CN115925686A - Meridianin derivatives, coupling synthesis method and application thereof promoted by Lewis acid - Google Patents

Meridianin derivatives, coupling synthesis method and application thereof promoted by Lewis acid Download PDF

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CN115925686A
CN115925686A CN202211347767.2A CN202211347767A CN115925686A CN 115925686 A CN115925686 A CN 115925686A CN 202211347767 A CN202211347767 A CN 202211347767A CN 115925686 A CN115925686 A CN 115925686A
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meridianin
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杨元勇
耿会丹
贾学敏
汤磊
陈飞
王会
陈伟
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Guizhou Medical University
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Abstract

The invention belongs to the technical field of synthesis of Meridianin derivatives, and particularly relates to a Meridianin derivative, a coupling synthesis method promoted by Lewis acid and application thereof. The method promotes indole 16 and 2-amino-4-chloropyrimidine 17 to directly synthesize Meridianin family and analogues thereof in one step through Lewis acid. The synthesis method has high yield and short route. The compound provided by the invention has better biological membrane inhibition activity, wherein IC 50 The better 4 compounds can reduce the MIC values of gentamicin sulfate and ceftriaxone sodium.

Description

Meridianin derivatives, coupling synthesis method and application thereof promoted by Lewis acid
Technical Field
The invention belongs to the technical field of synthesis of Meridianin derivatives, and particularly relates to a Meridianin derivative and coupling synthesis and application thereof promoted by Lewis acid.
Background
Indole is an aromatic heterocyclic organic compound formed by fusing a benzene ring and a pyrrole ring. Indole nuclei are widely present in a wide variety of biologically active and pharmacological molecules, and many clinical drugs, such as sumatriptan and indomethacin, contain indole fragments. Indole cores are also frequently present in alkaloids such as the cephaloenone C and Meridianin families, etc. (see figure 1). The Meridianin family and its respective derivatives have shown a variety of biological activities, including kinase inhibition, adipogenesis inhibition, anti-tumor activity, and anti-malarial activity, among others. Meridianin G analogs have been reported to have antibacterial activity against staphylococcus aureus, methicillin-resistant staphylococcus aureus, mycobacteria, escherichia coli, and pseudomonas aeruginosa. In addition, some Meridianin analogs have also been proposed as drugs for the treatment of neurodegenerative diseases and potential therapeutic approaches for alzheimer's disease.
There are several major methods for the synthesis of Meridianin:
(1) The most representative and most widely used strategy studied is Bredereck cyclization, the formation of the indole skeleton at the C-3 position by condensation of a carbonyl-containing group with a 2-aminopyrimidine system (usually with guanidine). In 2000, fresnel et al reported the results of the first synthesis of Meridianin C-E they developed. They underwent Friedel-Crafts acetylation at the indole 3-position to provide N-tosyl-3-acetylindoles (1 a-c) with different substituents. Treatment with dimethylformamide dimethyl acetal (DMF-DMA) at 110 deg.C gave enaminone intermediate (2 a-c) which was at K 2 CO 3 Treatment with guanidine hydrochloride in the presence resulted in N-demethylation of the phenyl and concomitant Bredereck cyclization to give Meridianin C and D. Then, hydrogen and Pd/C are used as catalysts for reduction and debenzylation to obtain Meridianin E;
(2) Catalyzing a coupling reaction between an indole nucleophilic reagent and an aminopyrimidine electrophilic reagent, namely bromination is carried out on N-tosyl-3-bromoindole (3) to obtain N-tosyl-3, 6-dibromo indole (4) by Jiang and colleagues, tert-butyl lithium is added into tetrahydrofuran at-78 ℃, trimethoxy borane and water are added for treatment to obtain N-tosyl-6-bromo-3-indolyl boric acid (5), the acid reacts with one equivalent of 2-amino-4-chloropyrimidine under the Pd catalysis condition to obtain N-tosymmeridin D (6), and finally sodium hydroxide is used for treating and removing N-tosyl to obtain meridin D (7);
(3) The monocyclic precursor is cyclized de novo to form an indole framework with an intercalating function, further modified to yield the target compound. Bleda et al prepared 4-benzyloxy-7-bromoindole (8), which is the starting material for the synthesis of Meridianin a and E, from 5-bromo-2-hydroxybenzaldehyde starting from benzyl protected hydroxyl groups in the presence of NaH, aldol condensation with ethyl azidoacetate at-15 ℃ in the presence of NaOEt, followed by refluxing in toluene, indolylation of the resulting ethyl α -azido- β -arylacrylate to form indole, followed by ester hydrolysis under LiOH and decarboxylation in quinoline at high temperature in the presence of copper. Indole (8) is reacted with acetyl chloride in the presence of tin (IV) tetrachloride at reflux temperature to give 3-acetylated indole (9), which is N-protected with p-toluenesulfonyl chloride to give the desired N-toluenesulfonyl-3-acetylindole (10). Then carrying out Bredereck cyclization to obtain a precursor 11, carrying out debromination on the precursor to obtain Meridianin A, and carrying out debenzylation to obtain Meridianin E; in addition, penoni et al reported that compound 12 reacts rapidly under Sonogashira conditions to give 2-amino-4- [ trimethylsilylethynyl ] pyrimidine intermediate 13, which is deprotected under basic conditions to convert to terminal alkyne 14. They cyclize with nitroso-aromatic hydrocarbons under standard conditions using compound 14 as a substrate to provide various Meridianin analogs 15 with substitutions.
