CN102558018A - Benzene sulfamide derivative and applications thereof in producing antibacterial drugs - Google Patents
Benzene sulfamide derivative and applications thereof in producing antibacterial drugs Download PDFInfo
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- CN102558018A CN102558018A CN2011104405573A CN201110440557A CN102558018A CN 102558018 A CN102558018 A CN 102558018A CN 2011104405573 A CN2011104405573 A CN 2011104405573A CN 201110440557 A CN201110440557 A CN 201110440557A CN 102558018 A CN102558018 A CN 102558018A
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Abstract
The invention relates to a benzene sulfamide derivative and applications thereof in producing antibacterial drugs. The benzene sulfamide derivative can be used for producing new effective drugs against drug-resistant gram-positive bacteria due to the strong inhibiting effect on methicillin-resistant staphylococcus aureus (MRSA), and for producing new antifungal drugs due to the strong synergistic inhibition effect on Candida albicans. The drugs can be used in the form of injection, tablets, pills, capsules, suspending agents or emulsion. The administration route of the drugs can be oral administration, percutaneous administration, intravenous injection or intramuscular injection. The chemical structural formula of the benzene sulfamide derivative is represented as formula (I), wherein R is H, CH3, C2H5 or CH(CH3)2; R' is H, 2-NO2 and 4-NO2; and X is 3-(1-H-indol-3-yl)-, 3-propionyloxy, and 3-propionyloxy (1-3 carbon) ester.
Description
Technical field
The present invention relates to benzene sulphenamide verivate and the purposes in preparation medicament for resisting gram-positive bacteria and preparation antifungal drug thereof; Particularly to methicillin-resistant staphylococcus aureus (methicillin-resistant Staphylococcus aureus; MRSA) etc. gram-positive microorganism has very strong restraining effect, and Candida albicans fungies such as (Candida albicans) is had very strong coordinate repression.
Technical background
Methicillin-resistant staphylococcus aureus (methicillin-resistant Staphylococcus aureus MRSA) is a kind of super resistant organism bacterium, its to multiple antibiotic resistance in continuous enhancing.At present few in number to the microbiotic of the real onset of MRSA, clinical only vancomyein (vancomycin) commonly used, daptomycin (daptomycin), Linezolid (linezolid), WAY-GAR 936 (tigecycline) and the general medicines such as (ceftobiprole) of cephalo pyrrole.The research and development chemical structure is novel, and the novel drug-resistance bacteria medicine that toxicity is lower becomes very urgent.
Current era is the significant problem that influences human health by fungus-caused infection of invasion type such as Candida albicans, cryptococcus and aspergillus tubigensis.At present, the medicament of curing fungi infestation depends on type chemicals few in number, is the azole of representative like KETOKONAZOL, polyene antibiotics and amphotericin B or the like.Because the resistance problem that these antifungal drug life-time service produce is obvious day by day, it is extremely urgent that new active drug is synthesized in design.
Sulphenamide compounds and biological activity thereof are studied less, and people discover recently, and this compounds shows and suppresses AHAS enzyme (Wang J-G.; Et al., Bioorg.Med.Chem.2007,15; 374-380), desinsection (Sun R., et al., J.Agric.Food Chem.2009; 57 (9), 3661-3668; The people of Wangqing County etc., CN 101602752A; The people of Wangqing County etc., CN 1927831B) biological activity such as.People such as Turos find that the lactam analog compound of some nitrogen time sulfonylation shows antibacterial activity (Turos E., et al., Tetrahedron, 2000,56,5571-5578; O ' Driscoll M et al., 2008,16,7832-7837.).Further investigation to this compounds is expected to find to have the active micromolecular compound of important biomolecule.
Summary of the invention
The object of the present invention is to provide a kind of new benzene sulphenamide analog derivative and prepare in the medicament for resisting gram-positive bacteria and purposes, particularly methicillin-resistant staphylococcus aureus resistance (MRSA) medicine in the antifungal drug and the application of collaborative anti-candida albicans in preparation.
