CN102558018B - Benzene sulphenamide derivative and the purposes in preparation antibacterials thereof - Google Patents
Benzene sulphenamide derivative and the purposes in preparation antibacterials thereof Download PDFInfo
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- CN102558018B CN102558018B CN201110440557.3A CN201110440557A CN102558018B CN 102558018 B CN102558018 B CN 102558018B CN 201110440557 A CN201110440557 A CN 201110440557A CN 102558018 B CN102558018 B CN 102558018B
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Abstract
The present invention relates to benzene sulphenamide analog derivative and the purposes in preparation antibacterials thereof.Benzene sulphenamide analog derivative of the present invention has very strong restraining effect to methicillin-resistant staphylococcus aureus (MRSA), can be used for preparing novel effective overriding resistance gram positive bacterium medicine; There is very strong coordinate repression to Candida albicans, can be used for preparing novel antifungal drug.The form that these medicines can make injection, tablet, pill, capsule, suspension agent or emulsion uses.Its route of administration can be oral, through skin, vein or intramuscular injection.The chemical structural formula of described benzene sulphenamide analog derivative is such as formula shown in (I), and in formula, wherein 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.
Description
Technical field
The present invention relates to benzene sulphenamide derivative and preparing medicament for resisting gram-positive bacteria and preparing the purposes in antifungal drug, particularly to methicillin-resistant staphylococcus aureus (methicillin-resistant Staphylococcus aureus, etc. MRSA) gram-positive microorganism has very strong restraining effect, has very strong coordinate repression to fungies such as Candida albicanss (Candida albicans).
Technical background
Methicillin-resistant staphylococcus aureus (methicillin-resistant Staphylococcus aureus, MRSA) is a kind of super resistant organism bacterium, its to the resistance of Multiple Classes of Antibiotics in continuous enhancing.Few in number to the microbiotic of the real onset of MRSA at present, the medicines such as clinical conventional only vancomycin (vancomycin), daptomycin (daptomycin), Linezolid (linezolid), Tigecycline (tigecycline) and Ceftobiprole (ceftobiprole).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 affecting 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, if KETOKONAZOL is the azole of representative, and polyene antibiotics and amphotericin B etc.The resistance problem produced due to these antifungal drug life-time service is day by day obvious, and the active drug that design and synthesis is new is extremely urgent.
Sulphenamide compounds and biological activity studied less, nearest people study discovery, such compounds exhibit goes out to suppress 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; Wangqing County people etc., CN 101602752A; Wangqing County people etc., CN1927831B) etc. biological activity.The 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.).The further investigation of this compounds is expected to the micromolecular compound finding there is important biomolecule activity.
Summary of the invention
The object of the present invention is to provide a kind of new benzene sulphenamide analog derivative and preparing the application with purposes, particularly methicillin-resistant staphylococcus aureus resistance (MRSA) medicine in antifungal drug and collaborative anti-candida albicans in medicament for resisting gram-positive bacteria.
Benzene sulphenamide derivative of the present invention is as shown in the formula shown in (I):
In formula, wherein 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-propionic acid (1-3 carbon) ester group.
Alternatively, benzene sulphenamide derivative 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 obtained by following reaction expression:
Mix waiting the substituted benzene of amount of substance time SULPHURYL CHLORIDE (II) and triethylamine in anhydrous diethyl ether, under-5 DEG C (cryosel bath), slowly dropping waits the L-amino acid ester (I) of amount of substance, 2h is reacted again under cryosel bath, TLC tracing detection, after reacting completely, filters, with washed with diethylether, and by filtrate reduced in volume, the frequent pressure column chromatography separating-purifying of crude product, obtains target compound (III).
Shown by 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 close to contrast medicine vancomycin had, therefore benzene sulphenamide derivative of the present invention can be used for the active compound preparing the infection for the treatment of resisting gram-positive bacteria.
Shown by the experiment of vitro inhibition fungi, benzene sulphenamide analog derivative dialogue look candidiasis (Candidaalbicans) of the present invention has very strong coordinate repression, and successful exceedes contrast medicine beauvericin.Therefore benzene sulphenamide derivative of the present invention can be used for the active compound preparing treatment anti-fungal infection.