There are several main routes of methods for the synthesis of Meridianin:
1. synthesis of Meridianin by Bredereck cyclization (2000, frisneda task group)
Figure SMS_1
2. Catalytic coupling reaction between indole nucleophiles and aminopyrimidines electrophiles (2000, jiang task group)
Figure SMS_2
3. Preparation of Meridianin family members from the De novo cyclization of monocyclic precursors
a. Starting from 5-bromo-2-hydroxybenzaldehyde (2001, bleda task group)
Figure SMS_3
b. 2-amino-4-chloropyrimidine as a raw material (Bleda project group 2010)
Figure SMS_4
Despite considerable progress in the preparation of the Meridianin family of indole derivatives, the direct and practical synthesis of the Meridianin family from indoles remains a significant challenge. We sought to develop a more efficient and direct process by promoting the direct one-step synthesis of the Meridianin family and its analogues with indole 16 and 2-amino-4-chloropyrimidine 17 via lewis acids. Here, we report the results of this synthetic method, using indium triflate as a promoter.
The route for one-step synthesis of the Meridianin family and derivatives thereof by coupling 2-amino-4-chloropyrimidine with lewis acid promoted indole is as follows:
Figure SMS_5
disclosure of Invention
In order to solve the defects of the prior art, the invention provides a Meridianin derivative, a coupling synthesis method promoted by Lewis acid and application thereof. The method promotes indole 16 and 2-amino-4-chloropyrimidine 17 to directly synthesize the Meridianin family and the analogues thereof in one step through Lewis acid. The synthesis method has high yield and short route.
The technical scheme provided by the invention is as follows:
novel derivatives of the Meridianin class having the formula:
Figure SMS_6
the overall synthetic route for compound 18y is as follows:
Figure SMS_7
the overall synthetic route for compound 18z is as follows:
Figure SMS_8
the overall synthetic route for compound 18aa is as follows:
Figure SMS_9
the compounds are provided for the first time and all have a biological membrane inhibiting effect.
The invention also provides a method for synthesizing the Meridianin derivatives in one step by the Lewis acid promoted coupling reaction, which comprises the following steps:
Figure SMS_10
R 1 -R 6 all are hydrogen;
or, R 1 Or R 2 Is hydrogen CH 3 And all are hydrogen;
or, R 1 And R 2 Are all hydrogen, R 3 -R 6 One of them is Br, cl, OH, F, NO 2 、CH 3 、CH 3 O or CF 3 ；
Or, R 3 -R 6 Two of the substituents are not hydrogen, and the two substituents are Br, cl and CH respectively 3 O or OH, and the two substituents are the same or different.
The synthesis method has the advantages of high yield, wide substrate range, few steps, mild conditions and the like, and the yield can reach 96%.
In particular, the reaction temperature is from 70 to 90 ℃, preferably 80 ℃, in particular, the In (OTf) used 3 The weight ratio of 2-amino-4-chloropyrimidine to (1.4-1.6) to 1, preferably In (OTf) used 3 The weight ratio of 2-amino-4-chloropyrimidine to 1.5.
The invention also provides application of the Meridianin derivatives in preparation of a biofilm inhibitor.
The inventor finds that the Meridianin has obvious biological membrane inhibition effect and can be used for preparing a biological membrane inhibitor. Especially against acinetobacter baumann ii 19606 strain.
Preferably, the structural formula of the Meridianin derivative is as follows:
Figure SMS_11
R 1 -R 6 all are hydrogen;
or, R 1 Or R 2 Is hydrogen CH 3 And all are hydrogen;
or, R 1 And R 2 Are all hydrogen, R 3 -R 6 One of them is Br, cl, OH, F, NO 2 、CH 3 、CH 3 O or CF 3 ；
Or, R 3 -R 6 Two of the substituents are not hydrogen, and the two substituents are Br, cl and CH respectively 3 O or OH, and the two substituents are the same or different.
More preferably, the structural formula of the Meridianin derivative is as follows:
Figure SMS_12
more preferably, the Meridianin derivative is the compound 18g, 18l, 18w or 18aa.
The four compounds have significant biofilm inhibition, especially against acinetobacter baumannii 19606 strain.
Preferably, the four compounds are combined with antibiotics, and have remarkable synergistic effect.
The invention uses simple and easily obtained indole and 2-amino-4-chloropyrimidine as starting materials, uses cheap indium trifluoromethanesulfonate as an accelerating agent to realize the coupling reaction between the indole and the 2-amino-4-chloropyrimidine, and obtains a natural product Meridianin A-G and derivatives thereof. The method has unique advantages on the substrate applicability, the reaction system has good substrate adaptability to electron-donating groups and electron-donating group-substituted indoles, and the Meridianin derivatives with structural diversity are efficiently generated.
Subjecting the prepared compound to IC 50 Among them, 9 compounds (table 2) have better biofilm inhibitory activity.
In addition, the IC 50 The 4 compounds with better values can reduce the MIC values of gentamicin sulfate and ceftriaxone sodium.
