CN112552258B - Thiazole amide isomagnanide derivative and preparation method and application thereof - Google Patents
Thiazole amide isomagnanide derivative and preparation method and application thereof Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
- C07D277/38—Nitrogen atoms
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- C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
- A01N43/74—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,3
- A01N43/78—1,3-Thiazoles; Hydrogenated 1,3-thiazoles
Abstract
The invention discloses a thiazole amide isomagnolia base derivative, a preparation method thereof and application of the derivative as a bacteriostatic agent, wherein the chemical structure of the derivative is shown as a general formula (I). Compared with the prior art, the invention provides the novel thiazole amide isomagnanide derivative which has good bacteriostatic activity and is cheap and easy to obtain. Part of the target isomagnoflorine derivatives particularly have strong inhibitory activity on wheat scab, tobacco brown spot, potato dry rot and potato blight, and are expected to be used for preparing novel natural product bacteriostats.
R is selected from C1-C4 alkyl, C1-C4 haloalkyl, substituted or unsubstituted phenyl, or
Wherein n =0-2,R 1 One or more selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen, nitro, aldehyde group or cyano; the substituted phenyl is phenyl substituted by C1-C4 alkyl, C1-C4 alkoxy, halogen, nitro, aldehyde or cyano.
Description
Technical Field
The invention belongs to the technical field of organic chemistry, and particularly relates to a thiazole amide isomagnolia base derivative, and a preparation method and application thereof.
Background
Isomagnoflorine (isomagnolone) with molecular formula of C 18 H 18 O 3 Molecular weight 282.13, a colorless oil. It is a biphenyl neolignan compound separated from the bark of star anise, and the plant is located in west Sichuan, north and east of Ataham, and has an altitude of 1800-3000 m. Kouno I et al (Kouno I, iwamoto C, KAMEDA Y, et al. A. New triphenyl-type neolignan and a biphenylneolignan from the bar of Illicium Simonisi [ J]A series of different sesquiterpenes, such as perillyl alcohol from the pericarp of Illicium verum koehne, dianhydrol and isoduritol from the bark of danniol, were isolated from the plant Illicium species, chemical and pharmaceutical bulletin,1994,42 (1): 112-114), and are believed to beIs a characteristic component of the illicium verum plant. Isomagnoflorine is reported to have good anticancer properties (Itogawa M, ito C, tokuda H, et al., cancer chemopreventive activity of photopropanoids and phytoquinones from Illicium plants [ J]Cancer Letters,2004,214 (2): 165-169.), anti-inflammatory (Huang D, deng H, chen W, et al, four new sesquiterpene lipids from the stem bar of Illicium burmanium [ J]Fitotterapia, 2014,92]Neurosciences letters,1981,25 (1): 83-88.), antidepressant (Li J, geng D, xu J, et al. Antipressant-like effect of a secreted from Illicium dunnianum tune in mice [ J]European journal of pharmacology,2013,707 (1-3): 112-119.), neurotrophic (Nakamura T, okuyama E, yamazaki M.Neurotropic Components from Star Anise: ilium verum HOOK. Fil [ J.]Chemical and pharmaceutical bulletin,1996,44 (10): 1908-1914), and the like.
The parent isomagnoflorine has various biological activities, but the synthesis and antibacterial activity research of the derivatives of the isomagnoflorine is not reported, and therefore, the isomagnoflorine derivatives with higher antibacterial activity are obtained by structurally modifying the isomagnoflorine.
Disclosure of Invention
The purpose of the invention is as follows: aiming at the technical problems, the invention provides a thiazole amide isomagnolia base derivative with high-efficiency antibacterial activity, and a preparation method and application thereof.
The technical scheme is as follows: in order to achieve the purpose of the invention, the technical scheme adopted by the invention is as follows:
a thiazole amido isomagnoline derivative has a chemical structure shown as a general formula (I):
r is selected from C1-C4 alkyl, C1-C4 haloalkyl, substituted or unsubstituted phenyl, or
Wherein n =0-2,R 1 One or more selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen, nitro, aldehyde group or cyano;
the substituted phenyl is phenyl substituted by C1-C4 alkyl, C1-C4 alkoxy, halogen, nitro, aldehyde or cyano.
Preferably, the substituted phenyl is phenyl mono-or di-substituted with a substituent selected from one or two of C1-C4 alkyl, C1-C4 alkoxy, halogen, nitro, aldehyde or cyano.
Preferably, said R 1 N =0-1, mono-or di-substituted.
Further preferably, said R is selected from the following:
the preparation method of the thiazole amide isomagnolia base derivative comprises the following steps:
(1) Taking isomagnoflorine (a) as a raw material, and carrying out bromination reaction on the isomagnoflorine (a) and copper bromide to obtain brominated isomagnoflorine (b);
(2) Reacting the bromo-isomagnoflorine (b) with thiourea to obtain amino thiazole substituted isomagnoflorine (c);
(3) Finally, the aminothiazole substituted isomagnoflorine (c) reacts with RCOOH to obtain the compound with the general formula (I);
wherein R is as described above.
Preferably, the reaction in the step (1) is carried out in ethyl acetate and chloroform, and the reaction temperature is 60-70 ℃.
Preferably, the reaction in the step (2) is carried out in absolute ethyl alcohol at the reaction temperature of 45-55 DEG C
Preferably, the reaction of step (3) is carried out in anhydrous dichloromethane, with the addition of HATU and triethylamine, and the reaction is carried out at room temperature.
Further preferred reaction procedures are as follows:
RCOOH is further preferably selected from acetic acid, chloroacetic acid, benzoic acid, (o, m, p) chlorobenzoic acid, (o, m, p) fluorobenzoic acid, (o, m, p) bromobenzoic acid, (o, m, p) methylbenzoic acid, (o, m, p) methoxybenzoic acid, 2, 4-dichlorobenzoic acid, 2-chloro-4-fluorobenzoic acid, p-cyanobenzoic acid, p-nitrobenzoic acid, p-aldehyde benzoic acid, phenylacetic acid, p-fluorophenylacetic acid, phenylpropionic acid.
The invention finally provides the application of the thiazole amide isomagnolia base derivative as a bacteriostatic agent. Experiments prove that the thiazole amide isomagnoflorine derivative has good inhibitory activity on four plant pathogenic fungi, namely wheat scab, tobacco brown spot, potato blight and potato dry rot, and part of compounds are obviously higher than that of the parent isomagnoflorine.
The technical effects are as follows: compared with the prior art, the invention provides a novel thiazole amide isomagnolia alkali derivative which has good bacteriostatic activity, particularly has good inhibitory activity on four plant pathogenic fungi including wheat scab, tobacco brown spot, potato wilt and potato dry rot, and is expected to be used for preparing a novel natural product bacteriostatic agent. In addition, the preparation method is simple, low in cost and high in yield.
Drawings
FIG. 1 is an IR spectrum of Compound 1 of the present invention;
FIG. 2 shows Compound 1 NMR of the present invention 1 H, spectrogram;
Detailed Description
The present invention is further illustrated by the following examples.
