CN114478418A - Cinfeline sulfuryl tetrazole sulfonamide derivative, intermediate and application thereof - Google Patents

Abstract

The invention discloses a synephrine sulfuryl tetrazole sulfamide derivative shown in a formula I, wherein R is phenyl, substituted phenyl or 3-pyridyl; the phenyl substituent is one or more and is independently selected from halogen, hydroxyl, amino, C1-C3 alkylamido, nitro, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, C1-C3 alkoxy or halogen-substituted C1-C3 alkoxy; through the activity tests of resisting human pathogenic bacteria and fungi, the derivatives synthesized by the invention have certain antibacterial and/or antifungal activity, are stronger than that of mother nucleus synephrine, particularly have partial high-activity molecules, and have the activity on candida tropicalis, candida parapsilosis, candida albicans and the like which is equivalent to or stronger than that of a positive control drug fluconazoleHas the potential of further developing antibacterial and/or antifungal medicines.

Description

Cinfeline sulfuryl tetrazole sulfonamide derivative, intermediate and application thereof

Technical Field

The invention belongs to the technical field of drug synthesis, and relates to a kind of synephrine sulfuryl tetrazole sulfonamide derivatives, intermediates and pharmaceutical application thereof.

Background

The development of resistance by bacteria is a normal evolutionary process. But due to the cross-use and/or abuse of antibacterial drugs in humans and animals, the progress of bacterial resistance is accelerated. Global antibiotic resistance and use monitoring system (GLASS) reports in the world health organization have confirmed that global antibiotic resistance is increasing in 2020, and mortality and morbidity are increasing particularly in low and medium income countries. The emergence and worldwide spread of multi-drug resistant pathogenic fungi pose a serious threat to human health. Since 2012, the impact of fungi on human life health has increased in a spiral fashion, and the global mortality rate of fungal diseases has surpassed that of malaria and breast cancer, comparable to that of tuberculosis and aids viruses. Therefore, the development of new antibacterial agents to solve the problem of drug resistance is urgent.

Synephrine (synephrine) is a natural small-molecular alkaloid, exists in the peel and pulp of citrus, and is one of the main components of the traditional Chinese medicine immature bitter orange. Synephrine has the biological activities of vasoconstriction, weight reduction, cell aging delay, asthma resistance, depression resistance, alopecia resistance, inflammation resistance, gastropathy treatment, bacteria resistance, fungi resistance and the like, is currently acquired in the pharmacopoeia of the three countries of northern Europe and German pharmacopoeia, is used in the industries of medicines, food, beverages and the like in the countries of Europe and America, and is most widely used as a weight-reducing health-care product and beverage. About 30 studies to date have shown that synephrine does not adversely affect the cardiovascular system at normal doses, nor act as an agonist, proving the safety of synephrine, and thus stimulating enthusiasm in studies of synephrine and its derivatives. However, few studies on the derivatives of synephrine at home and abroad are carried out so far, the synephrine molecules contain phenolic hydroxyl, alcoholic hydroxyl and secondary amine groups, the current studies mainly focus on the derivatives of the phenolic hydroxyl and the alcoholic hydroxyl, and some derivatives are found to have anti-tumor and weight-reducing activities, while the research on the derivatives of the secondary amine groups is not reported at present.

Azole compounds are currently the most widely used first-line antifungal drugs worldwide. Tetrazole compounds Picarbitrazox and tetrazolium-pyritinol are antifungal drugs already on the market.

Sulfa drugs (such as Sulfadiazine) are antibacterial drugs that have been developed earlier and used to date. Drugs containing sulfonamide groups are also widely used, such as Glimepiride (hypoglycemic), Furosemide (diuretic), Sildenafil (erectile dysfunction). The laboratory finds that some compounds containing sulfonamide have the activities of resisting tuberculosis (H37Rv), reducing blood fat (PCSK9), resisting tumors (IDO1, EZH2, Set8, hNNMT and the like).

The multi-target drug design strategy is a new idea for solving complex diseases, especially multi-target disease treatment at present. The pharmacophore linking method can introduce medicines with various action targets into a single molecule, and realize the design of multi-target medicines.

Disclosure of Invention

The synephrine molecule contains phenolic hydroxyl, alcoholic hydroxyl and secondary amino, not only can be used as a linker of a multi-target drug, but also can be used as one or more pharmacophores of the pharmacophores, and has potential research prospects. 1-methyl-5-mercapto-1H-tetrazole and sulfonyl are introduced to hydroxyl and amido of the synephrine mother nucleus, so that antifungal and/or antibacterial lead molecules with multi-target activity can be obtained. In view of the above, the invention aims to design and synthesize a kind of synephrine derivatives, introduce 1-methyl-5-mercapto-1H-tetrazole and sulfonyl on hydroxyl and amino of synephrine parent nucleus, and test the antibacterial activity of the derivatives.

Through research, the invention designs a molecular mode A shown in figure 1; in consideration of the stability and biological activity of molecules, oxidizing thioether bonds of the molecular mode A into sulfone groups to obtain a molecular mode B; in order to keep the molecular weight of the molecule as low as possible, the molecule has multi-target property and certain stability in vivo metabolism, a flexible alkyl chain is selected as a linker, and the structural mode TM of the target molecule is determined. Through the design of a synthetic route and the exploration of reaction conditions, 15 unreported new molecules are synthesized through multi-step reactions, and through the activity tests of resisting human pathogenic bacteria and fungi, the molecules have certain antibacterial and/or antifungal activity, and particularly have high-activity molecules. Therefore, the invention finally provides the following technical scheme:

1. the octalin sulfuryl tetrazole sulfonamide derivative shown in the formula I or the pharmaceutically acceptable salt thereof:

in the formula I, R is phenyl, substituted phenyl or 3-pyridyl; the phenyl substituent is one or more and is independently selected from halogen, hydroxyl, amino, C1-C3 alkylamido, nitro, C1-C3 alkyl, halogen substituted C1-C3 alkyl, C1-C3 alkoxy or halogen substituted C1-C3 alkoxy.

Further, the phenyl substituents are one or more independently selected from fluoro, bromo, hydroxy, amino, acetylamino, nitro, methyl, trifluoromethyl, methoxy or trifluoromethoxy.

Further, the phenyl substituents are one or more independently selected from fluorine, bromine, acetamido, nitro, methyl, trifluoromethyl or trifluoromethoxy.

Further, the octalin sulfuryl tetrazole sulfonamide derivative shown in the formula I is any one of the following compounds:

2. the intermediate shown in the formula II or the pharmaceutically acceptable salt thereof is used for preparing the octaverine sulfuryl tetrazole sulfamide derivative shown in the formula I or the pharmaceutically acceptable salt thereof:

in formula II, X is an amino protecting group; y is H, 4-halobutyl,

Or, X is H; y is

Further, the amino protecting group is tert-butyloxycarbonyl group, namely Boc; the 4-halogenated butyl is 4-bromobutyl or 4-chlorobutyl.

