CN114874152B - Synephrine benzoxazole sulfonamide derivative, intermediate, preparation method and application thereof - Google Patents

Synephrine benzoxazole sulfonamide derivative, intermediate, preparation method and application thereof Download PDF

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CN114874152B
CN114874152B CN202210579020.3A CN202210579020A CN114874152B CN 114874152 B CN114874152 B CN 114874152B CN 202210579020 A CN202210579020 A CN 202210579020A CN 114874152 B CN114874152 B CN 114874152B
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synephrine
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CN114874152A (en
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范莉
李文粒
张世木
杨大成
彭诗琦
周传武
李鑫
汪红伶
刘寒驰
李芬芬
谢文文
赵定兵
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Mianyang Diao Pharmaceutical Co ltd
Southwest University
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Abstract

The invention discloses a synephrine benzoxazole sulfonamide derivative shown in a formula I, wherein X is S or SO 2 The method comprises the steps of carrying out a first treatment on the surface of the R is phenyl, substituted phenyl or 3-pyridyl; the phenyl substituent is one or more and is independently selected from halogen, hydroxy, amino, C1-C3 alkanoylamino, nitro, C1-C3 alkyl, halogen substituted C1-C3 alkyl, C1-C3 alkoxy or halogen substituted C1-C3 alkoxy; the biological activity test results show that the derivative molecules and intermediates have certain antibacterial and/or antifungal activity, are stronger than that of the parent nucleus synephrine, especially have partial high-activity and broad-spectrum molecules, have quite even stronger activity than that of positive control salcin marketed medicines or fluconazole, and have the potential of further developing and developing antibacterial and/or antifungal medicines.

Description

Synephrine benzoxazole sulfonamide derivative, intermediate, preparation method and application thereof
Technical Field
The invention belongs to the technical field of drug synthesis, and relates to a synephrine benzoxazole sulfonamide derivative, an intermediate, a preparation method and application thereof.
Background
The design strategy of the multi-target medicine is a new idea for solving the problem of complex diseases, especially multi-target diseases. The pharmacophore connection method can introduce medicines with multiple action targets into a single molecule, so as to realize the design of the medicines with multiple targets.
Synephrine (synephrine) is a natural small-molecule alkaloid, which exists in the peel and pulp of citrus, and is one of the main components of traditional Chinese medicine immature bitter orange. Synephrine has biological activities of vasoconstriction, weight loss, cell aging delay, asthma resistance, depression resistance, alopecia resistance, inflammation resistance, stomach illness resistance, bacteria resistance, fungus resistance and the like, is currently carried in the northern Europe and the German pharmacopoeia, is used in the industries of medicines, food and beverage and the like in European and American countries, and is the most widely applied as a weight-losing health-care product and beverage. The synephrine contains phenolic hydroxyl, alcoholic hydroxyl and secondary amino, and can be used as a linker (linker) of a multi-target drug and one of pharmacophores, thereby having potential research prospect.
In the previous researches in the laboratory, the inventor designs a synephrine sulfonyl tetrazole sulfonamide derivative by respectively introducing 1-methyl-5-mercapto-1H-tetrazole and sulfonyl on phenolic hydroxyl and amino of synephrine, and although the antibacterial activity of the obtained molecule is not satisfactory, a few molecules have good antifungal activity and have the potential of further researches.
Disclosure of Invention
In view of the above, the present invention aims to design and synthesize a new class of synephrine derivatives, and it is desirable to find new molecules with better antibacterial and/or antifungal activity.
Through researches, the invention provides the following technical scheme:
1. synephrine benzoxazole sulfonamide derivatives represented by formula I or pharmaceutically acceptable salts thereof:
in the formula I, the compound (I),
x is S or SO 2 ；
R is phenyl, substituted phenyl or 3-pyridyl; the phenyl substituent is one or more and is independently selected from halogen, hydroxy, amino, C1-C3 alkanoylamino, nitro, C1-C3 alkyl, halogen substituted C1-C3 alkyl, C1-C3 alkoxy or halogen substituted C1-C3 alkoxy.
Further, the phenyl substituent is one or more, independently selected from fluorine, bromine, amino, acetamido, nitro, methyl, trifluoromethyl, methoxy or trifluoromethoxy.
Further, the synephrine benzoxazole sulfonamide derivative shown in the formula I is any one of the following compounds:
2. an intermediate of formula II:
in formula II, Y is tert-butoxycarbonyl (Boc) or H.
3. The preparation method of the synephrine benzoxazole sulfonamide derivative or the pharmaceutically acceptable salt thereof in the formula I comprises the following steps:
i. the synephrine and di-tert-butyl dicarbonate, namely Boc 2 O reacts to prepare an intermediate IM1;
reacting the intermediate IM1 with 1, 4-dibromobutane to obtain an intermediate IM2;
reacting the intermediate IM2 with 5-chloro-2-mercaptobenzoxazole to obtain an intermediate IM3, namely an intermediate shown in a formula II, wherein Y is Boc;
reacting the intermediate IM3 with HCl-ethyl acetate (HCl-EA) to obtain an intermediate IM4, namely an intermediate hydrochloride shown in a formula II, wherein Y is H;
v. intermediate IM4 is combined with compound RSO 2 Cl reacts to prepare a compound TM1, namely a synephrine benzoxazole sulfonamide derivative shown in a formula I, wherein X in the formula I is S;
reacting compound TM1 with m-chloroperoxybenzoic acid (mCPBA) to obtain compound TM2, namely synephrine benzoxazole sulfonamide derivative shown in formula I, wherein X is SO 2 ；
Compound RSO 2 And R in the structural formulas of Cl, TM1 and TM2 is the same as the definition in the synephrine benzoxazole sulfonamide derivative shown in the formula I.
Further, the preparation method of the synephrine benzoxazole sulfonamide derivative or the pharmaceutically acceptable salt thereof comprises the following steps:
i. the synephrine and Boc are combined 2 O reacts in ethanol solvent at 0-35 ℃ to prepare an intermediate IM1;
ii. intermediate IM1 and 1, 4-dibromobutane in base K 2 CO 3 Reacting in solvent N, N-Dimethylformamide (DMF) at 45 ℃ in the presence of the solvent to prepare an intermediate IM2;
intermediate IM2 and 5-chloro-2-mercaptobenzoxazole in base K 2 CO 3 Reacting in DMF at 45 ℃ in the presence of a solvent to obtain an intermediate IM3, namely an intermediate shown in a formula II, wherein Y is Boc;
reacting the intermediate IM3 with HCl-EA at 0-5 ℃ to obtain an intermediate IM4, namely an intermediate hydrochloride shown in a formula II, wherein Y is H;
v. intermediate IM4 is combined with compound RSO 2 Cl reacts in DMF at-15-25 ℃ in the presence of an acid-binding agent N, N-Diisopropylethylamine (DIPEA) to prepare a compound TM1, namely a synephrine benzoxazole sulfonamide derivative shown in a formula I, wherein X is S;
reacting compound TM1 with mCPBA in Dichloromethane (DCM) at 30deg.C to obtain compound TM2, namely synephrine benzoxazole sulfonamide derivative shown in formula I, wherein X is SO 2 。
4. Application of synephrine benzoxazole sulfonamide derivatives shown in formula I or pharmaceutically acceptable salts thereof in preparation of antibacterial and/or antifungal drugs.
5. The application of the intermediate shown in the formula II or pharmaceutically acceptable salt thereof in preparing antibacterial and/or antifungal medicines.
The term "pharmaceutically acceptable salt" in the present invention may be an acidic salt or a basic salt, such as an inorganic acid salt, an organic acid salt, an inorganic base salt or an organic base salt, unless otherwise specified. The term "halogen" refers to F, cl, br and I.
The invention has the beneficial effects that: the invention respectively introduces benzoxazolyl and sulfonyl on phenolic hydroxyl and amino of a synephrine mother nucleus, designs and synthesizes a synephrine benzoxazole sulfonamide derivative, and biological activity test results show that derivative molecules and intermediates have certain antibacterial and/or antifungal activity, which is stronger than that of synephrine, especially has partial high-activity and broad-spectrum molecules, has quite even stronger activity than that of positive control sarcin marketed drugs or fluconazole, and has the potential of further developing and developing antibacterial and/or antifungal drugs.
Detailed Description
In order to make the objects, technical solutions and advantageous effects of the present invention more apparent, preferred embodiments of the present invention will be described in detail below.
Main chemical reagent and instrument
Synephrine (Mianyang Di Australia pharmaceutical Co., ltd.); 1, 4-dibromobutane, di-tert-butyl dicarbonate (Boc) 2 O), 5-chloro-2-mercaptobenzoxazole, m-chloroperoxybenzoic acid (mCPBA) (Shanghai darey fine chemical Co., ltd., AR); n, N-diisopropylethylamine (DIPEA, new De chemical Co., ltd., AR); potassium carbonate (AR, new chemical industry limited of Chongqing city, before use, mortar for grinding, oven drying), p-nitrobenzenesulfonyl chloride, o-fluorobenzenesulfonyl chloride, p-fluorobenzenesulfonyl chloride, m-fluorobenzenesulfonyl chloride, o-bromobenzenesulfonyl chloride, m-bromobenzenesulfonyl chloride, p-trifluoromethoxybenzenesulfonyl chloride, m-trifluoromethoxybenzenesulfonyl chloride, p-trifluoromethylbenzenesulfonyl chloride, p-toluenesulfonyl chloride, 2, 6-difluorobenzenesulfonyl chloride, 2,4, 6-trimethylbenzenesulfonyl chloride, 3-pyridinesulfonyl chloride and acetamidobenzenesulfonyl chloride (AR, shanghai medical technology limited), the remaining reagents are all commercially pure or analytically pure products, the reaction solvent is dried, and the rest is directly used without purification.