Benzene sulphenamide verivate of the present invention is as shown in the formula shown in (I):
In the formula wherein R be H, CH
3, C
2H
5, or CH (CH
3)
2
R ' is H, 2-NO
2, 4-NO
2
X be 3-(1-H-indol-3-yl)-, 3-propionyloxy, 3-propionic acid (1-3 carbon) ester group.
Alternatively, benzene sulphenamide verivate of the present invention is:
(S)-3-(1-H-indol-3-yl)-1-(2-oil of mirbane sulfenamide groups) methyl propionate (SJL-1);
(S)-3-(1-H-indol-3-yl)-1-(2-oil of mirbane sulfenamide groups) ethyl propionate (SJL-2);
(S)-3-(1-H-indol-3-yl)-1-(2-oil of mirbane sulfenamide groups) isopropyl propionate (SJL-3);
(S)-3-(1-H-indol-3-yl)-1-(2,4-dinitrobenzene sulfenamide groups) methyl propionate (SJL-4);
(S)-2-(4-nitro-benzene sulfenamide groups)-valeric acid dimethyl ester (SJL-5).
Benzene sulfenamide groups analog derivative of the present invention is to obtain through following reaction expression:
The substituted benzene that waits amount of substance time SULPHURYL CHLORIDE (II) is mixed in anhydrous diethyl ether with triethylamine, and the L-amino acid ester (I) of amount of substance such as droppings slowly under-5 ℃ (cryosel bath) reacts 2h again under the cryosel bath; TLC follows the tracks of detection, after reacting completely, filters; Wash with ether; And filtrate decompression is concentrated, the frequent pressure column chromatography of bullion separates purifies, and gets target compound (III).
Show through the vitro inhibition germ experiment; Benzene sulphenamide analog derivative of the present invention has very strong restraining effect to methicillin-resistant staphylococcus aureus (MRSA); The effect near contrast medicine vancomyein that has, therefore benzene sulphenamide verivate of the present invention can be used for preparing the active compound that the treatment resisting gram-positive bacteria infects.
Show that through the experiment of vitro inhibition fungi benzene sulphenamide analog derivative dialogue look candidiasis of the present invention (Candida albicans) has very strong coordinate repression, effect obviously surpasses contrast medicine beauvericin.Therefore benzene sulphenamide verivate of the present invention can be used for preparing the active compound of treating anti-fungal infection.
The present invention also provides a kind of medicine that is used to treat gram positive bacteria infection, particularly treats the medicine that methicillin-resistant staphylococcus aureus resistance (MRSA) infects; This medicine contains above-mentioned benzene sulphenamide verivate and one or more pharmaceutically acceptable carriers.Said carrier comprises the conventional thinner of pharmaceutical field, vehicle, weighting agent, tackiness agent, wetting agent, disintegrating agent, absorption enhancer, tensio-active agent, absorption carrier, lubricant, synergistic agent etc.This medicine can be processed the form of injection, tablet, pill, capsule, suspension agent or emulsion and use.That its route of administration can be is oral, through skin, vein or intramuscular injection.
The present invention also provides a kind of medicine that is used to treat fungi infestation, particularly treats the medicine that anti-candida albicans infects; This medicine contains above-mentioned benzene sulphenamide verivate and one or more pharmaceutically acceptable carriers.Said carrier comprises the conventional thinner of pharmaceutical field, vehicle, weighting agent, tackiness agent, wetting agent, disintegrating agent, absorption enhancer, tensio-active agent, absorption carrier, lubricant etc.This medicine can be processed the form of injection, tablet, pill, capsule, suspension agent or emulsion and use.That its route of administration can be is oral, through skin, vein or intramuscular injection.
Substantive distinguishing features of the present invention can be able to embody from following embodiment, but only conduct explanation of these embodiment, rather than limit the invention.
Description of drawings
Fig. 1 is the infrared spectrogram of SJL-4.