3. The application of the synephrine sulfuryl tetrazole sulfonamide derivative shown in the formula I or the pharmaceutically acceptable salt thereof in preparing antibacterial and/or antifungal medicaments.

Further, the antibacterial drug is a drug against one or more of escherichia coli, acinetobacter baumannii and salmonella; the antifungal medicine is one or more of Candida tropicalis, Candida parapsilosis and Candida albicans.

4. The application of the intermediate shown in the formula II or the pharmaceutically acceptable salt thereof in preparing antibacterial and/or antifungal medicines.

Further, the antibacterial drug is a drug against one or more of escherichia coli, acinetobacter baumannii and salmonella; the antifungal medicine is one or more of Candida tropicalis, Candida parapsilosis and Candida albicans.

The term "pharmaceutically acceptable salt" as used herein, unless otherwise indicated, can 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. The term "halogen" refers to F, Cl, Br and I.

The invention has the beneficial effects that: according to the invention, 1-methyl-5-mercapto-1H-tetrazole and sulfonyl are respectively introduced into phenolic hydroxyl and amino of a synephrine mother nucleus, so that a class of synephrine sulfone tetrazole sulfonamide derivatives are designed and synthesized, and through the activity tests of resisting human pathogenic bacteria and fungi, the molecules have certain antibacterial and/or antifungal activity which is stronger than that of the synephrine mother nucleus, particularly, part of high-activity molecules exist, the activity on candida tropicalis, candida parapsilosis, candida albicans and the like is equivalent to or stronger than that of a positive control drug fluconazole, and the synephrine mother nucleus has the potential of further developing antibacterial and/or antifungal drugs.

Drawings

FIG. 1 is a design drawing of synephrine derivative TM.

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention more apparent, preferred embodiments of the present invention will be described in detail below.

Main chemical reagents and instruments

Synephrine (Mianyang Di Australia pharmaceutical Co., Ltd.); 1, 4-dibromobutane, di-tert-butyl dicarbonate (Boc)₂O, shanghairei fine chemicals, ltd, AR); 1-methyl-5-mercapto-1H-tetrazole (5-MMT, supra)Hadamard fine chemicals ltd, AR); m-chloroperoxybenzoic acid (mCPBA, shanghai dary fine chemical limited, AR); potassium carbonate (AR, obtained by porphyrizing with a mortar and drying in an oven before use, available from chongqing, titanium new chemical industries, ltd.), and all other reagents are commercially available chemically pure or analytically pure products, and the reaction solvent is dried and the rest are used directly without purification.

Nuclear magnetic resonance apparatus (Bruker, ADVANCE III)^TM600MHz, TMS as internal standard); high resolution mass spectrometry (QTOF-MS, Bruker Impact II, Bremen, Germany); automatic polarimeters (WZZ-2S, Shanghai precision scientific instruments, Inc.); melting point apparatus (X-6, Beijing Fukai Instrument Co., Ltd.).

1 Synthesis of target molecule TM

i. Synthesis of synephrine N-Boc intermediate IM1

Mixing synephrine and Boc₂O was reacted in ethanol at room temperature to afford synephrine N-Boc intermediate IM 1. The results of the synthesis experiments are shown in Table 1.

An operation example: a100 mL round bottom flask was charged with synephrine (8.451g,50mmol) and ethanol (EtOH) (10 mL), stirred rapidly at room temperature (20 deg.C) for 5min, then Boc was slowly added dropwise₂O (12.803g,55mmol), and after dropping, stirring rapidly at room temperature was continued and progress of the reaction was monitored by Thin Layer Chromatography (TLC). And after the reaction is finished, removing EtOH by spinning, adding a proper amount of Petroleum Ether (PE), performing ultrasonic treatment until a white solid is separated out, adding a proper amount of PE, stirring for 0.5h, performing suction filtration, drying, and weighing to obtain a white solid IM1 (pure product).

TABLE 1 Synthesis of intermediate IM1 Experimental results

Amino protecting groups are divided into three classes: alkoxycarbonyl, acyl and alkyl groups. The alkoxycarbonyl protecting group includes Cbz, Boc, Fmoc, Alloc, Teoc and the like. Considering that deprotection is carried out on an amino protecting group in the following reaction, a Cbz group removing method is harsh, aftertreatment is troublesome when an Fmoc group is removed, a Boc protecting group is stable to alkali, removal is simple and mild, aftertreatment is simple, tert-butyl cations generated by acidolysis can form isobutene, subsequent reactions cannot be influenced, and therefore, the Boc protecting group is preferably introduced on secondary amine.

Synephrine contains phenolic hydroxyl, alcoholic hydroxyl and aliphatic secondary amine groups, and the amino protection of synephrine needs to adopt a selective protection method. The research of the invention finds that Boc is adopted₂The O/EtOH method can react at room temperature (whether summer or winter) and has excellent effect, alkali is not needed, the reaction speed is high, the post-treatment is simple, the yield is high, the method has good selectivity, and the reactivity of alcoholic hydroxyl and phenolic hydroxyl in molecules is far lower than that of aliphatic amine. Therefore, Boc is preferred₂Amino protection was performed by O/EtOH.

Synthesis of intermediate IM2

Reaction of intermediate IM1 with 1, 4-dibromobutane at K₂CO₃Reaction in N, N-Dimethylformamide (DMF) at 45 ℃ in the presence of hydrogen peroxide affords intermediate IM 2. The results of the synthesis experiments are shown in Table 2.

An operation example: to a 100mL round bottom flask was added IM1, DMF, ground K₂CO₃The powder was stirred in a 45 ℃ oil bath for 0.5h, then 1, 4-dibromobutane was added dropwise, the reaction was stirred rapidly in a 45 ℃ oil bath, and the progress of the reaction was monitored by TLC (DCM: MeOH ═ 10: 1). After the reaction was stopped, the mixture was stirred at room temperature, and saturated Na was added₂CO₃The solution and Dichloromethane (DCM) were stirred for 0.5h, the organic phase was collected by liquid separation, washed with saturated NaCl solution (10 mL. times.3), anhydrous Na₂SO₄Drying and removing the solvent to obtain a light yellow liquid. Adding a proper amount of PE, quickly stirring until a white solid is separated out, performing suction filtration, collecting the white solid, washing the solid by the PE until no odor of the 1, 4-dibromobutane exists, obtaining a white solid IM2, drying and weighing.

TABLE 2 Synthesis of intermediate IM2 Experimental results

Synthesis of intermediate IM3

Intermediate IM2 and 5-MMT are reacted at K₂CO₃Reaction in DMF at 45 deg.C in the presence of hydrogen peroxide to obtain intermediate IM 3. The results of the synthesis experiments are shown in Table 3.