The present invention also provides a kind of medicine being used for the treatment of gram positive bacteria infection, particularly treats the medicine that methicillin-resistant staphylococcus aureus resistance (MRSA) infects; This medicine contains above-mentioned benzene sulphenamide derivative and one or more pharmaceutically acceptable carriers.Described carrier comprises the thinner, vehicle, weighting agent, tackiness agent, wetting agent, disintegrating agent, absorption enhancer, tensio-active agent, absorption carrier, lubricant, synergistic agent etc. of pharmaceutical field routine.The form that this medicine can make injection, tablet, pill, capsule, suspension agent or emulsion uses.Its route of administration can be oral, through skin, vein or intramuscular injection.
The present invention also provides a kind of medicine being used for the treatment of fungi infestation, particularly treats the medicine that anti-candida albicans infects; This medicine contains above-mentioned benzene sulphenamide derivative and one or more pharmaceutically acceptable carriers.Described carrier comprises the thinner, vehicle, weighting agent, tackiness agent, wetting agent, disintegrating agent, absorption enhancer, tensio-active agent, absorption carrier, lubricant etc. of pharmaceutical field routine.The form that this medicine can make injection, tablet, pill, capsule, suspension agent or emulsion uses.Its route of administration can be oral, through skin, vein or intramuscular injection.
Substantive distinguishing features of the present invention can be embodied from the following examples, but these embodiments are only as illustrating, instead of limits the invention.
Accompanying drawing explanation
Fig. 1 is the infrared spectrogram of SJL-4.
Fig. 2 is the infrared spectrogram of SJL-5.
Embodiment
Embodiment 1: the synthesis of compound S JL-1
2.04g (10mmol) L-Trp and 30mL anhydrous methanol are joined in 100mL flask, cryosel bath cooling, when temperature is down to-10 DEG C, 4mL sulfur oxychloride is added dropwise to wherein, in the process dripped, control temperature must not higher than-5 DEG C, dropwise rear backflow 5h, after completion of the reaction, the decompression unnecessary methyl alcohol of removing and sulfur oxychloride, obtaining white solid is dissolved in 30mL water, with anhydrous sodium carbonate, pH is adjusted to 8-9, extraction into ethyl acetate, anhydrous sodium sulfate drying spends the night, finally decompression removing solvent wherein obtains L-Trp methyl esters 1.96g (productive rate: 89.9%), next step reaction is directly used in without the need to process.
The sodium of 1.93g (84mmol) is slowly added in the methyl alcohol of 50mL, after reacting completely, 10.33g (83mmol) benzyl sulfhydrate of 25mL methyl alcohol will be dissolved in successively, be added dropwise to wherein under 13.13g (83mmol) o-Nitrochlorobenzene stirring at normal temperature, after adding, reflux 1h, is then cooled to room temperature, suction filtration obtains yellow solid, then obtains 2-nitrophenyl benzyl thioether 18.39g (productive rate: 90.3%) by recrystallizing methanol.
Then 6.8g (50mmol) SULPHURYL CHLORIDE is dissolved in 25mL trichloromethane is slowly added dropwise in the chloroform soln of the 80mL of 12.2g (50mmol) 2-nitrophenyl benzyl thioether under stirring at normal temperature, 45 DEG C are warming up to after dropwising, now reactant dissolves completely, control to react 0.5h at such a temperature, removal of solvent under reduced pressure obtains yellow oil, add 100mL sherwood oil wherein and obtain yellow fluffy solid, ether purifying obtains 5.23g ortho-nitrophenyl SULPHURYL CHLORIDE (productive rate: 55.2%).
Under cryosel bath, the ortho-nitrophenyl sulphur chlorine of the triethylamine of 0.51g (5mmol) and 0.95g (5mmol) is mixed with 20mL anhydrous ether solution, slowly drip 1.09g (5mmol) L-Trp methyl esters (being dissolved in 10mL anhydrous diethyl ether), 2h is reacted again under cryosel bath, TLC tracing detection, after reacting completely, filter, with washed with diethylether, and by filtrate reduced in volume, obtain yellow oil, normal pressure column chromatography for separation is purified, eluent: petrol ether/ethyl acetate=2: 1 (V/V), obtain yellow oil 1.05g (productive rate: 56.5%).
Equally, compound S JL-2, SJL-3 and SJL-4 of the present invention can be synthesized.
The synthesis of embodiment 2. compound S JL-5
With reference to L-Trp methyl esters synthetic method, Pidolidone methyl esters can be synthesized.
The p-Nitrophenyl chloride of 7.41g (47mmol) is dissolved in the acetone of 50mL, dissolve the sodium disulfide aqueous solution (brand-new) completely to be slowly added dropwise to wherein, dropwise post-heating backflow 4h, after having reacted, be cooled to room temperature, separate out light yellow solid, suction filtration, dry, use methylene dichloride recrystallization, obtain 1,2-bis-(4-oil of mirbane) disulfide 4.60g.