Drawings
FIG. 1 shows the hydrogen spectrum of compound 18 y.
Figure 2 carbon spectrum of compound 18 y.
FIG. 3 shows the hydrogen spectrum of compound 18 z.
FIG. 4 carbon spectrum of compound 18 z.
Figure 5 hydrogen spectrum of compound 18aa.
Figure 6 carbon spectrum of compound 18aa.
Detailed Description
The principles and features of this invention are described below in conjunction with examples which are set forth to illustrate, but are not to be construed to limit the scope of the invention.
1.1 determination of reaction conditions
Indole 16a as a model substrate, in (OTf) 3 The desired product 18a was provided in 96% yield (entry 12, table 1). The use of other Lewis acids leads to a decrease in yield or no formation of the desired product (entries 1 to 7). The reaction temperature was found to significantly affect the reactivity, and a 96% yield was obtained at 80 ℃ (entry 12). In addition, the reaction solvent also greatly affects the yield of the reaction (see entries 12-14 in Table 1). Finally, at 80 ℃ with 1.5 equivalents In (OTf) 3 The process 16a is determined as the optimum condition in the DCE (entry 12).
Figure SMS_13
TABLE 1
Figure SMS_14
Reaction conditions：16a(0.5mmol),acid(0.75mmol),17(0.6mmol),solvent(2mL),stirred for 4-10h at 80℃,then quenched by Saturated sodium bicarbonate(aq.).
1.2 substrate Range expansion
Under the optimal reaction conditions described above (table 1, entry 12), we examined the range of applicability of the indole substrate. We have found that indoles substituted at the 1,2,4-7 positions (16) are suitable for use in this reaction system to produce the corresponding Meridianin derivatives (18) in moderate to high yields. A series of substituents on the indole nucleus moiety, including Me, F, cl, br, CF 3 And NO 2 All have good tolerance. CF for electron deficient substrates 3 And NO 2 We found that the yield was relatively low (35% -51%). It is noteworthy that substrates with two electron donating groups 18v or two electron withdrawing groups 18m are also tolerant, obtained in yields of 60% and 62%, respectively.
2.1 instruments and apparatus
Of all substances separated 1 H NMR spectrum, 13 The C NMR spectra were determined on a nuclear magnetic resonance apparatus of the type Bruker AVANCE NEO 600. High resolution mass spectra were measured using a mass spectrometer. Silica gel (200-300 mesh) is adopted for column chromatography separation. Intermediate for removing compounds forming Meridianin B, E, FIn vitro, other chemicals and solvents were purchased commercially without further purification.
2.2 Experimental methods
To a 10mL Schlenk tube was added 2-amino-4-chloropyrimidine (0.6 mmol), indium trifluoromethanesulfonate (0.75 mmol), 1mL of dried 1, 2-dichloroethane, the resulting mixture was stirred at 80 ℃ for 0.5h, after cooling to room temperature, the corresponding indole or substituted indole (0.5 mmol) and 1mL of dried 1, 2-dichloroethane were added to the "Schlenk tube", and the reaction was continued at 80 ℃ until the reaction was complete. The resulting reaction solution was extracted with ethyl acetate (5 mL. Times.3). The organic phases obtained by extraction were combined and dried over anhydrous sodium sulfate, filtered, the solvent in the filtrate was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography with a mixture of petroleum ether and ethyl acetate to give the product.
Compounds 18a-18aa were prepared, and the validation data for each compound are as follows:
2-amino-4- (1H-indol-3-yl) pyrimidine (18 a) was obtained in a yield of 96%. 1 H NMR(400MHz,DMSO-d 6 )δ11.66(s,1H),8.58(d,J＝7.7Hz,1H),8.18(d,J＝2.8Hz,1H),8.10(d,J＝5.3Hz,1H),7.42(t,J＝10.7Hz,1H),7.23-7.06(m,2H),7.01(d,J＝5.3Hz,1H),6.40(s,2H). 13 C NMR(150MHz,DMSO-d 6 )δ163.97,163.15,157.45,137.48,128.68,125.80,122.85,122.42,120.73,114.14,112.29,105.77.HRMS(ESI)for C 12 H 10 N 4 :calculated for[M] + 211.0984,found 211.0980.
2-amino-4- (5-bromo-1H-indol-3-yl) pyrimidine (18 b) was obtained in 93% yield. 1 H NMR(600MHz,DMSO-d 6 )δ11.87(s,1H),8.75(d,J＝1.9Hz,1H),8.26(d,J＝2.8Hz,1H),8.10(d,J＝5.3Hz,1H),7.41(d,J＝8.6Hz,1H),7.29(dd,J＝8.6,2.0Hz,1H),7.00(d,J＝5.3Hz,1H),6.50(s,2H). 13 C NMR(150MHz,DMSO-d 6 )δ168.63,155.61,143.81,136.76,136.44,127.25,126.64,125.29,115.74,115.01,112.58,105.56.HRMS(ESI)for C 12 H 9 N 4 Br:calculated for[M] + 289.0089,found 289.0094.