An operation example: adding 5-MMT and DMF into a 100mL round-bottom flask, stirring, dissolving, and adding anhydrous K₂CO₃After stirring rapidly in a water bath at 45 ℃ for 0.5h, IM2 was added and the progress of the reaction was monitored by TLC (PE: EA: 5:1, DCM: MeOH: 10: 1). After the reaction was completed, the reaction mixture was cooled to room temperature, and 10mL of ice-cooled saturated Na was added₂CO₃Stirring for 10min, adding 20mL DCM, stirring for 10min, separating, collecting DCM phase, washing with saturated NaCl (10 mL. times.3), collecting organic phase, and anhydrous Na₂SO₄Drying, removing solvent to obtain white solid, checking by TLC, drying, weighing, and calculating the yield.

TABLE 3 Synthesis of intermediate IM3 Experimental results

Synthesis of intermediate IM4

The reaction is screened for the type and amount of the oxidant in the research. The oxidation of thioethers to sulfones is carried out with a large number of oxidizing agents. 4 oxidants were selected for experimental exploration due to strong oxidation ability, simple product post-treatment, etc.

To a 100mL round bottom flask was added 0.1eq IM3, various solvents, stirred for several minutes, and oxygen was addedThe reaction mixture was stirred in a 30 ℃ water bath, TLC (PE: EA: 5:1, PE: EA: 1) was monitored until the reaction was complete, and sodium sulfite was added to remove residual oxidizing agent. The experimental conditions are shown in Table 4. TLC results showed, H₂O₂Neither oxidation of IM3 (nor reaction upon heating to 40 ℃) occurred with potassium persulfate, whereas mCPBA and CH₃CO₃H can completely react the raw materials, but the reaction time of mCPBA is short, so that mCPBA is preferably used as an oxidizing agent; the amount of mCPBA was 2.5eq, 4eq, and 6eq, although sulfone occurred, but a large number of hetero points were formed, but the hetero point fluorescence was weak at 2.5eq, indicating that the hetero point content was likely to be low, and the amount of mCPBA was 2.0eq, since a small amount of sulfoxide was formed, the amount of mCPBA was optimal at 2.5 eq.

TABLE 4 Oxidation reaction conditions exploration experiment

Thus, the best method for oxidation of IM3 to sulfones is: intermediate IM3 was reacted with 2.5 equivalents of mCPBA in DCM at 30 ℃ to afford intermediate IM 4. The results of the synthesis experiments are shown in Table 5.

An operation example: to a 100mL round bottom flask, IM3 and DCM were added, stirred for several minutes, then mCPBA (content 75%) was added in one portion, monitored by TLC (PE: EA ═ 5:1, PE: EA ═ 1:1) until the reaction was complete, and 0.5 equivalent of Na was added₂SO₃Powder and saturated Na₂CO₃Adjusting pH of the solution to 9, stirring for 10min, adding DCM, stirring for 0.5h, separating, collecting organic phase, and collecting anhydrous Na₂SO₄Drying, removing the solvent by rotation to obtain a reddish brown viscous liquid, performing column chromatography on the viscous liquid PE with EA being 10: 1-8: 1(v/v) to obtain a white solid, performing TLC (thin layer chromatography) purification, weighing, and calculating the yield.

TABLE 5 synthetic Experimental results for intermediate IM4

Intermediate IM5 Synthesis

Boc is sensitive to acid, most of the Boc is removed by acid, and HCl-Ethyl Acetate (EA), concentrated hydrochloric acid and trifluoroacetic acid (TFA)/DCM are selected for the Boc removal condition exploration.

To a 50mL flask was added 0.1mmol of IM4, solvent and Boc removal reagent, stirred rapidly at room temperature and monitored by TLC. The experimental conditions are shown in Table 6. TLC results showed that the removal of Boc with TFA was fast, but very heterogeneous; although a single product can be obtained by removing Boc with concentrated hydrochloric acid, no solid is precipitated in the reaction process, and the purification is obtained by regulating pH and extracting from an aqueous phase for multiple times; and after the reaction is completed, the HCl-EA de-Boc is used for separating out a solid, and the solid is filtered by suction to obtain a white solid (IM5 hydrochloride) which is convenient to store, so the HCl-EA de-Boc is preferred.

TABLE 6 DeBoc reaction conditions exploration experiment

Therefore, the best method for removing Boc from IM4 is as follows: and reacting the intermediate IM4 with HCl-EA at room temperature to obtain an intermediate IM 5. The results of the synthesis experiments are shown in Table 7.

An operation example: to a 50mL round bottom flask was added IM4, HCl-EA was added dropwise, stirred rapidly at room temperature, and the reaction was monitored by TLC. And after the reaction is finished, removing the solvent by rotation, adding an appropriate amount of EA, stirring for a plurality of minutes, removing the solvent by rotation again, adding an appropriate amount of PE, stirring for a plurality of minutes, removing the solvent by rotation, drying, weighing, and calculating the yield.

TABLE 7 synthetic Experimental results for intermediate IM5

Synthesis of target molecules TMa-TMo

This reaction is a reaction between the secondary amine group of starting IM5 and a sulfonyl chloride to form a sulfonamide. Since IM5 has two reactive sites, an alcoholic hydroxyl group and a secondary amino group, the sulfonylation reaction conditions need to be explored in order to achieve a selective reaction.

Using p-toluenesulfonyl chloride (TsCl) as an example, the amounts of TsCl (Table 8, entries 1-4) and K were sequentially searched₂CO₃The amount (Table 8, entries 5-8), the temperature (Table 8, entries 9-13), the solvent (Table 8, entries 14-18), etc., on the reaction. To a 100mL round bottom flask was added IM5(0.1mmol) dissolved in DMF, solvent and K₂CO₃Rapidly stirring for 30min, and adding TsCl for reaction. TLC monitoring results show that the experimental results are the same when the amount of TsCl is 2eq or more than 2eq, the reaction speed is lower at 1eq, and the amount of TsCl is optimal at 2eq from the viewpoints of raw material saving and efficiency; k is₂CO₃When the amount of the compound (B) is less than 2eq, the reaction is incomplete, and when the amount of the compound (B) is more than 2eq, the experimental results are the same when the amount of the compound (B) is 2eq or 2eq, and thus K is₂CO₃The amount of (c) is most suitably 2 eq; the reaction at 0 to 5 ℃ is preferred because the reaction at 30 ℃ and 45 ℃ has more impurity points, the reaction at 0 ℃ and 20 ℃ has only two new points, the thick point is the main product point, namely the target molecular point (confirmed by the spectrum later), and the light point is the byproduct point, and the low-temperature reaction results are basically the same; DCM, DMF, Tetrahydrofuran (THF), acetone (acetone), diethyl ether (Et) were tested₂O) as a solvent, it was found that when DMF was used as a solvent, the light spot on TLC disappeared, indicating that alcoholic hydroxyl group and TsCl did not react, and selective reaction between alcoholic hydroxyl group and secondary amine group was achieved, so DMF was used as a solvent for the reaction most preferably.