Fig. 2 is the infrared spectrogram of SJL-5.
Embodiment
Embodiment 1: compound S JL-1's is synthetic
2.04g (10mmol) L-tryptophane and 30mL anhydrous methanol are joined in the 100mL flask, and cryosel is bathed cooling, when temperature is reduced to-10 ℃; The 4mL sulfur oxychloride is added dropwise to wherein, and controlled temperature must not be higher than-5 ℃ in the process that drips, and dropwises back backflow 5h; After reaction finished, unnecessary methyl alcohol and sulfur oxychloride were removed in decompression, obtain white solid it is dissolved in the 30mL water; With soda ash light pH is transferred to 8-9, ethyl acetate extraction, anhydrous sodium sulfate drying spends the night; The solvent that decompression is at last removed wherein obtains L-tryptophan methyl ester 1.96g (productive rate: 89.9%), need not processing and directly be used for next step reaction.
The sodium of 1.93g (84mmol) is slowly added in the methyl alcohol of 50mL, after reacting completely, will be dissolved in 10.33g (83mmol) benzyl sulfhydrate of 25mL methyl alcohol successively; 13.13g (83mmol) be added dropwise to wherein under the o-Nitrochlorobenzene stirring at normal temperature; After adding, reflux 1h is cooled to room temperature then; Suction filtration obtains yellow solid, gets 2-nitrophenyl benzyl thioether 18.39g (productive rate: 90.3%) with recrystallizing methanol again.
6.8g (50mmol) SULPHURYL CHLORIDE is dissolved in the 25mL trichloromethane slowly to be added dropwise to it in chloroform soln of 80mL of 12.2g (50mmol) 2-nitrophenyl benzyl thioether under stirring at normal temperature then; Be warming up to 45 ℃ after dropwising; This moment, reactant dissolved fully, was controlled under this temperature and reacted 0.5h, and removal of solvent under reduced pressure obtains yellow oil; Obtain yellow cotton-shaped solid to wherein adding the 100mL sherwood oil, the ether purifying gets 5.23g ortho-nitrophenyl SULPHURYL CHLORIDE (productive rate: 55.2%).
Cryosel is bathed down, mixes in the ortho-nitrophenyl sulphur chlorine of the triethylamine of 0.51g (5mmol) and 0.95g (5mmol) and the 20mL anhydrous ether solution, slowly drips 1.09g (5mmol) L-tryptophan methyl ester (being dissolved in the 10mL anhydrous diethyl ether); Under cryosel is bathed, react 2h again, TLC follows the tracks of detection, after reacting completely; Filter, with the ether washing, and filtrate decompression is concentrated; Obtain yellow oil; The normal pressure column chromatography for separation is purified, and eluent: petrol ether/ethyl acetate=2: 1 (V/V) obtains yellow oil 1.05g (productive rate: 56.5%).
Equally, can synthesize compound S JL-2, SJL-3 and SJL-4 of the present invention.
With reference to L-tryptophan methyl ester compound method, can synthesize the L-glutamic acid methyl ester.
The p-Nitrophenyl chloride of 7.41g (47mmol) is dissolved in the acetone of 50mL, and the dissolving back sodium disulfide aqueous solution (new system) fully slowly is added dropwise to wherein, dropwises post-heating backflow 4h; Reaction is cooled to room temperature after accomplishing, and separates out light yellow solid; Suction filtration, drying is used the methylene dichloride recrystallization; Obtain 1,2-two (4-oil of mirbane) disulfide 4.60g.
Under the stirring at room; The SULPHURYL CHLORIDE of 1.7g (12mmol) slowly is added dropwise to 3.70g (12mmol) 1, and in the 20mL dichloromethane solution of 2-two (4-oil of mirbane) disulfide, TLC follows the tracks of detection; The 2h afterreaction is complete, and solvent removed in vacuo and unnecessary SULPHURYL CHLORIDE get 4-oil of mirbane time SULPHURYL CHLORIDE 1.45g.
