent, under low temperature, drips chloracetyl chloride, and system is reacted under room temperature, and TLC detects anti-Should be complete, to divide and get dichloromethane layer, drying is processed rear pressure reducing and steaming solvent, and vacuum drying, obtains acylate 5.
The benzaldehyde of para aminoacetophenone and a series of replacements adopts ethanol to make reaction dissolvent, under 0 DEG C of cryogenic conditions, addsEnter sodium hydrate solid, under room temperature, stirring reaction spends the night, and Claisen-Schmidt reaction occurs, and pours reactant liquor into frozen water mixedIn compound, be stirred to and separate out solid, obtain a series of chalcone compounds 7a-7m.
With aprotic solvent, DMF makes reaction dissolvent, adds KI to make catalyst, and compound 5 is lived at 60 DEG C-70 DEG CChange, then add respectively 7a-7m chalcone compound, be warming up to subsequently 120 DEG C of-140 DEG C of reactions, nucleophilic substitution occurs. WillReactant liquor is cooled to room temperature, and through extraction, DMF is removed in eccysis, removes under reduced pressure after ethyl acetate, and silica gel column chromatography separates, and obtains one and isRow 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-OCH3；-2-Cl；-4-F；-2-Br；-4-isopropyl；-4-tertiarybutyl。
Under room temperature, METHIONINE 1 reacts in the aqueous solution of methyl alcohol with iodomethane, and stirring is spent the night, and generates methide2, then in the aqueous solution of sodium acid carbonate, be hydrolyzed, the pH value of the hierarchy of control, at 4-7, proceeds to oil bath by system subsequently and is heated to backStream reaction, TLC tracks to hydrolysis completely. By solution evaporate to dryness, through recrystallization, obtain compound 3. Compound 3 is at aqueous hydrochloric acid solutionMiddle backflow, 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 heavyCrystallization, suction filtration final vacuum is dry, obtains key intermediate---homoserine lactone hydrochloride 4.
The benzaldehyde of para aminoacetophenone and a series of replacements adopts ethanol to make reaction dissolvent, under 0 DEG C of cryogenic conditions, addsEnter sodium hydrate solid, under room temperature, stirring reaction spends the night, and Claisen-Schmidt reaction occurs, and pours reactant liquor into frozen water mixedIn compound, be stirred to and separate out solid, obtain a series of chalcone compounds 7a-7m.
Taking chalcone series compound 7a-7m as raw material, acetone is solvent, and potash is made catalyst, under low temperature, adds chlorineChloroacetic chloride, after return stirring reaction, pours reactant liquor in mixture of ice and water into and is stirred to and separates out solid, after suction filtration, dry processingObtain alpha-chloro acid amides chalcone derivative 9a-9m.
Taking homoserine lactone hydrochloride (4) as raw material, adopt the method for the synthetic ether of similar Williamson, respectively with notSame substrate alpha-chloro acid amides chalcone derivative (9a-9m) reaction, makes solvent with acetonitrile, adds acid binding agent after stirring and dissolvingK2CO3, catalyst KI, is heated to back flow reaction approximately under oil bath. After completion of the reaction, suction filtration is removed K2CO3, remove under reduced pressure after acetonitrile,Silica gel column chromatography separates, and obtains N-acetyl group homoserine lactone derivative 10a-10m.
Advantage of the present invention and innovative point are: 1, homoserine lactone parent nucleus and the acyl side-chain activity to this compoundsMost important, meanwhile, the quorum sensing that the introducing of aromatic rings also can improve this compounds suppresses active. Therefore, retainingUnder the prerequisite of homoserine lactone parent nucleus, attempt to introduce the chalcone with large conjugation group at the acyl side-chain end of compoundCompounds, simultaneously also because chalcone itself is a good active group, it has the biology such as antibacterial, antitumor widelyActive. 2, route preparation method is simple, can be prepared into key intermediate taking METHIONINE as raw material. And yield is high,Reach more than 70%.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is described further.