TABLE 8 Sulfonylation reaction conditions exploration experiment

In summary, the optimal conditions for the sulfonylation of intermediate IM5 are: k₂CO₃Taking alkali as raw material, taking DMF as solvent, feeding materials according to the molar ratio of IM5: TsCl: K at the temperature of 0-5 DEG C₂CO₃＝1:2:2。

The target molecules TMa to TMo were synthesized under the above-mentioned optimum reaction conditions, and the results are shown in Table 9.

An operation example: to a 100mL round bottom flask was added IM5(1mmol) dissolved in DMF, DMF and K₂CO₃Rapidly stirring in ice water bath (0-5 ℃) for 30min, and then adding RSO₂And (3) carrying out stirring reaction in an ice water bath (0-5 ℃), and monitoring the reaction by TLC. After the reaction is finished, H is added₂O and DCM 10mL each, stirring for 10min, separating, collecting DCM phase, washing with saturated NaCl, anhydrous Na₂SO₄Drying, performing column chromatography on PE (polyethylene) with EA being 8: 1-1: 3(v/v) to obtain TM, drying, weighing, and calculating the yield.

TABLE 9 Synthesis of the target molecule TMa-TMo

The structural formulas and structural characterization data of the intermediate IM and the target molecule TM are as follows:

IM1 white solid, m.p.88.5-90.1 ℃,

¹H NMR(600MHz, DMSO-d6)δ9.24(s,1H,H-1),7.10(t,J＝8.9Hz,2H,H-2),6.71(d,J＝8.2Hz,2H,H-3),5.32– 5.08(m,1H,H-4),4.61(dd,J＝10.8,5.7Hz,1H,H-5),3.21(d,J＝7.0Hz,1H,H-6),3.13(dd,J＝ 13.9,7.3Hz,1H,H-7),2.75(d,J＝9.6Hz,3H,H-8),1.36(d,J＝38.3Hz,9H,H-9).

IM 2: white solid, m.p.92.8-94.2 ℃,

¹H NMR(600MHz, DMSO-d6)δ7.20(d,J＝8.3Hz,2H,H-1),6.90(d,J＝8.1Hz,2H,H-2),5.46–5.13(m,1H,H-3), 4.66(dd,J＝11.0,5.5Hz,1H,H-4),3.99(t,J＝6.3Hz,2H,H-5),3.61(t,J＝6.7Hz,2H,H-6), 3.23(dt,J＝21.6,11.7Hz,1H,H-7),3.19–3.08(m,1H,H-8),2.76(d,J＝9.8Hz,3H,H-9),2.01 –1.91(m,2H,H-10),1.88–1.77(m,2H,H-11),1.35(d,J＝41.2Hz,9H,H-12).

IM3 white solid, m.p.95.5-96.9 ℃,

¹H NMR(600MHz, DMSO-d6)δ7.20(d,J＝8.3Hz,2H,H-1),6.90(d,J＝7.9Hz,2H,H-2),5.30(d,J＝29.7Hz,1H, H-3),4.66(d,J＝3.7Hz,1H,H-4),3.99(t,J＝6.3Hz,2H,H-5),3.61(t,J＝6.7Hz,2H,H-6),3.32 (s,3H,H-7),3.23(dd,J＝12.8,6.0Hz,1H,H-8),3.15(dd,J＝13.9,7.2Hz,1H,H-9),2.77(s,1H, H-10),2.02–1.90(m,2H,H-11),1.83(dt,J＝13.2,6.4Hz,2H,H-12),21.35(d,J＝41.3Hz,9H, H-13).

IM4 white solid, m.p.110.2-112.1 ℃,

¹H NMR(600MHz, DMSO-d6)δ7.20(d,J＝8.3Hz,2H,H-1),6.89(d,J＝7.9Hz,2H,H-2),5.39–5.21(m,1H,H-3), 4.66(dd,J＝11.3,5.5Hz,1H,H-4),4.31(s,3H,H-5),3.98(t,J＝6.1Hz,1H,H-6),3.91–3.84(m, 2H,H-7),3.27–3.18(m,2H,H-8),3.15(dd,J＝13.8,7.4Hz,1H,H-9),2.77(s,3H,H-10),1.95– 1.87(m,1H,H-11),1.87–1.78(m,2H,H-12),1.35(s,9H,H-13).

IM5 white solid, m.p.133.7-135.1 ℃,

¹H NMR(600MHz, CDCl₃)δ7.27(d,J＝9.0Hz,2H,H-1),6.89(d,J＝8.7Hz,2H,H-2),5.42(t,J＝8.1Hz,1H,H-3), 4.01(t,J＝6.0Hz,2H,H-4),3.91(s,3H,H-5),3.86(t,J＝8.7Hz,1H,H-6),3.44(dd,J＝14.0,7.3 Hz,3H,H-7,H-8),2.93(s,3H,H-9),2.02(dd,J＝14.9,7.5Hz,2H,H-10),1.95(dt,J＝12.3,6.0 Hz,2H,H-11).

TMa is white solid, m.p.110.0-111.1 ℃,

¹H NMR(600MHz, DMSO-d6):δ7.60(d,J＝8.1Hz,2H,H-1),7.40(d,J＝8.0Hz,2H,H-2),7.22(d,J＝8.5Hz,2H, H-3),6.87(d,J＝8.6Hz,2H,H-4),5.44(d,J＝4.2Hz,1H,H-5),4.69–4.62(m,1H,H-6),4.30(s, 3H,H-7),3.98(t,J＝6.0Hz,2H,H-8),3.90-3.84(m,2H,H-9),3.03(dd,J＝13.5Hz,7.9Hz,1H, H-10),2.97(dd,J＝13.4Hz,4.9,1H,H-11),2.66(s,3H,H-12),2.38(s,3H,H-13),1.94-1.88(m, 2H,H-14),1.84(dd,J＝13.1Hz,6.1,2H,H-15).¹³C NMR(151MHz,DMSO-d6)δ158.21, 153.17,143.61,135.66,134.88,130.27,127.78,127.54,114.56,71.48,67.04,57.69,55.42,36.95, 36.62,27.42,21.42,19.06.HR MS calcd for C22H29N5O6S2[M+H]+541.1898,found 541.1889. [M+Na]+546.1451,found 546.1442.

TMb is yellow solid, m.p.118.9-119.8 ℃,

¹H NMR(600MHz, DMSO-d6):δ8.02-7.91(d,J＝7.9Hz,2H,H-1),7.86(t,J＝7.7Hz,1H,H-2),7.81(t,J＝7.6Hz, 1H,H-3),7.25(d,J＝8.5Hz,2H,H-4),6.88(d,J＝8.5Hz,2H,H-5),5.51(s,1H,H-6),4.70(t,J＝ 16.7Hz,1H,H-7),4.31(s,3H,H-8),4.00(dt,J＝18.8Hz,5.9Hz,2H,H-9),3.94–3.83(m,2H, H-10),3.27(dd,J＝15.0Hz,4.2Hz,2H,H-11),2.88(s,3H,H-12),1.95–1.88(m,2H,H＝13), 1.88-1.81(m,2H,H-14).¹³C NMR(151MHz,DMSO-d6)δ158.28,153.18,148.30,135.42, 134.76,132.81,131.32,130.25,127.73,124.65,114.61,71.56,67.05,57.55,55.43,36.96,36.49, 27.42,19.06.HR MS calcd for C₂₁H₂₆N₆O₈S₂[M+NH₄]⁺572.1592,found 572.1580.[M+Na]⁺ 577.1146,found 577.1134.

