CN110372656B - 黄烷醇硫普罗宁衍生物及其制备方法和用途 - Google Patents
黄烷醇硫普罗宁衍生物及其制备方法和用途 Download PDFInfo
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- CN110372656B CN110372656B CN201910659867.0A CN201910659867A CN110372656B CN 110372656 B CN110372656 B CN 110372656B CN 201910659867 A CN201910659867 A CN 201910659867A CN 110372656 B CN110372656 B CN 110372656B
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- tiopronin
- flavanol
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- -1 Flavanol tiopronin derivative Chemical class 0.000 title claims abstract description 17
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- 229920002414 procyanidin Polymers 0.000 claims abstract description 23
- XFZJEEAOWLFHDH-UHFFFAOYSA-N (2R,2'R,3R,3'R,4R)-3,3',4',5,7-Pentahydroxyflavan(48)-3,3',4',5,7-pentahydroxyflavan Natural products C=12OC(C=3C=C(O)C(O)=CC=3)C(O)CC2=C(O)C=C(O)C=1C(C1=C(O)C=C(O)C=C1O1)C(O)C1C1=CC=C(O)C(O)=C1 XFZJEEAOWLFHDH-UHFFFAOYSA-N 0.000 claims abstract description 17
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- KMVWNDHKTPHDMT-UHFFFAOYSA-N 2,4,6-tripyridin-2-yl-1,3,5-triazine Chemical compound N1=CC=CC=C1C1=NC(C=2N=CC=CC=2)=NC(C=2N=CC=CC=2)=N1 KMVWNDHKTPHDMT-UHFFFAOYSA-N 0.000 description 4
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/06—Free radical scavengers or antioxidants
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/32—2,3-Dihydro derivatives, e.g. flavanones
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
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- Public Health (AREA)
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- Biochemistry (AREA)
- Toxicology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明属于医药技术领域,高聚体化合物降解领域,涉及黄烷醇硫普罗宁衍生物及其制备方法和用途,具体涉及3个黄烷醇硫普罗宁衍生物及其制备方法和在制备抗菌药物中的用途。本发明还提供了所述的黄烷醇硫普罗宁衍生物及其盐的合成方法,即将葡萄籽原花青素提取物,依次加入甲醇、浓盐酸、降解试剂硫普罗宁,混匀密闭,于55‑60℃反应,冰浴(0℃)终止反应,即得降解反应混合物,采用高速逆流色谱法分离纯化三种黄烷醇硫普罗宁衍生物1,2,3。本发明的黄烷醇硫普罗宁衍生物具有明显的抗菌活性和抗氧化活性,可以用于制备抗菌药物和抗氧化类保健品。