With reference to the final compound method of SJL-1, can synthesize SJL-5.
The structural formula and the physico-chemical parameter of target compound are seen table 1, and high resolution mass spectrum reaches
1H NMR sees table 2.
Embodiment 3: the anti-MRSA determination of activity of benzene sulphenamide verivate.
1. test materials
Mueller-Hinton Broth (the extensive and profound in meaning star biotechnology in Beijing Ltd), Tryptones (Britain OXOID company), yeast extract powder (Britain OXOID company); Sodium-chlor (Chemical Reagent Co., Ltd., Sinopharm Group); 96 porocyte culture plates (flat bottom) (Corning Incorporated), positive control medicine vancomyein (U.S. Amresco company), DMSO 99.8MIN. DMSO (Chemical Reagent Co., Ltd., Sinopharm Group); The MHB substratum (uses electronic balance to take by weighing 24 gram Mueller-Hinton Broth dry powder; Be dissolved in 1000 ml distilled waters, regulate pH to 7.2, use high-pressure steam sterilizing pan) at 121 ℃ of 20 minutes preparation gained of sterilizing down.Methicillin-resistant staphylococcus aureus MRSA (, being stored in-80 ℃ of refrigerators) with frozen glycerine tube side formula from the clinical separation Resistant strain of Beijing Chaoyang Hospital Attached to Capital Medical Univ., Bacillus subtilus (Bacillus subtilis ATCC6633).Compound S JL-1～SJL-5; The LB agar plate (uses electronic balance to take by weighing 10 gram Tryptone, 5 gram Yeast extract, 5 gram sodium-chlor; Be dissolved in 1000 ml distilled waters, regulate pH to 7.0, add 20 gram agar powders; Use high-pressure steam sterilizing pan to sterilize 20 minutes down at 121 ℃, it is subsequent use that branch is filled to sterile petri dish (30ml/ petridish) back of solidifying to be cooled).
2. bacterium liquid is prepared
Take out the frozen pipe of glycerine of preservation MRSA bacterial strain during mensuration, at room temperature thaw, strok method is inoculated in carries out activation on the LB agar plate, cultivates 20 hours in 37 ℃ of incubators; In 3mL MHB substratum, use the abundant mixing of vortex vibrator to become bacterium liquid mother liquor with the single bacterium colony of 3 MRSA of aseptic inoculation ring picking, it is dense to use blood counting chamber to detect bacterium; Use the MHB substratum that bacterium liquid mother liquor is diluted to 2 * 10
4Cell/mL becomes bacterium liquid for use.
3. soup is prepared
Taking by weighing testing compound with electronic analytical balance, is the compound solution that solvent is formulated as 1mg/mL with aseptic DMSO; Positive control medicine vancomyein uses aseptic DMSO to be formulated as the solution of 320 μ g/mL, and to use DMSO to dilute successively be 8 concentration gradients such as 160 μ g/mL, 80 μ g/mL, 40 μ g/mL, 20 μ g/mL, 10 μ g/mL, 5 μ g/mL, 2.5 μ g/mL.