Embodiment 1:
(S, E)-2-((4-(3-(4-chlorphenyl) acryloyl group) phenyl) amine)-N-(2-carbonyl oxolane-3-yl) secondAcid amides
In the mixed solution of 200mL water and 30mL methyl alcohol, add 10.12g (67.7mmol) METHIONINE, after mixing,Start slowly to drip in confined conditions the about 5.1mL of iodomethane (1.2eq), drip and finish, under room temperature, stirring reaction spends the night, until systemBecome clear shape. After reduced pressure concentration, in system, drip NaHCO3The aqueous solution (5.69g is dissolved in 80mL water), drips and finishes, by systemProceed to oil bath and be heated to back flow reaction approximately 6 hours, after TLC detection reaction is complete, remove solvent under reduced pressure, obtain jonquilleous oilyThing, acetone and ethanol (V:V=1:9) recrystallization obtains a large amount of white solids. White solid is dissolved in to 100mL hydrochloric acid (6molL-1) in solution, adding the about 10h of hot reflux, system is claret, and TLC detection reaction is complete. System is cooled to room temperature, uses respectivelyEther and washed with dichloromethane are closely colourless to water layer, and decompression is used second alcohol and water recrystallization after steaming solvent, and suction filtration final vacuum is dry,Obtain white solid homoserine lactone hydrochloride 6.89g, yield 74%.
1.40g (0.01mol) homoserine lactone hydrochloride is dissolved in 15mL water and 15mL carrene mixed solvent,Add 2.52gNaHCO3(0.03mol) stirring and dissolving to system is clarified. Under room temperature, slowly drip chloracetyl chloride 920 μ L(0.012mol), react after about 6h, TLC detection reaction is complete, divides and gets dichloromethane layer, and anhydrous sodium sulfate drying reduces pressure after processingBoil off solvent, vacuum drying, obtains the chloro-N-of white solid (S)-2-(2-carbonyl oxolane-3-yl) acetamide 1.3g, yield72％。
In 100mL round-bottomed flask, add 0.27g (2mmol) para aminoacetophenone, be dissolved in 25mL ethanol, add successively0.52g (2.02mmol) 4-chloro-benzaldehyde and 0.12g NaOH, stir and spend the night under room temperature. Next day, pour reactant liquor into frozen waterIn mixture, be stirred to and separate out i.e. (E)-1-(4-aminophenyl)-3-(4-chlorphenyl) third-2-alkene-1-ketone of a large amount of yellow solids0.38g, productive rate 74%.
In 25mL round-bottomed flask, add 96mg (0.54mmol) (S)-the chloro-N-of 2-(2-carbonyl oxolane-3-yl) secondAcid amides and KI 270mg, add 10mLDMF stirring and dissolving, under 60 DEG C of oil baths, reacts 2h. Then, in reaction system, add139mg (0.54mmol) (E)-1-(4-aminophenyl)-3-(4-chlorphenyl) third-2-alkene-1-ketone, be heated to 120 DEG C of reactions approximately6h, is cooled to room temperature by reactant liquor, ethyl acetate extraction, and DMF is removed in washing, removes after ethyl acetate silica gel column chromatography under reduced pressureSeparate by (eluant, eluent: acetone/benzinum=2/3), obtaining yellow solid is target compound 157mg, productive rate 73%.
Embodiment 2:
(S, E)-N-(4-(3-(4-chlorphenyl) acryloyl group phenyl)-2-((2-carbonyl oxolane-3-yl) amino) secondAcid amides
In the mixed solution of 200mL water and 30mL methyl alcohol, add 10.12g (67.7mmol) METHIONINE, after mixing,Start slowly to drip in confined conditions the about 5.1mL of iodomethane (1.2eq), drip and finish, under room temperature, stirring reaction spends the night, until systemBecome clear shape. After reduced pressure concentration, in system, drip NaHCO3The aqueous solution (5.69g is dissolved in 80mL water), drips and finishes, by systemProceed to oil bath and be heated to back flow reaction approximately 6 hours, after TLC detection reaction is complete, remove solvent under reduced pressure, obtain jonquilleous oilyThing, acetone and ethanol (V:V=1:9) recrystallization obtains a large amount of white solids. White solid is dissolved in to 100mL hydrochloric acid (6molL-1) in solution, adding the about 10h of hot reflux, system is claret, and TLC detection reaction is complete. System is cooled to room temperature, uses respectivelyEther and washed with dichloromethane are closely colourless to water layer, and decompression is used second alcohol and water recrystallization after steaming solvent, and suction filtration final vacuum is dry,Obtain 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 successively0.52g (2.02mmol) 4-chloro-benzaldehyde and 0.12g NaOH, stir and spend the night under room temperature. Next day, pour reactant liquor into frozen waterIn mixture, be stirred to and separate out i.e. (E)-1-(4-aminophenyl-3-(4-chlorphenyl) third-2-alkene-1-ketone of a large amount of yellow solids0.38g, productive rate 74%.