2-amino-4- (6-bromo-1H-Indol-3-yl pyrimidine (18 c) in a yield of 90%. 1 H NMR(600MHz,DMSO-d 6 )δ12.49(d,J＝1.9Hz,1H),8.74(d,J＝3.2Hz,1H),8.61(d,J＝8.6Hz,1H),8.13(d,J＝6.9Hz,1H),7.73(d,J＝1.6Hz,1H),7.41(d,J＝6.9Hz,1H),7.37(dd,J＝8.6,1.8Hz,1H). 13 C NMR(150MHz,DMSO-d 6 )δ164.00,162.64,157.66,138.36,129.56,124.88,124.71,123.48,115.15,114.89,114.30,105.67.HRMS(ESI)for C 12 H 9 N 4 Br:calculated for[M] + 289.0089,found 289.0110.
2-amino-4- (7-bromo-1H-indol-3-yl) pyrimidine (18 d) was obtained in 90% yield. 1 H NMR(600MHz,DMSO-d 6 )δ12.61(d,J＝1.8Hz,1H),8.80(d,J＝3.3Hz,1H),8.71(d,J＝8.0Hz,1H),8.16(d,J＝6.9Hz,1H),7.52(d,J＝2.9Hz,1H),7.51(d,J＝3.5Hz,1H),7.20(t,J＝7.8Hz,1H). 13 C NMR(150MHz,DMSO-d 6 )δ163.99,162.62,157.75,135.77,129.69,127.58,125.08,122.54,122.13,115.36,105.93,104.85.HRMS(ESI)for C 12 H 9 N 4 Br:calculated for[M] + 289.0089,found 289.0112.
2-amino-4- (4-chloro-1H-indol-3-yl) pyrimidine (18 e) was obtained in 97% yield. 1 H NMR(600MHz,DMSO-d 6 )δ11.87(s,1H),8.17(d,J＝5.1Hz,1H),7.75(d,J＝2.7Hz,1H),7.45(dd,J＝7.7,1.2Hz,1H),7.18-7.10(m,2H),6.79(d,J＝5.1Hz,1H),6.43(s,2H). 13 C NMR(150MHz,DMSO-d 6 )δ163.66,162.36,157.00,138.62,129.30,125.07,122.95,122.54,121.66,115.99,111.85,111.70.HRMS(ESI)for C 12 H 9 N 4 Cl:calculated for[M] + 245.0594,found 245.0592.
2-amino-4- (5-chloro-1H-indol-3-yl) pyrimidine (18 f) in 97% yield HRMS (ESI) for C 12 H 9 N 4 Cl:calculated for[M] + 245.0594,found 245.0592.
2-amino-4- (6-chloro-1H-indol-3-yl) pyrimidine (18 g) was obtained in 96% yield. 1 H NMR(600MHz,DMSO-d 6 )δ12.49(d,J＝1.8Hz,1H),8.76(d,J＝3.2Hz,1H),8.66(d,J＝8.6Hz,1H),8.13(d,J＝6.9Hz,1H),7.59(d,J＝1.8Hz,1H),7.41(d,J＝6.9Hz,1H),7.26(dd,J＝8.6,1.9Hz,1H). 13 C NMR(150MHz,DMSO-d 6 )δ163.98,162.62,157.75,135.77,129.67,127.58,125.08,122.52,122.13,115.36,105.94,104.84.
2-amino-4- (7-chloro-1H-indol-3-yl) pyrimidine (18H) was obtained in 96% yield. 1 H NMR(600MHz,DMSO-d 6 )δ12.02(s,1H),8.60(dd,J＝8.0,0.8Hz,1H),8.27(s,1H),8.13(d,J＝5.3Hz,1H),7.27–7.25(m,1H),7.13(t,J＝7.8Hz,1H),7.07(d,J＝5.3Hz,1H),6.47(s,2H). 13 C NMR(151MHz,DMSO-d 6 )δ163.66,162.36,157.00,138.62,129.30,125.07,122.95,122.54,121.66,115.99,111.85,111.70.HRMS(ESI)for C 12 H 9 N 4 Cl:calculated for[M] + 245.0594,found 245.0589.
2-amino-4- (4-hydroxy-1H-indol-3-yl) pyrimidine (18 i) was obtained in a yield of 64%.
2-amino-4- (5-hydroxy-1H-indol-3-yl) pyrimidine (18 j) was obtained in 61% yield. 1 H NMR(600MHz,DMSO-d 6 )δ11.41(s,1H),8.77(d,J＝5.7Hz,1H),8.08(dd,J＝5.3,1.2Hz,1H),8.05(d,J＝2.6Hz,1H),7.81(d,J＝2.4Hz,1H),7.25-7.21(m,1H),6.93(dd,J＝5.3,1.1Hz,1H),6.72-6.68(m,1H),6.28(s,2H). 13 C NMR(150MHz,DMSO-d 6 )δ163.94,163.31,157.32,152.22,131.91,128.93,126.65,113.45,112.54,112.52,106.88,105.75.HRMS(ESI)for C 12 H 10 N 4 O:calculated for[M] + 227.0933,found 227.0926.
2-amino-4- (4-fluoro-1H-indol-3-yl) pyrimidine (18 k) was obtained in 84% yield. 1 H NMR(600MHz,DMSO-d 6 )δ12.62(s,1H),8.44(d,J＝3.1Hz,1H),8.26(d,J＝6.7Hz,1H),7.41(d,J＝8.1Hz,1H),7.38(d,J＝7.1Hz,1H),7.28(td,J＝8.0,4.9Hz,1H),7.05(dd,J＝12.2,7.9Hz,1H).HRMS(ESI)for C 12 H 9 N 4 F:calculated for[M] +
229.0889,found 229.0886.