Nuclear magnetic resonance equipment (Bruker ADVANCE III) TM 600MHz, switzerland, TMSAn internal standard); high resolution mass spectrometer (QTOF-MS, bruker Impact II, bremen, germany); automatic polarimeter (WZZ-2S, shanghai precision scientific instruments Co., ltd.); melting point tester (X-6, beijing Fukai instruments Co., ltd.); ultraviolet analyzer (ZF-1, shanghai Gu Cun electro-optical instruments).
1 Synthesis of target molecule TM
The synthetic route is as follows:
i. synthesis of intermediate IM1
The synephrine and Boc are combined 2 O reacts in ethanol solvent at 0-35 ℃ to prepare the intermediate IM1.
Operation example: into a 100mL round bottom flask was added synephrine (8.458 g,50 mmol) and ethanol (EtOH) (10 mL), and after rapid stirring at room temperature (30 ℃ C.) for 5min, boc was slowly added dropwise 2 O (12.874 g,55 mmol), after the dropwise addition, stirring rapidly at room temperature was continued and the progress of the reaction was monitored by Thin Layer Chromatography (TLC). After the reaction is finished, removing EtOH by rotation, adding a proper amount of Petroleum Ether (PE), stirring by ultrasound until white solid is separated out, adding a proper amount of PE, stirring for 0.5h, filtering, drying, weighing to obtain 13.258g of white solid IM1 (pure product), and obtaining the yield of 99.2%, m.p.88.5-90.1 ℃.
Synthesis of intermediate IM2
Intermediate IM1 and 1, 4-dibromobutane in base K 2 CO 3 Reacting in DMF at 45 deg.C to obtain intermediate IM2.
Operation example: to a 100mL round bottom flask was added intermediate IM1 (4.013 g,20 mmol), DMF (2 mL), triturated K 2 CO 3 After stirring the powder (3.112 g,22.5 mmol) in an oil bath at 45℃for 0.5h, 1, 4-dibromobutane (6.432 g,30 mmol) was added dropwise and the reaction was stirred rapidly in an oil bath at 45℃and monitored by TLC (DCM: meOH=10:1). After the reaction is finished, adding proper amount of saturated Na 2 CO 3 The solution was stirred with an appropriate amount of Dichloromethane (DCM) at room temperature for 0.5h, the organic phase was collected, washed with saturated NaCl solution (10 mL. Times.3), anhydrous Na 2 SO 4 Drying, spin-removing solvent to obtain yellowish liquid, addingAdding a proper amount of PE, rapidly stirring until white solid is separated out, filtering, collecting the white solid, washing the PE until the PE has no 1, 4-dibromobutane smell, drying, and weighing to obtain a crude product. The crude product was purified by column chromatography with PE: EA (ethyl acetate) =10:1-5:1 (v/v) to give 5.423g of white solid IM 2.4% in 67.4% yield, m.p.92.8-94 ℃.
Synthesis of intermediate IM3
Intermediate IM2 and 5-chloro-2-mercaptobenzoxazole are reacted in the presence of base K 2 CO 3 Reacting in DMF at 45 deg.C to obtain intermediate IM3.
Operation example: to a 100mL round bottom flask was added 5-chloro-2-mercaptobenzoxazole (9.288 g,50 mmol), DMF (4 mL), stirred to dissolve, and anhydrous K was added 2 CO 3 (6.911 g,50 mmol), stirring rapidly at room temperature (32 ℃) for 0.5h, adding intermediate IM2 (8.051 g,20 mmol), stirring rapidly at 45℃in an oil bath, and monitoring the progress of the reaction by TLC (PE: EA=5:1, DCM: meOH=10:1). After the completion of the reaction, the reaction mixture was cooled to room temperature, and ice-cooled saturated Na was added thereto 2 CO 3 The solution (10 mL), stirred for 10min, DCM (20 mL) was added, stirred for 10min, the organic phase was collected, washed with saturated NaCl solution (10 mL. Times.3), anhydrous Na 2 SO 4 Drying and spin-off of the solvent gave a pink solid IM 3.079 g, yield 99.4%, m.p.151.2-153.7deg.C.
Synthesis of intermediate IM4
Intermediate IM3 is reacted with HCl-Ethyl Acetate (EA) at a temperature of between-15 and 25 ℃ to prepare intermediate IM4.
Operation example to a 100mL round bottom flask was added intermediate IM3 (7.605 g,15 mmol), 3mol/LHCl-EA (30 mL,90 mmol) was added dropwise, the reaction was stirred rapidly with an ice water bath (0-5 ℃ C.) and TLC monitored for progress. After the reaction, the solvent is removed by rotating, adding an appropriate amount of EA, stirring for a few minutes, removing the solvent again by rotating, adding an appropriate amount of PE, stirring for a few minutes, removing the solvent again, adding diethyl ether (20 mL), stirring for dispersion, and carrying out suction filtration to obtain pink solid IM4 6.058g, with the yield of 91.1%, m.p.168.9-169.8 ℃.
Synthesis of target molecule TM1
Intermediate IM4 and compound RSO 2 Cl is subjected to ice water bath (0-5 ℃) reaction in DMF solvent in the presence of DIPEA serving as an acid binding agentAccordingly, the target molecule TM1 was produced.
Operation example: into a 100mL round bottom flask was added intermediate IM4 (1 mmol), DMF (1.5 mL), DIPEA (0.5 mL,3 mmol) was added dropwise, and the mixture was stirred rapidly in an ice water bath (0-5 ℃ C.) for 30min, followed by RSO 2 Cl (2 mmol), ice-water bath (0-5 ℃ C.) and TLC monitored the progress of the reaction. After the reaction was completed, water (10 mL) and DCM (10 mL) were added, stirred for 10min, the organic phase was collected, washed with saturated NaCl solution, and dried Na 2 SO 4 Drying, spin-removing solvent, purifying by column chromatography (PE: EA=12:1-8:1, v/v) to obtain TM1, drying, weighing, and calculating the yield. The synthesis results are shown in Table 1.
TABLE 1 Synthesis of TM1
Synthesis of target molecule TM2
Target molecule TM1 was reacted with mCPBA in solvent DCM at 30℃to give target molecule TM2.
Operation example: to a 100mL round bottom flask were added the target molecule TM1 (0.5 mmol), DCM (1.5 mL) and mCPBA (1.25 mmol), the reaction was stirred rapidly at 30deg.C and TLC monitored the progress of the reaction. After the reaction was completed, ice-cold saturated NaHCO was added 3 The solution (5 mL) and DCM (5 mL) were stirred for 5min, the organic phase was collected, washed with water (10 mL. Times.3), anhydrous Na 2 SO 4 Drying, spin-removing solvent, column chromatography (PE: ea=5:1-2:1, v/v) purification to give TM2, drying, weighing, and calculating the yield. The synthesis results are shown in Table 2.
TABLE 2 Synthesis of TM2
The structural formula and structural characterization data of the intermediate IM3 and the target molecules TM1 and TM2 are as follows:
IM3:Pink solid,m.p.151.2-153.7℃,(2mg/mL,DMSO). 1 H NMR(600MHz,DMSO-d6)δ7.74(s,1H,H-1),7.67(d,J＝8.6Hz,1H,H-2),7.36(dd,J＝8.6,1.9Hz,1H,H-3),7.19(d,J＝8.2Hz,2H,H-4),6.88(d,J＝7.5Hz,2H,H-5),5.29(d,J＝32.1Hz,1H,H-6),4.64(d,J＝27.8Hz,1H,H-7),4.04–3.93(m,2H,H-8),3.41(t,J＝7.0Hz,2H,H-9),3.32(s,3H,H-10),3.24(dd,J＝29.0,17.8Hz,1H,H-11),3.14(dd,J＝13.7,7.2Hz,1H,H-12),1.94(dd,J＝14.1,7.0Hz,2H,H-13),1.90–1.80(m,2H,H-14),1.37(s,3H,H-15),1.29(s,6H,H-16).
IM4:Pink solid,m.p.169.7.2-172.3℃,(2mg/mL,DMSO). 1 H NMR(600MHz,DMSO-d6)δ7.72(s,1H,H-1),7.67(d,J＝8.8Hz,1H,H-2),7.40(dd,J＝8.9,1.9Hz,1H,H-3),7.19(d,J＝7.8Hz,2H,H-4),6.84(d,J＝8.2Hz,2H,H-5),5.79(d,J＝4.8Hz,1H,H-6),4.75(q,J＝4.3Hz,1H,H-7),4.06–4.01(m,1H,H-8),4.01(t,J＝5.8Hz,2H,,H-9),3.14(t,J＝8.4Hz,2H,H-10),3.04(dd,J＝6.1,4.3Hz,1H,H-11),3.00(dd,J＝6.0,4.4Hz,1H,H-12),2.51(s,3H,H-13),1.90–1.80(m,2H,H-14),1.75–1.60(m,2H,H-15).
TM1a:White solid,m.p.82.3-83.5℃,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ7.66(d,J＝7.4Hz,2H,H-1),7.54(s,1H,H-2),7.33(d,J＝8.6Hz,1H,H-3),7.29(d,J＝7.8Hz,2H,H-4),7.28(d,J＝7.8Hz,2H,H-5),7.20(d,J＝8.6Hz,1H,H-6),6.87(d,J＝7.5Hz,2H,H-7),4.86(d,J＝8.6Hz,1H,H-8),4.01(t,J＝5.7Hz,1H,H-9),3.38(t,J＝6.9Hz,2H,H-10),3.26(dd,J＝13.9,8.9Hz,1H,H-11),2.99(d,J＝14.1Hz,1H,H-12),2.79(s,3H,H-13),2.41(s,2H,H-14),2.08–2.01(m,2H,H-15),2.01–1.92(m,2H,H-16). 13 C NMR(151MHz,CDCl 3 )δ166.75,159.06,158.71,150.43,143.63,143.06,134.39,133.31,129.78,127.43,127.28,123.97,118.43,114.57,110.45,71.79,67.17,58.29,36.76,28.18,26.13,21.49.HR MS calcd for C 27 H 29 ClN 2 O 5 S 2 ,[M+H] + :561.1279,found:561.1280；[M+Na] + :583.1099,found:583.1099.