Description
技术领域
本发明属于医药技术领域,高聚体化合物降解领域,涉及黄烷醇硫普罗宁衍生物及其制备方法和用途,具体涉及3个黄烷醇硫普罗宁衍生物及其制备方法和在制备抗菌药物中的用途。
背景技术
葡萄籽是葡萄酒、葡萄饮料生产过程中的副产物,大多数情况下作为废物被丢弃,不能得到充分的利用,从而造成了资源的大量浪费。原花青素是葡萄籽中的重要的组成成分,其具有多种生物活性和药理作用(抗氧化活性、抗肿瘤、抗菌、心血管保护作用、降低血压、调节血脂平衡、降血糖等),在药品、食品、保健品、化妆品等多个领域中具有广阔的应用前景。关于原花青素的众多活性研究中,尤其以葡萄籽原花青素研究最为广泛和深入。葡萄籽原花青素作为不同的黄烷-3-醇单元连接而成的聚合体,其生物活性与聚合度密切相关。依据聚合度的高低,可分为低聚原花青素与高聚原花青素,聚合度不同、结构不同,生物利用度、活性效果亦不同。研究表明,黄烷-3-醇单体和低聚原花青素可被吸收入血,而高聚原花青素由于其分子结构较大很难被吸收入血,生物利用度低。因此,将高聚原花青素降解转化为可被吸收的活性小分子衍生物是开发原花青素的重要方向。
硫普罗宁是一种新型含游离巯基的甘氨酸衍生物。临床上用于病毒性肝炎,酒精性肝炎,药物性肝炎,重金属中毒性肝炎,脂肪肝及肝硬化早期治疗等。由于其含有游离的巯基,因此在酸性条件下,可以作为一种新型亲核试剂,降解葡萄籽原花青素聚合物,从而获得结构新颖的小分子黄烷醇硫普罗宁衍生物。
现有的抗菌药物大多数源于天然产物或者其代谢产物,天然产物因其结构类型丰富,生物活性广泛,成为药物研究的重要对象。葡萄籽中的原花青素是一种无害的多酚类化合物,本研究从废物再利用的角度,对其进行二次开发,通过化学降解反应,在酸性条件下,以临床常见用药且毒副作用安全的硫普罗宁为亲核试剂从葡萄籽原花青素提取物中设计发明获得3个结构新颖的小分子黄烷醇硫普罗宁衍生物,并对其抗菌活性及体外抗氧化活性进行研究。
发明内容
本发明所解决的技术问题是提供三个黄烷醇硫普罗宁衍生物,并提供一种大量制备所述三个化合物的方法。通过对该三种化合物进行体外抗菌实验,结果表明所述的化合物均具有良好的抗菌活性。
本发明提供如下结构的三种化合物及其异构体:
本发明所述化合物的合成路线如下:
在酸性条件下加热,葡萄籽原花青素(Grape Seed Proanthocyanidins)中的原花青素聚合物的黄烷醇结构单元之间的C4-C8或C4-C6键发生断裂,释放末端单元,上部和中间延伸单元的裂解碎片形成碳正离子与亲核试剂硫普罗宁(Tiopronin)生成稳定的衍生物CT,ECT与ECGT。
进一步地,本发明还提供了大量制备三种化合物的高速逆流方法,该方法包括如下步骤:
(1)称取葡萄籽原花青素提取物,依次加入甲醇、浓盐酸、降解试剂硫普罗宁,混匀密闭,于55-60℃反应,冰浴(0℃)终止反应,加入水,调节pH值,乙酸乙酯萃取,乙酸乙酯层冻干,即得降解反应混合物粉末。干燥器内保存备用(2)以正己烷-乙酸乙酯-甲醇-水混合物为两相溶剂体系;
(3)称取步骤(1)的硫普罗宁与原花青素提取物降解反应混合物粉末,加入步骤(2)中的溶剂体系,振摇、溶解、过滤;
(4)高速逆流色谱法分离得4个组分,分别命名为A,B,C,D,A为儿茶素(Catechin),表儿茶素(Epicatechin),CT的混合物,组分B为表儿茶素没食子酸酯(ECG),组分C为ECT,组分D为ECGT。
其中,
步骤(1)中,调节pH值为7.0-7.3;
步骤(1)中,硫普罗宁与原花青素提取物的质量比为:1:1。
步骤(2)中,正己烷-乙酸乙酯-甲醇-水的体积比为:0.12:1.5:0.5:1
步骤(4)中,流速为2.5mL/min,柱温为35℃,转速为950r/min,先采用正接正转的洗脱模式,进样后运行一段时间,采用反接正转模式。