Example 1 Synthesis of Thiazolylamidoisomagna base derivatives
(1) Synthesis of thiaisomagnoflorine (b)
Accurately weighing copper bromide (9.5mmol, 2126mg) and isomagnoflorine (4.8mmol, 1343mg), adding the copper bromide and the isomagnoflorine into a 100mL round-bottom flask, adding 5mL ethyl acetate and 5mL trichloromethane solution into the flask, stirring and dissolving, refluxing and stirring at 66 ℃, detecting by TLC until the reaction is finished, filtering the copper bromide while the reaction is hot after the reaction is finished, washing and recovering the copper bromide by ethyl acetate, combining washing liquor and filtrate, recovering a solvent, and separating the obtained mixture by column chromatography (petroleum ether: ethyl acetate = 10) to obtain the thioisomagnoflorine (b), wherein the yield is 90 percent.
(2) Synthesis of aminothiazole substituted isomagnoflorine (c)
Weighing thiourea (5.1mmol, 391mg) and adding the thiourea into the compound (b), dissolving the compound in 5mL absolute ethanol, refluxing and stirring at 50 ℃, detecting by TLC, after the reaction is finished, carrying out column chromatography (petroleum ether: ethyl acetate = 2) separation after the solvent is dried, and obtaining aminothiazole substituted isomagnoflorine (c) with the yield of 94%.
(3) Synthesis of Thiazolylamidoisomagna base derivatives (Compound 1)
Weighing the compound (c) (0.15mmol, 50mg), benzoic acid (0.22 mmol), HATU (0.22mmol, 83.6 mg) in a 25mL round-bottom flask, adding 2mL of anhydrous dichloromethane solution for dissolving, adding 0.06mL of triethylamine solution (0.45 mmol) into the reaction solution, stirring overnight at room temperature under nitrogen protection, detecting by TLC until the reaction is finished, washing with saturated saline after the reaction is finished, extracting with dichloromethane (3X 20 mL), combining organic phases, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and separating by thin layer chromatography (PTLC) to obtain a pure product of the target compound 1, wherein the structure is as follows:
physicochemical constants and spectral data for compound 1: white solid, yield: 42%; melting point: 146-148 ℃; IR cm -1 (KBr):3060,2918,1675,1543,1468,1301,1265,1210,700； 1 H NMR(400MHz CDCl 3 )δ:7.90(d,J＝8Hz,2H,-Ph),7.55–7.59(m,1H,-Ph),7.45-7.52(m,4H,-Ph),6.99(d,J＝8.4Hz,2H,-Ph),6.93(d,J＝7.2Hz,1H,-Ph),6.75-6.82(m,2H,-Ph),6.01-6.08(m,1H,-CH＝CH 2 ),5.08-5.14(m,2H,-C 2 H＝CH),3.47(d,J＝6.4Hz,2H,-C 2 H-CH＝CH 2 ),2.52(s,3H,-C 3 H-C 3 H 3 NS)； 13 C NMR(100MHz CDCl 3 )δ:164.45,156.39,155.15,145.43,143.65,143.14,136.37,132.91,131.75,129.77,129.62,128.95,127.79,127.50,125.46,121.88,119.95,117.91,116.89,115.82,34.03,12.17；MS(ESI)m/z calcd for C 26 H 22 N 2 O 3 S([M+H]+)443.14,found 443.35.
Example 2 Synthesis of Thiazolylamidoisomagnoflorine derivatives (Compound 2)
physicochemical constants and spectral data for compound 2: yellow solid, yield: 56.8 percent; melting point: 158-160 ℃; IR cm -1 (KBr):3068,2918,2850,1654,1551,1469,1306,1264,1209,743； 1 H NMR(400MHz CDCl 3 )δ:7.74(d,J＝8Hz,1H,-Ph),7.48(d,J＝8.4Hz,2H,-Ph),7.42(d,J＝2.4Hz,2H,-Ph),7.33-7.35(m,1H,-Ph),7.00(d,J＝8.4Hz,2H,-Ph),6.92(t,J＝4.4Hz,1H,-Ph),6.79(d,J＝4.4Hz,2H,-Ph),5.99-6.09(m,1H,-CH＝CH 2 ),5.08-5.13(m,2H,-C 2 H＝CH),3.46(d,J＝6Hz,2H,-C 2 H-CH＝CH 2 ),2.51(s,3H,-C 3 H-C 3 H 3 NS)； 13 C NMR(100MHz CDCl 3 )δ:163.48,156.25,154.10,145.44,144.49,143.20,136.38,132.57,132.28,131.31,130.82,130.70,130.06,129.77,127.74,127.27,125.42,122.19,119.93,117.83,116.88,115.78,34.02,12.20；MS(ESI)m/z calcd for C 26 H 21 35 ClN 2 O 3 S([M+H]+)477.10,found 477.35；calcd for C 26 H 21 37 ClN 2 O 3 S([M+H]+)479.10,found 479.34.
Example 3 Synthesis of Thiazolylamidoisomagnoflorine derivatives (Compound 3)
Compound 3 was synthesized by reacting compound (c) with 3-chlorobenzoic acid using the procedure described in example 1, compound 3 having the following structure:
physicochemical constants and spectral data of compound 3: brown solid, yield: 71.1 percent; melting point: 133-135 ℃; IR cm -1 (KBr):3072,2918,2850,1667,1553,1469,1311,1262,1206,739； 1 H NMR(400MHz CDCl 3 )δ:7.91(s,1H,-Ph),7.79(d,J＝7.2Hz,1H,-Ph),7.49(d,J＝8Hz,1H,-Ph),7.44(d,J＝7.6Hz,2H,-Ph),7.35(t,J＝8Hz,1H,-Ph),6.98(d,J＝8Hz,2H,-Ph),6.93(d,J＝7.2Hz,1H,-Ph),6.76-6.83(m,2H,-Ph),6.00-6.10(m,1H,-CH＝CH 2 ),5.09-5.14(m,2H,-C 2 H＝CH),3.47(d,J＝6Hz,2H,-C 2 H-CH＝CH 2 ),2.50(s,3H,-C 3 H-C 3 H 3 NS)； 13 C NMR(100MHz CDCl 3 )δ:176.77,163.61,156.74,156.20,145.49,142.85,136.34,135.12,133.36,132.93,130.15,129.81,128.52,128.22,127.84,125.72,125.65,121.95,120.00,117.77,117.11,115.85,34.03,12.12；MS(ESI)m/z calcd for C 26 H 21 35 ClN 2 O 3 S([M+H]+)477.10,found 477.38；calcd for C 26 H 21 37 ClN 2 O 3 S([M+H]+)479.10,found 479.40.
Example 4 Synthesis of Thiazolylamidoisomagnoflorine derivatives (Compound 4)
Compound 4 was synthesized by reacting compound (c) with 4-chlorobenzoic acid using the procedure described in example 1, compound 4 having the following structure:
physicochemical constants and spectral data of compound 4: yellow solid, yield: 75.3 percent; melting point: 166-168 ℃; IR cm -1 (KBr):2918,1669,1538,1467,1288,1262,1203,856； 1 H NMR(400MHz CDCl 3 )δ:7.74(d,J＝8Hz,2H,-Ph),7.41(d,J＝8Hz,2H,-Ph),7.34(d,J＝7.6Hz,2H,-Ph),6.93(d,J＝8.4Hz,3H,-Ph),6.78(t,J＝8Hz,1H,-Ph),6.73(d,J＝8Hz,1H,-Ph),6.00-6.10(m,1H,-CH＝CH 2 ),5.09-5.14(m,2H,-C 2 H＝CH),3.47(d,J＝6.4Hz,2H,-C 2 H-CH＝CH 2 ),2.51(s,3H,-C 3 H-C 3 H 3 NS)； 13 C NMR(100MHz CDCl 3 )δ:163.92,156.50,155.86,145.46,143.41,142.85,139.20,136.33,130.12,129.74,129.08,129.04,127.83,125.62,121.95,119.98,117.64,117.05,115.85,34.04,12.13；MS(ESI)m/z calcd for C 26 H 21 35 ClN 2 O 3 S([M+H]+)477.10,found 477.36；calcd for C 26 H 21 37 ClN 2 O 3 S([M+H]+)479.10,found 479.31.