TM1b:yellow solid,m.p.115.1-116.9℃,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ8.36(d,J＝8.5Hz,2H,H-1),7.98(d,J＝8.5Hz,2H,H-2),7.56(s,1H,H-3),7.36(d,J＝8.6Hz,1H,H-4),7.30(s,2H,H-5),7.23(d,J＝8.3Hz,1H,H-6),6.90(d,J＝8.3Hz,2H,H-7),4.93(dd,J＝8.3,3.1Hz,1H,H-8),4.05(t,J＝5.9Hz,2H,H-9),3.41(t,J＝7.1Hz,2H,H-10),3.36(dd,J＝14.2,8.6Hz,1H,H-11),3.20(dd,J＝14.2,3.2Hz,1H,H-12),2.91(s,3H,H-13),2.08(dd,J＝14.4,7.2H,2H,H-14),2.01(dd,J＝13.3,6.3Hz,2H,H-15). 13 C NMR(151MHz,CDCl 3 )δ166.73,158.94,150.43,150.09,143.84,143.06,133.08,129.82,128.49,127.24,124.36,123.98,118.42,114.70,110.46,72.34,67.20,57.80,36.61,32.02,28.15,26.12.HR MS calcd for C 26 H 26 ClN 3 O 7 S 2 ,[M+H] + :592.0973,found:592.0983.
TM1c:yellow solid,m.p.105.9-108.2℃,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ7.99(d,J＝7.6Hz,1H,H-1),7.68(p,J＝7.5Hz,2H,H-2),7.61(d,J＝7.5Hz,1H,H-3),7.53(s,1,H-4),7.33(d,J＝8.6Hz,1H,H-5),7.28(d,J＝8.0Hz,2H,H-6),7.20(d,J＝8.6Hz,1H,H-7),6.87(d,J＝7.9Hz,2H,H-8),4.92(dd,J＝8.6,2.7Hz,1H,H-9),4.01(t,J＝5.9Hz,2H,H-10),3.45(dd,J＝14.7,8.9Hz,2H,H-11),3.38(t,J＝7.1Hz,1H,,H-12),3.35(dd,J＝14.8,2.9Hz,1H,H-13),2.99(s,3H,H-14),2.04(dt,J＝14.5,7.1Hz,2H,H-15),2.00–1.93(m,2H,H-16). 13 C NMR(151MHz,CDCl 3 )δ166.75,158.81,150.43,148.23,143.06,133.61,133.28,132.22,131.61,130.98,127.25,124.17,123.97,118.42,114.67,110.46,72.23,67.18,57.61,36.35,32.04,28.17,26.13.HR MS calcd for C 26 H 26 ClN 3 O 7 S 2 ,[M+H] + :592.0973,found:592.0979.
TM1d:White solid,m.p.126.2-127.8℃,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ7.92(t,J＝7.4Hz,1H,H-1),7.63–7.51(m,2H,H-2),7.36(d,J＝8.6Hz,1H,H-3),7.32(d,J＝8.4Hz,2H,H-4),7.28–7.27(m,1H,H-5),7.22(dd,J＝14.2,8.8Hz,1H,H-6),6.89(d,J＝7.7Hz,2H,H-7),4.94(d,J＝8.3Hz,1H,H-8),4.04(t,J＝5.8Hz,2H,H-9),3.45–3.41(m,2H,H-10),3.40(d,J＝7.8Hz,1H,H-11),3.26(d,J＝14.5Hz,1H,H-12),2.94(s,3H,H-13),2.07(dt,J＝14.2,7.1Hz,2H,H-14),2.04–1.95(m,2H,H-15). 13 C NMR(151MHz,CDCl 3 )δ166.74,158.82,150.43,143.07,139.64,135.80,133.20,130.66,130.15,127.28,125.87,123.97,118.43,114.65,110.45,72.14,67.18,58.01,36.75,32.04,28.17,26.13.HR MS calcd for C 26 H 26 ClFN 2 O 5 S 2 ,[M+H] + :565.1028,found:565.1035.
TM1e:White solid,m.p.97.6-98.5,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ7.60(d,J＝7.8Hz,1H,H-1),7.57(s,1H,H-2),7.54(d,J＝8.0Hz,1H,H-3),7.51(d,J＝8.6Hz,1H,H-4),7.36(d,J＝8.6Hz,1H,H-5),7.32(s,1H,H-6),7.31(s,1H,H-7),7.23(d,J＝8.6Hz,1H,H-8),6.90(d,J＝8.2Hz,2H,H-9),4.91(d,J＝6.3Hz,1H,H-10),4.05(t,J＝5.9Hz,2H,H-11),3.41(t,J＝7.1Hz,2H,H-12),3.32(dd,J＝14.1,8.7Hz,1H,H-13),3.11(d,J＝12.4Hz,1H,H-14),2.86(s,3H,H-15),2.08(dt,J＝14.3,7.1Hz,2H,H-16),2.04–1.95(m,2H,H-17). 13 C NMR(151MHz,CDCl 3 )δ166.73,163.34,161.67,158.82,150.44,143.08,133.19,130.97,129.83,127.26,123.96,123.10,123.08,120.03,119.89,118.44,114.79,114.65,110.45,72.11,67.18,58.08,36.74,32.03,28.17,26.13.HR MS calcd for C 26 H 26 ClFN 2 O 5 S 2 ,[M+H] + :565.1028,found:565.1033.
TM1f:White solid,m.p.112.8-114.5℃,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ7.92(t,J＝7.4Hz,1H,H-1),7.59(d,J＝7.1Hz,1H,H-2),7.57(s,1H,H-3),7.36(d,J＝8.6Hz,1H,H-4),7.32(d,J＝8.4Hz,2H,H-5),7.29–7.27(m,1H,H-6),7.23(d,J＝8.4Hz,1H,H-7),7.21(d,J＝9.3Hz,1H,H-8),6.89(d,J＝7.7Hz,1H,H-9),4.94(d,J＝8.3Hz,1H,H-10),4.04(t,J＝5.8Hz,2H,H-11),3.43(d,J＝7.1Hz,2H,H-12),3.40(d,J＝7.8Hz,1H,H-13),3.26(d,J＝14.5Hz,1H,H-14),2.94(s,3H,H-15),2.07(dt,J＝14.2,7.1Hz,2H,H-16),2.04–1.94(m,2H,H-17). 13 C NMR(151MHz,CDCl 3 )δ166.73,158.74,150.44,143.09,134.98,134.92,133.36,131.37,129.82,127.26,124.47,124.45,123.96,118.44,117.16,114.61,110.44,72.20,67.17,57.85,36.43,36.41,32.04,28.17,26.13.HR MS calcd for C 26 H 26 ClFN 2 O 5 S 2 ,[M+H] + :565.1028,found:565.1015./>
TM1g:White solid,m.p.96.9-98.2℃,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ7.78(d,J＝7.9Hz,2H,H-1),7.58(t,J＝7.2Hz,1H,H-2),7.54(s,1H,H-3),7.33(d,J＝8.6Hz,1H,H-4),7.28(d,J＝8.0Hz,2H,H-5),7.20(d,J＝8.6Hz,1H,H-6),6.87(d,J＝8.1Hz,2H,H-7),4.88(d,J＝8.4Hz,1H,H-8),4.01(t,J＝5.9Hz,2H,H-9),3.38(t,J＝7.0Hz,2H,H-10),3.34–3.24(m,1H,H-11),3.02(d,J＝14.1Hz,1H,H-12),2.81(s,3H,H-13),2.10–2.00(m,2H,H-14),2.01–1.90(m,1H,H-15). 13 C NMR(151MHz,CDCl 3 )δ166.74,158.74,150.44,143.07,137.46,133.27,132.78,129.83,129.48,129.17,127.37,127.28,123.97,118.44,114.60,110.45,71.89,67.18,58.24,36.76,32.04,28.18,26.13.HR MS calcd for C 26 H 25 ClF 2 N 2 O 5 S 2 ,[M+H] + :583.0934,found:583.0933.
TM1h:White solid,m.p.70.2-71.6℃,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ7.57(s,1H,H-1),7.51(t,J＝7.1Hz,1H,H-2),7.36(d,J＝8.6Hz,1H,H-3),7.33(d,J＝8.0Hz,2H,H-4),7.29(s,1H,H-5),7.23(d,J＝8.5Hz,1H,H-6),7.04(d,J＝9.1Hz,1H,H-7),7.02(d,J＝9.1Hz,1H,H-8),6.90(d,J＝7.9Hz,2H,H-9),4.98(dd,J＝8.5,2.8Hz,1H,H-10),4.04(t,J＝5.9Hz,2H,H-11),3.46(dd,J＝14.6,8.7Hz,2H,H-12),3.41(t,J＝7.1Hz,1H,H-13),3.34(dd,J＝14.7,2.5Hz,1H,H-14),3.01(s,3H,H-15),2.07(dt,J＝14.4,7.1Hz,2H,H-16),2.03–1.97(m,2H,H-7). 13 C NMR(151MHz,CDCl 3 )δ166.74,160.47,160.11,158.78,150.43,143.07,134.36,134.28,134.21,133.36,129.83,127.26,123.96,118.43,114.63,113.24,113.21,113.08,113.05,110.45,72.41,67.17,57.79,36.44,32.04,28.17,26.13.HR MS calcd for C 26 H 26 BrClN 2 O 5 S 2 ,[M+H] + :625.0228,found:625.0219.