具体地,在25℃恒温条件下,采用正接正转的洗脱模式,固定相以35mL/min的流速充满分离柱,调节高速逆流色谱仪转速至950rpm平衡1min后,流动相以2.5ml/min的流速进入分离柱,此时固定相流出分离柱,待固定相不再流出,只有流动相流出分离柱时,两相达到平衡。
将供试品溶液通过定量环进样。再运行225min后切换至反接正转模式。反接正转:上相为流动相,下相为固定相。流动相流速为2.5ml/min。波长280nm下检测降解产物,根据色谱图收集各产物组分,冻干备用,超高效液相色谱法检测纯度。高速逆流色谱共收集到4个组分,分别命名为A,B,C,D。
经超高效液相色谱法分析,组分A为儿茶素(Catechin),表儿茶素(Epicatechin),CT的混合物。组分B为表儿茶素没食子酸酯(ECG),组分C为ECT,组分D为ECGT。
化合物CT,ECT和ECGT的结构信息数据归属如下:
CT:(+)-Catechin-4β-S-tiopronin methyl ester:C21H23NO9S,yellow powder,HR-ESI-TOF-MS m/z,464.1629[M-H]-(error 0.5ppm);
ECT:(-)-Epicatechin-4β-S-tiopronin methyl ester:C21H23NO9S,yellowpowder,HR-ESI-TOF-MS m/z,464.1030[M-H]-(error 2ppm);
ECGT:(-)-Epicatechin gallate-4β-S-tiopronin methyl ester;C28H27NO13S,yellow powder,HR-ESI-TOF-MS m/z,616.1136[M-H]-(error 0.9ppm);
CT,ECT,ECGT的NMR数据归属见表1:
表1 CT,ECT,ECGT的NMR数据
进一步地,本发明所述化合物的绝对构型通过运用TDDFT(时间依赖的密度泛函理论)方法进行ECD计算确定,将实验测出的谱图与计算得到的(1R2R3S4S)-CT的ECD图谱进行比较,图谱吻合,表现为204-230nm区域有负Cotton效应,在231-276nm有正Cotton效应(见附图17)。因此,确定该化合物的绝对构型为(1R2R3S4S)-CT。ECT与ECGT与CT的手性中心位置相同,降解转化方式相同,因此ECT与ECGT的绝对构型为(1R2S3S4S)-ECT,(1R2S3S4S)-ECGT。
本发明对制备得到的三种化合物CT,ECT,ECGT对金黄色葡萄球菌,大肠埃希菌的抑菌活性进行了测试与评价。结果显示,化合物CT,ECT有显著的抑菌活性。因此,本发明中制备的CT,ECT可用于开发抑菌药物。
本发明对制备得到的三种化合物CT,ECT,ECGT的体外抗氧化活性进行了测试与评价。结果表明,三种化合物均具有明显的抗氧化活性,可以用于开发抗氧化保健品、特殊用途食品。
附图说明
图1为本发明CT的1H NMR谱;
图2为本发明CT的13C NMR谱;
图3为本发明CT的HSQC谱;
图4为本发明CT的HMBC谱;
图5为本发明ECT的1H NMR谱;
图6为本发明ECT的13C NMR谱;
图7为本发明ECT的HSQC谱;
图8为本发明ECT的HMBC谱;
图9为本发明ECGT的1H NMR谱;
图10为本发明ECGT的13C NMR谱;
图11为本发明ECGT的HSQC谱;
图12为本发明ECGT的HMBC谱;
图13为本发明CT(A)、ECT(B)、ECGT(C)的母离子与CT(D)、ECT(E)、ECGT(F)的子离子高分辨质谱图
图14为高速逆流色谱图;
图15为高速逆流组分A,B,C,D的液相色谱图;
图16为本发明CT,ECT,ECGT可能存在的构型;
图17为本发明CT的ECD谱。
具体实施方式
下面实施例有助于本领域技术人员更好的理解本发明,但不以任何方式限制本发明。
实施例1化合物CT,ECT,ECGT的合成与大量制备