2-amino-4- (6-fluoro-1H-indol-3-yl) pyrimidine (18 l) was obtained in a yield of 90%. 1 H NMR(600MHz,DMSO-d 6 )δ12.46(s,1H),8.74(d,J＝3.1Hz,1H),8.67(dd,J＝8.8,5.7Hz,1H),8.12(d,J＝6.9Hz,1H),7.41(d,J＝6.9Hz,1H),7.34(dd,J＝9.5,2.3Hz,1H),7.11(td,J＝9.3,2.3Hz,1H).HRMS(ESI)for C 12 H 9 N 4 F:calculated for[M] + 229.0889,found 229.0887.
2-amino-4- (5, 6-dichloro-1H-indol-3-yl) pyrimidine (18 m) was obtained in 62% yield. 1 H NMR(600MHz,DMSO-d 6 )δ12.60(d,J＝2.2Hz,1H),8.84(s,1H),8.81(d,J＝3.2Hz,1H),8.15(d,J＝6.9Hz,1H),7.78(s,1H),7.41(d,J＝6.9Hz,1H). 13 C NMR(150MHz,DMSO-d 6 )δ164.02,162.27,157.77,136.34,131.07,125.66,124.77,123.95,123.51,113.87,113.82,105.55.HRMS(ESI)for C 12 H 8 N 4 Cl 2 :calculated for[M] + 279.0204,found 279.0208.
2-amino-4- (5-nitro-1H-indol-3-yl) pyrimidine (18 n) was obtained in 38% yield. 1 H NMR(600MHz,DMSO-d 6 )δ12.93(s,1H),9.40(d,J＝2.3Hz,1H),8.94(d,J＝3.1Hz,1H),8.22(d,J＝6.8Hz,1H),8.15(dd,J＝9.0,2.3Hz,1H),7.72(d,J＝9.0Hz,1H),7.47(d,J＝6.8Hz,1H).HRMS(ESI)for C 12 H 9 N 5 O 2 :calculated for[M] +
256.0834,found 256.0828.
2-amino-4- (6-nitro-1H-indol-3-yl) pyrimidine (18 o) was obtained in 51% yield. 1 H NMR(600MHz,DMSO-d 6 )δ12.95(d,J＝2.0Hz,1H),9.03(d,J＝3.2Hz,1H),8.83(d,J＝8.9Hz,1H),8.42(d,J＝2.1Hz,1H),8.22(d,J＝6.8Hz,1H),8.06(dd,J＝8.9,2.1Hz,1H),7.46(d,J＝6.8Hz,1H). 13 C NMR(150MHz,DMSO-d 6 )δ164.03,161.96,158.12,142.88,136.03,134.58,130.57,123.14,115.52,115.05,109.07,105.80.HRMS(ESI)for C 12 H 9 N 5 O 2 :calculated for[M] + 256.0834,found 256.0834.
2-amino-4- (2-methyl-1H-indol-3-yl) pyrimidine (18 p) was obtained in 86% yield. 1 H NMR(600MHz,DMSO-d 6 )δ11.49(s,1H),8.20-8.15(m,1H),7.34(d,J＝7.9Hz,1H),7.12-7.03(m,1H),6.81(d,J＝5.3Hz,1H),6.40(s,1H),2.68(s,2H). 13 C NMR(150MHz,DMSO-d 6 )δ163.92,163.33,157.78,138.72,135.63,127.25,121.55,120.94,120.40,111.27,110.34,108.03,14.77.HRMS(ESI)for C 12 H 12 N 4 :calculated for[M] + 225.1140,found 225.1132.
2-amino-4- (6-methyl-1H-indol-3-yl) pyrimidine (18 q) was obtained in 93% yield. 1 H NMR(600MHz,DMSO-d 6 )δ11.50(s,1H),8.43(d,J＝8.1Hz,1H),8.10(d,J＝2.8Hz,1H),8.09(d,J＝5.3Hz,1H),7.22(s,1H),6.98(d,J＝5.3Hz,1H),6.95(dd,J＝8.2,1.0Hz,1H),6.38(s,2H),2.41(s,3H). 13 C NMR(150MHz,DMSO-d 6 )δ
164.00,163.17,157.38,137.93,131.50,128.09,123.72,122.54,122.46,114.09,112.07,105.70,21.80.HRMS(ESI)for C 12 H 12 N 4 :calculated for[M] + 225.1140,found 225.1132.
2-amino-4- (7-methyl-1H-indol-3-yl) pyrimidine (18 r) was obtained in 94% yield. 1 H NMR(600MHz,DMSO-d 6 )δ12.37(s,1H),8.71(d,J＝3.3Hz,1H),8.50(d,J＝7.9Hz,1H),8.10(d,J＝6.8Hz,1H),7.43(d,J＝6.9Hz,1H),7.15(t,J＝7.6Hz,1H),7.08(d,J＝7.1Hz,1H),2.51(s,3H). 13 C NMR(150MHz,DMSO-d 6 ).HRMS(ESI)for C 12 H 12 N 4 :calculated for[M] + 225.1140,found 225.1135.