In 50ml round-bottomed flask, add 0.51g (E)-1-(4-aminophenyl)-3-(4-chlorphenyl) third-2-alkene-1-ketone,Be dissolved in 25ml acetone, add successively 332mgK2CO3(1.2eq) He 180 μ l chloracetyl chlorides (1.2eq); R.t stirs after 3h, willReactant liquor is poured in mixture of ice and water and is stirred to and separates out a large amount of solids, suction filtration, and washing filter cake, vacuum drying obtains 0.53g (E)-2-Chloro-N-(4-(3-(4-chlorphenyl) acryloyl group) phenyl) acetamide solid, productive rate is 70%.
In 25mL round-bottomed flask, add 150mg (0.45mmol) (E)-the chloro-N-of 2-(4-(3-(4-chlorphenyl) acryloylBase) phenyl) acetamide and 62mg (0.45mmol) homoserine lactone hydrochloride, add 10mL acetonitrile stirring and dissolving, then addAcid binding agent K2CO3187mg (1.35mmol), catalyst KI15mg (0.09mmol), is heated to the about 6h of back flow reaction under oil bath.It is complete that TLC follows the tracks of reaction, and suction filtration is removed K2CO3, removing under reduced pressure after acetonitrile, silica gel column chromatography separates (eluant, eluent: acetone/benzinum=1/2), obtain yellow solid, i.e. target compound 118mg, productive rate 66%.
Adopt chemical constitution and the nuclear magnetic data of the synthetic the compounds of this invention of said method as follows:
Compound 8a
1HNMR(DMSO-d6,400MHz):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-andAr-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-CH2-),4.37-4.32(t,J＝8.0Hz,1H,-CH-NH),4.22-4.18(dd,J＝20.0Hz,J＝8.0Hz,1H,-O-CH2-),3.85-3.84(d,J＝4.0Hz,2H,-HN-CH 2-),2.41-2.35(m,1H,-O-CH2-CH 2-CH),2.24-2.14(m,1H,-O-CH2-CH 2-CH)；13CNMR(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
1HNMR(DMSO-d6,400MHz):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-CH2-),4.35-4.33(t,J＝8.0Hz,1H,-CH-NH),4.22-4.19(dd,J＝20.0Hz,J＝8.0Hz,1H,-O-CH2-),3.85(s,2H,-HN-CH 2-),2.41-2.36(m,1H,-O-CH2-CH 2-CH),2.25-2.14(m,1H,-O-CH2-CH 2-CH)；13CNMR(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
1HNMR(DMSO-d6,400MHz):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-Hand-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-CH2-),4.36-4.32(t,J＝8.0Hz,1H,-CH-NH),4.22-4.18(dd,J＝20.0Hz,J＝8.0Hz,1H,-O-CH2-),3.85-3.80(m,2H,-HN-CH 2-),2.39-2.35(m,1H,-O-CH2-CH 2-CH),2.25-2.17(m,1H,-O-CH2-CH 2-CH)；13CNMR(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
1HNMR(DMSO-d6,400MHz):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-andAr-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-CH2-),4.37-4.33(t,J＝8.0Hz,1H,-CH-NH),4.25-4.19(dd,J＝20.0Hz,J＝8.0Hz,1H,-O-CH2-),3.86-3.85(d,J＝4.0Hz,2H,-HN-CH 2-),2.41-2.36(m,1H,-O-CH2-CH 2-CH),2.22-2.17(m,1H,-O-CH2-CH 2-CH)；13CNMR(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
1HNMR(DMSO-d6,400MHz):δ8.60-8.58(d,J＝8.0Hz,1H,-CO-NH),8.09-8.02(m,5H,-CO-HC＝CH-andAr-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-CH2-),4.37-4.33(t,J＝8.0Hz,1H,-CH-NH),4.23-4.18(dd,J＝20.0Hz,J＝8.0Hz,1H,-O-CH2-),3.86-3.85(d,J＝4.0Hz,2H,-HN-CH 2-),2.42-2.35(m,1H,-O-CH2-CH 2-CH),2.24-2.14(m,1H,-O-CH2-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
1HNMR(DMSO-d6,400MHz):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-andAr-H),7.70-7.66(2H,CO-HC＝CH-andAr-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-CH2-),4.37-4.32(t,J＝8.0Hz,1H,-CH-NH),4.25-4.19(dd,J＝20.0Hz,J＝8.0Hz,1H,-O-CH2-),3.86-3.85(d,J＝4.0Hz,2H,-HN-CH 2-),2.42-2.36(m,1H,-O-CH2-CH 2-CH),2.22-2.17(m,1H,-O-CH2-CH 2-CH)；13CNMR(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