称取葡萄籽原花青素提取物粉末(原花青素含量79%,天津尖峰科技有限公司生产)约1g,置于500ml具塞反应瓶中,依次加入甲醇200ml,浓盐酸6.6ml,硫普罗宁1g,混匀密闭,于55℃反应60min,冰浴(0℃)终止反应,加入大量水,并用0.1M NaHCO3调节pH 7.0,旋转蒸发甲醇溶剂,然后用乙酸乙酯萃取3次,每次20ml,合并萃取层,加入适量的无水硫酸钠除水,40℃减压浓缩乙酸乙酯层,真空冻干成粉末。称取400mg粉末,加入20ml预平衡的下相溶剂体系,充分振摇溶解,经0.45μm微孔滤膜滤过,在25℃恒温条件下,采用正接正转的洗脱模式,收集组分A,收集组分C,225min后切换至反接正转模式,收集组分D。对组分A减压浓缩得到浓缩液,进入半制备液相色谱二次分离,获得化合物CT。对组分B减压浓缩,真空冻干成粉末,获得化合物ECT。对组分D减压浓缩,真空冻干成粉末,获得化合物ECGT。一步高速逆流法可以成功分离获得A,B,C,D四个组分。ECG,ECT and ECGT的产量为6.5,29.8 and10.3mg,其纯度分别为90.3%,93.7% and 89.5%。
实施例2化合物CT,ECT,ECGT的抑菌活性的测定
实验菌株:
金黄色葡萄球菌Staphylococcus aureus[CMCC(B)209P]
大肠埃希菌Escherichia coli[CMCC(B)44102]
实验方法:
将三种菌新鲜斜面培养物用营养肉汤培养基洗下,制成菌悬液(浓度为:106cfu/mL)。在所有的孔中加入已制得的菌悬液100μl,其中第1列1-6行加180ml营养肉汤培养基,第2-10列第1-6行每孔加入100μl营养肉汤培养基,利用移液器移取六种化合物各20μl加入第1列1-6行已有的180μl营养肉汤培养基的孔内,用移液器吹吸均匀(或震荡摇匀),从第一列的各孔中吸取100μl加入下一列对应的各孔并混匀,依次进行等倍稀释(每次稀释必须混匀才可进行下一次操作),最后将第8行孔中吸取100μl弃去,作为实验组。第9列加入氨苄青霉素(1mg/ml)作为阳性对照。第10列每孔加入100ul菌悬液作为阴性对照,将酶标板置于37℃培养箱中培养18h后用移液器小心吹吸各培养孔以混匀,再次测定培养孔的OD600。最低抑菌浓度(MIC)的确定:含供试药培养孔的OD600低于或等于阳性对照孔的OD600,该培养孔的药物浓度即为MIC。
实验结果见表2:
表2.化合物CT,ECT,ECGT的抗菌活性(MIC)
实验结论:
化合物CT与ECT对金黄色葡萄球菌(S.aureus)和大肠杆菌(E.coli)均有良好的抑制作用,而ECGT对这两种细菌没有抑制作用,可能与其自身的化学结构有关。
实施例3化合物CT,ECT,ECGT的体外抗氧化活性的测定
DPPH自由基清除能力测定法:
DPPH储备液的制备:称取DPPH约7.96mg,精密称定,置于100ml棕色量瓶中,加入甲醇定容至刻度,摇匀,制得浓度为201.8μmol/L DPPH储备液溶液,于4℃下避光保存。
DPPH工作液的制备:精密量取DPPH储备液8ml,置于25ml棕色量瓶中加入甲醇定容至刻度,摇匀,在517nm处测定DPPH溶液,调节吸收度为0.66(±0.02),制得浓度为65.58μmol/L DPPH工作液溶液,于4℃下避光保存。
DPPH自由基清除能力测定:96孔板中每孔依次加入DPPH工作液200μl,不同浓度的供试品溶液或trolox对照溶液5μl,以DPPH工作液200μl+甲醇5μl为空白,每个浓度设3个复孔。室温下暗处放置60min,用酶联免疫检测仪测定供试品、对照和空白溶液在517nm处的吸光度,计算清除率。
ABTS自由基清除能力的测定法:
PBS缓冲溶液配制:分别称取磷酸二氢钾(KH2PO4)0.135g,磷酸氢二钠(Na2HPO4·12H2O)1.790g,氯化钠(NaCl)4.001g,氯化钾(KCl)0.101g,置500ml量瓶中,加浓盐酸调pH至7.41,加水定容至刻度,摇匀,即得。
ABTS溶液配制:称取ABTS约96.0mg,精密称定,置25mL量瓶中,加PBS缓冲溶液定容至刻度,摇匀,得摩尔浓度为6.999mmol/L的ABTS储备液;
过硫酸钾溶液配制:称取过硫酸钾(K2S2O8)约33.5mg,置50mL量瓶中,加PBS缓冲溶液定容至刻度,摇匀,得摩尔浓度为2.479mmol/L的ABTS储备液;
ABTS工作液的配制:将ABTS溶液与过硫酸钾溶液等体积混合,制得ABTS工作母液避光贮存12-16h。精密量取ABTS工作母液适量,乙醇稀释40-50倍,调节吸收度0.66±0.03,制得ABTS工作液。