TMc yellow solid, m.p.117.1-118.2 ℃,

¹H NMR(600MHz, DMSO-d6):δ8.38(d,J＝8.8Hz,2H,H-1),8.00(d,J＝8.8Hz,2H,H-2),7.23(d,J＝8.5Hz,2H, H-3),6.87(d,J＝8.5Hz,2H,H-4),5.49(d,J＝4.3Hz,1H,H-5),4.79–4.61(m,1H,H-6),4.30(s, 3H,H-7)3.97(t,J＝6.0Hz,2H,H-8),3.91–3.83(m,2H,H-9),3.17(dd,J＝13.6Hz,8.2Hz,1H, H-10),3.10(dd,J＝13.7Hz,4.5Hz,1H,H-11),2.78(s,3H,H-12),1.94–1.87(m,2H,H-13),1.85 (dd,J＝12.9Hz,6.1Hz,1H,H-14).¹³C NMR(151MHz,DMSO-d6)δ158.23,153.09,150.15, 143.64,135.16,128.96,127.83,124.99,114.58,71.10,67.35,67.07,57.71,57.33,56.91,36.87, 36.32,27.30,19.02.HR MS calcd for C₂₁H₂₆N₆O₈S₂[M+NH₄]⁺572.1592,found 572.1582. [M+Na]⁺577.1146,found 577.1135.

TMd white solid, m.p.107.2-108.9 ℃,

¹H NMR(600MHz, DMSO-d6):δ10.34(s,1H,H-1),7.77(d,J＝8.7Hz,2H,H-2),7.66(d,J＝8.7Hz,2H,H-3),7.23 (d,J＝8.5Hz,2H,H-4),6.88(d,J＝8.5Hz,2H,H-5),5.44(d,J＝4.3Hz,1H,H-6),4.69-4.63(m, 1H,H-7),4.30(s,3H,H-8),3.98(t,J＝6.0Hz,2H,H-9),3.92-3.83(m,2H,H-10),3.03(dd,J＝ 13.5Hz,7.9Hz,1H,H-11),2.97(dd,J＝13.5,4.8,1H,H-12),2.66(s,3H,H-13),2.08(s,3H, H-14),1.9-1.87(m,2H,H-15),1.87-1.81(m,2H,H-16).¹³C NMR(151MHz,DMSO-d6)δ170.31, 158.15,153.01,143.27,135.25,132.08,131.67,128.64,127.87,119.50,114.55,71.26,67.03, 57.36,57.04,55.41,36.83,36.47,27.23,24.32,19.04,19.00.HR MS calcd for C₂₃H₃₀N₆O₇S₂ [M+Na]⁺589.1510,found 589.1495.

TMe is a yellow oily liquid, and the color of the yellow oily liquid,

¹H NMR(600MHz,DMSO-d6):δ7.73(d,J ＝7.3Hz 2H,H-1),7.68(t,J＝7.3Hz,1H,H-2),7.61(t,J＝7.5Hz,2H,H-3),7.23(d,J＝8.4Hz, 1H,H-4),6.88(d,J＝8.4,1H,H-5),5.46(s,1H,H-6),4.68(s,1H,H-7),4.30(s,3H,H-8), 4.01–3.95(m,1H,H-9),3.92–3.84(m,1H,H-10),3.07(dd,J＝13.4Hz,8.0Hz,1H,H-11),3.00(dd, J＝13.5Hz,4.7Hz,1H,H-12),2.69(s,3H,H-13),1.90(d,J＝6.6Hz,1H,H-14),1.85(d,J＝ 6.5Hz,1H,H-15).¹³C NMR(151MHz,DMSO-d6)δ158.23,153.18,137.86,135.65,133.25, 129.82,127.78,127.48,114.57,71.50,67.05,57.68,55.43,36.95,36.62,27.43,19.12,19.07.HR MS calcd for C₂₁H₂₇N₅O₆S₂[M+Na]⁺532.1295,found 532.1292.

TMf is a yellow oily liquid,

¹H NMR(600MHz,DMSO-d6):δ7.81(dd, J＝8.6Hz,5.2,2H,H-1),7.43(t,J＝8.7Hz,2H,H-2),7.23(d,J＝8.5Hz,2H,H-3),6.88(d,J＝ 8.5Hz,1H,H-4),5.47(s,1H,H-5),4.67(s,1H,H-6),4.30(s,3H,H-7),3.98(t,J＝6.0Hz,2H, H-8),3.90–3.85(m,2H,H-9),3.08(dd,J＝13.5Hz,8.0Hz,1H,H-10),3.01(dd,J＝13.6Hz,4.7, 1H,H-11),2.70(s,3H,H-12),1.95–1.89(m,2H,H-13),1.88–1.80(m,1H,H-14).¹³C NMR(151 MHz,DMSO-d6)δ164.00,158.24,153.17,135.59,131.78,130.58,130.52,127.78,117.02,116.87, 114.57,71.37,67.04,57.61,55.42,36.96,36.52,27.42,19.06.HR MS calcd for C₂₁H₂₆FN₅O₆S₂ [M+Na]⁺550.1201,found 550.1196.

TMg is yellow oily liquid, and the color of the liquid is changed,

¹H NMR(600MHz,DMSO-d6):δ7.78(t,J ＝6.8Hz,1H,H-1),7.72(d,J＝4.6Hz,1H,H-2),7.48–7.42(m,1H,H-3),7.39(t,J＝7.6Hz,2H, H-4),7.22(d,J＝8.4Hz,2H,H-5),6.87(d,J＝8.5Hz,2H,H-6),5.49(d,J＝4.3Hz,1H,H-7), 4.72–4.61(m,1H,H-8),4.30(s,3H,H-9),3.97(t,J＝5.9Hz,2H,H-10),3.92–3.81(m,2H,H-11), 3.20(dd,J＝13.8Hz,8.1,1H,H-12),3.15(dd,J＝13.9Hz,4.8Hz,1H,H-13),2.78(s,3H,H-14), 1.94–1.87(m,2H,H-15),1.8–1.79(m,2H,H-16).¹³C NMR(151MHz,DMSO-d6)δ169.48, 158.21,153.18,143.58,135.71,131.97,131.33,129.12,128.70,127.79,119.20,114.56,71.48, 67.04,57.69,55.43,36.95,36.62,27.42,19.06.HR MS calcd for C₂₁H₂₆FN₅O₆S₂[M+Na]⁺ 550.1201,found 550.1195.