1HNMR(DMSO-d6,400MHz):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-andAr-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-CH2-),4.37-4.33(t,J＝8.0Hz,1H,-CH-NH),4.25-4.18(dd,J＝20.0Hz,J＝8.0Hz,1H,-O-CH2-),3.86-3.85(d,J＝4.0Hz,2H,-HN-CH 2-),2.42-2.36(m,1H,-O-CH2-CH 2-CH),2.22-2.17(m,1H,-O-CH2-CH 2-CH)；13CNMR(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
1HNMR(DMSO-d6,400MHz):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-CH2-),4.37-4.33(t,J＝8.0Hz,1H,-CH-NH),4.25-4.18(dd,J＝20.0Hz,J＝8.0Hz,1H,-O-CH2-),3.84(s,2H,-HN-CH 2-),3.83(s,3H,-OCH 3-),2.42-2.35(m,1H,-O-CH2-CH 2-CH),2.25-2.14(m,1H,-O-CH2-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
1HNMR(DMSO-d6,400MHz):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-CH2-),4.37-4.33(t,J＝8.0Hz,1H,-CH-NH),4.25-4.18(dd,J＝20.0Hz,J＝8.0Hz,1H,-O-CH2-),3.85(s,2H,-HN-CH 2-),2.42-2.35(m,1H,-O-CH2-CH 2-CH),2.25-2.14(m,1H,-O-CH2-CH 2-CH)；13CNMR(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
1HNMR(DMSO-d6,400MHz):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-CH2-),4.37-4.32(t,J＝8.0Hz,1H,-CH-NH),4.25-4.18(dd,J＝20.0Hz,J＝8.0Hz,1H,-O-CH2-),3.85(s,2H,-HN-CH 2-),2.42-2.35(m,1H,-O-CH2-CH 2-CH),2.25-2.14(m,1H,-O-CH2-CH 2-CH)；13CNMR(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
1HNMR(DMSO-d6,400MHz):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-Hand-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-CH2-),4.37-4.33(t,J＝8.0Hz,1H,-CH-NH),4.23-4.18(dd,J＝20.0Hz,J＝8.0Hz,1H,-O-CH2-),3.86-3.84(d,J＝8.0Hz,2H,-HN-CH 2-),2.42-2.35(m,1H,-O-CH2-CH 2-CH),2.24-2.14(m,1H,-O-CH2-CH 2-CH)；13CNMR(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
1HNMR(DMSO-d6,400MHz):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-CH2-),4.37-4.33(t,J＝8.0Hz,1H,-CH-NH),4.25-4.19(dd,J＝20.0Hz,J＝8.0Hz,1H,-O-CH2-),3.85-3.84(d,J＝4.0Hz,2H,-HN-CH 2-),2.42-2.36(m,1H,-O-CH2-CH 2-CH),2.25-2.15(m,1H,-O-CH2-CH 2-CH),1.3(s,1H,-CH(CH3)2),1.23-1.21(d,J＝8.0Hz,6H,-CH(CH 3 ) 2)；13CNMR(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
1HNMR(DMSO-d6,400MHz):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-CH2-),4.37-4.33(t,J＝8.0Hz,1H,-CH-NH),4.23-4.18(dd,J＝20.0Hz,J＝8.0Hz,1H,-O-CH2-),3.85-3.84(d,J＝4.0Hz,2H,-HN-CH 2-),2.42-2.35(m,1H,-O-CH2-CH 2-CH),2.25-2.14(m,1H,-O-CH2-CH 2-CH),1.30(s,4H,-C(CH 3 ) 3),1.23-1.21(d,J＝8.0Hz,5H,-C(CH 3 ) 3)；13CNMR(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
1HNMR(DMSO-d6,400MHz):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-CH2-),4.21-4.16(td,1H,-O-CH2-),3.71-3.66(t,1H,-CH-NH),3.53(s,2H,-HN-CH 2-),2.96(brs,1H,-NH-CH2),2.48-2.43(m,1H,-O-CH2-CH 2-CH),2.10-2.00(m,1H,-O-CH2-CH 2-CH)；13CNMR(DMSO-d6,101MHz)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
1HNMR(CDCl3,400MHz):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-andAr-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-CH2-),4.27-4.20(td,1H,-O-CH2-),3.68-3.58(m,3H,-CH-NHand-HN-CH 2-),2.66-2.59(m,1H,-O-CH2-CH 2-CH),2.38(brs,1H,-NH-CH2),2.18-2.13(m,1H,-O-CH2-CH 2-CH)；13CNMR(CDCl3,101MHz)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
1HNMR(CDCl3,400MHz):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-andAr-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-CH2-),4.27-4.20(td,1H,-O-CH2-),3.68-3.58(m,3H,-CH-NHand-HN-CH 2-),2.66-2.59(m,1H,-O-CH2-CH 2-CH),2.38(brs,1H,-NH-CH2),2.18-2.13(m,1H,-O-CH2-CH 2-CH)；13CNMR(CDCl3,101MHz)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
1HNMR(CDCl3,400MHz):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-CH2-),4.29-4.22(td,1H,-O-CH2-),3.72-3.58(m,3H,-CH-NHand-HN-CH 2-),2.68-2.62(m,1H,-O-CH2-CH 2-CH),2.63(brs,1H,-NH-CH2),2.18-2.12(m,1H,-O-CH2-CH 2-CH)；13CNMR(CDCl3,101MHz)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