Example 5 Synthesis of Thiazolylamidoisomagnoflorine derivatives (Compound 5)
Compound 5 was synthesized by reacting compound (c) with 2-bromobenzoic acid using the procedure described in example 1, compound 5 having the following structure:
physicochemical constants and spectral data of compound 5: yellow solid, yield: 72.2 percent; melting point: 68-70 ℃; IR cm -1 (KBr):3056,2918,2849,1675,1544,1468,1300,1262,1209,740； 1 H NMR(400MHz CDCl 3 )δ:7.55(t,J＝7.6Hz,2H,-Ph),7.43(d,J＝8.4Hz,2H,-Ph),7.31-7.33(m,2H,-Ph),6.98(d,J＝8.4Hz,2H,-Ph),6.92(d,J＝4Hz,1H,-Ph),6.81(s,2H,-Ph),5.99-6.09(m,1H,-CH＝CH 2 ),5.08-5.13(m,2H,-C 2 H＝CH),3.45(d,J＝6.4Hz,2H,-C 2 H-CH＝CH 2 ),2.50(s,3H,-C 3 H-C 3 H 3 NS)； 13 C NMR(100MHz CDCl 3 )δ:164.61,156.25,154.38,145.45,144.32,143.08,136.36,134.89,133.87,132.39,130.11,129.84,129.71,127.73,127.62,125.47,122.12,119.94,119.81,117.74,116.96,115.79,34.02,12.21；MS(ESI)m/z calcd for C 26 H 21 79 BrN 2 O 3 S([M+H]+)521.05,found 521.36；calcd for C 26 H 21 81 BrN 2 O 3 S([M+H]+)523.05,found 523.33.
Example 6 Synthesis of Thiazolylamidoisomagnoflorine derivatives (Compound 6)
Compound 6 was synthesized by reacting compound (c) with 3-bromobenzoic acid using the procedure described in example 1, compound 6 having the following structure:
physicochemical constants and spectral data of compound 6: yellow solid, yield: 69%; melting point: 72-75 ℃; IR cm -1 (KBr):3072,2918,2849,1664,1545,1469,1303,1264,1208,732； 1 H NMR(400MHz CDCl 3 )δ:7.97(s,1H,-Ph),7.76(d,J＝8Hz,1H,-Ph),7.62(d,J＝8Hz,,1H,-Ph),7.43(d,J＝8.4Hz,2H,-Ph),7.28(s,1H,-Ph),6.94(d,J＝8Hz,3H,-Ph),6.78(t,J＝8Hz,1H,-Ph),6.73(d,J＝8Hz,1H,-Ph),6.00-6.10(m,1H,-CH＝CH 2 ),5.09-5.14(m,2H,-CH 2 ＝CH),3.47(d,J＝6.4Hz,2H,-C 2 H-CH＝CH 2 ),2.51(s,3H,-C 3 H-C 3 H 3 NS)； 13 C NMR(100MHz CDCl 3 )δ:163.54,156.38,155.66,145.45,144.07,143.00,136.36,135.56,133.95,130.94,130.26,129.80,129.52,127.76,126.07,125.51,122.97,122.18,119.95,117.70,116.95,115.82,34.02,12.13；MS(ESI)m/z calcd for C 26 H 21 79 BrN 2 O 3 S([M+H]+)521.05,found 521.36；calcd for C 26 H 21 81 BrN 2 O 3 S([M+H]+)523.05,found 523.34.
Example 7 Synthesis of Thiazolylamidoisomagnoflorine derivatives (Compound 7)
Compound 7 was synthesized by reacting compound (c) with 4-bromobenzoic acid using the procedure described in example 1, compound 7 having the following structure:
physicochemical constants and spectral data of compound 7: white solid, yield: 52.7 percent; melting point: 165-168 ℃; IR cm -1 (KBr):2919,2850,1663,1534,1469,1307,1266,1204,746； 1 H NMR(400MHz CDCl 3 )δ:7.66(d,J＝8.4Hz,2H,-Ph),7.49(d,J＝8.4Hz,2H,-Ph),7.39(d,J＝8.8Hz,2H,-Ph),6.92(d,J＝8.4Hz,3H,-Ph),6.79(t,J＝8Hz,1H,-Ph),6.73(d,J＝8Hz,1H,-Ph),6.00-6.10(m,1H,-CH＝CH 2 ),5.09-5.14(m,2H,-C 2 H＝CH),3.47(d,J＝6.4Hz,2H,-C 2 H-CH＝CH 2 ),2.50(s,3H,-C 3 H-C 3 H 3 NS)； 13 C NMR(100MHz CDCl 3 )δ:164.05,156.31,155.55,145.44,144.22,142.95,136.35,132.02,130.82,129.81,129.63,129.08,127.78,127.64,125.54,122.10,119.96,117.63,116.97,115.84,34.03,12.13；MS(ESI)m/z calcd for C 26 H 21 79 BrN 2 O 3 S([M+H]+)521.05,found 521.44；calcd for C 26 H 21 81 BrN 2 O 3 S([M+H]+)523.05,found 523.37.
Example 8 Synthesis of Thiazolylamidoisomagnoflorine derivatives (Compound 8)
Compound 8 was synthesized by reacting compound (c) with 2-fluorobenzoic acid using the procedure described in example 1, compound 8 having the following structure:
physicochemical constants and spectral data for compound 8: white solid, yield: 63.8 percent; melting point: 170-172 ℃; IR cm -1 (KBr):2917,2849,1670,1549,1469,1307,1266,1211,753； 1 H NMR(400MHz CDCl 3 )δ:8.18(t,J＝7.6Hz,1H,-Ph),7.58(d,J＝7.6Hz,3H,-Ph),7.33(t,J＝8Hz,1H,-Ph),7.20(d,J＝8.8Hz,1H,-Ph),7.07(d,J＝8.4Hz,2H,-Ph),6.93(d,J＝3.6Hz,1H,-Ph),6.80(d,J＝4Hz,2H,-Ph),6.00-6.10(m,1H,-CH＝CH 2 ),5.08-5.14(m,2H,-C 2 H＝CH),3.47(d,J＝6.4Hz,2H,-C 2 H-CH＝CH 2 ),2.52(s,3H,-C 3 H-C 3 H 3 NS)； 13 C NMR(100MHz CDCl 3 )δ:160.42,159.51,156.22,153.55,145.34,144.67,143.33,136.40,134.96,134.87,132.32,130.36,129.91,127.65,125.31,122.37,119.91,119.01,118.91,118.09,116.66,116.57,116.32,115.79,34.02,12.20；MS(ESI)m/z calcd for C 26 H 21 FN 2 O 3 S([M+H]+)461.13,found 461.38.