TMh the yellow oily liquid is mixed with the water,

¹H NMR(600MHz,DMSO-d6)δ7.66(dd, J＝14.4,7.5Hz,1H,H-1),7.59(d,J＝7.8Hz,1H,H-2),7.54(t,J＝7.7Hz,2H,H-3,H-4),7.24 (d,J＝8.5Hz,2H,H-5),6.88(d,J＝8.6Hz,2H,H-6),5.46(d,J＝4.4Hz,1H,H-7),4.71–4.64(m, 1H,H-8),4.30(s,3H,H-9),3.98(t,J＝6.0Hz,2H,H-10),3.91–3.82(m,2H,H-11),3.13(dd,J＝ 13.6,8.0Hz,1H,H-12),3.06(dd,J＝13.6,4.8Hz,1H,H-13),2.73(s,3H,H-14),1.91(dt,J＝ 14.5,5.8Hz,2H,H-15),1.85(dd,J＝13.0,6.0Hz,2H,H-16).¹³C NMR(151MHz,DMSO-d6)δ 163.15,161.50,158.23,153.15,140.05,135.51,135.14,132.20,132.15,131.73,127.81,123.78, 121.69,120.34,114.54,114.44,71.34,67.01,57.53,55.39,36.96,36.52,27.41,19.06.HR MS calcd for C21H26FN5O6S2[M+Na]+550.1201,found 550.1200.

TMi white solid, m.p.122.5-123.9 ℃,

¹H NMR(600MHz,DMSO -d6):δ7.94(d,J＝7.7Hz,1H,H-1),7.79(t,J＝7.3Hz,1H,H-2),7.57(dd,J＝14.6Hz,7.5,2H, H-3),7.22(d,J＝8.4Hz,2H,H-4),6.88(d,J＝8.5Hz,2H,H-5),5.51(d,J＝4.2Hz,1H,H-6),4.69 (d,J＝4.8Hz,1H,H-7),4.32(s,3H,H-8),3.99(dd,J＝16.0Hz,10.1Hz,2H,H-9),3.93–3.83(m, 2H,H-10),3.24(t,J＝10.6Hz,2H,H-11,H-12),2.82(s,3H,H-13),1.98–1.89(m,2H,H-14), 1.89–1.80(m,2H,H-15).¹³C NMR(151MHz,DMSO-d6)δ158.23,153.19,145.42,135.55, 135.46,131.61,131.51,128.02,127.64,121.54,121.26,121.15,119.44,114.58,71.73,67.04, 57.48,55.44,36.94,36.32,27.43,19.07.HR MS calcd for C₂₂H₂₆FN₅O₇S₂[M+Na]⁺616.1118, found 616.1112.

TMj white solid, m.p.115.4-116.2 ℃,

¹H NMR(600MHz,DMSO -d6):δ8.07(d,J＝8.3,2H,H-1),8.02(d,J＝8.3Hz,1H,H-2),7.32–7.29(m,2H,H-3),6.87(t,J＝ 9.9Hz,2H,H-4),5.92(d,J＝14.4Hz,1H,H-5),4.30(s,3H,H-6),4.23(t,J＝6.5Hz,1H,H-7), 3.98(t,J＝5.9,2H,H-8),3.92–3.84(m,2H,H-9),3.13(dd,J＝39.7Hz,16.2Hz,2H,H-10,H-11), 3.00(s,3H,H-12),1.93–1.87(m,2H,H-13),1.87–1.80(m,2H,H-14).¹³C NMR(151MHz, DMSO-d6)δ167.42,157.90,141.00,132.20,131.97,129.13,128.38,127.28,125.63,115.23, 113.06,67.10,65.49,55.41,36.95,33.02,30.48,27.39,19.04.HR MS calcd for C₂₂H₂₆F₃N₅O₆S₂ [M+Na]⁺600.1169,found 60.1161.

TMk white solid, m.p.136.4-137.8 ℃,

¹H NMR(600MHz,DMSO -d6):δ8.01(s,1H,H-1),7.93(d,J＝7.1Hz,1H,H-2),7.86(d,J＝6.0Hz,1H,H-3),7.59(dd,J＝ 10.4Hz,5.4Hz,1H,H-4),7.31(d,J＝6.4Hz,2H,H-5),6.86(d,J＝6.4Hz,2H,H-6),5.90(d,J＝ 14.4Hz,1H,H-7),4.31(s,1H,H-8),4.30(s,3H,H-9),3.98(s,2H,H-12,H-13),3.88(s,4H, H-10,H-11),2.99(s,3H,H-14),1.88(d,J＝21.2Hz,2H,H-15),1.82(dd,J＝24.5Hz,4.8Hz,2H, H-16).¹³C NMR(151MHz,DMSO-d6)δ158.23,153.19,138.93,136.20,135.65,134.46,131.58, 128.63,127.69,119.77,114.61,72.00,67.06,57.97,55.44,55.34,36.95,36.52,27.43,19.11,19.07. HR MS calcd for C₂₁H₂₆Br₃N₅O₆S₂[M+Na]⁺610.0400,found 610.0391.

TMl white solid, m.p.136.0-137.1 ℃,

¹H NMR(600MHz,DMSO- d6):δ7.97–7.92(m,1H,H-1),7.85(d,J＝7.5Hz,1H,H-2),7.57(dd,J＝13.3Hz,5.9Hz,1H,H-3), 7.54(dd,J＝10.7Hz,4.4,1H,H-4),7.22(d,J＝8.4Hz,2H,H-5),6.87(d,J＝8.4Hz,2H,H-6), 5.51(d,J＝4.3Hz,1H,H-7),4.74–4.65(m,1H,H-8),4.31(s,3H,H-9),3.98(t,J＝5.9Hz,2H, H-10),3.91–3.83(m,2H,H-11),3.34–3.29(m,2H,H-12),2.84(s,3H,H-13),1.94–1.87(m,2H, H-14),1.87–1.80(m,2H,H-15).¹³C NMR(151MHz,DMSO-d6)δ158.23,153.19,138.93, 136.20,134.46,131.58,129.12,128.63,127.69,119.77,114.61,72.00,67.06,57.97,55.44,55.34, 36.95,36.52,27.43,19.07.HR MS calcd for C₂₁H₂₆Br₃N₅O₆S₂[M+Na]⁺610.0400,found 610.0390.