4. measure the minimal inhibitory concentration that medicine suppresses MRSA
Get aseptic 96 porocyte culture plates, use 8 road micropipets to pipette 40 each hole of μ L MHB substratum to 96 porocyte culture plate; Use micropipet to draw the vancomyein solution of 8 concentration gradients described in the 2 μ L steps 3, add in 8 holes of 96 porocyte culture plates, first row positive control group; Use micropipet to draw the aseptic DMSO of 2 μ L, add in 8 holes of 96 porocyte culture plates the 12 row negative control group; Use micropipet to draw 2 μ L compound solution to be detected, add successively in 96 porocyte culture plate secondary series to the, 11 each hole of row; Use 8 road micropipets to pipette the bacterium liquid for use described in the 40 μ L steps 2, add in 96 each hole of porocyte culture plate; Above-mentioned 96 porocyte culture plates are placed 37 ℃ of incubators; Cultivate after 16 hours; Observe the MRSA upgrowth situation in each hole of 96 orifice plates, it is active to be in the hole of cloudy state added compound nonreactive MRSA, is in the hole of clear state that added compound is preliminary judges that to have anti-MRSA active.Detected each had the active compound of anti-MRSA, and to carry out 2 times of gradient dilutions successively from the starting point concentration of 1mg/mL be 1mg/mL; 500 μ g/mL, 250 μ g/mL, 125 μ g/mL; 62.5 μ g/mL; 31.25 μ g/mL, 15.625 μ g/mL, the compound solution of 8 different concns of 7.8125 μ g/mL; The mensuration that uses the same method uses ELIASA to read the light absorption value OD600 in each hole.For each compound, the MRSA growth is the minimum inhibitory concentration of this compound to MRSA by the pairing compound final concentration in hole (compound solution concentration/40) that suppresses fully.
Equally, can measure the biological activity that benzene sulphenamide verivate suppresses subtilis.
Embodiment 4. benzene sulphenamide verivate anti-candida albicans biological activity determinations
1. test materials
YPD Agar (U.S. BD Difco company); RPMI Media 1640 (U.S. Gibco company); 96 porocyte culture plates (flat bottom) (Corning Incorporated), compound S JL-1～SJL-5, positive control medicine KETOKONAZOL (U.S. sigma company); Beauvericin (U.S. sigma company), DMSO 99.8MIN. DMSO (Chemical Reagent Co., Ltd., Sinopharm Group).Candida albicans (Candida albicans) reference culture SC5314.
2. bacterium liquid is prepared
The corresponding section of reference implementation example 3.
3. soup is prepared
The corresponding section of reference implementation example 3.
4. measure the anti-candida albicans and the collaborative anti-mycotic activity of compound
The corresponding section of reference implementation example 3.
Collaborative anti-mycotic activity method for measuring is that with above-mentioned anti-mycotic activity method for measuring difference needing in the RPMI1640 of its use liquid nutrient medium, to add final concentration is the KETOKONAZOL of 0.004 μ g/mL basically, over against shining the drug use beauvericin.
The interaction that produces when medicine is used is judged by FICI (part inhibition concentration index, the fractional inhibitory concertration index).Its method of calculation are FICI=(MICdrug A in combination/MICdrug A alone)+(MICdrug B in combination/MICdrug B alone); (" drug A in combination " refers to the minimum inhibitory concentration of A medicine when drug combination; " drug B in combination " refers to the minimum inhibitory concentration of B medicine when drug combination; " drug A alone " refers to the minimum inhibitory concentration of A medicine when independent medication; " drug B alone " refers to the minimum inhibitory concentration of B medicine when independent medication, and MIC gets the MIC50 value and calculates).In this example, the value of (MICdrug A in combination/MICdrug A alone) is 0.004/0.016=0.25.
When FICI＞4, both show as antagonism; When FICI＜0.5, both show as Synergistic active; When 0.5＜FICI＜4, it is active that both show as stack.
The test result of target compound anti-microbial activity is seen table 3.
The physico-chemical parameter of table 1. target compound
Table 2. target compound
1HNMR and high resolution mass spectrum
The anti-MRSA of table 3. benzene sulphenamide analog derivative, subtilis (Bacillus subtilis), Candida albicans (Candida albicans) and the biological activity result who works in coordination with antimycotic (synergistic anti Candida albicans)
Claims (8)
1. benzene sulphenamide verivate, it is suc as formula the compound shown in (I):
It is characterized in that
R is H, CH
3, C
2H
5, or CH (CH
3)
2
R ' is H, 2-NO
2, 4-NO
2
X be 3-(1-H-indol-3-yl)-, 3-propionyloxy, 3-propionyloxy (1-3 carbon) ester group.