TM1i:White solid,m.p.78.2-80.7℃,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ8.10(d,J＝7.8Hz,1H,H-1),7.73(d,J＝7.8Hz,1H,H-2),7.54(s,1H,H-3),7.44(t,J＝7.6Hz,1H,H-4),7.38(t,J＝7.6Hz,1H,H-5),7.33(d,J＝8.6Hz,2H,H-6),7.27(d,J＝11.0Hz,1H,H-7),7.20(d,J＝8.6Hz,2H,H-8),4.92(d,J＝8.0Hz,1H,H-9),4.01(t,J＝5.8Hz,2H,H-10),3.46(dd,J＝14.7,8.9Hz,2H,H-11),3.38(t,J＝6.0Hz,1H,H-12),3.36(d,J＝12.6Hz,1H,H-13),2.96(s,3H,H-14),2.04(dt,J＝14.1,7.0Hz,2H,H-15),2.00–1.92(m,2H,H-16). 13 C NMR(151MHz,CDCl 3 )δ166.73,158.73,150.43,143.08,138.31,135.75,133.64,133.46,132.45,129.83,127.59,127.22,123.96,120.22,118.44,114.62,110.45,72.19,67.17,58.08,36.28,32.04,28.17,26.13.HR MS calcd for C 26 H 26 BrClN 2 O 5 S 2 ,[M+H] + :625.0228,found:625.0209./>
TM1j:White solid,m.p.107.8-109.6,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ7.93(d,J＝7.9Hz,2H,H-1),7.80(d,J＝7.9Hz,2H,H-2),7.56(s,1H,H-3),7.36(d,J＝8.5Hz,1H,H-4),7.31(d,J＝7.6Hz,2H,H-5),7.23(d,J＝8.6Hz,1H,H-6),6.92(t,J＝15.6Hz,2H,H-7),4.92(d,J＝8.3Hz,1H,H-8),4.05(t,J＝5.7Hz,2H,H-9),3.41(t,J＝7.0Hz,2H,,H-10),3.33(dd,J＝14.0,8.8Hz,1H,H-11),3.13(d,J＝14.2Hz,1H,H-12),2.88(s,3H,H-13),2.07(dt,J＝14.2,7.0Hz,2H,H-14),2.04–1.96(m,2H,H-15). 13 C NMR(151MHz,CDCl 3 )δ166.74,158.86,150.43,143.04,141.36,133.15,129.84,127.83,127.25,126.31,126.29,123.98,118.42,114.67,110.45,72.21,67.19,57.97,36.68,32.03,28.16,26.12.HR MS calcd for C 27 H 26 ClF 3 N 2 O 5 S 2 ,[M+H] + :615.0997,found:615.1005.
TM1k:White solid,m.p.81.3-82.9℃,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ7.86(d,J＝8.4Hz,2H,H-1),7.57(s,1H,H-2),7.37(s,1H,H-3),7.35(s,2H,H-4),7.31(d,J＝8.1Hz,2H,H-5),7.23(d,J＝8.6Hz,1H,H-6),6.90(d,J＝8.1Hz,2H,H-7),4.92(d,J＝7.9Hz,1H,H-8),4.05(t,J＝5.9Hz,2H,H-9),3.41(t,J＝7.1Hz,2H,H-10),3.32(dd,J＝14.1,8.8Hz,1H,H-11),3.10(d,J＝14.0Hz,1H,H-12),2.86(s,3H,H-13),2.07(dd,J＝14.2,7.0Hz,2H,H-14),2.01(dd,J＝13.3,6.5Hz,2H,H-15). 13 C NMR(151MHz,CDCl 3 )δ166.72,158.84,152.23,150.44,143.08,136.06,133.18,129.83,129.47,127.26,123.97,121.01,118.44,114.65,110.45,72.10,67.19,58.05,36.69,32.03,28.17,26.12.HR MS calcd for C 27 H 26 ClF 3 N 2 O 6 S 2 ,[M+H] + :631.0946,found:631.0955
TM1l:White solid,m.p.75.3-77.1℃,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ7.95(s,1H,H-1),7.74(d,J＝7.8Hz,2H,H-2),7.57(s,1H,H-13),7.41(t,J＝8.0Hz,1H,H-4),7.36(d,J＝8.6Hz,1H,H-5),7.31(d,J＝7.7Hz,2H,H-6),7.24(d,J＝8.6Hz,1H,H-7),6.91(d,J＝7.6Hz,2H,H-8),4.91(d,J＝8.2Hz,1H,H-9),4.05(t,J＝5.8Hz,2H,H-10),3.42(t,J＝7.0Hz,2H,H-11),3.33(dd,J＝14.1,8.8Hz,1H,H-12),3.12(d,J＝14.1Hz,1H,H-13),2.87(s,3H,H-14),2.08(dt,J＝14.6,7.2Hz,2H,H-15),2.03–1.96(m,2H,H-16). 13 C NMR(151MHz,CDCl 3 )δ166.74,158.72,150.43,146.07,143.07,135.80,134.37,133.43,132.15,129.82,127.21,126.46,123.96,120.21,118.43,114.60,110.44,72.21,67.16,57.75,36.38,32.04,28.18,26.13.HR MS calcd for C 27 H 26 ClF 3 N 2 O 6 S 2 ,[M+H] + :631.0946,found:631.0954.
TM1m:White solid,m.p.70.1-72.9℃,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ7.85–7.78(m,2H,H-1),7.56(s,1H,H-2),7.36(d,J＝8.6Hz,1H,H-3),7.31(d,J＝8.1Hz,2H,H-4),7.29(m,1H,H-5),7.23(d,J＝9.0Hz,21H,,H-6),7.20(s,1H,H-7),6.90(d,J＝8.2Hz,1H,H-8),4.91(d,J＝8.5Hz,1H,H-9),4.04(t,J＝5.9Hz,2H,H-10),3.41(t,J＝7.1Hz,2H,H-11),3.31(dd,J＝14.0,8.8Hz,1H,H-12),3.07(d,J＝14.1Hz,1H,H-13),2.84(s,3H,H-14),2.13–2.04(m,2H,H-15),2.04–1.97(m,2H,H-14). 13 C NMR(151MHz,CDCl 3 )δ166.73,164.33,158.79,150.44,143.08,133.23,130.07,130.01,127.26,123.97,118.43,116.48,116.33,114.62,110.45,72.00,67.18,58.10,36.69,32.03,28.17,26.13.HR MS calcd for C 26 H 27 ClN 2 O 5 S 2 ,[M+H] + :547.1123,found:547.1120；[M+Na] + :569.0942,found:569.0939.
TM1n:yellow oil,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ9.02(s,1H,H-1),8.79(d,J＝3.8Hz,1H,H-2),8.11(d,J＝7.7Hz,1H,H-3),7.53(s,1H,H-4),7.51–7.46(m,1H,H-5),7.33(d,J＝8.6Hz,1H,H-6),7.28(s,2H,H-7),7.20(d,J＝8.6Hz,1H,H-8),6.87(d,J＝7.9Hz,2H,H-9),4.89(d,J＝7.7Hz,1H,H-10),4.02(t,J＝5.8Hz,2H,H-11),3.38(t,J＝6.7Hz,2H,H-12),3.36–3.31(m,1H,H-13),3.13(d,J＝14.2Hz,1H,H-14),2.87(s,3H,H-15),2.08–2.01(m,2H,H-16),1.97(dd,J＝13.5,6.3Hz,2H,H-17). 13 C NMR(151MHz,CDCl 3 )δ166.72,159.40,158.88,152.45,150.44,147.54,143.09,135.83,135.65,133.12,129.82,127.25,124.07,124.02,123.97,118.44,114.70,110.45,72.04,72.01,67.19,57.87,36.48,36.45,32.03,28.16,26.12.HR MS calcd for C 25 H 26 ClN 3 O 5 S 2 ,[M+H] + :548.1063,found:548.1075.
TM1o:White solid,m.p.116.7-118.0℃,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ7.54(s,1H,H-1),7.33(d,J＝8.6Hz,1H,H-2),7.22(d,J＝8.8Hz,2H,H-3),7.19(s,1H,H-4),6.94(s,2H,H-5),6.84(d,J＝7.9Hz,2H,H-6),4.88(d,J＝7.9Hz,1H,,H-7),4.01(t,J＝5.8Hz,2H,H-8),3.38(t,J＝7.3Hz,2H,H-9),3.36–3.29(m,1H,H-10),3.23(d,J＝13.9Hz,1H,H-11),2.86(s,3H,H-12),2.59(s,6H,H-13),2.29(s,3H,H-14),2.04(dt,J＝14.3,7.1Hz,2H,H-15),1.97(dd,J＝13.1,6.4Hz,2H,H-16). 13 C NMR(151MHz,CDCl 3 )δ166.74,158.67,150.44,142.67,140.31,133.66,132.04,129.84,127.15,123.97,118.44,114.58,110.45,71.71,67.17,56.93,34.78,32.04,28.18,26.13,22.86,20.93.HR MS calcd for C 29 H 33 ClN 2 O 5 S 2 ,[M+H] + :589.1592,found:589.1601.
TM1p:Colorless liquid,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ10.30(s,1H,H-1),7.66(d,J＝7.4Hz,2H,H-2),7.54(s,1H,H-3),7.33(d,J＝8.6Hz,1H,H-1),7.29(d,J＝7.8Hz,1H,H-5),7.28(d,J＝7.8Hz,2H,H-6),7.20(d,J＝8.6Hz,1H,H-7),6.87(d,J＝7.5Hz,2H,H-8),4.86(d,J＝8.6Hz,1H,H-9),4.01(t,J＝5.7Hz,2H,H-10),3.38(t,J＝6.9Hz,2H,H-11),3.26(dd,J＝13.9,8.9Hz,1H,H-12),2.99(d,J＝14.1Hz,1H,H-13),2.79(s,3H,H-14),2.41(s,3H,H-15),2.08–2.01(m,2H,H-16),2.01–1.92(m,2H,H-17). 13 C NMR(151MHz,CDCl 3 )δ166.75,159.06,158.71,150.43,143.63,143.06,134.39,133.31,129.78,127.43,127.28,123.97,118.43,114.57,110.45,71.79,67.17,58.29,36.76,28.18,26.13,21.49.HR MS calcd for C 28 H 30 ClN 3 O 6 S 2 ,[M+H] + :604.1337,found:604.1346.
