WO2021000062A1 - 化合物sclerotiorin与利福平联用在制备抗结核病药物中的应用 - Google Patents

化合物sclerotiorin与利福平联用在制备抗结核病药物中的应用 Download PDF

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WO2021000062A1
WO2021000062A1 PCT/CN2019/093937 CN2019093937W WO2021000062A1 WO 2021000062 A1 WO2021000062 A1 WO 2021000062A1 CN 2019093937 W CN2019093937 W CN 2019093937W WO 2021000062 A1 WO2021000062 A1 WO 2021000062A1
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sclerotiorin
slt
compound
tuberculosis
rifampicin
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陆勇军
陈冬妮
佘志刚
沈冬
王庆琳
何磊
袁培博
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中山大学
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61P31/06—Antibacterial agents for tuberculosis

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  • the invention relates to the technical field of anti-tuberculosis drugs, and more specifically, to the application of the compound sclerotiorin and rifampicin in the preparation of anti-tuberculosis drugs.
  • Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis that seriously endangers human health. In 2011, the World Health Organization reported that about 1.4 million people died of tuberculosis (TB) and 8.7 million newly discovered patients. One of the key issues concerning tuberculosis is that it is prone to drug resistance. Drug-resistant tuberculosis (DR-TB) is a disease for which the global public urgently needs to discover and develop new treatments for tuberculosis. In China, drug-resistant tuberculosis is on the rise. At present, the situation of tuberculosis prevention and treatment is still very serious, and the research and development of anti-tuberculosis drugs is imminent.
  • DR-TB Drug-resistant tuberculosis
  • the compound sclerotiorin was first isolated from Penicillium sclerotiorum by two British scientists. It is a yellow solid and its molecular formula is C 21 H 23 O 5 Cl. Sclerotiorin shows a wide range of biological activities and has potential in medicine and pesticides. Application prospects. Patent 201610886626.6 discloses the application of the compound sclerotiorin in the preparation of anti-tuberculosis drugs.
  • the purpose of the present invention is to overcome the above-mentioned shortcomings and shortcomings of the prior art, and provide the application of the compound sclerotiorin and rifampicin in the preparation of anti-tuberculosis drugs.
  • the present invention uses Mycobacterium tuberculosis (Mtb) H37Rv (Rv) aerosol infection BALB/c mouse model to study the in vivo activity of the compound Sclerotiorin (SLT) alone and in combination with rifampicin (RIF) against Mycobacterium tuberculosis,
  • SLT Sclerotiorin
  • RIF rifampicin
  • the application of the compound sclerotiorin and rifampicin in the preparation of anti-Mycobacterium tuberculosis drugs, and the dose of the compound sclerotiorin and rifampin is 100-300mg/kg+10mg/kg.
  • the dose of the compound sclerotiorin and rifampin is 100 mg/kg+10 mg/kg.
  • the dose of the compound sclerotiorin and rifampicin is 300 mg/kg+10 mg/kg.
  • tuberculosis is tuberculosis in mice; and the Mycobacterium tuberculosis is Mycobacterium tuberculosis in mice.
  • the present invention has the following beneficial effects:
  • the present invention discloses the application of compound sclerotiorin in combination with rifampin in the preparation of anti-tuberculosis drugs.
  • the present invention adopts the Mtb H37Rv aerosol infection BALB/c mouse model to study the compound sclerotiorin alone or in combination with rifampin for anti-tuberculosis
  • the results showed that compared with the no-treatment group and before treatment, when the doses were 100mg/kg and 300mg/kg, SLT had a significant bactericidal effect on Mycobacterium tuberculosis in mice, especially When SLT is used in combination with RIF, the bactericidal effect in the body is enhanced, showing a very obvious synergistic effect.