Example 9 Synthesis of Thiazolylamidoisomagnoflorine derivatives (Compound 9)
Compound 9 was synthesized by reacting compound (c) with 3-fluorobenzoic acid using the procedure described in example 1, compound 9 having the following structure:
physicochemical constants and spectral data of compound 9: white solid, yield: 63.8 percent; melting point: 158-160 ℃; IR cm -1 (KBr):2918,2849,1669,1545,1469,1303,1267,1208,746； 1 H NMR(400MHz CDCl 3 )δ:7.53-7.60(m,2H,-Ph),7.33-7.43(m,3H,-Ph),7.18(t,J＝8Hz,1H,-Ph),6.92-6.94(m,3H,-Ph),6.78(t,J＝7.6Hz,1H,-Ph),6.71(d,J＝8Hz,1H,-Ph),5.99-6.09(m,1H,-CH＝CH 2 ),5.08-5.14(m,2H,-C 2 H＝CH),3.46(d,J＝6.4Hz,2H,-C 2 H-CH＝CH 2 ),2.50(s,3H,-C 3 H-C 3 H 3 NS)； 13 C NMR(100MHz CDCl 3 )δ:163.96,163.51,161.49,156.28,155.07,145.40,144.36,143.07,136.35,134.28,134.21,130.52,130.44,129.84,129.74,127.75,125.47,122.89,122.22,119.94,119.85,119.64,117.77,116.86,115.83,115.04,114.81,34.02,12.16；MS(ESI)m/z calcd for C 26 H 21 FN 2 O 3 S([M+H]+)461.13,found 461.39.
Example 10 Synthesis of Thiazolylamidoisomagnoflorine derivatives (Compound 10)
Compound 10 was synthesized by reacting compound (c) with 4-fluorobenzoic acid using the procedure described in example 1, compound 10 having the following structure:
physicochemical constants and spectral data for compound 10: yellow solid, yield: 44.2 percent; melting point: 168-170 ℃; IR cm -1 (KBr):2919,2850,1667,1537,1508,1468,1259,1200,1157,850； 1 H NMR(400MHz CDCl 3 )δ:7.87-7.90(m,2H,-Ph),7.45(d,J＝8.4Hz,2H,-Ph),7.07(t,J＝8.4Hz,2H,-Ph),6.94-6.98(m,3H,-Ph),6.74-6.82(m,2H,-Ph),6.00-6.10(m,1H,-CH＝CH 2 ),5.09-5.15(m,2H,-C 2 H＝CH),3.47(d,J＝6Hz,2H,-C 2 H-CH＝CH 2 ),2.51(s,3H,-C 3 H-C 3 H 3 NS)； 13 C NMR(100MHz CDCl 3 )δ:163.64,156.41,155.46,145.43,143.70,142.99,136.34,130.12,130.03,129.74,129.43,128.05,127.80,125.54,121.96,119.97,117.77,116.94,116.14,115.92,115.86,34.04,12.16；MS(ESI)m/z calcd for C 26 H 21 FN 2 O 3 S([M+H]+)461.13,found 461.30.
EXAMPLE 11 Synthesis of Thiazolylamidoisomagnoflorine derivatives (Compound 11)
physicochemical constants and spectral data of compound 11: white solid, yield: 52.7 percent; melting point: 140 to 143 ℃; IR cm -1 (KBr):2919,1666,1541,1469,1302,1263,1208,668； 1 H NMR(400MHz CDCl 3 )δ:7.44-7.48(m,3H,-Ph),7.35(t,J＝7.2Hz,1H,-Ph),7.20-7.24(m,2H,-Ph),6.91-6.99(m,3H,-Ph),6.78-6.79(m,2H,-Ph),5.97-6.07(m,1H,-CH＝CH 2 ),5.07-5.12(m,2H,-C 2 H＝CH),3.44(d,J＝6.4Hz,2H,-C 2 H-CH＝CH 2 ),2.52(s,3H,-C 3 H-C 3 H 3 NS),2.49(s,3H,-C 3 H-Ph)； 13 C NMR(100MHz CDCl 3 )δ:166.66,156.18,154.78,145.35,143.96,143.24,137.91,136.34,132.91,131.68,131.36,129.89,129.72,127.74,127.18,126.01,125.35,121.64,119.91,117.87,116.77,115.80,34.00,20.27,12.17；MS(ESI)m/z calcd for C 27 H 24 N 2 O 3 S([M+H]+)457.15,found 457.37.
Example 12 Synthesis of Thiazolylamidoisomagnoflorine derivatives (Compound 12)
Compound 12 was synthesized by reacting compound (c) with 3-methylbenzoic acid using the procedure described in example 1, compound 12 having the following structure:
physicochemical constants and spectral data for compound 12: brown solid, yield: 56.8 percent; melting point: 52-55 ℃; IR cm -1 (KBr):3050,2918,2850,1670,1541,1469,1299,1263,1208,735； 1 H NMR(400MHz CDCl 3 )δ:7.77(s,1H,-Ph),7.73(d,J＝6Hz,1H,-Ph),7.50(d,J＝8.4Hz,2H,-Ph),7.36(d,J＝6Hz,2H,-Ph),7.02(d,J＝8.4Hz,2H,-Ph),6.93(d,J＝6Hz,1H,-Ph),6.79-6.80(m,2H,-Ph),6.00-6.10(m,1H,-CH＝CH 2 ),5.08-5.14(m,2H,-C 2 H＝CH),3.47(d,J＝6.4Hz,2H,-C 2 H-CH＝CH 2 ),2.51(s,3H,-C 3 H-C 3 H 3 NS),2.41(s,3H,-C 3 H-Ph)； 13 C NMR(100MHz CDCl 3 )δ:164.75,156.26,155.28,145.41,144.18,143.20,138.80,136.37,133.56,131.90,130.00,129.87,128.78,128.21,127.73,125.40,124.58,121.86,119.93,117.85,116.82,115.81,34.03,21.36,12.15；MS(ESI)m/z calcd for C 27 H 24 N 2 O 3 S([M+H]+)457.15,found 457.41.
Example 13 Synthesis of Thiazolylamidoisomagnoflorine derivatives (Compound 13)
physicochemical constants and spectral data for compound 13: yellow solid, yield: 54.9 percent; melting point: 160-163 ℃; IR cm -1 (KBr):2917,2850,1671,1541,1468,1294,1264,1200,668； 1 H NMR(400MHz CDCl 3 )δ:7.80(d,J＝7.6Hz,2H,-Ph),7.49(d,J＝8.4Hz,2H,-Ph),7.28(s,2H,-Ph),7.00(d,J＝8.4Hz,2H,-Ph),6.93(d,J＝6.8Hz,1H,-Ph),6.75-6.82(m,2H,-Ph),6.00-6.10(m,1H,-CH＝CH 2 ),5.08-5.14(m,2H,-C 2 H＝CH),3.47(d,J＝6.4Hz,2H,-C 2 H-CH＝CH 2 ),2.50(s,3H,-C 3 H-C 3 H 3 NS),2.42(s,3H,-C 3 H-Ph)； 13 C NMR(100MHz CDCl 3 )δ:164.43,156.19,155.01,145.39,144.23,143.58,143.23,136.38,130.12,129.82,129.60,129.11,127.72,127.46,125.36,121.86,119.91,117.88,116.78,115.80,34.02,21.60,12.17；MS(ESI)m/z calcd for C 27 H 24 N 2 O 3 S([M+H]+)457.15,found 457.34.