TMm white solid, m.p.115.4-116.2 ℃,

¹H NMR(600MHz,DMSO -d6):δ7.56(s,1H,H-1),7.34(d,J＝7.5Hz,1H,H-2),7.28(d,J＝7.7Hz,1H,H-3),7.19(d,J＝ 8.5Hz,2H,H-4),6.87(d,J＝8.5,Hz 2H,H-5),5.48(d,J＝4.3Hz,1H,H-6),4.70–4.61(m,1H, H-7),4.31(s,3H,H-8),3.98(t,J＝5.9Hz,2H,H-9),3.92–3.84(m,2H,H-10),3.28–3.17(m,2H, H-11,H-12),2.78(s,3H,H-13),2.42(s,3H,H-14),2.34(s,3H,H-15),1.96–1.88(m,2H,H-16), 1.88–1.81(m,2H,H-17).¹³C NMR(151MHz,DMSO-d6)δ158.22,153.19,137.46,136.23, 135.71,134.32,133.64,133.20,129.36,127.66,114.59,71.80,67.06,57.14,55.44,36.95,36.02, 27.43,20.82,19.97,19.07.HR MS calcd for C₂₃H₃₁N₅O₆S₂[M+Na]⁺560.1608, found 560.1602, TMn yellow oily liquid,

¹H NMR(600MHz,DMSO-d6):δ7.69 (ddd,J＝32.1Hz,5.6,3.3,2H,H-1),7.08(d,J＝8.5Hz,2H,H-2),6.80(d,J＝8.5Hz,2H,H-3), 5.39(d,J＝4.3Hz,1H,H-4),4.58(d,J＝5.8Hz,1H,H-5),4.30(s,3H,H-6),3.97(t,J＝6.0Hz,2H, H-7),3.91–3.84(m,2H,H-8),3.15(dd,J＝13.9Hz,7.4Hz,1H,H-9),3.11(dd,J＝14.0Hz,5.4Hz, 1H,H-10),2.70(s,3H,H-11),2.43(s,6H,H-12),2.27(s,3H,H-13),1.94–1.87(m,2H,H-14), 1.87–1.80(m,2H,H-15).¹³C NMR(151MHz,DMSO-d6)δ158.19,153.16,142.61,139.95, 136.32,135.78,132.19,127.52,114.51,79.64,71.33,67.03,55.41,36.96,34.67,27.42,22.74, 20.88,19.08.HR MS calcd for C₂₄H₃₃N₅O₆S₂[M+Na]⁺574.1764,found 574.1758.

TMo the yellow oily liquid is mixed with the water,

¹H NMR(600MHz,DMSO-d6):δ8.92(d, J＝1.3Hz,1H,H-1),8.85(d,J＝3.6Hz,1H,H-2),8.16(d,J＝8.0Hz,1H,H-3),7.64(dd,J＝ 7.7Hz,5.0,1H,H-4),7.25(d,J＝8.5Hz,2H,H-5),6.88(d,J＝8.5Hz,2H,H-6),5.49(d,J＝4.2Hz, 1H,H-7),4.76–4.61(m,1H,H-8),4.31(s,3H,H-9),3.99(t,J＝5.8Hz,2H,H-10),3.92–3.82(m, 2H,H-11),3.18(dd,J＝13.6Hz,8.2Hz,1H,H-12),3.10(dd,J＝13.6Hz,4.4Hz,1H,H-13),2.76 (d,J＝16.6Hz,3H,H-14),1.96–1.88(m,2H,H-15),1.88–1.81(m,2H,H-16).¹³C NMR(151 MHz,DMSO-d6)δ158.26,153.72,153.19,147.79,135.54,135.47,134.77,127.79,124.84,114.59, 71.24,67.06,57.46,55.44,55.34,36.95,36.33,27.43,19.07.HR MS calcd for C₂₀H₂₆N₆O₆S₂ [M+H]⁺511.1428,found 511.1422.[M+Na]⁺533.1247,found 533.1240.

2 biological Activity assay of target molecules

2.1 Activity against human pathogenic bacteria

Diseases caused by bacterial infection affect human health. The development of antibacterial drugs saves countless lives. The Minimum Inhibitory Concentrations (MIC) of intermediate IM and target molecule TM against staphylococcus aureus (s.aureus) ATCC 25129 and ATCC 14125, micrococcus luteus (m.luteus), escherichia coli (e.coli) ATCC 25922, acinetobacter baumannii (a.baumann) ATCC 19606, salmonella (s.enteritidis) ATCC 13076, pseudomonas aeruginosa (p.aeruginosa) ATCC 27853 were determined according to the microdilution method recommended by the national committee for standardization of clinical laboratories (NCCLS). Wherein Staphylococcus aureus and Micrococcus luteus are gram-positive bacteria (G)⁺Bacteria), Escherichia coli, Acinetobacter baumannii, Salmonella, Pseudomonas aeruginosa as gram-negative bacteria (G)^-Bacteria). Clinafloxacin (CLX), Norfloxacin (NOR), Ciprofloxacin (CIP), Sarafloxacin (SAR), Enrofloxacin (ENO), Balofloxacin (BAL), Lomefloxacin (LOM), Gatifloxacin (GAT) were used as positive controls. The MIC test results are shown in table 10.

TABLE 10 results of the Activity test of the target molecule TM against human pathogenic bacteria

Note that the unit with partial MIC values is (μ g/mL)/(μmol/mL).

In general, the target molecule TM vs G^-The inhibitory activity of the bacteria is stronger than that of G⁺And (5) bacteria. For Salmonella, the MIC values for the target molecules TMh, TMo and intermediate IM1 were 128. mu.g/mL, which is stronger than the mother nucleus synephrine (MIC)>256. mu.g/mL). For Acinetobacter baumannii, the MIC values (0.217-0.251 mu mol/mL) of 15 target molecules TMa-TMo are smaller than those of marketed drugs NOR, ENO, LOM and GAT (0.341-0.401 mu mol/mL), which indicates that the bacteriostatic activity of the molecules is stronger than that of the marketed drugs. For E.coli, the MIC value of intermediate IM5 was 4. mu.g/mL (0.00984. mu. mol/mL) which was much stronger than that of the parent synephrine (256. mu.g/mL, 1.531. mu. mol/mL); MIC values (0.00456 mu mol/mL and 0.00425 mu mol/mL) of IM3 and IM4 are lower than that of 8 positive control medicaments (0.00512-0.00626 mu mol/mL), which indicates that molecules with improved anti-Escherichia coli activity can be obtained by derivatization on phenolic hydroxyl of synephrine, and the activity is even stronger than that of the tested fluoroquinolone with strong antibacterial activity; in addition, oxidation of IM3 to sulfone gave IM4, with the MIC value of IM4 of 0.00425. mu. mol/mL being lower than 0.00456. mu. mol/mL for IM3, indicating bacteriostatic activity, IM4>IM3 that the thioether bond has been changed to a sulfone group has a tendency to improve the antibacterial activity of the synephrine derivatives.

2.2 Activity against human pathogenic fungi

Fungal infections include common superficial or mucosal infections and severe systemic Invasive Fungal Infections (IFI), affecting millions of people worldwide. IFIs are mainly caused by opportunistic fungal pathogens such as candida, aspergillus fumigatus (a. fumigatus) and cryptococcus neoformans (c. neoformans).