  • SLT and RIF found in existing studies, it has a significant improvement.
  • Figure 1 shows the therapeutic effect of SLT alone and in combination with RIF on Mycobacterium tuberculosis in mice; among them, D0 means before treatment; Ut means no treatment group; RIF means rifampicin alone administration group, the dose is 10mg /kg; S100 represents the compound sclerotiorin alone administration group, the dose is 100mg/kg; S300 represents the compound sclerotiorin alone administration group, the dose is 300mg/kg; S100+RIF represents the compound sclerotiorin and rifampin combined administration group, the dose is 100mg/kg STL+10mg/kg; S300+RIF means the compound sclerotiorin and rifampicin combined administration group, the dose is 300mg/kg STL+10mg/kg.
  • the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the technical field.
  • the compound sclerotiorin (SLT) is a yellow powder.
  • the preparation method accurately weigh the drug into a centrifuge tube, add 0.5% CMC-Na (sodium carboxymethyl cellulose) for quantification, shake and mix well, and ultrasonically break it to a concentration of 10 mg. /mL, 30mg/mL solution. In order to ensure that the amount of medicine is sufficient during the experiment, all medicines are formulated into 12 mL and re-formulated every Friday.
  • CMC-Na sodium carboxymethyl cellulose
  • the anti-tuberculosis drug rifampicin (RIF) comes from TCI company (Lot.2GHF-TF). It is a dark red powder.
  • the preparation method accurately weigh the drug into a 50mL centrifuge tube and add 0.5% CMC-Na (carboxymethyl cellulose). Sodium) quantify, shake and mix thoroughly and ultrasonically break to make 10mg/mL, and the administration volume is 100mL/kg.
  • mice were sourced from the Laboratory Animal Center of Southern Medical University, animal qualification number (44002100015806); age at the beginning of the experiment: 4-6 weeks, weight at the beginning of the experiment: 18 ⁇ 2g, number: 40, gender: female , Group mark: each cage is numbered separately.
  • the mouse feed was provided by Beijing Keyao Xieli Feed Co., Ltd.; drinking water: purified water sterilized by high temperature and high pressure.
  • Contaminants The levels of contaminants in food and water should not reach levels that interfere with and affect the results of the research. Breeding environment: SPF animal room breeding, temperature: 22-24 °C, humidity: 45-80%, light: 150-300Lx, 12h day and night alternate.
  • Reagents and instruments OADC, 7H9 agar and H11 agar (all BD companies in the United States); constant temperature incubator (Shanghai Yiheng Scientific Instrument Co., Ltd.).
  • the dose of compound sclerotiorin (SLT) was set to 100mg/kg and 300mg/kg; the dose of rifampicin (RIF) was set to this laboratory's usual dose: 10mg/kg.
  • mice died everywhere on the second day (Day-28) and the 28th day (Day0) after infection. The lungs were removed and fully ground. After 10-fold serial dilution, they were plated to detect CFU.
  • the drug was administered according to the dosage of each group; it was administered every day for 5 days a week for a total of 4 weeks.
  • mice were killed. After extracting the lungs and fully grinding and diluting them, they were plated to detect CFU.
  • the data are expressed as mean ⁇ standard deviation (x ⁇ s), and the Student-t test is used for statistical analysis of the data. Compared with the untreated group, p ⁇ 0.05 is considered to be statistically different.
  • the SLT single-use group has a very significant difference when the dosage is 100mg/kg and 300mg/kg;