1HNMR(CDCl3,400MHz):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-CH2-),4.26-4.21(td,1H,-O-CH2-),3.70-3.49(3H,-CH-NHand-HN-CH 2-),2.67-2.20(brs,1H,-NH-CH2),2.19-2.18(m,2H,-O-CH2-CH 2-CH)；13CNMR(CDCl3,101MHz)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
1HNMR(CDCl3,400MHz):δ9.56(s,1H,Ar-NH),8.05-8.02(d,J＝12.0Hz,2H,Ar-H),7.84-7.78(3H,-HC＝CH-andAr-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-CH2-),4.28-4.22(td,1H,-O-CH2-),3.71-3.54(m,3H,-CH-NHand-HN-CH 2-),2.68-2.61(m,1H,-O-CH2-CH 2-CH),2.36(brs,1H,-NH-CH2),2.19-2.13(m,1H,-O-CH2-CH 2-CH)；13CNMR(CDCl3,101MHz)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
1HNMR(DMSO-d6,400MHz):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-CH2-),4.21-4.14(td,1H,-O-CH2-),3.70-3.66(t,J＝8.0Hz,1H,-CH-NH),3.53(s,2H,-HN-CH 2-),2.96(brs,1H,-NH-CH2),2.48-2.45(m,1H,-O-CH2-CH 2-CH),2.10-2.02(m,1H,-O-CH2-CH 2-CH)；13CNMR(CDCl3,101MHz)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
1HNMR(CDCl3,400MHz):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＝CHandAr-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-CH2-),4.24-4.18(td,1H,-O-CH2-),3.85(s,3H,-OCH3),3.66-3.56(m,3H,-CH-NHand-HN-CH 2-),2.63-2.57(m,1H,-O-CH2-CH 2-CH),2.29(brs,1H,-NH-CH2),2.14-2.08(m,1H,-O-CH2-CH 2-CH)；13CNMR(CDCl3,101MHz)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
1HNMR(CDCl3,400MHz):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-andAr-H),7.39(1H,Ar-H),4.49-4.44(td,1H,-O-CH2-),4.28-4.22(td,1H,-O-CH2-),3.71-3.66(m,1H,-CH-NH)3.50(s,2H,-HN-CH 2-),2.68-2.61(m,1H,-O-CH2-CH 2-CH),2.34(brs,1H,-NH-CH2),2.17-2.14(m,1H,-O-CH2-CH 2-CH)；13CNMR(CDCl3,101MHz)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
1HNMR(DMSO-d6,400MHz):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-CH2-),4.21-4.15(td,1H,-O-CH2-),3.71-3.64(m,1H,-CH-NH),3.53(s,2H,-HN-CH 2-),2.96(brs,1H,-NH-CH2),2.49-2.43(m,1H,-O-CH2-CH 2-CH),2.08-2.00(m,1H,-O-CH2-CH 2-CH)；13CNMR(DMSO-d6,101MHz)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
1HNMR(CDCl3,400MHz):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-andAr-H),7.57-7.52(m,3H,Ar-Hand-HC＝CH-),7.33-7.28(t,J＝8.0Hz,1H,Ar-H),4.48-4.44(td,1H,-O-CH2-),4.28-4.22(td,1H,-O-CH2-),3.71-3.55(m,3H,-CH-NHand-HN-CH 2-),2.68-2.61(m,1H,-O-CH2-CH 2-CH),2.36(brs,1H,-NH-CH2),2.22-2.14(m,1H,-O-CH2-CH 2-CH)；13CNMR(CDCl3,101MHz)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
1HNMR(CDCl3,400MHz):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-andAr-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-CH2-),4.25-4.21(td,1H,-O-CH2-),3.70-3.58(m,3H,-CH-NHand-HN-CH 2-),2.99-2.93(m,1H,-O-CH2-CH 2-CH),2.66-2.60(m,1H,-CH(CH3)2),2.37(brs,1H,-NH-CH2),2.22-2.07(m,1H,-O-CH2-CH 2-CH),1.30-1.28(d,J＝8.0Hz,6H,-CH(CH 3)2)；13CNMR(CDCl3,101MHz)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
1HNMR(CDCl3,400MHz):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-andAr-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-CH2-),4.23-4.19(td,1H,-O-CH2-),3.69-3.49(m,3H,-CH-NHand-HN-CH 2-),2.64-2.58(m,1H,-O-CH2-CH 2-CH),2.31(brs,1H,-NH-CH2),2.20-2.12(m,1H,-O-CH2-CH 2-CH),1.35(s,9H,-C(CH3)3)；13CNMR(CDCl3,101MHz)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 synthetic target compound of the present invention is thin to human liver cancer cell HePG2 and two kinds of tumours of human esophagus cancer cell EC-109Born of the same parents system has carried out activity experiment, and experimental result shows that derivative has certain antitumor activity.