MIC values of the target molecule TM against aspergillus fumigatus-resistant strains, candida tropicalis (c.tropicalis) -resistant strains, candida parapsilosis (c.parapsilosis) ATCC 22019, candida albicans (c.albicans) -resistant strains, and candida albicans ATCC 90023 were determined using Fluconazole (Fluconazole) as a positive control drug by the minimal broth dilution method recommended by NCCLS. Among them, Candida tropicalis, Candida parapsilosis and Candida albicans belong to the Candida species. The MIC test results are shown in table 11.

TABLE 11 results of anti-human pathogenic fungi Activity test of target molecule TM

Note that the unit with partial MIC values is (μ g/mL)/(μmol/mL).

As can be seen from Table 11, the target molecule TM and the intermediate IM were not sensitive to drug-resistant Aspergillus fumigatus, but had inhibitory activity against drug-resistant Candida tropicalis, Candida parapsilosis and Candida albicans, as well as non-drug-resistant strains.

For drug-resistant candida tropicalis, the MIC values of most of TM are less than that of synephrine, the MIC values of the intermediates IM4 and IM5 are 0.136 and 0.158 mu mol/mL respectively, namely the activity IM4 is greater than that of IM5, and the introduction of the amide group can improve the biological activity of synephrine mother nucleus; surprisingly, the MIC value of TMn is 0.063 mu mol/mL, the activity is higher than that of intermediates IM4 and IM5 and a positive control drug fluconazole (MIC is 0.104 mu mol/mL), and the introduction of the secondary amino group of synephrine into sulfonyl group is possible to enhance the inhibitory effect on candida tropicalis.

For Candida parapsilosis ATCC 22019, the MIC values (0.631-0.008. mu. mol/mL) for both the target molecule TM and intermediate IM were less than for synephrine (1.531. mu. mol/mL), indicating that both of them were more active than the parent synephrine; MIC values of IM3 and IM4 are 0.146. mu. mol/mL and 0.136. mu. mol/mL respectively, which indicates that the activity of the sulfone type molecule is stronger than that of the thioether type molecule, and the design of the target molecule is positive; the MIC value of 10 of the 15 target molecules is less than 0.136 mu mol/mL and stronger than that of IM3, which indicates that the activity of most sulfonylated products is stronger than that of Boc protected products, and indicates that sulfonylation is possible to enhance the anti-Candida parapsilosis 22019 activity; the activity of TMf was best (MIC 0.008 μmol/mL) comparable to that of fluconazole, a positive control drug (MIC 0.007 μmol/mL). The analysis of the structure-activity relationship shows that the following relationship exists between the substituent on the sulfonamide ring and the activity: the more electrons are supplied, the lower the bacteriostatic activity is; the same substituent is used for the para-position, the ortho-position and the meta-position.

For drug-resistant candida albicans, MIC values of 9 target molecules and an azole-containing intermediate IM3-IM5 are all smaller than those of synephrine, which indicates that high-activity molecules can be obtained by derivation of amido and hydroxyl of the synephrine; TMf and TMo (MIC 0.014 μmol/mL) were comparable to fluconazole (MIC 0.013 μmol/mL) and TMn (MIC 0.007 μmol/mL) was more 2-fold more active than fluconazole, further indicating that modifications to synephrine were an effective way to find highly active antifungal molecules.

For candida albicans ATCC 90023, the MIC values for 7 target molecules were less than synephrine, i.e. activity was greater than that of the mother nucleus. The intermediate activity IM5(MIC 0.158 mu mol/mL) > IM4(MIC 0.272 mu mol/mL) > IM3(MIC 0.584 mu mol/mL) indicates that the oxidation of thioether bonds into sulfone and the removal of Boc groups can enhance the capability of inhibiting Candida albicans; it is highly desirable that the activity of TMd (MIC 0.007 μmol/mL) and TM1f (MIC 0.008 μmol/mL) is comparable to that of fluconazole (MIC 0.007 μmol/mL), with potential for further investigation.

Finally, it is noted that the above-mentioned preferred embodiments illustrate rather than limit the invention, and that, although the invention has been described in detail with reference to the above-mentioned preferred embodiments, it will be understood by those skilled in the art that various changes in form and detail may be made therein without departing from the scope of the invention as defined by the appended claims.

Claims (10)

1. The octalin sulfuryl tetrazole sulfonamide derivative shown in the formula I or the pharmaceutically acceptable salt thereof:

in the formula I, R is phenyl, substituted phenyl or 3-pyridyl; the phenyl substituent is one or more and is independently selected from halogen, hydroxyl, amino, C1-C3 alkylamido, nitro, C1-C3 alkyl, halogen substituted C1-C3 alkyl, C1-C3 alkoxy or halogen substituted C1-C3 alkoxy.

2. The derivatives of synephrine sulfonyl tetrazole sulfonamides or the pharmaceutically acceptable salts thereof of claim 1, wherein: the phenyl substituents are one or more and are independently selected from fluorine, bromine, hydroxyl, amino, acetamido, nitro, methyl, trifluoromethyl, methoxy or trifluoromethoxy.

3. The derivatives of synephrine sulfonyl tetrazole sulfonamides or the pharmaceutically acceptable salts thereof of claim 2, wherein: the phenyl substituents are one or more and are independently selected from fluorine, bromine, acetamido, nitro, methyl, trifluoromethyl or trifluoromethoxy.

4. The synephrine sulfonyl tetrazole sulfonamide derivatives or the pharmaceutically acceptable salts thereof as claimed in claim 3, wherein: the octalin sulfuryl tetrazole sulfonamide derivative shown in the formula I is any one of the following compounds:

5. an intermediate represented by formula II or a pharmaceutically acceptable salt thereof, for use in the preparation of the derivatives of synephrine-sulfone-tetrazole sulfonamide according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof:

in formula II, X is an amino protecting group; y is H, 4-halobutyl,

Or, X is H; y is

6. The intermediate of claim 5, or a pharmaceutically acceptable salt thereof, wherein the amino protecting group is t-butyloxycarbonyl (Boc); the 4-halogenated butyl is 4-bromobutyl or 4-chlorobutyl.

7. The use of the derivatives of octavirinylsulfonyl tetrazole sulfonamides or the pharmaceutically acceptable salts thereof as claimed in any one of claims 1 to 4 in the preparation of antibacterial and/or antifungal medicaments.

8. The use of claim 7, wherein the antibacterial agent is an agent against one or more of escherichia coli, acinetobacter baumannii, and salmonella; the antifungal medicine is one or more of Candida tropicalis, Candida parapsilosis and Candida albicans.

9. Use of the intermediate of claim 5 or 6 or a pharmaceutically acceptable salt thereof for the preparation of an antibacterial and/or antifungal medicament.

10. The use of claim 9, wherein the antibacterial agent is an agent against one or more of escherichia coli, acinetobacter baumannii, and salmonella; the antifungal medicine is one or more of Candida tropicalis, Candida parapsilosis and Candida albicans.

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