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Abstract

本发明公开了化合物sclerotiorin与利福平联用在制备抗结核病药物中的应用。本发明采用结核分歧杆菌(Mtb)H37Rv(Rv)气溶胶感染BALB/c小鼠模型，研究化合物Sclerotiorin(SLT)单独以及与利福平(RIF)联合使用时抗结核分枝杆菌的体内活性，结果发现，与无治疗组及治疗前相比，在给药剂量为100mg/kg和300mg/kg时，SLT对体内结核分枝杆菌均有明显杀菌作用，当与RIF联合使用时，体内杀菌作用增强，表现出非常明显的协同效应，且SLT呈剂量依赖关系。

Description

化合物sclerotiorin与利福平联用在制备抗结核病药物中的应用 技术领域
本发明涉及抗结核病药物技术领域，更具体地，涉及化合物sclerotiorin与利福平联用在制备抗结核病药物中的应用。
背景技术
结核病是一个由结核分枝杆菌(Mycobacterium tuberculosis)引起的严重危害人类健康的传染性疾病。2011世界卫生组织报道，约有140万人死于结核病(TB)和870万的新发现患者。关注结核病的一个关键问题是它容易产生耐药性，耐药结核病(DR-TB)是一个全球性的公众迫切需要发现和开发新的治疗结核病方法的疾病。在中国，耐药性结核病呈不断上升的趋势。目前，结核病防治形势仍十分严峻，抗结核药物的研制与开发迫在眉睫。
化合物sclerotiorin最早是由两位英国科学家从Penicillium sclerotiorum菌中分离得到，为黄色的固体，其分子式为C 21H 23O 5Cl，sclerotiorin显示了广泛的生物活性，在医药、农药方面都有潜在的应用前景。专利201610886626.6公开了化合物sclerotiorin在制备抗结核病药物中的应用，其研究结果表明在40μM化合物sclerotiorin与0.025mg/L利福平处理下，细胞内的结核分枝杆菌数量减少了84％，然而其仅显示了细胞水平的抗菌效果，且联合效用仅表现出叠加效果，不具有实际应用价值。
发明内容
本发明的目的在于克服现有技术的上述缺陷和不足，提供化合物sclerotiorin与利福平联用在制备抗结核病药物中的应用。
本发明的上述目的是通过以下技术方案给予实现的：
本发明采用结核分歧杆菌(Mtb)H37Rv(Rv)气溶胶感染BALB/c小鼠模型，研究化合物Sclerotiorin(SLT)单独以及与利福平(RIF)联合使用时抗结核分枝杆菌的体内活性，结果发现，与无治疗组及治疗前相比，当给药剂量为100mg/kg和300mg/kg时，SLT对小鼠体内结核分枝杆菌均有明显杀菌作用；尤其是意见发现：当100mg/kg和300mg/kg SLT与10mg/kg RIF联合使用时，体内杀菌作用增强，表现出非常明显的协同效应，与现有已知研究结果截然不同，且 SLT呈剂量依赖关系。
因此，本发明的下列应用均在本发明的保护范围内：
化合物sclerotiorin与利福平联用在制备抗结核病药物中的应用，所述化合物sclerotiorin与利福平的剂量为100～300mg/kg+10mg/kg。
化合物sclerotiorin与利福平联用在制备抗结核分枝杆菌药物中的应用，所述化合物sclerotiorin与利福平的剂量为100～300mg/kg+10mg/kg。
优选地，化合物sclerotiorin与利福平的剂量为100mg/kg+10mg/kg。
优选地，化合物sclerotiorin与利福平的剂量为300mg/kg+10mg/kg。
具体地，所述结核病为小鼠结核病；所述结核分枝杆菌为小鼠体内的结核分枝杆菌。
与现有技术相比，本发明具有以下有益效果：
本发明公开了化合物sclerotiorin与利福平联用在制备抗结核病药物中的应用，本发明采用Mtb H37Rv气溶胶感染BALB/c小鼠模型，研究化合物Sclerotiorin单独以及与利福平联合使用时抗结核分枝杆菌的体内活性，结果发现，与无治疗组及治疗前相比，当给药剂量为100mg/kg和300mg/kg时，SLT对小鼠体内结核分枝杆菌均有明显杀菌作用，尤其是当SLT与RIF联合使用时，体内杀菌作用增强，表现出非常明显的协同效应，与现有研究中发现的SLT与RIF的叠加作用相比，具有显著的进步。
附图说明
图1为SLT单独以及与RIF联合用药时对小鼠体内的结核分枝杆菌的治疗效果；其中，D0表示治疗前；Ut表示无治疗组；RIF表示利福平单独给药组，剂量为10mg/kg；S100表示化合物sclerotiorin单独给药组，剂量为100mg/kg；S300表示化合物sclerotiorin单独给药组，剂量为300mg/kg；S100+RIF表示化合物sclerotiorin与利福平联合给药组，剂量为100mg/kg STL+10mg/kg；S300+RIF表示化合物sclerotiorin与利福平联合给药组，剂量为300mg/kg STL+10mg/kg。
具体实施方式
以下结合说明书附图和具体实施例来进一步说明本发明，但实施例并不对本发明做任何形式的限定。除非特别说明，本发明采用的试剂、方法和设备为本技术领域常规试剂、方法和设备。