TM2a:white solid,m.p.106.2-108.5℃,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ7.85(d,J＝1.7Hz,1H,H-1),7.66(d,J＝8.2Hz,2H,H-1),7.61(d,J＝8.8Hz,1H,H-3),7.55–7.51(m,2H,H-4),7.31(s,1H,,H-5),7.29(d,J＝5.9Hz,2H,H-6),6.82(d,J＝8.6Hz,2H,H-7),4.87(dd,J＝8.8,3.3Hz,1H,H-8),3.99(t,J＝5.8Hz,2H,H-9),3.67–3.62(m,2H,H-10),3.26(dd,J＝14.1,8.8Hz,1H,H-11),2.99(dd,J＝14.1,3.4Hz,1H,H-12),2.79(s,3H,H-13),2.41(s,3H,H-14),2.19–2.10(m,2H,H-15),2.02–1.93(m,2H,H-16). 13 C NMR(151MHz,CDCl 3 )δ171.07,167.71,159.54,158.39,149.49,143.62,140.48,130.83,129.76,128.79,127.42,127.30,122.01,114.52,112.84,71.79,68.18,60.34,38.79,36.75,28.93,27.66,19.41,14.16.HRMS calcd for C 27 H 29 ClN 2 O 7 S 2 ,[M+Na] + :615.0997,found:615.0995.
TM2b:yellow solid,m.p.146.7-148.0℃,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ8.31(d,J＝10.3Hz,2H,H-1),7.92(d,J＝10.4Hz,2H,H-2),7.72(d,J＝1.7Hz,1H,H-3),7.65(d,J＝8.8Hz,1H,H-4),7.41(dd,J＝8.9,1.9Hz,1H,H-5),7.20(d,J＝8.2Hz,2H,H-6),6.84(d,J＝8.2Hz,1H,H-7),4.91(q,J＝5.4Hz,1H,H-8),4.00(dd,J＝7.2,4.1Hz,2H,H-9),3.55(ddd,J＝35.7,13.0,5.6Hz,1H,H-10,H-11),3.35–3.26(m,2H,H-12),2.67(s,3H,H-13),1.98–1.86(m,2H,H-14),1.86–1.79(m,2H,H-15). 13 C NMR(151MHz,CDCl 3 )δ161.35,158.63,149.81,149.46,142.69,139.65,133.63,131.15,127.88,127.28,126.09,124.44,118.72,115.43,112.57,69.67,67.88,57.39,51.64,36.71,28.04,21.29.HR MS calcd for C 26 H 26 ClN 3 O 9 S 2 ,[M+Na] + :646.0691,found:646.0685.
TM2c:yellow solid,m.p.137.6-138.9℃,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ7.85(d,J＝1.7Hz,1H,H-1),7.66(d,J＝8.2Hz,1H,H-2),7.61(d,J＝8.8Hz,2H,H-3,4),7.55–7.51(m,1H,H-5,6),7.31(s,1H,H-7),7.29(d,J＝5.9Hz,2H,H-8),6.82(d,J＝8.6Hz,2H,H-9),4.87(dd,J＝8.8,3.3Hz,1H,H-10),3.99(t,J＝5.8Hz,2H,H-11),3.67–3.62(m,2H,H-12),3.26(dd,J＝14.1,8.8Hz,1H,H-13),2.99(dd,J＝14.1,3.4Hz,1H,H-14),2.79(s,3H,H-15),2.19–2.10(m,1H,H-16),2.02–1.93(m,1H,H-17). 13 C NMR(151MHz,CDCl 3 )δ158.50,149.49,140.48,133.60,132.02,131.57,131.02,129.12,127.27,124.17,122.03,114.62,112.85,72.21,69.45,66.79,57.61,54.38,36.33,27.65,19.41.HR MS calcd for C 26 H 26 ClN 3 O 9 S 2 ,[M+Na] + :646.0691,found:646.0688.
TM2d:white solid,m.p.122.3-124.8℃,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ7.92(s,1H,H-1),7.73–7.66(m,2H,H-2),7.53(d,J＝1.8Hz,1H,H-3),7.38(t,J＝7.9Hz,2H,H-4),7.33(d,J＝8.6Hz,1H,H-5),7.28(d,J＝8.5Hz,2H,H-6),7.20(dd,J＝8.6,2.0Hz,1H,H-7),4.88(dd,J＝8.6,3.6Hz,1H,H-8),4.02(t,J＝6.0Hz,2H,H-9),3.38(t,J＝7.1Hz,2H,H-10),3.29(dd,J＝14.2,8.6Hz,1H,H-11),3.10(dd,J＝14.2,3.7Hz,1H,H-12),2.83(s,3H,H-13),2.08–2.01(m,2H,H-14),2.01–1.92(m,2H,H-15). 13 C NMR(151MHz,CDCl 3 )δ166.71,158.85,150.46,143.12,139.79,138.81,135.76,130.62,130.16,129.84,127.26,125.85,123.95,123.23,118.46,114.69,110.42,72.19,67.22,58.02,36.73,32.05,28.18,26.15.HR MS calcd for C 26 H 26 ClFN 2 O 7 S 2 ,[M+Na] + :619.0746,found:619.0745.
TM2e:white solid,m.p.117.7-119.6℃,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ7.84(d,J＝1.7Hz,1H,H-1),7.61(d,J＝8.8Hz,1H,H-2),7.57(d,J＝7.8Hz,1H,H-3),7.54(dd,J＝8.8,1.9Hz,1H,H-4),7.52–7.45(m,2H,H-5,H-6),7.32–7.28(m,1H,H-7),7.28(d,J＝8.6Hz,2H,H-8),6.83(d,J＝8.6Hz,2H,H-9),4.88(dd,J＝8.6,3.4Hz,1H,H-10),4.00(t,J＝5.7Hz,2H,H-11),3.73–3.60(m,2H,H-12),3.29(dd,J＝14.2,8.7Hz,1H,H-13),3.08(dd,J＝14.2,3.5Hz,1H,H-14),2.84(s,3H,H-15),2.21–2.10(m,2H,H-16),2.02–1.95(m,2H,H-17). 13 C NMR(151MHz,CDCl 3 )δ163.35,161.68,159.53,158.51,149.49,140.48,133.49,132.03,130.97,129.12,127.30,123.07,122.03,119.89,114.78,114.60,112.84,72.07,66.79,58.07,54.38,36.74,27.67,19.41.HR MS calcd for C 26 H 26 ClFN 2 O 7 S 2 ,[M+H] + :597.0927,found:597.0935；[M+Na] + :619.0746,found:619.0749.
TM2f:white solid,m.p.129.4-131.2℃,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ7.91(t,J＝7.2Hz,1H,H-1),7.58(dd,J＝10.9,4.9Hz,1H,H-2),7.56(d,J＝1.4Hz,1H,H-3),7.35(d,J＝8.6Hz,1H,H-4),7.31(d,J＝8.5Hz,2H,H-5),7.27(d,J＝6.4Hz 1H,H-6),7.22(ddd,J＝15.7,7.8,5.0Hz,1H,H-7,H-8),6.89(d,J＝8.6Hz,2H,H-9),4.93(dd,J＝8.7,3.5Hz,1H,H-10),4.04(t,J＝6.0Hz,2H,H-11),3.44–3.38(m,2H,H-12),3.42–3.39(m,1H,H-13),3.26(dd,J＝14.5,3.5Hz,1H,H-14),2.94(s,3H,H-15),2.11–2.03(m,2H,H-16),2.03–1.95(m,2H,H-17). 13 C NMR(151MHz,CDCl 3 )δ166.72,158.76,157.96,150.45,143.11,134.92,134.86,133.46,131.34,129.84,127.24,124.44,124.41,123.95,118.45,117.28,117.13,114.65,110.41,72.25,67.21,57.86,57.85,36.41,36.39,32.05,28.18,26.15.HR MS calcd for C 26 H 26 ClFN 2 O 7 S 2 ,[M+Na] + :619.0746,found:619.0742./>
TM2g:white solid,m.p.119.2-122.4℃,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ7.45(d,J＝1.7Hz,1H,H-1),7.43–7.36(m,1H,H-2),7.25(d,J＝8.6Hz,1H,H-3),7.22(d,J＝8.5Hz,2H,H-4),7.11(dt,J＝12.2,6.1Hz,1H,H-5),6.92(t,J＝8.8Hz,2H,H-6),6.79(d,J＝8.6Hz,2H,H-7),4.86(dd,J＝8.6,3.6Hz,1H,H-8),3.93(t,J＝6.0Hz,2H,H-9),3.36(dd,J＝14.6,8.7Hz,1H,H-10),3.30(t,J＝7.1Hz,1H,H-11),3.24(dd,J＝14.6,3.6Hz,1H,H-12),2.90(s,3H,H-13),2.00–1.93(m,1H,H-14),1.92–1.84(m,1H,H-15). 13 C NMR(151MHz,CDCl 3 )δ166.73,160.45,158.79,158.74,150.45,143.10,133.45,129.83,128.80,127.25,123.95,118.44,117.13,114.67,113.21,113.18,113.05,113.02,110.42,72.43,67.21,57.78,36.41,32.05,28.18,26.15.HR MS calcd for C 26 H 26 ClF 2 N 2 O 7 S 2 ,[M+Na] + :637.0652,found:637.0649.