Example 14 Synthesis of Thiazolylamidoisomagnoflorine derivatives (Compound 14)
Compound 14 was synthesized by reacting compound (c) with 2-methoxybenzoic acid using the procedure described in example 1, compound 14 having the following structure:
physicochemical constants and spectral data for compound 14: white solid, yield: 71.6 percent; melting point: 170-173; IR cm -1 (KBr):2917,1657,1541,1468,1305,1260,755； 1 H NMR(400MHz CDCl 3 )δ:8.30(d,J＝7.6Hz,1H,-Ph),7.59(d,J＝8.4Hz,2H,-Ph),7.53(t,J＝7.6Hz,1H,-Ph),7.13(t,J＝7.2Hz,1H,-Ph),7.04(t,J＝8.8Hz,3H,-Ph),6.92(d,J＝4Hz,1H,-Ph),6.78(d,J＝4.4Hz,2H,-Ph),6.02-6.09(m,1H,-CH＝CH 2 ),5.08-5.14(m,2H,-C 2 H＝CH),4.08(s,3H,-OC 3 H-Ph)；3.47(d,J＝6.4Hz,2H,-C 2 H-CH＝CH 2 ),2.51(s,3H,-C 3 H-C 3 H 3 NS), 13 C NMR(100MHz CDCl 3 )δ:162.52,157.77,156.09,154.19,145.35,144.63,143.42,136.41,134.37,132.69,130.76,129.96,127.65,125.25,121.96,121.70,119.88,119.23,118.04,116.64,115.76,111.56,56.29,34.02,12.17；MS(ESI)m/z calcd for C 27 H 24 N 2 O 4 S([M+H]+)473.15,found 473.41.
Example 15 Synthesis of Thiazolylamidoisomagnoflorine derivatives (Compound 15)
Compound 15 was synthesized by reacting compound (c) with 3-methoxybenzoic acid using the procedure described in example 1, compound 15 having the following structure:
physicochemical constants and spectral data for compound 15: yellow solid, yield: 33%; melting point: 135-137 ℃; IR cm -1 (KBr):3073,2917,2849,1676,1551,1467,1265,1046,668； 1 H NMR(400MHz CDCl 3 )δ:7.42(t,J＝8.4Hz,3H,-Ph),7.36(d,J＝7.6Hz,1H,-Ph),7.28(t,J＝8Hz,1H,-Ph),7.05(d,J＝8Hz,1H,-Ph),6.93-6.96(m,3H,-Ph),6.74-6.81(m,2H,-Ph),6.02-6.08(m,1H,-CH＝CH 2 ),5.09-5.14(m,2H,-C 2 H＝CH),3.84(s,3H,-OC 3 H-Ph),3.47(d,J＝6.4Hz,2H,-C 2 H-CH＝CH 2 ),2.51(s,3H,-C 3 H-C 3 H 3 NS), 13 C NMR(100MHz CDCl 3 )δ:164.55,159.90,156.23,155.02,145.45,144.42,143.15,136.39,133.41,130.04,129.84,129.75,127.76,125.40,121.94,119.90,119.26,117.78,116.86,115.80,112.46,55.46,34.02,12.16；MS(ESI)m/z calcd for C 27 H 24 N 2 O 4 S([M+H]+)473.15,found 473.37.
EXAMPLE 16 Synthesis of Thiazolylamidoisomagnoflorine derivatives (Compound 16)
Compound 16 was synthesized by reacting compound (c) with 4-methoxybenzoic acid using the procedure described in example 1, compound 16 having the following structure:
physicochemical constants and spectral data for compound 16: yellow solid, yield: 29 percent; melting point: 168-170 ℃; IR cm -1 (KBr):2919,2850,1663,1605,1533,1513,1470,1258,1174,668； 1 H NMR(400MHz CDCl 3 )δ:7.83-7.86(m,2H,-Ph),7.48-7.51(m,2H,-Ph),6.90-7.01(m,5H,-Ph),6.77-6.81(m,2H,-Ph),6.00-6.10(m,1H,-CH＝CH 2 ),5.08-5.14(m,2H,-C 2 H＝CH),3.86(s,3H,-OC 3 H-Ph)；3.47(d,J＝6.4Hz,2H,-C 2 H-CH＝CH 2 ),2.50(s,3H,-C 3 H-C 3 H 3 NS), 13 C NMR(100MHz CDCl 3 )δ:163.96,163.21,156.15,145.40,144.28,143.23,136.39,130.29,129.79,129.41,127.72,125.36,124.18,121.75,119.91,117.84,116.79,115.80,114.13,55.52,34.02,12.17；MS(ESI)m/z calcd for C 27 H 24 N 2 O 4 S([M+H]+)473.15,found 473.37.
Example 17 Synthesis of Thiazolylamidoisomagnoflorine derivatives (Compound 17)
Compound 17 was synthesized by reacting compound (c) with 2, 4-dichlorobenzoic acid using the procedure described in example 1, compound 17 having the following structure:
physicochemical constants and spectral data for compound 17: yellow solid, yield: 35.6 percent; melting point: 70-73 ℃; IR cm -1 (KBr):2918,2849,1668,1555,1469,1304,1262,1209,668； 1 H NMR(400MHz CDCl 3 )δ:7.53(t,J＝6Hz,1H,-Ph),7.41(d,J＝7.2Hz,2H,-Ph),7.36(s,1H,-Ph),7.21-7.23(m,1H,-Ph),6.99(d,J＝8Hz,2H,-Ph),6.95(d,J＝4.4Hz,1H,-Ph),6.82(d,J＝3.6Hz,2H,-Ph),6.00-6.10(m,1H,-CH＝CH 2 ),5.09-5.14(m,2H,-C 2 H＝CH),3.47(d,J＝6.4Hz,2H,-C 2 H-CH＝CH 2 ),2.50(s,3H,-C 3 H-C 3 H 3 NS), 13 C NMR(100MHz CDCl 3 )δ:162.92,156.62,155.11,145.53,143.26,142.81,138.23,136.32,132.44,131.42,130.53,129.59,128.82,127.86,127.56,125.74,122.07,120.03,117.56,117.25,115.86,34.05,12.22；MS(ESI)m/z calcd for C 26 H 20 35 Cl 2 N 2 O 3 S([M+H]+)511.06,found 511.35；calcd for C 26 H 20 37 Cl 2 N 2 O 3 S([M+H]+)513.06,found 513.34.