2-amino-4- (4-methoxy-1H-indol-3-yl) pyrimidine (18 s) was obtained in 67% yield. 1 H NMR(600MHz,DMSO)δ12.38(s,1H),8.27(d,J＝2.7Hz,2H),8.06(s,1H),7.66(d,J＝5.5Hz,1H),7.24(t,J＝7.9Hz,1H),7.18(d,J＝7.9Hz,1H),6.82(d,J＝7.8Hz,1H),3.96(s,3H).HRMS(ESI)for C 13 H 12 N 4 O:calculated for[M] + 241.1089,found 241.1082.
2-amino-4- (5-methoxy-1H-indol-3-yl) pyrimidine (18 t) was obtained in 78% yield. 1 H NMR(600MHz,DMSO-d 6 )δ11.58(s,1H),8.16(d,J＝2.9Hz,1H),8.09(d,J＝2.5Hz,1H),8.08(d,J＝5.4Hz,1H),7.33(d,J＝8.8Hz,1H),7.00(d,J＝5.5Hz,1H),6.87–6.77(m,1H),6.52(s,2H),3.83(s,3H). 13 C NMR(150MHz,DMSO-d 6 )δ163.76,163.39,157.05,154.86,132.51,129.24,126.40,113.77,112.82,112.38,105.56,104.97,55.98.HRMS(ESI)for C 13 H 12 N 4 O:calculated for[M] + 241.1089,found 241.1082.
2-amino-4- (6-methoxy-1H-indol-3-yl) pyrimidine (18 u) was obtained in 67% yield. 1 H NMR(600MHz,DMSO-d 6 )δ11.45(s,1H),8.44(d,J＝8.7Hz,1H),8.07(d,J＝5.3Hz,1H),8.05(d,J＝2.8Hz,1H),6.97(d,J＝5.3Hz,1H),6.92(d,J＝2.3Hz,1H),6.75(dd,J＝8.8,2.3Hz,1H),6.37(s,2H),3.79(s,3H). 13 C NMR(150MHz,DMSO-d 6 )δ163.97,163.12,157.32,156.33,138.27,127.45,123.57,119.99,114.20,110.83,105.62,95.05,55.58.HRMS(ESI)for C 13 H 12 N 4 O:calculated for[M] + 241.1089,found 241.1087.
2-amino-4- (5, 6-dimethoxy-1H-indol-3-yl) pyrimidine (18 v) was obtained in 60% yield. 1 H NMR(600MHz,DMSO)δ11.35,8.08,8.07,8.06,7.99,7.99,6.96,6.95,6.94,6.40,3.84,3.79. 13 C NMR(150MHz,DMSO)δ163.87,163.35,157.16,147.24,145.72,131.81,126.83,118.73,113.99,105.48,105.45,95.51,56.60,55.98.HRMS(ESI)for C 13 H 12 N 4 O:calculated for[M] + 241.1089,found 241.1082.
2-amino-4- (6-trifluoromethyl-1H-indol-3-yl) pyrimidine (18 w) was obtained in 35% yield. 1 H NMR(600MHz,DMSO-d 6 )δ12.08(s,1H),8.80(d,J＝8.4Hz,1H),8.43(d,J＝2.9Hz,1H),8.15(d,J＝5.3Hz,1H),7.79(s,1H),7.39(dd,J＝8.5,1.4Hz,1H),7.05(d,J＝5.3Hz,1H),6.51(s,2H).HRMS(ESI)for C 13 H 12 N 4 O:calculated for[M] + 241.1089,found 241.1082.
2-amino-4- (N-methylindol-3-yl) pyrimidine (18 x): 1 H NMR(600MHz,DMSO-d 6 )δ8.60(d,J＝7.9Hz,1H),8.19(s,1H),8.11(d,J＝5.4Hz,1H),7.49(d,J＝8.2Hz,1H),7.27–7.22(m,1H),7.21–7.15(m,1H),6.95(d,J＝5.4Hz,1H),6.48(s,2H),3.85(s,3H). 13 C NMR(150MHz,DMSO-d 6 )δ163.71,162.93,157.10,138.00,132.81,126.19,123.00,122.57,121.08,113.08,110.69,105.62,33.41.
2-amino-4- (4-hydroxy-6-bromo-1H-indol-3-yl) pyrimidine (18 y): 1 H NMR(600MHz,DMSO-d 6 )δ14.21(s,1H),11.90(s,1H),8.28(d,J＝2.9Hz,1H),8.17(d,J＝5.4Hz,1H),7.14(d,J＝5.4Hz,1H),7.00(d,J＝1.6Hz,1H),6.85(s,2H),6.52(d,J＝1.6Hz,1H). 13 C NMR(150MHz,DMSO-d 6 )δ162.10,160.27,159.39,153.49,140.04,129.47,117.00,114.46,114.20,108.94,105.53,104.85.HRMS(ESI)for C 13 H 12 N 4 O:calculated for[M] + 241.1089,found 241.1082.