Under stirring at room temperature, the SULPHURYL CHLORIDE of 1.7g (12mmol) is slowly added dropwise to 3.70g (12mmol) 1, in the 20mL dichloromethane solution of 2-bis-(4-oil of mirbane) disulfide, TLC tracing detection, react completely after 2h, solvent removed in vacuo and unnecessary SULPHURYL CHLORIDE obtain 4-oil of mirbane time SULPHURYL CHLORIDE 1.45g.
With reference to the final synthetic method of SJL-1, SJL-5 can be synthesized.
The structural formula of target compound and physico-chemical parameter in table 1, high resolution mass spectrum and
1h NMR is in table 2.
Embodiment 3: the anti-MRSA determination of activity of benzene sulphenamide derivative.
1. test materials
Mueller-Hinton Broth (Beijing extensive and profound in meaning star biotechnology limited liability company), Tryptones (OXOID company of Britain), yeast extract powder (OXOID company of Britain), sodium-chlor (Chemical Reagent Co., Ltd., Sinopharm Group), 96 porocyte culture plates (flat bottom) (Corning Incorporated), positive control medicine vancomycin (Amresco company of the U.S.), dimethyl sulfoxide (DMSO) DMSO (Chemical Reagent Co., Ltd., Sinopharm Group), MHB substratum (uses electronic balance to take 24 grams of Mueller-HintonBroth dry powder, be dissolved in 1000 ml distilled waters, regulate pH to 7.2, high-pressure steam sterilizing pan sterilizing at 121 DEG C is used to prepare gained in 20 minutes).Methicillin-resistant staphylococcus aureus MRSA is (from the clinical separation Resistant strain of Beijing Chaoyang Hospital Attached to Capital Medical Univ.,-80 DEG C of refrigerators are stored in frozen glycerine pipe mode), Bacillus subtilus (Bacillus subtilisATCC6633).Compound S JL-1 ~ SJL-5, LB agar plate (uses electronic balance to take 10 grams of Tryptone, 5 grams of Yeast extract, 5 grams of sodium-chlor, be dissolved in 1000 ml distilled waters, regulate pH to 7.0, add 20 grams of agar powders, use high-pressure steam sterilizing pan sterilizing 20 minutes at 121 DEG C, point to be filled to sterile petri dish (30ml/ culture dish) to be cooled solidify rear for subsequent use).
2. bacterium liquid prepares
Take out the glycerine cryopreservation tube of preservation MRSA bacterial strain during mensuration, at room temperature thaw, method of scoring is inoculated on LB agar plate and activates, and cultivates 20 hours in 37 DEG C of incubators; With aseptic inoculation ring picking 3 mono-bacterium colonies of MRSA in 3mL MHB substratum, using turbula shaker fully to mix becomes bacterium liquid mother liquor, uses blood counting chamber to detect bacterium dense; Use MHB substratum that bacterium liquid mother liquor is diluted to 2 × 10
4cell/mL, becomes stand-by bacterium liquid.
3. liquid prepares
Testing compound is taken, with aseptic DMSO for solvent is formulated as the compound solution of 1mg/mL with electronic analytical balance; Positive control medicine vancomycin uses aseptic DMSO to be formulated as the solution of 320 μ g/mL, and to dilute successively with DMSO 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 of Drug inhibition MRSA
Get aseptic 96 porocyte culture plates, use 8 road micropipets to pipette the 40 each holes of μ L MHB substratum to 96 porocyte culture plate; Use micropipet to draw the vancomycin solution of 8 concentration gradients described in 2 μ L steps 3, adding in 8 holes of 96 porocyte culture plate first rows, is positive controls; Use micropipet to draw the aseptic DMSO of 2 μ L, adding in 8 holes of 96 porocyte culture plates the 12 row, is negative control group; Use micropipet to draw 2 μ L compound solution to be detected, add 96 porocyte culture plate secondary series successively in the 11 each hole of row; Use 8 road micropipets to pipette the stand-by bacterium liquid described in 40 μ L steps 2, add in the 96 each holes of porocyte culture plate; Above-mentioned 96 porocyte culture plates are placed in 37 DEG C of incubators, cultivate after 16 hours, observe the MRSA upgrowth situation in the 96 each holes of orifice plate, compound nonreactive MRSA added in the hole in cloudy state is active, and it is active that compound added in the hole in clear state tentatively judges to have anti-MRSA.It is 1mg/mL that each detected compound with anti-MRSA activity is carried out 2 times of gradient dilutions successively from the starting point concentration of 1mg/mL, 500 μ g/mL, 250 μ g/mL, 125 μ g/mL, 62.5 μ g/mL, the compound solution of 31.25 μ g/mL, 15.625 μ g/mL, 7.8125 μ g/mL 8 different concns; Use the same method mensuration, uses microplate reader to read the light absorption value OD600 in each hole.For each compound, MRSA grows the final compound concentration (compound solution concentration/40) corresponding to hole be totally constrained and is the minimum inhibitory concentration of this compound to MRSA.