TM2h:yellow solid,m.p.144.6-146.7℃,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ7.94(s,1H,H-1),7.76–7.69(m,2H,H-2,H-3),7.55(d,J＝1.7Hz,1H,H-4),7.40(t,J＝7.9Hz,1H,H-5),7.35(d,J＝8.6Hz,1H,H-6),7.30(d,J＝8.5Hz,2H,H-7),7.22(dd,J＝8.6,1.9Hz,1H,H-8),6.90(d,J＝8.2Hz,1H,H-9),4.90(dd,J＝8.6,3.6Hz,1H,H-10),4.04(t,J＝6.0Hz,2H,H-11),3.41(t,J＝7.1Hz,2H,H-12),3.32(dd,J＝14.2,8.6Hz,1H,H-13),3.13(dd,J＝14.2,3.7Hz,1H,H-14),2.86(s,3H,H-15),2.10–2.04(m,2H,H-16),2.00(dt,J＝12.6,6.1Hz,2H,H-17). 13 C NMR(151MHz,CDCl 3 )δ166.72,158.84,150.45,143.10,139.79,135.76,133.28,130.62,130.15,129.84,127.26,125.85,123.96,123.22,118.45,114.69,110.42,72.19,67.22,58.01,36.72,32.05,28.18,26.15.HR MS calcd for C 26 H 26 BrClN 2 O 7 S 2 ,[M+Na] + :678.9946,found:678.9945.
TM2i:yellow solid,m.p.151.0-153.4℃,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ7.76(dd,J＝8.5,1.4Hz,1H,H-1),7.72(d,J＝1.7Hz,1H,H-2),7.70(dd,J＝8.0,1.3Hz,1H,H-3),7.65(d,J＝8.8Hz,1H,H-4),7.56(ddd,J＝8.4,7.2,1.3Hz,1H,H-5),7.40(ddd,J＝8.1,5.1,1.7Hz,2H,H-6,H-7),7.20(d,J＝8.6Hz,2H,H-1),6.84(d,J＝8.2Hz,2H,H-9),4.91(q,J＝5.4Hz,1H,H-10),4.00(dd,J＝7.2,4.1Hz,2H,H-11),3.64–3.51(m,1H,H-12,H-13),3.36–3.24(m,4H,H-14),2.72(s,3H,H-15),1.97–1.86(m,2H,H-16),1.86–1.79(m,2H,H-17). 13 C NMR(151MHz,CDCl 3 )δ161.35,158.63,149.46,139.65,137.61,135.08,134.81,133.65,131.15,129.41,129.00,127.28,126.09,122.25,118.72,115.43,112.57,69.67,67.88,57.34,51.64,36.86,28.04,21.29.HR MS calcd for C 26 H 26 BrClN 2 O 7 S 2 ,[M+Na] + :678.9946,found:678.9949./>
TM2j:white solid,m.p.109.7-111.0℃,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ7.83(d,J＝8.1Hz,2H,H-1),7.77(d,J＝1.5Hz,1H,H-2),7.70(d,J＝8.2Hz,2H,H-3),7.54(d,J＝8.8Hz,1H,H-4),7.47(dd,J＝8.9,1.6Hz,1H,H-5),7.21(s,2H,H-6),6.76(d,J＝8.5Hz,2H,H-7),4.82(dd,J＝8.5,3.5Hz,1H,H-8),3.93(t,J＝5.7Hz,2H,H-9),3.69–3.50(m,2H,H-10),3.23(dd,J＝14.2,8.7Hz,1H,H-11),3.03(dd,J＝14.2,3.5Hz,1H,H-12),2.78(s,3H,H-13),2.12–2.04(m,2H,H-14),1.95–1.87(m,2H,H-15). 13 C NMR(151MHz,CDCl 3 )δ158.56,149.49,140.48,133.45,132.03,130.84,129.12,128.80,127.82,127.28,126.31,122.02,114.62,112.84,72.16,66.81,57.98,54.37,36.68,27.67,19.40.HR MS calcd for C 27 H 26 ClF 3 N 2 O 7 S 2 ,[M+Na] + :669.0714,found:669.0710.
TM2k:white solid,m.p.132.6-134.1℃,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ7.84(dd,J＝7.3,5.3Hz,2H,H-1,H-2),7.61(d,J＝8.8Hz,1H,H-3),7.54(dd,J＝8.8,1.9Hz,1H,H-4),7.33(d,J＝8.4Hz,2H,H-5),7.28(d,J＝8.5Hz,2H,H-6),6.83(d,J＝8.5Hz,2H,H-7),4.89(dd,J＝8.6,3.5Hz,1H,H-8),4.00(t,J＝5.8Hz,2H,H-9),3.78–3.56(m,2H,H-10),3.29(dd,J＝14.1,8.7Hz,1H,H-11),3.07(dd,J＝14.2,3.5Hz,1H,H-12),2.83(s,3H,H-13),2.21–2.08(m,2H,H-14),2.01–1.95(m,2H,H-15). 13 C NMR(151MHz,CDCl 3 )δ158.54,154.86,149.49,142.38,130.16,129.58,129.46,129.13,127.30,122.76,122.03,121.02,114.62,112.84,111.00,110.35,72.06,66.81,58.04,54.38,36.69,27.67,19.40.HR MS calcd for C 27 H 26 ClF 3 N 2 O 8 S 2 ,[M+Na] + :685.0663,found:685.0662.
TM2l:white solid,m.p.115.4-117.6℃,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ8.05(d,J＝7.9Hz,1H,H-1),7.62(t,J＝7.9Hz,1H,H-2),7.56(d,J＝1.7Hz,1H,H-3),7.41(t,J＝7.7Hz,2H,H-4,H-5),7.35(d,J＝8.6Hz,1H,H-6),7.30(d,J＝8.5Hz,2H,H-7),7.22(dd,J＝8.6,1.8Hz,1H,H-8),6.89(d,J＝8.5Hz,1H,H-9),4.93(dd,J＝8.7,3.5Hz,2H,H-10),4.03(t,J＝6.0Hz,2H,H-11),3.41(dd,J＝14.5,7.7Hz,2H,H-12),3.40(t,J＝7.2Hz,1H,H-13),3.28(dd,J＝14.7,3.6Hz,1H,H-14),2.95(s,3H,H-15),2.11–2.03(m,2H,H-16),1.99(dt,J＝12.8,6.2Hz,2H,H-17). 13 C NMR(151MHz,CDCl 3 )δ166.73,163.37,158.74,150.45,146.08,143.11,134.31,133.51,132.12,131.11,129.84,127.20,126.43,123.94,120.21,118.44,114.65,110.41,72.25,67.20,57.75,36.35,32.05,28.18,26.15.HR MS calcd for C 27 H 26 ClF 3 N 2 O 8 S 2 ,[M+Na] + :685.0663,found:685.0636.
TM2m:Colorless liquid,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ7.79–7.74(m,1H,H-1),7.72(d,J＝2.0Hz,1H,H-2),7.72–7.69(m,2H,H-3),7.65(dd,J＝5.2,3.5Hz,1H,H-4),7.64–7.60(m,2H,H-5),7.41(dd,J＝8.9,1.9Hz,1H,H-6),7.20(d,J＝8.2Hz,2H,H-7),6.84(d,J＝8.2Hz,2H,H-8),4.91(q,J＝5.4Hz,1H,H-9),4.00(dd,J＝7.2,4.1Hz,1H),H-10,3.55(ddd,J＝36.1,13.0,5.5Hz,1H,H-11,12),3.35–3.26(m,2H,H-13),2.67(s,3H,H-14),1.98–1.86(m,2H,H-15),1.86–1.79(m,2H,H-16). 13 C NMR(151MHz,CDCl 3 )δ166.73,164.31,158.79,150.44,143.10,133.38,130.05,129.99,127.25,123.95,118.43,116.43,116.28,114.66,110.43,72.07,67.23,58.06,36.66,32.05,28.18,26.15.HR MS calcd for C 26 H 27 ClN 2 O 7 S 2 ,[M+Na] + :643.1310,found:643.1309.
TM2n:yellow oil,m.p.156.7-158.5℃,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ8.90(d,J＝35.7Hz,1H,H-1),8.71(d,J＝4.2Hz,1H,H-2),8.05–7.96(m,1H,H-3),7.45(t,J＝3.8Hz,1H,H-4),7.38(dt,J＝14.6,7.3Hz,1H,H-5),7.24(t,J＝13.7Hz,1H,H-6),7.20(d,J＝7.1Hz,2H,H-7),7.12(dd,J＝8.6,1.9Hz,1H,H-8),6.80(t,J＝8.9Hz,2H,H-9),4.82(dd,J＝8.6,3.5Hz,1H,H-10),3.94(t,J＝6.0Hz,2H,H-11),3.31(t,J＝7.1Hz,2H,H-12),3.26(dd,J＝14.2,8.7Hz,1H,H-13),3.07(dd,J＝14.2,3.6Hz,1H,H-14),2.79(s,3H,H-15),2.00–1.93(m,2H,H-16),1.90(dt,J＝12.6,6.1Hz,2H,H-17). 13 C NMR(151MHz,CDCl 3 )δ166.71,158.87,152.85,150.45,147.83,143.10,135.25,134.97,133.27,129.84,127.23,123.95,123.84,118.44,114.73,110.42,72.20,67.23,57.86,36.55,32.04,28.17,26.14.HR MS calcd for C 25 H 26 ClN 3 O 7 S 2 ,[M+H] + :580.0971,found:580.0973；[M+Na] + :602.0793,found:602.0790.
TM2o:white solid,m.p.128.7.7-129.6℃,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ7.54(d,J＝1.8Hz,1H,H-1),7.32(d,J＝8.6Hz,1H,H-2),7.22(d,J＝8.7Hz,2H,H-3),7.20–7.18(m,1H,H-4),6.94(s,1H,H-5),6.83(t,J＝11.8Hz,2H,H-6),4.94–4.78(m,1H,H-7),4.01(t,J＝6.0Hz,2H,H-8),3.38(t,J＝7.1Hz,2H,H-9),3.36–3.30(m,1H,H-10),3.26–3.17(m,1H,H-11),2.86(s,3H,H-12),2.58(s,6H,H-13),2.29(s,3H,H-14),2.08–2.00(m,2H,H-15),1.97(dt,J＝12.5,6.1Hz,2H,H-6). 13 C NMR(151MHz,CDCl 3 )δ166.72,158.70,150.45,143.10,142.61,140.31,133.74,132.01,129.85,127.13,123.95,118.45,114.62,110.41,71.76,67.21,56.94,34.78,32.06,28.18,26.15,22.81,20.89.HR MS calcd for C 29 H 33 ClN 2 O 7 S 2 ,[M+Na] + :601.0840,found:601.0837.