Example 18 Synthesis of Thiazolylamidoisomagnoflorine derivatives (Compound 18)
Compound 18 was synthesized by reacting compound (c) with 2-chloro-4-fluorobenzoic acid using the procedure described in example 1, compound 18 having the following structure:
physicochemical constants and spectral data for compound 18: white solid, yield: 60 percent; melting point: 155-158 ℃; IR cm -1 (KBr):3073,2920,1674,1549,1470,1305,1265,1210,925； 1 H NMR(400MHz CDCl 3 )δ:7.59-7.67(m,1H,-Ph),7.40-7.43(m,2H,-Ph),7.09-7.11(m,1H,-Ph),6.95-6.99(m,4H,-Ph),6.81(d,J＝4Hz,2H,-Ph),5.99-6.09(m,1H,-CH＝CH 2 ),5.08-5.14(m,2H,-C 2 H＝CH),3.46(d,J＝6.4Hz,2H,-C 2 H-CH＝CH 2 ),2.49(s,3H,-C 3 H-C 3 H 3 NS), 13 C NMR(100MHz CDCl 3 )δ:156.34,154.50,145.51,144.29,142.98,136.33,132.87,132.79,132.47,129.73,129.63,129.59,128.73,127.83,125.63,122.19,119.99,118.19,117.94,117.61,117.55,117.15,117.08,115.83,114.70,114.58,34.04,12.21；MS(ESI)m/z calcd for C 26 H 20 35 ClFN 2 O 3 S([M+H]+)495.09,found 495.39；calcd for C 26 H 20 37 ClFN 2 O 3 S([M+H]+)497.09,found 497.36.
Example 19 Synthesis of Thiazolylamidoisomagnoflorine derivatives (Compound 19)
Compound 19 was synthesized by reacting compound (c) with 4-cyanobenzoic acid using the procedure described in example 1, compound 19 having the following structure:
physicochemical constants and spectral data for compound 19: yellow solid, yield: 40 percent; melting point: 191 to 193 ℃; IR cm -1 (KBr):2919,2850,2233,1674,1537,1467,1290,1261,1201,668； 1 H NMR(400MHz CDCl 3 )δ:7.86(d,J＝8Hz,2H,-Ph),7.63(d,J＝8Hz,2H,-Ph),7.36(d,J＝8.4Hz,2H,-Ph),6.95(d,J＝7.2Hz,1H,-Ph),6.90(d,J＝8.4Hz,2H,-Ph),6.80(t,J＝7.6Hz,1H,-Ph),6.72(d,J＝8Hz,1H,-Ph),6.00-6.10(m,1H,-CH＝CH 2 ),5.10-5.15(m,2H,-C 2 H＝CH),3.47(d,J＝6.4Hz,2H,-C 2 H-CH＝CH 2 ),2.52(s,3H,-C 3 H-C 3 H 3 NS)； 13 C NMR(100MHz CDCl 3 )δ:163.37,156.54,155.52,145.48,144.05,142.75,136.29,135.80,132.43,129.68,129.22,128.16,127.95,125.79,122.53,120.06,117.72,117.54,117.14,116.01,115.92,34.05,12.17；MS(ESI)m/z calcd for C 27 H 21 N 3 O 3 S([M+H]+)468.13,found 468.29.
Example 20 Synthesis of Thiazolylamidoisomagnoflorine derivatives (Compound 20)
Compound 20 was synthesized by reacting compound (c) with 4-nitrobenzoic acid using the procedure described in example 1, compound 20 having the following structure:
physicochemical constants and spectral data for compound 20: yellow solid, yield: 27.7 percent; melting point: 172-174 ℃; IR cm -1 (KBr):2920,2850,1675,1543,1467,1344,1263,851,668； 1 H NMR(400MHz CDCl 3 )δ:8.19(d,J＝8.4Hz,2H,-Ph),7.98(d,J＝8.8Hz,2H,-Ph),7.37(d,J＝8.4Hz,2H,-Ph),6.95(d,J＝7.2Hz,1H,-Ph),6.90(d,J＝8.4Hz,2H,-Ph),6.80(t,J＝7.6Hz,1H,-Ph),6.74(d,J＝8Hz,1H,-Ph),6.00-6.10(m,1H,-CH＝CH 2 ),5.10-5.15(m,2H,-C 2 H＝CH),3.47(d,J＝6.4Hz,2H,-C 2 H-CH＝CH 2 ),2.51(s,3H,-C 3 H-C 3 H 3 NS)； 13 C NMR(100MHz CDCl 3 )δ:163.21,156.56,155.64,150.08,145.49,144.20,142.73,137.48,136.30,129.77,129.25,128.81,127.94,125.78,123.83,122.61,120.03,117.51,117.14,115.91,34.05,12.16；MS(ESI)m/z calcd for C 26 H 21 N 3 O 5 S([M+H]+)488.12,found 488.38.
Example 21 Synthesis of Thiazolylamidoisomagnoflorine derivatives (Compound 21)
Compound 21 was synthesized by reacting compound (c) with 4-aldehyde benzoic acid using the procedure described in example 1, compound 21 having the following structure:
physicochemical constants and spectral data of compound 21: yellow solid, yield: 26.7 percent; melting point: 106-110 ℃; IR cm -1 (KBr):3073,2920,1674,1549,1470,1305,1265,1210,925； 1 H NMR(400MHz CDCl 3 )δ:10.05(s,1H,-CHO),7.92(d,J＝8Hz,2H,-Ph),7.84(d,J＝7.6Hz,2H,-Ph),7.35(d,J＝8.4Hz,2H,-Ph),6.93(d,J＝7.2Hz,1H,-Ph),6.85(d,J＝8.4Hz,2H,-Ph),6.78(t,J＝7.6Hz,1H,-Ph),6.70(d,J＝8Hz,1H,-Ph),6.00-6.08(m,1H,-CH＝CH 2 ),5.09-5.14(m,2H,-C 2 H＝CH),3.47(d,J＝6.4Hz,2H,-C 2 H-CH＝CH 2 ),2.51(s,3H,-C 3 H-C 3 H 3 NS)； 13 C NMR(100MHz CDCl 3 )δ:191.38,163.82,156.50,155.52,145.48,144.22,142.92,138.88,136.96,136.34,130.78,129.91,129.64,129.41,128.34,127.83,125.61,122.32,119.98,118.28,117.68,117.05,115.85,34.04,12.12；MS(ESI)m/z calcd for C 27 H 22 N 2 O 4 S([M+H]+)471.13,found 471.33.
EXAMPLE 22 Synthesis of Thiazolylamidoisomagnoflorine derivatives (Compound 22)
Compound 22 was synthesized by reacting compound (c) with phenylacetic acid using the procedure described in example 1, compound 22 having the following structure:
physicochemical constants and spectral data for compound 22: brown solid, yield: 21.4 percent; melting point: 155 to 158 ℃; IR cm -1 (KBr):3077,2995,2920,1655,1560,1469,1310,1264,719,668； 1 H NMR(400MHz CDCl 3 )δ:7.46(d,J＝8Hz,2H,-Ph),7.27-7.38(m,5H,-Ph),7.03(d,J＝8.4Hz,2H,-Ph),6.93(s,1H,-Ph),6.77(d,J＝4Hz,2H,-Ph),5.99-6.09(m,1H,-CH＝CH 2 ),5.08-5.14(m,2H,-C 2 H＝CH),3.72(s,2H,-C 2 H-CONH),3.46(d,J＝6.4Hz,2H,-C 2 H-CH＝CH 2 ),2.45(s,3H,-C 3 H-C 3 H 3 NS)； 13 C NMR(100MHz CDCl 3 )δ:168.76,156.41,154.86,145.40,143.73,143.09,136.35,133.11,129.91,129.78,129.53,129.21,127.84,127.72,125.46,121.79,119.94,117.92,116.86,115.81,43.23,34.01,12.05；MS(ESI)m/z calcd for C 27 H 24 N 2 O 3 S([M+H]+)457.15,found 457.34.