2. benzene sulphenamide verivate is characterized in that it is:
(S)-3-(1-H-indol-3-yl)-1-(2-oil of mirbane sulfenamide groups) methyl propionate;
(S)-3-(1-H-indol-3-yl)-1-(2-oil of mirbane sulfenamide groups) ethyl propionate;
(S)-3-(1-H-indol-3-yl)-1-(2-oil of mirbane sulfenamide groups) isopropyl propionate;
(S)-3-(1-H-indol-3-yl)-1-(2,4-dinitrobenzene sulfenamide groups) methyl propionate;
(S)-2-(4-nitro-benzene sulfenamide groups)-valeric acid dimethyl ester.
3. its preparation method of the said benzene sulphenamide of claim 1 analog derivative is characterized in that comprising the steps:
The substituted benzene that waits amount of substance time SULPHURYL CHLORIDE (II) and triethylamine are mixed in anhydrous diethyl ether, and adding waits the L-amino acid ester (I) of amount of substance under-5 ℃, again reaction 2h under cryosel is bathed; TLC follows the tracks of detection, after reacting completely, filters; Wash with ether; And filtrate decompression is concentrated, the frequent pressure column chromatography of bullion separates purifies, and gets target compound (III).
4. the sulphenamide verivate of the said benzene of claim 1 is as the purposes in the preparation antibacterials.
5. according to the described purposes of claim 4, it is characterized in that described antibacterials are medicines of methicillin-resistant staphylococcus aureus resistance resistance gram positive bacteriums such as (MRSA).
6. according to the described purposes of claim 4, it is characterized in that described antibacterials are medicines of fungies such as anti-candida albicans.
7. antibacterials is characterized in that it contains claim 1 described benzene sulphenamide verivate and one or more pharmaceutically acceptable carriers.Said carrier comprises the conventional thinner of pharmaceutical field, vehicle, weighting agent, tackiness agent, wetting agent, disintegrating agent, absorption enhancer, tensio-active agent, absorption carrier, lubricant, synergistic agent etc.
8. antibacterials according to claim 7 is characterized in that it is injection, tablet, pill, capsule, suspension agent or the emulsion that contains this medicine.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115677607A (en) * | 2022-11-16 | 2023-02-03 | 遵义医科大学 | Isoxazole amide derivative and preparation method and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2005232082A (en) * | 2004-02-19 | 2005-09-02 | National Institute Of Advanced Industrial & Technology | New n-sulfenylamino acid ester compound and method for producing the same |
| JP4238361B2 (en) * | 2004-02-19 | 2009-03-18 | 独立行政法人産業技術総合研究所 | Method for producing N-sulfenylamino acid ester compound |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2005232082A (en) * | 2004-02-19 | 2005-09-02 | National Institute Of Advanced Industrial & Technology | New n-sulfenylamino acid ester compound and method for producing the same |
| JP4238361B2 (en) * | 2004-02-19 | 2009-03-18 | 独立行政法人産業技術総合研究所 | Method for producing N-sulfenylamino acid ester compound |
Non-Patent Citations (2)
| Title |
|---|
| MARTIN J. WANNER: "Synthesis of Enantiopure (S)-Indolylglycine by Organocatalyzed Friedel–Crafts Alkylation of Indole", 《EUR. J. ORG. CHEM》, 31 December 2008 (2008-12-31), pages 180 - 185 * |
| SHANG JIAN-LI: "Synthesis and Crystal Structure of (S)-Ethyl-2-(2-methoxy-phenylsulfenamido)-3-(1H-indol-3-yl)propanoate", 《结构化学》, vol. 30, no. 2, 28 February 2011 (2011-02-28), pages 252 - 256 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115677607A (en) * | 2022-11-16 | 2023-02-03 | 遵义医科大学 | Isoxazole amide derivative and preparation method and application thereof |
| CN115677607B (en) * | 2022-11-16 | 2023-10-31 | 遵义医科大学 | Isoxazole amide derivative and preparation method and application thereof |
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