TM2p:Colorless liquid,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ7.85(s,1H,H-1),7.74–7.69(m,2H,H-2),7.67(d,J＝8.6Hz,2H,H-3),7.55(d,J＝1.1Hz,1H,H-4),7.34(t,J＝8.4Hz,1H,H-5),7.28(d,J＝5.8Hz,2H,H-6),7.22(dd,J＝8.6,1.9Hz,1H,H-7),6.88(d,J＝8.5Hz,2H,H-8),4.87(dd,J＝8.6,3.4Hz,1H,H-9),4.03(t,J＝6.0Hz,2H,H-10),3.40(t,J＝7.1Hz,2H,H-11),3.29(dd,J＝14.1,8.7Hz,1H,H-12),3.03(dd,J＝14.2,3.3Hz,1H,H-13),2.80(s,3H,H-14),2.20(s,3H,H-15),2.09–2.03(m,2H,H-16),2.02–1.94(m,2H,H-17). 13 CNMR(151MHz,CDCl 3 )δ168.75,166.74,158.76,150.44,143.09,142.18,133.32,132.17,129.84,128.58,127.26,123.96,119.50,118.42,114.66,110.44,71.91,67.22,58.14,36.70,32.05,28.17,26.15,24.57.HR MS calcd for C 28 H 30 ClN 3 O 8 S 2 ,[M+Na] + :636.1236,found:636.1230.
2 target molecule and intermediate biological Activity test
2.1 antibacterial Activity
The test was performed according to the national clinical laboratory standardization committee (NCCLS) recommended microdilution method; test strain: gram positive bacteria: micrococcus luteus (Micrococcus luteus), staphylococcus aureus (Staphyloccocus aureus ATCC25129, ATCC 14125), gram negative bacteria: coli (Escherichia coli ATCC 25922), acinetobacter baumannii (Acinetobacter baumannii ATCC 19606), pseudomonas aeruginosa (Pseudomonas aeruginosa ATCC 27853) and salmonella (Salmonella Enteritidis ATCC 13076), and the test bacteria are all human pathogenic bacteria; positive controls were Ciprofloxacin (CLX), norfloxacin (NOR), ciprofloxacin (CIP), sarafloxacin (SAR), enrofloxacin (ENO), balofloxacin (BAL), lomefloxacin (LOM), gatifloxacin (GAT). The test results are shown in Table 3.
TABLE 3 inhibition of bacterial Activity of target molecules and intermediates
In general, most of the TM1 molecules show inhibitory activities with different intensities on Acinetobacter baumannii and are insensitive to other 6 human pathogenic bacteria; TM2 has inhibitory activity with different intensity on Acinetobacter baumannii and micrococcus luteus, and is insensitive to other 5 human pathogenic bacteria; the intermediate IM4 has the inhibitory activity on 5 human pathogens which is equivalent to or stronger than that of 8 kinds of drugs on the market.
For Acinetobacter baumannii, most of the TM1/TM2 target molecules have weaker inhibitory activity than CLX, CIP, SAR and BAL, but are comparable to GAT, LOM, ENO, NOR; wherein, TM2p (mic=0.404 μmol·ml) -1 The numerals in parentheses are MIC values) and TM1h/1i/1k/1l (0.406 to 0.409. Mu. Mol. ML) -1 ) Is equivalent to NOR (0.401. Mu. Mol. ML) -1 ) The ratio of TM2h/2i/2j/2k/2l (0.387-0.390. Mu. Mol.mL) -1 ) Even more active thanNOR; both TM2 (sulfone) and TM1 (thioether) have better active molecules, but overall TM2 is slightly more active than TM1. Inhibitory Activity of 3 intermediates (IM 2, IM3, IM 4) (0.145-0.318. Mu. Mol.mL) -1 ) And NOR, ENO, LOM, GAT (0.401, 0.356, 0.364, 0.341. Mu. Mol. ML) -1 ) Is equivalent or stronger than IM4 (0.145. Mu. Mol. ML) -1 ) Is only weaker than CIP and CLX, but is more than 2 times stronger than the activity of the other 6 sand drugs, even NOR, ENO, LOM and GAT. TM1 and TM2 all target molecules and all intermediates are more active than the parent synephrine.
For Micrococcus luteus, the inhibitory activity of TM1i and TM2h/2j/2l was stronger than that of synephrine and most intermediates, especially TM2l (0.048. Mu. Mol. ML -1 ) Is also stronger than ENO and NOR (0.089, 0.050 mu mol.mL) -1 ) With LOM, SAR (0.046, 0.042. Mu. Mol. ML) -1 ) Is equivalent in activity.
Notably, intermediate IM4 also showed superior antimicrobial activity against pseudomonas aeruginosa, micrococcus luteus, salmonella and staphylococcus aureus ATCC25129, indicating that the molecule has broad-spectrum antimicrobial properties with great research potential. For Pseudomonas aeruginosa, the inhibitory activity of IM4 (0.018. Mu. Mol. ML -1 ) Far stronger than CIP>0.768μmol·mL -1 ). For Micrococcus luteus, the inhibitory activity of IM4 (0.009. Mu. Mol. ML) -1 ) And CLX, CIP, BAL, GAT (0.005-0.006. Mu. Mol.mL) -1 ) Equivalent is SAR (0.042. Mu. Mol. ML) -1 ) Is 4.6 times that of LOM (0.046. Mu. Mol. ML) -1 ) Is 5 times that of NOR (0.050. Mu. Mol. ML) -1 ) Is 5.5 times that of ENO (0.089. Mu. Mol.mL) -1 ) 9.8 times of (3). For Salmonella, inhibitory Activity of IM4 (0.009. Mu. Mol. ML) -1 ) And 8 kinds of sarcin medicine (0.005-0.006 mu mol.mL) -1 ) Equivalent. Inhibitory Activity against Staphylococcus aureus ATCC25129, IM4 (0.009. Mu. Mol. ML -1 ) And NOR, CIP, SAR, ENO, BAL, LOM, GAT (0.005-0.006. Mu. Mol.mL) -1 ) Quite much stronger than CLX.
2.2 antifungal Activity
The test was performed using the NCCLS recommended micro-broth dilution method, testing the strain: human pathogenic fungi: candida tropicalis (Candida utilis) resistant strains, aspergillus fumigatus (Aspergillus fumigatus) resistant strains, candida parapsilosis (Candida parapsilosis) ATCC22019, candida albicans (Candida albicans) resistant strains, candida albicans ATCC 90023; non-human pathogenic fungi: pichia pastoris GS115; fluconazole (Fluconazole) was used as a positive control. The test results are shown in Table 4.
TABLE 4 inhibition Activity of target molecules and intermediates against fungi
Note that: -indicating no test.
In general, the target molecules TM1, TM2 and intermediates exhibit different levels of inhibitory activity against 5 human pathogenic fungi, and many molecules are sensitive to human pathogenic fungi. TM1 is insensitive to the non-human pathogen Pichia pastoris, but the intermediate IM4 has activity on Pichia pastoris (0.036. Mu. Mol.mL) -1 ) Is fluconazole (0.104 mu mol.mL) -1 ) Is 2.8 times as large as the above. As can also be seen from Table 4, IM4 shows high inhibitory activity against 5 strains of fungi, IM3 against 4 strains of fungi, TM2f/3f, TM2j/3j and TM2l against 3 strains of fungi, exhibiting broad spectrum.
For drug-resistant candida tropicalis, 2 intermediates (0.036. Mu. Mol.mL -1 ,0.126μmol·mL -1 ) 6 TM2 molecules (0.109-0.452. Mu. Mol.mL) -1 ) And 5 TM3 molecules (0.207-0.428. Mu. Mol.mL) -1 ) The inhibition activity is stronger than that of the parent synephrine>1.53μmol·mL -1 ). Intermediate IM4 (0.036. Mu. Mol. ML) -1 ) Is far more inhibitory than fluconazole (0.104 mu mol.mL) -1 ) And the activity sequence of the intermediate is IM4>IM3(0.126μmol·mL -1 )>IM2(≧0.636μmol·mL -1 ) It is shown that the introduction of 5-chloro-2-mercaptobenzoxazole into synephenol hydroxyl can improve the antifungal activity of the corresponding molecule, and even the activity can exceed that of fluconazole. Although TM 1-Most of the TM2 molecules have weak inhibitory activity on drug-resistant candida tropicalis, but TM1o has strong antibacterial activity (0.109 mu mol.mL) -1 ) Equivalent to fluconazole. As a whole, TM1 is more active than TM2. MIC value of sulfone type TM2o obtained by oxidizing thioether type TM1o was 0.207. Mu. Mol.mL -1 The activity is greatly reduced compared with TM1o; the activity is stronger than the number of molecules of the parent nucleus synephrine, the TM2 number is 5, the TM1 number is 6, and the part shows that the inhibition activity of the TM1 thioether type molecule on the drug-resistant candida tropicalis is stronger than the TM2 sulfone type molecule.
For drug-resistant Aspergillus fumigatus, the TM1/TM2 has 15 molecules with equivalent activity to fluconazole (0.404-0.468 mu mol.mL) -1 ) Activity of TM2l, TM2m (0.194, 0.222. Mu. Mol. ML) -1 ) Is more than fluconazole (0.418 mu mol.mL) -1 ). Intermediate IM4 (0.036. Mu. Mol. ML) -1 ) The antibacterial activity of the composition is 8 times that of fluconazole, and the composition shows excellent activity. 4 intermediates (0.036-0.985. Mu. Mol.mL) -1 ) 11 TM1 molecules (0.036-0.453. Mu. Mol.mL) -1 ) And 7 TM2 molecules (0.194-0.417. Mu. Mol.mL) -1 ) Is more inhibitory than the parent synephrine (1.531. Mu. Mol. ML) -1 ). Intermediate Activity IM4>IM3(0.505μmol·mL -1 )>IM2(0.636μmol·mL -1 )>IM1(0.958μmol·mL -1 ) It was further demonstrated that the introduction of 5-chloro-2-mercaptobenzoxazole onto the phenolic hydroxyl group of synephrine and sulfonyl onto the secondary amine can increase the inhibitory activity against aspergillus fumigatus. As a whole, TM2 is more active than TM1. Furthermore, sulfone type TM2l (0.194. Mu. Mol.mL) -1 ) The activity is far higher than that of thioether type TM1l (0.406 mu mol.mL) -1 ) The synephrine sulfone derivative is shown to be capable of improving the inhibitory activity on drug-resistant aspergillus fumigatus.