2-amino-4- (4-hydroxy-7-bromo-1H-indol-3-yl) pyrimidine (18 z): 1 H NMR(600MHz,DMSO-d 6 )δ13.89(s,1H),11.94(s,1H),7.25(d,J＝5.4Hz,1H),7.19(d,J＝8.2Hz,1H),6.90(s,2H),6.37(d,J＝8.2Hz,1H).HRMS(ESI)for C 13 H 12 N 4 O:calculated for[M] + 241.1089,found 241.1082.
2-amino-4- (5, 6-dibromo-1H-indol-3-yl) pyrimidine (18 aa): 1 H NMR(600MHz,DMSO-d 6 )δ11.94(s,1H),8.96(s,1H),8.31(d,J＝2.8Hz,1H),8.12(d,J＝5.3Hz,1H),7.84(s,1H),7.01(d,J＝5.3Hz,1H),6.58(s,2H). 13 C NMR(150MHz,DMSO-d 6 )δ163.99,162.30,157.75,137.19,130.98,127.05,126.63,116.99,116.63,115.39,113.70,105.60.HRMS(ESI)for C 13 H 12 N 4 O:calculated for[M] + 241.1089,found 241.1082.
3.1 determination of Minimum Inhibitory Concentration (MIC)
According to the American society for Clinical and Laboratory Standards (CLSI), taking a ring of bacteria liquid from a refrigerator at the temperature of-80 ℃ into a sterile centrifuge tube containing 10mL of MHB culture medium, and culturing for 21h in a constant temperature shaking incubator at the temperature of 37 ℃; then 200 mul of activated bacteria liquid is taken to be put into a sterile centrifuge tube containing 10mL of MHB culture medium, after the bacteria liquid is cultured for 3 hours at the constant temperature of 37 ℃, the concentration of the bacteria liquid is adjusted to 1 multiplied by 10 6 CFU/mL (OD 600=0.1 bacteria concentration of 1X 10) 8 CFU/mL) [27] . The compound to be tested is prepared into 20.48mg/mL for later use. The 96-well polystyrene plate was numbered, and 10. Mu.L of the prepared compound was added to each well from column 3; add 10. Mu.L MHB per well; add 100. Mu.L and 90. Mu.L of MHB in columns 1 and 3, respectively; mixing column 3, sucking 100 μ L of the mixture, adding into column 4, diluting to column 12, sucking 100 μ L of the mixture in column 12, and discarding; column 2 to column 12 respectively100. Mu.L of the prepared bacterial suspension was added. Column 1 is blank control group, column 2 is negative control group; the final concentration of the drugs is 1024, 512, 256, 128, 64, 32, 16, 8 (mu g/mL), and the final concentration of the bacterial liquid is 1 × 10 6 CFU/mL, total volume of 200. Mu.L. After the 96-well plate is placed in a 37 ℃ constant temperature incubator for 21h, the turbidity condition of the culture medium in the observation hole is compared, and the clear concentration of one hole is the lowest inhibitor concentration for the bacteria.
3.2、IC 50 Testing
The strain source is as follows: baumann ii ATCC19606 was isolated from a patient in a hospital affiliated to the medical university of guizhou.
MHB broth was formulated to a concentration of 1.0X 10 according to CLSI 6 CFU/mL bacterial suspension, preparing the compounds with better activity screened in the activity test into 6mmol/L, 4mmol/L, 3mmol/L, 2mmol/L, 1.2mmol/L and 0.6mmol/L in sequence for standby. The 96-well plate is numbered and LB medium is placed around the plate to prevent evaporation. MHB culture medium is added to column 2 to serve as a blank control group, and 10 mu L DMSO and 190 mu L LMHB bacteria-containing culture medium are added to column 3 to serve as a solvent control group; sequentially adding 10 mu L of the prepared compound into the 4 th to 9 th columns according to the concentration gradient; adding 190 μ L MHB containing bacteria culture medium into each well; the remaining wells were filled with MHB medium. The final concentration of the medicine is 300, 200, 150, 100, 60, 30 μ M, and the final concentration of the bacterial liquid is 1 × 10 6 CFU/mL, total volume of 200. Mu.L. Putting the 96-well plate into a constant-temperature incubator at 37 ℃ for culturing for 21h, adopting a crystal violet staining method to stain the biomembrane, and measuring the OD value of the solution in the culture well by using an ELX800 type enzyme-linked immunosorbent assay detector at 590 nm; and calculating the biological membrane inhibition rate of the compound under different concentrations. IC50 of the resulting compound was calculated using GraphPad Prism 5 software.
3.3 chessboard combination
MHB broth was formulated according to CLSI to a concentration of 1.0X 10 6 CFU/mL bacterial suspension, and preparing the compound with better activity screened in the activity test into 20.48mg/mL for standby. Numbering 96-well plates, adding twice MIC concentration of antibiotics into horizontal wells, sequentially diluting twice, adding prepared antibiotics into vertical wellsThe 30.72mg/mL compound is sequentially diluted backwards twice to establish a checkerboard; well 1 was blank and 200 μ L of MHB broth was added; taking the 2 nd hole as a solvent control, adding 190 mu L of bacterial liquid and 10 mu L of DMSO solution; after the plates are paved, putting the plates into a constant temperature culture at 37 ℃ for 21h; the turbidity in the comparative wells was observed to give the MIC of the compound, and the Fractional Inhibitory Concentration Index (FICI) was calculated.