1, experimental technique:
(1) preparation of RPMI-1640: under aseptic condition, get appropriate serum-free RPMI1640 culture medium, be added toAfter in 10% hyclone, rock evenly; And then rock after adding dual anti-(streptomysin 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 buffer salt: take 1.56gNa2HPO4,0.2gKH2PO4,0.2gKCl, 8.0gNaCl,After taking, be dissolved in 950mL ultra-pure water, by clean glass bar stirring and dissolving, and then add ultra-pure water constant volume until 1000mL. PutBe placed in clean infusion bottle, on bottle stopper, insert syringe needle, cooling after sterilizing 20min under 121 DEG C of HTHPs, be positioned over iceIn case, keep 4 DEG C for subsequent use.
(3) bed board: by RPMI-1640, pancreatin and PBS preheating in 37 DEG C of water-baths. Cover with in the blake bottle of cellNutrient solution discards, and with PBS cleaning twice, adds 1mL pancreatin, jiggles and mixes, and puts into incubator 2min. After cell dissociation is completeAdd in time 2mL nutrient solution, cell is broken into suspension with suction pipe, be transferred to centrifuge tube centrifugal, discard the supernatant after centrifugal, addEnter 1mL1640 nutrient solution and mix, continue to add to 2mL, fully mix. Cell suspension to the tally that takes a morsel is counted, and obtains carefullyBorn of the same parents' sum. Calculate the volume of required cell quantity and cell suspension according to the plate number of the cell number of the required paving in every hole and bed board. GetCell suspension, joins in 96 orifice plates, and every hole 100 μ L, rock gently cell is mixed after adding, and put into incubator and cultivate 24h,Make cell attachment.
(4) dosing: medicine to be measured is mixed with to 10mg/mL original liquid with DMSO, gets the original liquid of 10mg/mL when dosing and joinBecome 3 concentration gradients, be respectively 50,10,5 μ g/mL, from high to low, every Kong Jun adds 100 μ L to concentration, and each concentration is established four againHole; Negative control group need add 100 μ L culture mediums, adds to put into incubator after medicine and cultivate 48h, adds afterwards 5mg/mlMTT,20 μ L/ holes, continue after cultivation 4h-6h, the supernatant in orifice plate to be discarded, and add DMSO, 150 μ L/ holes, jolting in shaking table10min, the absorbance survey 490nm on enzyme-linked immunosorbent assay instrument time, calculates inhibiting rate.
(5) further screening: get inhibiting rate and be greater than 50% sample and carry out half inhibiting rate (IC50)
Experiment. By testing sample 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/mLConcentration joins in 96 orifice plates, and method is the same, and the absorbance while measuring 490nm calculates IC by SPSS statistical software50Value.(2) experimental data and result
The synthetic antitumor activity of compound data of the present invention are in table 1
Pharmacologically active (the IC of the serial target compound of table 1 to two kinds of tumour cells50)
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 suppress activity or activity very to human liver cancer cell HePG2Little, and human esophagus cancer cell EC-109 is had to good anti tumor activity in vitro, there is potential using value.
Embodiment 4:
The synthetic target compound of the present invention detects bacterium minimal inhibitory concentration MIC and and utilizes the false unit cell of verdigrisBacterium las system liquid screening model PAOMWI (QSIS-lasI) (being again pz1) measures its IC50Value, experimental result display sectionDerivative has certain quorum sensing to suppress active.