For Candida parapsilosis ATCC22019, all TM1 molecules (0.013-0.406. Mu. Mol.mL -1 ) TM2 molecule (0.006-0.442 mu mol/mL) -1 ) Intermediate (0.008-0.577 mu mol/mL) -1 ) Are all stronger than the parent synephrine (1.531 mu mol.mL) -1 ) The method comprises the steps of carrying out a first treatment on the surface of the The MIC of each of the TM1 and TM2 molecules is less than or equal to 0.113 mu mol.mL -1 The intensity of activity is not completely one-to-one, and may be related to the overall nature of the molecule; wherein, TM1g/1m/2f/2g/2j (0.025-0.029 mu mol.mL) -1 ) And TM1l/2m (0.013-0.014. Mu. Mol.mL) -1 ) Has strong inhibitory activity, and TM2l activity (0.006. Mu. Mol. ML) -1 ) Even stronger than fluconazole (0.007 mu mol.mL) -1 ). Activity of intermediate IM3 (0.008. Mu. Mol. ML) -1 ) And fluconazole (0.007. Mu. Mol.mL) -1 ) Quite, it is shown that the introduction of 5-chloro-2-mercaptobenzoxazole on synephenol hydroxyl can improve the antibacterial activity of molecules on candida parapsilosis. Overall activity analysis found that most TM2 was more active than the corresponding TM1, indicating that the synephrine sulfide derivatives after oxidation were able to increase antibacterial activity against candida parapsilosis.
For drug-resistant candida albicans, the activity of most target molecules and intermediates is stronger than that of parent synephrine; 7 TM1 molecules (0.007-0.108. Mu. Mol.mL) -1 ) 3 TM2 target molecules (0.048-0.215 mu mol.mL) -1 ) And 2 intermediates (0.072 to 0.126. Mu. Mol.mL) -1 ) Exhibits a strong antibacterial activity. Wherein the activity of TM2d/2g/2i/3l (0.048-0.057. Mu. Mol.mL) -1 ) Slightly weaker than fluconazole (0.014. Mu. Mol.mL) -1 ) Activity of TM2f (0.014. Mu. Mol. ML) -1 ) As with fluconazole, TM2l activity (0.007. Mu. Mol. ML) -1 ) Is stronger than fluconazole. Intermediate Activity IM4 (0.072. Mu. Mol.mL) -1 )>IM3(0.126μmol·mL -1 )>IM2(0.318μmol·mL -1 )>IM1(0.958μmol·mL -1 ) It was demonstrated that derivatization of synephrine at each step can increase antifungal activity. The activities of TM1 j-TM 1p and TM2 j-TM 2p are in one-to-one correspondence, which indicates that the activity of the synephrine sulfone type derivative TM2 is reduced compared with that of the thioether type derivative TM1 as a whole.
For Candida albicans ATCC90023, 3 intermediates, 10 TM1 molecules and 13 TM2 molecules were more active than the parent synephrine (1.531. Mu. Mol. ML -1 ) The method comprises the steps of carrying out a first treatment on the surface of the Has 2 intermediates (0.009-0.126. Mu. Mol.mL) -1 ) 5 TM1 molecules (0.004-0.052. Mu. Mol.mL) -1 ) And 5 TM2 molecules (0.006-0.107. Mu. Mol.mL) -1 ) Exhibits a strong antibacterial activity; wherein, TM1e/2e (0.013-0.014. Mu. Mol.mL) -1 ) Is weaker than fluconazole, intermediate IM4 (0.009. Mu. Mol. ML) -1 ) And TM2f (0.007. Mu. Mol. ML) -1 ) Is equivalent to fluconazole (0.007 mu mol.mL) -1 ) TM1f (0.004. Mu. Mol. ML) -1 )、TM1h(0.006μmol·mL -1 ) And TM2k (0.006. Mu. Mol. ML) -1 ) Is more active than fluconazole.
The TM1/TM2 activity data show that the antifungal activity rules of the synephrine thioether-type/sulfone-type derivatives are not uniform, and the thioether-type derivatives have stronger activity on drug-resistant aspergillus fumigatus and candida parapsilosis ATCC 22019; the sulfone derivative has stronger activity for drug-resistant candida tropicalis and drug-resistant candida albicans; for candida albicans ATCC90023, there is no rule. These data indicate that both sulfone/thioether structures are likely to increase inhibitory activity against certain human pathogenic fungi, possibly related to the overall nature of the molecule.
Finally, it is noted that the above-mentioned preferred embodiments are only intended to illustrate rather than limit the invention, and that, although the invention has been described in detail by means of the above-mentioned preferred embodiments, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention as defined by the appended claims.

Claims (6)

1. The synephrine benzoxazole sulfonamide derivative shown in the formula I or the pharmaceutically acceptable salt thereof is characterized in that,
in the formula I, X is S or SO 2 R is 2-fluorophenyl or 3-trifluoromethoxy, i.e., compound TM1f, TM2f, TM1l or TM2l;
or X is S, R is 3-bromophenyl or 2,4, 6-trimethyl, namely a compound TM1h or TM1o;
alternatively, X is SO 2 R is 4-trifluoromethoxy or phenyl, i.e. compound TM2k or TM2m;
2. an intermediate of formula II:
in formula II, Y is tert-butoxycarbonyl, i.e., boc or H.
3. The method for preparing the synephrine benzoxazole sulfonamide derivative or the pharmaceutically acceptable salt thereof according to claim 1, which is characterized by comprising the following steps:
i. the synephrine and di-tert-butyl dicarbonate, namely Boc 2 O reacts to prepare an intermediate IM1;
reacting the intermediate IM1 with 1, 4-dibromobutane to obtain an intermediate IM2;
reacting the intermediate IM2 with 5-chloro-2-mercaptobenzoxazole to obtain an intermediate IM3, namely an intermediate shown in a formula II, wherein Y is Boc;
reacting the intermediate IM3 with HCl-ethyl acetate, namely HCl-EA to prepare an intermediate IM4, namely hydrochloride of the intermediate shown in a formula II, wherein Y is H;
v. intermediate IM4 is combined with compound RSO 2 Cl reacts to prepare a compound TM1, namely a synephrine benzoxazole sulfonamide derivative shown in a formula I, wherein X in the formula I is S;
reacting compound TM1 with m-chloroperoxybenzoic acid (mCPBA) to obtain compound TM2 (synephrine benzoxazole sulfonamide derivative shown in formula I, wherein X is SO 2 ；
Compound RSO 2 R in the formulae Cl, TM1 and TM2 is as defined for R in the formula I as claimed in claim 1.
4. A process for the preparation of synephrine benzoxazole sulfonamide derivatives or pharmaceutically acceptable salts thereof according to claim 3, comprising the steps of:
i. the synephrine and Boc are combined 2 O reacts in ethanol solvent at 0-35 ℃ to prepare an intermediate IM1;
ii. intermediate IM1 and 1, 4-dibromobutane in base K 2 CO 3 Reacting in solvent N, N-Dimethylformamide (DMF) at 45 ℃ in the presence of the solvent to prepare an intermediate IM2;
intermediate IM2 and 5-chloro-2-mercaptobenzoxazole in base K 2 CO 3 Reacting in DMF at 45 ℃ in the presence of a solvent to obtain an intermediate IM3, namely an intermediate shown in a formula II, wherein Y is Boc;
reacting the intermediate IM3 with HCl-EA at 0-5 ℃ to obtain an intermediate IM4, namely an intermediate hydrochloride shown in a formula II, wherein Y is H;
v. intermediate IM4 is combined with compound RSO 2 Cl reacts in DMF at minus 15-25 ℃ in the presence of N, N-diisopropylethylamine, namely DIPEA, as acid-binding agent to prepare the compound TM1, namely synephenzene shown in formula IAnd oxazole sulfonamide derivatives, wherein X is S;
reacting compound TM1 with mCPBA in dichloromethane solvent (DCM) at 30deg.C to obtain compound TM2 (synephrine benzoxazole sulfonamide derivative shown in formula I), wherein X is SO 2 。
5. Use of a synephrine benzoxazole sulfonamide derivative of claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of an antibacterial and/or antifungal drug, wherein the bacterium is acinetobacter baumannii (Acinetobacter baumannii) and/or micrococcus luteus (Micrococcus luteus), and the fungus is one or more of Candida tropicalis (Candida tropicalis), aspergillus fumigatus (Aspergillus fumigatus), candida parapsilosis (Candida parapsilosis), and Candida albicans (Candida albicans).
6. Use of the intermediate of claim 2, or a pharmaceutically acceptable salt thereof, for the preparation of an antibacterial and/or antifungal drug, wherein the bacterium is one or more of acinetobacter baumannii (Acinetobacter baumannii), pseudomonas aeruginosa (Pseudomonas aeruginosa), micrococcus luteus (Micrococcus luteus), salmonella (Salmonella Enteritidis) and staphylococcus aureus (Staphyloccocus aureus), and the fungus is one or more of Candida tropicalis (Candida tropical), aspergillus fumigatus (Aspergillus fumigatus), candida parapsilosis (Candida parapsilosis), candida albicans (Candida albicans) and pichia pastoris (pichia pastoris).
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