除非特别说明，以下实施例所用试剂和材料均为市购。
化合物sclerotiorin(SLT)为黄色粉末，配制方法：准确称取药物离心管中，加入0.5％CMC-Na(羧甲基纤维素钠)定量，充分震荡混匀后超声波破碎，配置成浓度分别为10mg/mL，30mg/mL的溶液。为保证实验过程中药物量充足，所有药物均配制为12mL，每周五重新配制。
抗结核药物利福平(RIF)来源TCI公司(Lot.2GHF-TF)，为暗红色粉末，配制方法：准确称取药物于50mL离心管中，加入0.5％CMC-Na(羧甲基纤维素钠)定量，充分震荡混匀后超声波破碎，配成10mg/mL，给药容积100mL/kg。
BALB/c小鼠来源南方医科大学实验动物中心，动物合格证号(44002100015806)；开始试验时的年龄：4～6周，开始试验时的体重：18±2g，数量：40只，性别：雌性，分组标记：每笼分别编号。
小鼠饲料由北京科澳协力饲料有限公司提供；饮水：高温高压消毒灭菌的纯净水。污染物：食物和水中的污染物含量不应达到干扰和影响研究结果的水平。饲养环境：SPF级动物房饲养，温度：22～24℃，湿度：45～80％，光照：150～300Lx，12h昼夜交替。
试剂与仪器：OADC、7H9琼脂和H11琼脂(均为美国BD公司)；恒温培养箱(上海一恒科学仪器有限公司)。
实施例1
一、方法
1、剂量设置
在本实验中，化合物sclerotiorin(SLT)剂量设定为100mg/kg和300mg/kg；利福平(RIF)设置剂量为本实验室常用剂量：10mg/kg。
2、动物适应期检查
实验所需全部动物均在具有资质的实验动物场地进行饲养，动物检疫和检查由相关人员负责。
3、剂量设置与组
实验设计，如表1：
表1给药分组
组别【共7组】 小鼠数量(只) 剂量
(CMC钠盐)灌胃 5 (对照)
(RIF)灌胃 5 10mg/kg
SLT灌胃 5 100mg/kg
SLT灌胃 5 300mg/kg
(SLT+RIF)灌胃 5 100mg/kg+10mg/kg
(SLT+RIF)灌胃 5 300mg/kg+10mg/kg
感染后，治疗前的组 10 感染次日和感染后4周各杀5只
4、实验方法
(1)菌株培养
从-80℃冰箱取保存的Mtb H37Rv，接入7H9液体培养基培养，加入玻璃珠打散待其OD600值达到0.8。
(2)动物感染及分组
选取4～6周龄的雌性BALB/c小鼠，让其在实验室适应数天。治疗前1天(Day-1)，菌液稀释100倍，采用气溶胶感染的方式感染H37Rv；
(3)给药与检测
①于感染后第二天(Day-28)和第28天(Day0)各处死5只小鼠，摘取肺并充分研磨，10倍系列稀释后铺板检测CFU。
②感染后第28天按照每组的喂药剂量开始给药；每天给药，一周给药5天，共给药4周。
③喂药4周后，处死所有小鼠。摘取肺并充分研磨稀释后，铺板检测CFU。
5、数据处理及统计分析
数据以均值±标准差(x±s)表示，采用Student-t test对数据进行统计学分析，与未治疗组进行比较，p<0.05即为具有统计学差异。
二、实验结果
SLT单独以及与RIF联合用药时对小鼠体内的结核分枝杆菌的治疗效果如图1和表2所示：
表2不同浓度sclerotiorin与利福平组合的体内抑菌效果
Figure PCTCN2019093937-appb-000001
Figure PCTCN2019093937-appb-000002
小鼠CFU检测结果数据分析如表3所示：
表3小鼠CFU检测结果数据分析
Figure PCTCN2019093937-appb-000003
SLT与RIF联用效果：
根据联合效用指标公式计算(参见第114页三)(参见“中医科研设计与统计学”,贺石林等,第114页,湖南科学技术出版社,2005年6月)，进行联合效用计算：
当10mg/kg RIF与100mg/kg SLT联用时，为协同效应：
V t＝P A+P B-P A×P B＝(1-3.86/5.21)+(1-3.60/5.21)-(1-3.86/5.21)×(1-3.60/5.21)＝0.4894
Q＝V 0/V t＝2.99/0.4894＝6.11(>1.2)；
当10mg/kg RIF与300mg/kg SLT联用时，为协同效应：
V t＝P A+P B-P A×P B＝(1-3.69/5.21)+(1-3.60/5.21)-(1-3.69/5.21)×(1-3.60/5.21)＝0.5101
Q＝V 0/V t＝2.69/0.5101＝5.27(>1.2)。
三、结论
1、SLT单用
1)SLT单用与D0相比，SLT对体内结核分枝杆菌均有明显杀菌作用；
2)SLT单用与无治疗组相比，在给药剂量为100mg/kg和300mg/kg时，均有非常明显的差异；
3)SLT单用与RIF治疗组相比没有显著差异；
4)SLT单用高剂量组和单用低剂量组相比，有差异。
2、SLT与RIF联合使用
1)SLT与RIF联合使用与非治疗组相比，随SLT的给药剂量增加，体内杀菌作用而增强，表现出协同效应；
2)SLT与RIF联合使用与RIF治疗组相比，有极其显著差异；
3)SLT与RIF联合使用与SLT单用治疗组相比，有极其显著差异；
4)SLT与RIF联合使用时，高剂量组与低剂量组相比有极其显著差异。