Example 23 Synthesis of Thiazolylamidoisomagnoflorine derivatives (Compound 23)
Compound 23 was synthesized by reacting compound (c) with 4-fluorophenylacetic acid using the procedure described in example 1, compound 23 having the following structure:
physicochemical constants and spectral data for compound 23: yellow solid, yield: 25.4 percent; melting point: 158-160 ℃; IR cm -1 (KBr):3049,2973,2919,2849,1686,1546,1509,1468,1265,1221,1156,835； 1 H NMR(400MHz CDCl 3 )δ:7.48(d,J＝8.4Hz,2H,-Ph),7.18-7.22(m,2H,-Ph),7.00(t,J＝8.4Hz,4H,-Ph),6.93(d,J＝6.8Hz,1H,-Ph),6.75-6.81(m,2H,-Ph),6.01-6.07(m,1H,-CH＝CH 2 ),5.09-5.14(m,2H,-C 2 H＝CH),3.59(s,2H,-C 2 H-CONH),3.46(d,J＝6Hz,2H,-C 2 H-CH＝CH 2 ),2.46(s,3H,-C 3 H-C 3 H 3 NS)； 13 C NMR(100MHz CDCl 3 )δ:168.61,161.14,156.80,155.32,145.45,142.86,142.48,136.31,131.16,131.08,129.84,128.81,128.64,127.85,125.67,121.76,120.02,117.95,117.04,116.16,115.94,115.87,42.08,34.04,12.07；MS(ESI)m/z calcd for C 27 H 23 FN 2 O 3 S([M+H]+)475.14,found 475.42.
Example 24 Synthesis of Thiazolylamidoisomagnoflorine derivatives (Compound 24)
Compound 24 was synthesized by reacting compound (c) with acetic acid using the procedure described in example 1, compound 24 having the structure:
physicochemical constants and spectral data for compound 24: white solid, yield: 58.4 percent; melting point: 108-110 ℃; IR cm -1 (KBr):3078,3000,2921,1654,1557,1470,1296,1266,1224,1201,985,852,740； 1 H NMR(400MHz CDCl 3 )δ:7.53(d,J＝8Hz,2H,-Ph),7.05(d,J＝8.4Hz,2H,-Ph),6.94(d,J＝6.4Hz,1H,-Ph),6.78-6.83(m,2H,-Ph),6.00-6.10(m,1H,-CH＝CH 2 ),5.09-5.14(m,2H,-C 2 H＝CH),3.47(d,J＝6.4Hz,2H,-C 2 H-CH＝CH 2 ),2.48(s,3H,-C 3 H-C 3 H 3 NS),1.81(s,3H,-C 3 H-CONH)； 13 C NMR(100MHz CDCl 3 )δ:168.08,156.61,155.90,145.45,143.01,136.33,129.95,129.66,127.83,125.61,121.47,120.03,117.98,116.93,115.86,34.04,22.52,12.03；MS(ESI)m/z calcd for C 21 H 20 N 2 O 3 S([M+H]+)381.12,found 381.22.
Example 25 Synthesis of Thiazolylamidoisomagnoflorine derivatives (Compound 25)
Compound 25 was synthesized by reacting compound (c) with chloroacetic acid using the procedure described in example 1, compound 25 having the following structure:
physicochemical constants and spectral data of compound 25: white solid, yield: 52.9 percent; melting point: 173-175 ℃; IR cm -1 (KBr):3179,3061,2999,2874,1654,1583,1496,1470,1267,1225,853； 1 H NMR(400MHz CDCl 3 )δ:7.54(d,J＝8.4Hz,2H,-Ph),7.06(d,J＝8.4Hz,2H,-Ph),6.93(d,J＝4Hz,1H,-Ph),6.80(d,J＝4.4Hz,2H,-Ph),6.00-6.10(m,1H,-CH＝CH 2 ),5.09-5.14(m,2H,-C 2 H＝CH),4.18(s,2H,-C 2 H-CONH),3.47(d,J＝6.4Hz,2H,-C 2 H-CH＝CH 2 ),2.50(s,3H,-C 3 H-C 3 H 3 NS)； 13 C NMR(100MHz CDCl 3 )δ:164.04,156.73,153.84,145.44,143.45,143.00,136.34,129.87,129.01,127.80,125.58,122.43,120.00,118.02,116.98,115.84,41.91,34.03,12.19；MS(ESI)m/z calcd for C 21 H 19 35 ClN 2 O 3 S([M+H]+)415.08,found 415.21；calcd for C 21 H 19 37 ClN 2 O 3 S([M+H]+)417.08,found 417.21.
EXAMPLE 26 Synthesis of Thiazolylamidoisomagnoflorine derivatives (Compound 26)
Compound 26 was synthesized by reacting compound (c) with propionic acid using the procedure described in example 1, compound 26 having the structure:
physicochemical constants and spectral data for compound 26: yellow solid, yield: 40.9 percent; melting point: 70-73 ℃; IR cm -1 (KBr):3059,2920,2852,1685,1549,1497,1469,1264,1211,1167,981,837,668； 1 H NMR(400MHz CDCl 3 )δ:7.45(d,J＝7.6Hz,2H,-Ph),7.16-7.23(m,3H,-Ph),7.08(d,J＝6.8Hz,2H,-Ph),6.98(d,J＝8Hz,2H,-Ph),6.93(d,J＝6.8Hz,1H,-Ph),6.75-6.81(m,2H,-Ph),6.00-6.10(m,1H,-CH＝CH 2 ),5.09-5.14(m,2H,-C 2 H＝CH),3.46(d,J＝6Hz,2H,-C 2 H-CH＝CH 2 ),2.91(t,J＝7.6Hz,2H,-C 2 H-Ph),2.46(s,3H,-C 3 H-C 3 H 3 NS),2.39-2.43(m,2H,-C 2 H-CONH)； 13 C NMR(100MHz CDCl 3 )δ:170.07,156.39,145.43,143.51,142.97,140.01,136.34,129.86,128.51,128.24,127.76,126.38,125.55,121.56,119.98,117.87,116.92,115.85,37.30,34.03,30.79,12.07；MS(ESI)m/z calcd for C 28 H 26 N 2 O 3 S([M+H]+)471.17,found 471.42.
Application example: experiment for inhibiting activity of plant pathogenic fungi:
1. experimental Material
Anhydrous glucose, agar and acetone
2. Sample to be tested
Isomagnoflorine, target compound 1-26 and hymexazol
3. Test strains
Wheat scab (Fusarium graminearum), alternaria tabaci (Alternaria alternata), potato blight (Fusarium solani), and potato wilt (Fusarium oxysporum). The test strains were purchased and introduced to the agricultural academy of Henan province, and then subcultured in this laboratory.
4. The bioassay method comprises the following steps:
preparing a PDA culture medium: peeling fresh potatoes, weighing 200g, dicing, adding ultrapure water, boiling for about 30min, filtering out potato residues by using a plurality of layers of gauze, only keeping filtrate, and adding ultrapure water to ensure that the volume of the filtrate is 1000mL. And weighing 20g of glucose, adding the glucose into the filtrate, stirring and dissolving, then weighing 20g of agar, adding the agar into the filtrate, stirring uniformly, filtering to remove residues, subpackaging the culture solution in a plurality of 250mL triangular flasks, and sealing. The dishes and the culture solution were sterilized in an autoclave (121 ℃ C., 30 min), and about 12.5mL of PDA culture solution was poured into each dish while it was still hot, and cooled and solidified for use.