2, experimental technique:
1. the detection of compound to bacterium minimal inhibitory concentration MIC
(1) picking bacterium monoclonal is in fresh MH culture medium, is cultured to growth logarithmic phase in 37 DEG C, 150rpm shaking table.
(2) use LB fluid nutrient medium that bacterium liquid is diluted to OD600≈ 0.05, is divided into 11 groups, and three every group parallel, by twoTimes dilution method add respectively compound to different final concentrations (312.5 μ Μ, 0.625mM, 1.25mM, 2.5mM, 5mM, 10mM,20mM, 40mM, 80mM, 160mM), one group that does not add sample is made as positive controls, by bacterium liquid in 37 DEG C, leave standstill and cultivate 20h,And detect its OD600。
(3) interpretation of result: can suppress bacterial strain and occur that the lowest concentration of drug rising appreciably is minimal inhibitory concentrationMIC。
2. compound detects (IC to the activity of pseudomonas aeruginosa las system50)
(1) picking pseudomonas aeruginosa QSIS2 monoclonal is in LB fluid nutrient medium, in 37 DEG C. 150rpm is cultured to logarithmPhase.
(2) be diluted to OD with fresh aseptic ABT culture medium600=0.1, get 96 orifice plates, every hole adds the above-mentioned bacterium of 50 μ lLiquid, 50 μ l contain the LB culture medium of sucrose (56mg/ml), and final concentration is gentamicin and the 3-oxygen dodecanoyl Kosé of 80 μ g/mlPropylhomoserin lactone 3-oxo-C12-HSL (20nM). In addition respectively by testing sample with 1 μ M, 2 μ M, 4 μ M, 8 μ M, 16 μ M, 32 μ M, 64 μM, 128 μ M, 256 μ M concentration join in 96 orifice plates. The positive contrast of furanone C30, the negative contrast of methyl alcohol.
(3) cultivate 9h at 37 DEG C, add TTC dyeing, then under 600nm wavelength, survey absorbance. All compounds are oftenIn inferior test, establish 12 multiple holes, in triplicate more than. Calculate IC by SPSS statistical software50Value.
(2) experimental data and result
The determination data of the synthetic compound minimal inhibitory concentration of the present invention is in table 2
The minimum inhibitory concentration MIC (mM) of table 2 target compound
Note: a is the strain of wild type pseudomonas aeruginosa; B is for being the two disappearance of rhlI and lasI (PAOMWI), pqs system completePseudomonas aeruginosa mutant strain
The compounds of this invention detects data in table 3 to the activity of pseudomonas aeruginosa las system
Activity (the IC of table 3 target compound to pseudomonas aeruginosa las system50)
Note: a. data are expressed as: mean value ± standard deviation (n=3); B.NS shows there is no remarkable inhibiting activity; C. furanMutter ketone C30 as positive control, and methyl alcohol is as negative control
(3) conclusion
Above-mentioned experimental result shows that all derivatives of serial II of the present invention (10a-10m) are equal to quorum sensing systemObviously do not suppress active. And serial I (8a-8m) has good quorum sensing inhibition activity, with this serial invention compoundAs quorum-quenching medicine, there is potential using value.
Claims (7)
1.N-acyl homoserine lactones compounds, is characterized in that, has structure shown in general formula I:
General formula I
Wherein R Wei – H;-Cl;-Br;-Ph;-3,5-dichloride base;-2-F;-3,4-dichloride base;-3-OCH3;-4-F;-4-is differentPropyl group;-4-the tert-butyl group.
2.N-acetyl group homoserine lactone compounds, is characterized in that having structure shown in general formula I I:
General formula I I
Wherein R Wei – H;-Cl;-Br;-Ph;-3,5-dichloride base;-2-F;-3,4-dichloride base;-3-OCH3;-4-F;-4-isopropylBase;-4-the tert-butyl group.