Claims (6)

  1. 化合物sclerotiorin与利福平联用在制备抗结核病药物中的应用，其特征在于，化合物sclerotiorin与利福平的剂量为100～300mg/kg+10mg/kg。
  2. 化合物sclerotiorin与利福平联用在制备抗结核分枝杆菌药物中的应用，其特征在于，化合物sclerotiorin与利福平的剂量为100～300mg/kg+10mg/kg。
  3. 根据权利要求1或2所述的应用，其特征在于，化合物sclerotiorin与利福平的剂量为100mg/kg+10mg/kg。
  4. 根据权利要求1或2所述的应用，其特征在于，化合物sclerotiorin与利福平的剂量为300mg/kg+10mg/kg。
  5. 根据权利要求1所述的应用，其特征在于，所述结核病为小鼠结核病。
  6. 根据权利要求2所述的应用，其特征在于，所述结核分枝杆菌为小鼠体内的结核分枝杆菌。
PCT/CN2019/093937 2019-06-29 2019-06-29 化合物sclerotiorin与利福平联用在制备抗结核病药物中的应用 WO2021000062A1 (zh)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130197071A1 (en) * 2012-01-27 2013-08-01 University Of Southern California Production of lipoxygenase inhibitors via fungal biosynthetic pathway
CN106420755A (zh) * 2016-10-11 2017-02-22 中山大学 化合物sclerotiorin在制备抗结核病药物中的应用
CN108658924A (zh) * 2017-03-28 2018-10-16 中国海洋大学 核丛青霉素作为农业杀菌剂的应用

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130197071A1 (en) * 2012-01-27 2013-08-01 University Of Southern California Production of lipoxygenase inhibitors via fungal biosynthetic pathway
CN106420755A (zh) * 2016-10-11 2017-02-22 中山大学 化合物sclerotiorin在制备抗结核病药物中的应用
CN108658924A (zh) * 2017-03-28 2018-10-16 中国海洋大学 核丛青霉素作为农业杀菌剂的应用

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