CN114404416A - 溴氧喹啉及其衍生物在制备抗菌药物中的应用 - Google Patents
溴氧喹啉及其衍生物在制备抗菌药物中的应用 Download PDFInfo
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- SNFYAFUAOWWVOA-UHFFFAOYSA-N quinolin-2-yl hypobromite Chemical compound C1=CC=CC2=NC(OBr)=CC=C21 SNFYAFUAOWWVOA-UHFFFAOYSA-N 0.000 title claims abstract description 30
- 229940124350 antibacterial drug Drugs 0.000 title claims abstract description 6
- 241000228212 Aspergillus Species 0.000 claims abstract description 9
- 229940091771 aspergillus fumigatus Drugs 0.000 claims description 26
- 241001225321 Aspergillus fumigatus Species 0.000 claims description 25
- 239000003814 drug Substances 0.000 claims description 20
- 239000007788 liquid Substances 0.000 claims description 6
- 244000052616 bacterial pathogen Species 0.000 claims description 5
- 229940121375 antifungal agent Drugs 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 239000006071 cream Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000000499 gel Substances 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims description 2
- 238000002347 injection Methods 0.000 claims description 2
- 239000007924 injection Substances 0.000 claims description 2
- 239000006187 pill Substances 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 230000000843 anti-fungal effect Effects 0.000 claims 1
- 239000002674 ointment Substances 0.000 claims 1
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 8
- 241000233866 Fungi Species 0.000 abstract description 7
- 230000000144 pharmacologic effect Effects 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 description 18
- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 description 15
- 229960004130 itraconazole Drugs 0.000 description 15
- 150000001875 compounds Chemical class 0.000 description 8
- 230000001580 bacterial effect Effects 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- 208000015181 infectious disease Diseases 0.000 description 5
- 201000002909 Aspergillosis Diseases 0.000 description 3
- 208000036641 Aspergillus infections Diseases 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 3
- 206010017533 Fungal infection Diseases 0.000 description 3
- 208000031888 Mycoses Diseases 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 239000003429 antifungal agent Substances 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 238000005034 decoration Methods 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- ZDASUJMDVPTNTF-UHFFFAOYSA-N 5,7-dibromo-8-quinolinol Chemical compound C1=CN=C2C(O)=C(Br)C=C(Br)C2=C1 ZDASUJMDVPTNTF-UHFFFAOYSA-N 0.000 description 1
- 241000228197 Aspergillus flavus Species 0.000 description 1
- 241000228245 Aspergillus niger Species 0.000 description 1
- 241001465318 Aspergillus terreus Species 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000003904 antiprotozoal agent Substances 0.000 description 1
- 230000003385 bacteriostatic effect Effects 0.000 description 1
- 238000002815 broth microdilution Methods 0.000 description 1
- 229960002880 broxyquinoline Drugs 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000009422 growth inhibiting effect Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- BCEHBSKCWLPMDN-MGPLVRAMSA-N voriconazole Chemical compound C1([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)=NC=NC=C1F BCEHBSKCWLPMDN-MGPLVRAMSA-N 0.000 description 1