3.4、IC 50 Test results
IC of compound 18a-18aa on Acinetobacter baumannii 50 Measuring to obtain IC 50 The compound numbers of the values and the measured values thereof are shown in the following table.
TABLE 2MIC assay results
Figure SMS_15
As a result, as shown in table 2, compounds 18g, 18l, 18w and 18aa had inhibitory effects on biofilm of acinetobacter baumannii 19606 strain. In particular, compound 18aa has a strong anti-biofilm effect on a. Baumann ni 19606, IC 50 Down to 46.25. Mu.M.
3.5 results of chessboard combination
Compounds 18g, 18l, 18w and 18aa were administered in antibiotic combinations with gentamicin sulfate and ceftriaxone sodium, respectively, and their inhibitory effect on a. Baumann ii ATCC19606 was observed.
TABLE 3 results of the combination of the checkerboard method
Figure SMS_16
Figure SMS_17
The synergy of compounds with various antibiotics was assessed by checkerboard titration assay on microwell plates and expressed as the sum of Fractional Inhibitory Concentration (FIC) indices for each drug as suggested by NCCLS. FICI = MIC (comb A) /MIC (alone A) +MIC (comb B) /MIC (alone B) Namely MIC when the A medicine is combined/MIC when the A medicine is used singly + MIC when the B medicine is combined/MIC when the B medicine is used singly. When FICI is less than or equal to 0.5, A and B have synergistic effect; when 1 is more than or equal to FICI>At 0.5, A and B have additive effect; when 2 is more than or equal to FICI>1, A and B have no interaction; when FICI>2, A and B have antagonistic action.
The results are shown in Table 3, and the FICI values of the compounds 18g, 18l, 18w and 18aa, which are respectively combined with gentamicin sulfate and ceftriaxone sodium, are less than 0.5, so that the compounds 18g, 18l, 18w and 18aa have certain synergistic effect with aminoglycoside and cephalosporin antibiotics. When the compound is used together with gentamicin sulfate in aminoglycoside antibiotics, the MIC is reduced by 2 to 3 times; when the compound is used together with ceftriaxone sodium in cephalosporin antibiotics, the MIC is reduced by 4 to 5 times.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.

Claims (9)

  1. Meridianin derivatives of the formula:
    Figure FDA0003917801030000011
  2. 2. a method for synthesizing Meridianin derivatives in one step by a coupling reaction promoted by Lewis acid is characterized by comprising the following steps:
    Figure FDA0003917801030000012
    R 1 -R 6 all are hydrogen;
    or, R 1 Or R 2 Is hydrogen CH 3 And all are hydrogen;
    or, R 1 And R 2 Are each hydrogen, R 3 -R 6 One of them is Br, cl, OH, F, NO 2 、CH 3 、CH 3 O or CF 3 ；
    Or, R 3 -R 6 Two of the substituents are not hydrogen, and the two substituents are Br, cl and CH respectively 3 O or OH, and the two substituents are the same or different.
  3. 3. A process for the synthesis of Meridianin-type derivatives according to claim 2, characterized in that:
    the reaction temperature is 70-90 ℃;
    in (OTf) used 3 The weight ratio of the 2-amino-4-chloropyrimidine to the compound (1.4-1.6) is 1.
  4. 4. A method of synthesising a Meridianin derivative according to claim 2 wherein:
    the reaction temperature is 80 ℃;
    in (OTf) used 3 The weight ratio of the compound to 2-amino-4-chloropyrimidine was 1.5.
  5. 5. An application of a Meridianin derivative in preparing a biofilm inhibitor.
  6. 6. The use as claimed in claim 5, wherein the Meridianin derivatives have the following general structural formula:
    Figure FDA0003917801030000021
    R 1 -R 6 all are hydrogen;
    or, R 1 Or R 2 Is hydrogen CH 3 And all are hydrogen;
    or, R 1 And R 2 Are each hydrogen, R 3 -R 6 One of them is Br, cl, OH, F, NO 2 、CH 3 、CH 3 O or CF 3 ；
    Or, R 3 -R 6 Two of the substituents are not hydrogen, and the two substituents are Br, cl and CH respectively 3 O or OH, and the two substituents are the same or different.
  7. 7. The use according to claim 6, wherein the Meridianin derivative has the following structural formula:
    Figure FDA0003917801030000022
    Figure FDA0003917801030000031
  8. 8. use according to claim 7, characterized in that the Meridianin derivative is the compound 18g, 18l, 18w or 18aa.
  9. 9. Use according to claim 7, characterized in that: is administered in combination with antibiotics.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113121528A (en) * 2020-01-15 2021-07-16 中国科学院上海药物研究所 Multi-target inhibition compound, composition, functional molecule and application thereof
CN114605334A (en) * 2022-03-23 2022-06-10 贵州医科大学 2-aminopyrimidine compound, preparation method, application and biomembrane inhibitor

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113121528A (en) * 2020-01-15 2021-07-16 中国科学院上海药物研究所 Multi-target inhibition compound, composition, functional molecule and application thereof
CN114605334A (en) * 2022-03-23 2022-06-10 贵州医科大学 2-aminopyrimidine compound, preparation method, application and biomembrane inhibitor

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Title
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