Equally, the biological activity that benzene sulphenamide derivative suppresses subtilis can be measured.
Embodiment 4. benzene sulphenamide derivative anti-candida albicans biological activity determination
1. test materials
YPD Agar (BD Difco company of the U.S.), RPMI Media 1640 (Gibco company of the U.S.), 96 porocyte culture plates (flat bottom) (Corning Incorporated), compound S JL-1 ~ SJL-5, positive control medicine KETOKONAZOL (sigma company of the U.S.), beauvericin (sigma company of the U.S.), dimethyl sulfoxide (DMSO) DMSO (Chemical Reagent Co., Ltd., Sinopharm Group).Candida albicans (Candida albicans) reference culture SC5314.
2. bacterium liquid prepares
The corresponding section of reference example 3.
3. liquid prepares
The corresponding section of reference example 3.
4. measure the anti-candida albicans of compound and collaborative anti-mycotic activity
The corresponding section of reference example 3.
The basic difference with above-mentioned anti-mycotic activity method for measuring of collaborative anti-mycotic activity method for measuring is, adds the KETOKONAZOL that final concentration is 0.004 μ g/mL, positive control drug use beauvericin in the RPMI1640 liquid nutrient medium that need use at it.
Medicine with the use of time produce interaction judged by FICI (fractional inhibitory concentration index, the fractional inhibitoryconcertration index).Its method of calculation are FICI=(MICdrug A in combination/MICdrug Aalone)+(MICdrug B in combination/MICdrug B alone), (" drug A in combination " refers to the minimum inhibitory concentration of the A medicine when drug combination, " drug B in combination " refers to the minimum inhibitory concentration of the B medicine when drug combination, " drug A alone " refers to the minimum inhibitory concentration of the A medicine when independent medication, " drug B alone " refers to the minimum inhibitory concentration of the B medicine when independent medication, MIC gets MIC50 value and calculates).In this example, the value of (MICdrug A in combination/MICdrug A alone) is 0.004/0.016=0.25.
As FICI > 4, both show as antagonism; As FICI < 0.5, both show as Synergistic active; As 0.5 < FICI < 4, it is active that both show as superposition.
The test result of target compound anti-microbial activity is in table 3.
The physico-chemical parameter of table 1. target compound
Table 2. target compound
1hNMR and high resolution mass spectrum
The biological activity result of the anti-MRSA of table 3. benzene sulphenamide analog derivative, subtilis (Bacillus subtilis), Candida albicans (Candidaalbicans) and collaborative antimycotic (synergistic anti Candida albicans)
Claims (4)
1. a benzene sulphenamide derivative, is characterized in that this benzene sulphenamide derivative is:
2. benzene sulphenamide derivative described in claim 1 is as the purposes prepared in methicillin-resistant staphylococcus aureus resistance and anti-candida albicans medicine.
3. antibacterials, is characterized in that it contains benzene sulphenamide derivative according to claim 1 and one or more pharmaceutically acceptable carriers; Described carrier comprises thinner, vehicle, weighting agent, tackiness agent, wetting agent, disintegrating agent, absorption enhancer, tensio-active agent, absorption carrier, lubricant, the synergistic agent of pharmaceutical field routine.
4. antibacterials according to claim 3, is characterized in that it is injection, tablet, pill, capsule, suspension agent or emulsion containing described antibacterials.
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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 |
|---|
| Synthesis and Crystal Structure of (S)-Ethyl-2-(2-methoxy-phenylsulfenamido)-3-(1H-indol-3-yl)propanoate;SHANG Jian-Li;《结构化学》;20110228;第30卷(第2期);252-256 * |
| Synthesis of Enantiopure (S)-Indolylglycine by Organocatalyzed Friedel–Crafts Alkylation of Indole;Martin J. Wanner;《Eur. J. Org. Chem》;20081231;180–185 * |
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