3. the method for preparation compound as claimed in claim 1, is characterized in that, it comprises the following steps:
（Ⅰ）
R Wei – H;-Cl;-Br;-Ph;-3,5-dichloride base;-2-F;-3,4-dichloride base;-3-OCH3;-4-F;-4-isopropyl;-The 4-tert-butyl group;
Under room temperature, METHIONINE 1 reacts in the aqueous solution of methyl alcohol with iodomethane, and stirring is spent the night, and generates methide 2, continuesAnd be hydrolyzed in the aqueous solution of sodium acid carbonate, the pH value of the hierarchy of control, at 4-7, proceeds to system subsequently oil bath and is heated to reflux anti-Should, TLC tracks to hydrolysis completely; Solution evaporate to dryness, through recrystallization, is obtained to solid chemical compound 3; Compound 3 is in aqueous hydrochloric acid solutionReflux, 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 heavily tyingCrystalline substance, dry key intermediate---the homoserine lactone hydrochloride 4 that obtains of suction filtration final vacuum;
Homoserine lactone hydrochloride 4 under Schotten-Baumann reaction condition, adopts dichloromethane with chloracetyl chlorideAlkane: water as solvent, sodium acid carbonate is made acid binding agent, under low temperature, drips chloracetyl chloride, and system is reacted under room temperature, TLC detection reactionCompletely, divide and get dichloromethane layer, drying is processed rear pressure reducing and steaming solvent, and vacuum drying, obtains acylate 5;
The benzaldehyde of para aminoacetophenone and a series of replacements adopts ethanol to make reaction dissolvent, under 0 DEG C of cryogenic conditions, adds hydrogenSodium oxide molybdena solid, under room temperature, stirring reaction spends the night, and Claisen-Schmidt reaction occurs, and pours reactant liquor into mixture of ice and waterIn be stirred to and separate out solid, obtain a series of chalcone compounds 7a-7m;
With aprotic solvent, DMF makes reaction dissolvent, adds KI to make catalyst, and compound 5 activates at 60 DEG C-70 DEG C, thenAdd respectively 7a-7m chalcone compound, be warming up to subsequently 120 DEG C of-140 DEG C of reactions; Reactant liquor is cooled to room temperature, through extractionGet, DMF is removed in eccysis, removes under reduced pressure after ethyl acetate, and silica gel column chromatography separates, and obtains a series of target compound 8a-8m.
4. the method for preparation compound as claimed in claim 2, is characterized in that, it comprises the following steps:
（Ⅱ）
R Wei – H;-Cl;-Br;-Ph;-3,5-dichloride base;-2-F;-3,4-dichloride base;-3-OCH3;-4-F;-4-isopropylBase;-4-the tert-butyl group;
Under room temperature, METHIONINE 1 reacts in the aqueous solution of methyl alcohol with iodomethane, and stirring is spent the night, and generates methide 2, continuesAnd be hydrolyzed in the aqueous solution of sodium acid carbonate, the pH value of the hierarchy of control, at 4-7, proceeds to system subsequently oil bath and is heated to reflux anti-Should, TLC tracks to hydrolysis completely; By solution evaporate to dryness, through recrystallization, obtain compound 3; Compound 3 returns in aqueous hydrochloric acid solutionStream, TLC detection reaction is complete; System is cooled to room temperature, and through washing, decompression steams after solvent to obtain crude product, and crude product is through recrystallization,Suction filtration final vacuum is dry, obtains key intermediate---homoserine lactone hydrochloride 4;
The benzaldehyde of para aminoacetophenone and a series of replacements adopts ethanol to make reaction dissolvent, under 0 DEG C of cryogenic conditions, adds hydrogenSodium oxide molybdena solid, under room temperature, stirring reaction spends the night, and Claisen-Schmidt reaction occurs, and pours reactant liquor into mixture of ice and waterIn be stirred to and separate out solid, obtain a series of chalcone compounds 7a-7m;
Taking chalcone series compound 7a-7m as raw material, acetone is solvent, and potash is made catalyst, under low temperature, adds chloracetylChlorine, after return stirring reaction, pours reactant liquor in mixture of ice and water into and is stirred to and separates out solid, after suction filtration, dry processing α-Chloroamides chalcone derivative 9a-9m;
Taking homoserine lactone hydrochloride 4 as raw material, adopt the method for the synthetic ether of similar Williamson, respectively from differentSubstrate alpha-chloro acid amides chalcone derivative (9a-9m) reaction, makes solvent with acetonitrile, adds acid binding agent after stirring and dissolvingK2CO3, catalyst KI, is heated to back flow reaction under oil bath; After completion of the reaction, suction filtration is removed K2CO3, remove after acetonitrile silicon under reduced pressureGlue column chromatography separates, and obtains N-acetyl group homoserine lactone derivative 10a-10m.
5. N-acyl homoserine lactones compounds as claimed in claim 1 is in the application of preparing aspect medicine, its featureBe, use it for and prepare anti esophageal cancer medicine.
6. N-acetyl group homoserine lactone compounds as claimed in claim 2 is the application of preparing aspect medicine, its spyLevy and be, use it for and prepare anti esophageal cancer medicine.
7. N-acyl homoserine lactones compounds as claimed in claim 1 is in the application of preparing aspect medicine, its featureBe, use it for preparation antibacterium quorum sensing and suppress medicine.
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