- 229960004740 voriconazole Drugs 0.000 description 1
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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
- A61K31/47—Quinolines; Isoquinolines
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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
- A61P31/10—Antimycotics
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Abstract
本发明公开了溴氧喹啉及其衍生物的抗菌药理活性，本发明通过大量实验筛选开发出溴氧喹啉及其衍生物对曲霉真菌等真菌表现出良好的抗菌活性。有望开发成新的抗菌药物，具有重要的应用价值。
Description
技术领域
本发明属于生物医药领域，具体涉及溴氧喹啉在制备抗菌药物中的应用。
背景技术
随着免疫抑制剂、广谱抗生素和抗癌药的广泛使用，真菌感染(IFI)现象日益增多，经常出现在器官移植者、造血干细胞移植受者、ICU和外科手术患者身上。其中，曲霉感染在血液科和ICU最常见。与人类感染相关的曲霉有30多种，90％曲霉病由烟曲霉引起，其次是黄曲霉、土曲霉、黑曲霉。由于真菌在进化上和人类比较接近，造成用于治疗真菌感染的药物非常有限。唑类药物(如伊曲康唑、伏立康唑)美国感染疾病协会指南推荐的治疗和预防曲霉感染的一线用药。近年来，曲霉病原菌的耐药或多重耐药菌株的出现严重危及人民群众的身体健康，如果患者被曲霉多药耐药菌感染，将造成感染治疗失败和复发。开发新型抗耐药菌感染药物已成为公共卫生领域的迫切要求。
药物再利用是挖掘新抗耐药菌感染药物的好方式。溴氧喹啉(Broxyquinoline)是美国FDA批准的药物化合物，属于抗原虫剂。已有研究报道，溴氧喹啉有抗病毒的作用。目前还没有关于溴氧喹啉抗耐药真菌的报道，特别是对具有耐药性曲霉的抗菌报道。所以它是一个很有潜力的抗真菌药物，尤其是对抗耐药曲霉菌。
发明内容
本发明的目的是在溴氧喹啉现有药理活性的基础上，通过大量实验筛选出其新的临床用途，开发出溴氧喹啉对曲霉属致病菌(包括敏感烟曲霉菌和耐伊曲康唑烟曲霉菌)表现出良好的抗菌活性。
本申请提供了一种有效抑制包括敏感烟曲霉和耐伊曲康唑烟曲霉在内的真菌的生长从而发挥抗菌活性的化合物溴氧喹啉，因此，本发明筛选出溴氧喹啉可用于制备真菌抑制剂。
作为优选方案，将溴氧喹啉与药学上可接受的载体制备成片剂、颗粒剂、胶囊剂、丸剂、散剂、膏剂、口服液、注射剂、凝胶剂或乳膏。
有益效果：本发明通过筛选实验发现，溴氧喹啉对敏感烟曲霉、耐伊曲康唑烟曲霉的最低抑菌浓度MIC都是1μg/ml。而对照药物伊曲康唑对敏感烟曲霉、耐伊曲康唑烟曲霉的最低抑菌浓度MIC分别为1μg/ml、＞16μg/ml。这说明溴氧喹啉具有良好的抗烟曲霉真菌效果，尤其是对耐药烟曲霉菌具有很好的抗菌活性。烟曲霉是重要的引发临床发生真菌感染的致病菌，本发明具有重要的临床意义。
附图说明
图1溴氧喹啉对耐伊曲康唑烟曲霉生长抑制作用。
具体实施方式
本发明通过大量实验筛选，发现溴氧喹啉可以体外抑制敏感烟曲霉、耐伊曲康唑烟曲霉的生长。下面结合具体实施对本发明作进一步阐述，但这些实施例不应解释为限制本发明。
实施例1溴氧喹啉显著抑制耐伊曲康唑烟曲霉的生长。
测试的化合物：溴氧喹啉。
检测方法：收集耐伊曲康唑烟曲霉菌株Afcyp51AG54W的菌悬液，将其稀释浓度104，取2μl菌悬液接种到无药培养基和含药培养基(含12μg/ml溴氧喹啉)，37℃培养48h后观察菌落生长。具体实验结果如图1所示，溴氧喹啉显著抑制耐伊曲康唑烟曲霉的生长。
实施例2溴氧喹啉对敏感烟曲霉、耐伊曲康唑烟曲霉的体外最低抑菌浓度MIC。
测试的化合物：溴氧喹啉。
MIC是指最低抑菌浓度，是测量抗菌药物的抗菌活性大小的一个指标，指在体外培养真菌48小时后能抑制培养基内病原菌生长的最低药物浓度。
MIC测定方法：测定选用的真菌包括1个敏感烟曲霉、6个耐伊曲康唑烟曲霉。临床现有抗真菌药物伊曲康唑作为阳性对照药。参照CLSI(美国临床标准协会)M38-A2指南采用微量肉汤稀释法对溴氧喹啉进行了抗菌活性和最低抑菌浓度的测定。新鲜菌悬液悬浮于液体培养基，然后转移至含有待测化合物(溴氧喹啉)的96孔板。第一孔为待测化合物最高浓度均为16μg/ml，浓度依次倍半稀释，第8孔待测化合物最低浓度均为0.125μg/ml，第9孔为菌液作为生长阳性对照，第10孔只加培养基作为空白阴性对照，37℃培养48h，菌液完全澄清的最低化合物浓度可认为是最低抑菌浓度。溴氧喹啉对敏感烟曲霉、耐伊曲康唑烟曲霉的最低抑菌浓度MIC均为1μg/ml。具体实验结果如表1所示。
表1溴氧喹啉的抗菌活性
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。
Claims (5)
1.溴氧喹啉及其衍生物在制备抗菌药物中的应用。
2.根据权利要求1所述的应用，其特征在于，所述的致病菌包括曲霉属真菌。
3.根据权利要求2所述的应用，其特征在于，所述的曲霉属真菌包括敏感烟曲霉菌株和耐药烟曲霉菌株。
4.根据权利要求1～3任一项所述的应用，其特征在于，将溴氧喹啉及其衍生物与药学上可接受的载体制备成片剂、颗粒剂、胶囊剂、丸剂、散剂、膏剂、口服液、注射剂、凝胶剂或乳膏。
5.一种抗真菌的药物，奇特在于，它包括溴氧喹啉及其衍生物。
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2021
- 2021-12-31 CN CN202111658994.2A patent/CN114404416A/zh active Pending
Non-Patent Citations (2)
| Title |
|---|
| DAFNA BEN YAAKOV等: "The quinoline bromoquinol exhibits broad-spectrum antifungal activity and induces oxidative stress and apoptosis in Aspergillus fumigates", 《JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY》 * |
| SÉBASTIEN C. ORTIZ: "Spore Germination as a Target for Antifungal Therapeutics", 《ANTIMICROBIAL AGENTS AND CHEMOTHERAPY》 * |
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