ABTS自由基清除能力的测定:于96孔板中每孔依次加入ABTS工作液200μl,不同浓度的供试品溶液或trolox对照溶液10μl,以ABTS工作液200μl+甲醇10μl为空白,每个浓度设3个复孔。室温下反应10min,用酶联免疫检测仪测定供试品、对照和空白溶液在734nm处的吸光度,计算清除率。
FRAP法测定总抗氧化能力:
300mmol/L醋酸-醋酸钠缓冲液(pH 3.6)的配制:称取无水醋酸纳约0.4554g,置250mL量瓶中,加入冰醋酸3.97mL,加水定容至刻度,摇匀,即得。
10mmol/L TPTZ(40mmol/L HCl)溶液的配制:称取TPTZ约0.1558g,置100mL量瓶中,加入浓盐酸0.17mL,加水定容至刻度,摇匀。
20mmol/L FeC13溶液:称取FeC13·6H2O 0.2747g,置50mL量瓶中,加水定容至刻度,摇匀,即得。
FRAP工作液的配制:将50ml 300mmol/L醋酸一醋酸钠缓冲液(pH3.6),5mLl0mmol/L TPTZ溶液与5mL 20mmol/L FeCl3溶液混匀,备用。FRAP工作液需临用时新鲜配制。
FeSO4标准曲线的绘制:称取FeSO4·7H2O约139.0mg,精密称定,置50mL量瓶中,加水定容至刻度,摇匀,得摩尔浓度为10.00mmol/L的FeSO4储备液。精密量取FeSO4储备液适量,用水稀释成浓度分别为0.5002,1.000,1.500,2.000,2.501mmol/L的标准系列溶液。
总抗氧化能力测定:于96孔板中依次加入FRAP工作液180μl,不同浓度的标准系列溶液、供试品溶液或trolox对照溶液,每个浓度设3个复孔,以FRAP工作液180μl+甲醇5μl为空白,37℃下反应10min,用酶联免疫检测仪测定标准系列溶液、空白溶液和供试品溶液在593nm处的吸光度A,以FeSO4溶液浓度为纵坐标,A为横坐标绘制标准曲线。
统计学分析
统计分析采用SPSS 22.0软件,计算EC50值以平均数(Means)±标准差(S)表示,进行单因素方差(one-way ANOVA)分析和双变量相关性分析,并用Dunnett’s test分析方法比较组间差异。
表3.DPPH法测定CT,ECT,ECGT的抗氧化活性及其线性范围(n=3)
表4.ABTS法测定CT,ECT,ECGT抗氧化活性及其线性范围(n=3)
表5.FRAP法测定CT,ECT,ECGT抗氧化活性及其线性范围(n=3)
Claims (10)
2.一种权利要求1所述的黄烷醇硫普罗宁衍生物及其盐的合成方法,其特征在于,称取葡萄籽原花青素提取物,依次加入甲醇、浓盐酸、降解试剂硫普罗宁,混匀密闭,于55-60℃反应,0℃冰浴终止反应,即得降解反应混合物,采用高速逆流色谱法分离纯化得三种黄烷醇硫普罗宁衍生物1,2与3。
3.如权利要求2所述的合成方法,其特征在于,包括如下步骤:
(1)硫普罗宁与原花青素降解反应混合物的制备;
(2)以正己烷-乙酸乙酯-甲醇-水混合物为两相溶剂体系;
(3)称取硫普罗宁与原花青素降解反应混合物,加入步骤(2)中的溶剂体系,振摇、溶解、过滤;
(4)高速逆流色谱法分离得1,2,3。
4.如权利要求3所述的合成方法,其特征在于,步骤(1)中,称取葡萄籽原花青素提取物,依次加入甲醇、浓盐酸、降解试剂硫普罗宁,混匀密闭,于55-60℃反应,0℃冰浴终止反应,加入水,调节pH值,乙酸乙酯萃取,乙酸乙酯层冻干,即得降解反应混合物。
5.如权利要求4所述的合成方法,其特征在于,硫普罗宁与原花青素提取物的质量比为:1:1;所述pH值为7.0-7.3。
6.如权利要求3所述的合成方法,其特征在于,步骤(2)中所述的正己烷-乙酸乙酯-甲醇-水的体积比为:0.12:1.5:0.5:1。
7.药物组合物,包含权利要求1所述的黄烷醇硫普罗宁衍生物及其盐和药学上可接受的载体。
8.权利要求1所述的黄烷醇硫普罗宁衍生物及其盐在制备抗菌药物或抗氧化药物中的应用。
9.权利要求7所述的药物组合物在制备抗菌药物或抗氧化药物中的应用。
10.如权利要求8或9所述的应用,其特征在于,所述的抗菌药为抗金黄色葡萄球菌或抗大肠埃希菌药物。
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