Activating and passaging strains: taking out the strain to be tested which is frozen in a refrigerator, inoculating the strain to be tested into a solidified culture dish by using a puncher and an inoculating loop under the aseptic condition, repeating each strain for three times, and putting the inoculated strain into an incubator at 28 ℃ for culture. Continuously culturing for 3 generations after the mycelium grows, observing the growth condition of the mycelium, and storing in a refrigerator at-4 deg.C if the growth condition is good. The strain was taken out 3 days before the experiment and activated once as described above, and placed in an incubator for use.
Preparing a liquid medicine: the compound 7.5mg was weighed and dissolved completely in 2mL of acetone solution to prepare a drug solution.
Preparation of a drug-containing culture medium: transferring the sterilized culture solution to a 200mL liquid phase bottle while the culture solution is hot, fixing the volume to 150mL, adding the prepared medicine solution, fully mixing to prepare a medicine-containing culture solution with the volume of 50 mu g/mL, and cooling and solidifying the medicine-containing culture solution; 2mL of acetone solution was added to 150mL of the culture medium to prepare a drug-free medium plate as a blank control.
Inoculating and culturing the fungus cake: punching activated strains to be tested on the edges of bacterial colonies by using a puncher with the inner diameter of 6mm to prepare bacterial cakes, picking the bacterial cakes into culture dishes containing a medicine-containing culture medium by using an inoculating loop, inoculating one bacterial cake into each culture dish, enabling the side with the hyphae to face downwards, covering with a mark, repeating the steps for three times for each group, and culturing in a constant-temperature incubator at the temperature of 28 ℃.
Measurement of data: the culture dishes in the incubator are cultured for 72 hours, the diameter of the colony on each dish is measured by a cross method after the culture dishes are taken out, and the inhibition rate is calculated according to the following formula.
Hypha growth inhibition (%) = (average value of blank colony diameter-average value of compound colony diameter)/(average value of blank colony diameter-0.6 cm)
5. Activity results:
the inhibition conditions of the isomagnoflorine, the hymexazol and the target compounds 1-26 are measured under the condition that the concentration is 50 mu g/mL by a hypha growth rate method, wherein acetone is used as a blank control, and the hymexazol is used as a positive control. The growth rate of the test strains containing the drug within 72 hours is measured, and specific activity data are shown in the following table 1. As can be seen from the table, for the tobacco alternaria alternate, the bacteriostatic activity of 15 compounds is superior to that of the parent isomagnoflorine, wherein the bacteriostatic activity of the compounds 3 and 23 is more than 60 percent and is superior to that of a positive control medicament hymexazol; for wheat scab, the activity of 12 compounds is better than that of isomagnoflorine, wherein the compounds 20-24 and 26 are more prominent, the bacteriostasis rates are respectively 61.9%, 63.5%, 64.2%, 53.6%, 58.2% and 58.5%, and the inhibition activity is better than that of hymexazol; the isomagnoflorine has a weak inhibition activity on potato dry rot, the inhibition rate of the isomagnoflorine is 29.5%, the majority of the inhibition activity of the target compound is higher than that of the parent compound, wherein the compounds 22 and 23 show the inhibition activity superior to hymexazol, and the inhibition rates are 47.5% and 51.1% respectively. For potato blight bacteria, the inhibition rate of most target compounds is higher than that of a parent isomagnoflorine, wherein the inhibition rates of the compounds 1-16 and 22 exceed that of a positive drug hymexazol, the compounds 3 and 6 are best in performance, the inhibition rates are respectively 60.6% and 66.5%, and the inhibition rates are superior to that of the positive drug hymexazol.
TABLE 1 inhibitory Activity of target Compounds 1-30 against four plant pathogenic fungi
Note: hymexazol is a positive drug; the concentration of the test drug is 50 mug/mL; the activity values are the average of three sets of data.
In conclusion, the thiazole amide isomagnoline derivatives 3, 20-24 and 26 prepared by introducing thiazole amide groups through structure optimization show better antibacterial activity, and the inhibition rate of the thiazole amide isomagnoline derivatives on tobacco gibberellin, wheat gibberellin, potato dry rot or potato blight bacteria is superior to that of a market bacteriostatic agent hymexazol, so that the thiazole amide isomagnoline derivatives prepared by the invention are expected to be used as efficient natural product bacteriostatic agents.
Claims (8)
1. A thiazole amide isomagnoline derivative has a chemical structure shown as a general formula (I):
r is selected from C1-C4 alkyl, C1-C4 haloalkyl, substituted or unsubstituted phenyl, or
Wherein n =1 or 2,R 1 One selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen, nitro, aldehyde group or cyano;
the substituted phenyl is phenyl substituted by C1-C4 alkyl, C1-C4 alkoxy, halogen, nitro, aldehyde or cyano.
2. The thiazolylamidoisomagnanide derivative of claim 1, wherein said substituted phenyl is mono-or di-substituted with a substituent selected from one or two of C1-C4 alkyl, C1-C4 alkoxy, halogen, nitro, aldehyde, or cyano.
3. The thiazolylamidoisomagnanidine derivative of claim 1, wherein R is selected from the group consisting of:
4. a process for the preparation of thiazolylamidoisomagnoline derivatives as claimed in any one of claims 1 to 3, comprising the steps of:
(1) Taking isomagnoflorine (a) as a raw material, and carrying out bromination reaction on the isomagnoflorine (a) and copper bromide to obtain brominated isomagnoflorine (b);
(2) Reacting the bromo-isomagnoflorine (b) with thiourea to obtain amino thiazole substituted isomagnoflorine (c);
(3) Finally, the amido thiazole substituted isomagnoflorine (c) reacts with RCOOH to obtain the compound with the general formula (I);
wherein R is as defined in any one of claims 1 to 3.
5. The method for preparing thiazolylamidoisomagnoline derivatives according to claim 4, wherein the reaction of step (1) is performed in ethyl acetate and chloroform at a temperature of 60-70 ℃.
6. The method for preparing thiazolylamidoisomagnanidine derivatives according to claim 4, wherein the reaction in step (2) is performed in absolute ethanol at a temperature of 45-55 ℃.
7. The method for preparing thiazolylamidoisomagnoline derivatives according to claim 4, wherein the reaction of step (3) is performed in anhydrous dichloromethane while HATU and triethylamine are added, and the reaction is performed at room temperature.
8. Use of thiazolylamidoisomagnoline derivatives according to any one of claims 1 to 3 as bacteriostatic agents.
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| CN1419547A (en) * | 2000-01-24 | 2003-05-21 | 盐野义制药株式会社 | Compounds exhibiting thrombopoietin receptor agaonism |
| CN1516696A (en) * | 2001-01-26 | 2004-07-28 | 盐野义制药株式会社 | Halogen compounds having thrombopoietin receptor agonism |
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| CN1419547A (en) * | 2000-01-24 | 2003-05-21 | 盐野义制药株式会社 | Compounds exhibiting thrombopoietin receptor agaonism |
| CN1516696A (en) * | 2001-01-26 | 2004-07-28 | 盐野义制药株式会社 | Halogen compounds having thrombopoietin receptor agonism |
| CN111996614A (en) * | 2020-07-14 | 2020-11-27 | 嘉兴市爵拓科技有限公司 | Antibacterial nanofiber material and application thereof |
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