CN106518861B - 含苯并杂环取代的n-酰基高丝氨酸内酯类化合物、其制备方法及应用 - Google Patents
含苯并杂环取代的n-酰基高丝氨酸内酯类化合物、其制备方法及应用 Download PDFInfo
- Publication number
- CN106518861B CN106518861B CN201610986981.0A CN201610986981A CN106518861B CN 106518861 B CN106518861 B CN 106518861B CN 201610986981 A CN201610986981 A CN 201610986981A CN 106518861 B CN106518861 B CN 106518861B
- Authority
- CN
- China
- Prior art keywords
- acyl homoserine
- homoserine lactones
- class compound
- replaced containing
- benzheterocycle
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 43
- UKAUYVFTDYCKQA-UHFFFAOYSA-N -2-Amino-4-hydroxybutanoic acid Natural products OC(=O)C(N)CCO UKAUYVFTDYCKQA-UHFFFAOYSA-N 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 230000018612 quorum sensing Effects 0.000 claims abstract description 9
- 230000000844 anti-bacterial effect Effects 0.000 claims abstract description 6
- 229960001082 trimethoprim Drugs 0.000 claims abstract description 6
- IEDVJHCEMCRBQM-UHFFFAOYSA-N trimethoprim Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 IEDVJHCEMCRBQM-UHFFFAOYSA-N 0.000 claims abstract description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- 239000003054 catalyst Substances 0.000 claims description 12
- LRWGOVMIZOIYFL-UHFFFAOYSA-N oxolan-2-ylidenemethanone Chemical compound O=C=C1CCCO1 LRWGOVMIZOIYFL-UHFFFAOYSA-N 0.000 claims description 12
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 12
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 10
- -1 2- sulfydryl benzo thiophene Azoles Chemical class 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 9
- YXIWHUQXZSMYRE-UHFFFAOYSA-N 1,3-benzothiazole-2-thiol Chemical compound C1=CC=C2SC(S)=NC2=C1 YXIWHUQXZSMYRE-UHFFFAOYSA-N 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 claims description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 8
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 claims description 8
- 229940079593 drug Drugs 0.000 claims description 6
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical class CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 4
- 235000019441 ethanol Nutrition 0.000 claims description 4
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 4
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 claims description 4
- 229940080818 propionamide Drugs 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 235000009518 sodium iodide Nutrition 0.000 claims description 4
- 239000004615 ingredient Substances 0.000 claims description 3
- ASSKVPFEZFQQNQ-UHFFFAOYSA-N 2-benzoxazolinone Chemical compound C1=CC=C2OC(O)=NC2=C1 ASSKVPFEZFQQNQ-UHFFFAOYSA-N 0.000 claims description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims 3
- CGKQZIULZRXRRJ-UHFFFAOYSA-N Butylone Chemical compound CCC(NC)C(=O)C1=CC=C2OCOC2=C1 CGKQZIULZRXRRJ-UHFFFAOYSA-N 0.000 claims 3
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims 3
- 235000017557 sodium bicarbonate Nutrition 0.000 claims 3
- 150000003851 azoles Chemical class 0.000 claims 1
- 239000000470 constituent Substances 0.000 claims 1
- 239000000825 pharmaceutical preparation Substances 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 7
- 229940124350 antibacterial drug Drugs 0.000 abstract description 5
- 239000002246 antineoplastic agent Substances 0.000 abstract description 5
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 5
- 239000006125 LAS system Substances 0.000 abstract description 4
- 238000012360 testing method Methods 0.000 abstract description 4
- 241000589517 Pseudomonas aeruginosa Species 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 3
- 238000000338 in vitro Methods 0.000 abstract description 2
- 238000010791 quenching Methods 0.000 abstract description 2
- 238000006467 substitution reaction Methods 0.000 abstract description 2
- 238000010189 synthetic method Methods 0.000 abstract description 2
- 229910052799 carbon Inorganic materials 0.000 description 10
- 229910052760 oxygen Inorganic materials 0.000 description 8
- 229910052717 sulfur Inorganic materials 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 229910052698 phosphorus Inorganic materials 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- DPGLBHQUHFJRJS-RQOWECAXSA-N (5z)-4-bromo-5-(bromomethylidene)furan-2-one Chemical compound Br\C=C1/OC(=O)C=C1Br DPGLBHQUHFJRJS-RQOWECAXSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 150000004780 naphthols Chemical class 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 2
- FLFWJIBUZQARMD-UHFFFAOYSA-N 2-mercapto-1,3-benzoxazole Chemical compound C1=CC=C2OC(S)=NC2=C1 FLFWJIBUZQARMD-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 230000000994 depressogenic effect Effects 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229960001866 silicon dioxide Drugs 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 101150079123 Bad gene Proteins 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- QJPWUUJVYOJNMH-VKHMYHEASA-N L-homoserine lactone Chemical compound N[C@H]1CCOC1=O QJPWUUJVYOJNMH-VKHMYHEASA-N 0.000 description 1
- 241000960592 Pseudomonas aeruginosa group Species 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 230000029918 bioluminescence Effects 0.000 description 1
- 238000005415 bioluminescence Methods 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000011221 initial treatment Methods 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 208000013223 septicemia Diseases 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明属于药物化学领域，公开了一类具有细菌群体感应抑制活性的含苯并杂环取代的N‑酰基高丝氨酸内酯类化合物、其合成方法及其应用。其制备方法简单，条件温和，收率高。体外活性试验结果表明,本发明含苯并杂环取代的N‑酰基高丝氨酸内酯化合物对铜绿假单胞菌LAS系统和PQS系统具有明显的抑制作用，可应用于制备抗细菌群体感应、抗菌增效剂、抗菌或抗肿瘤药物。其化学结构通式如下：
Description
技术领域
本发明涉及一类新型含苯并杂环取代的N-酰基高丝氨酸内酯类化合物、其制备方法及应用，属于药物化学领域。
背景技术
在菌群生长过程中，细菌能够不断产生化学信号分子并分泌到周围环境中，当信号分子的浓度达到一定阈值时，就会调控或启动菌体相关基因的表达如生物发光、生物被膜的形成、毒性基因的表达等，以适应环境的变化，这一调控系统被称为细菌的群体感应(QS)信号系统。
20世纪70年代末，科学家们发现利用天然的或者人工合成的群体感应调节剂包括激动剂或抑制剂可以干扰信号系统的传导，调节细菌不良基因的表达。细菌群体感应调节剂不干扰体内细胞的正常生理功能，只是通过调节病原菌有害基因的表达，从而使其失去致病能力，因此被视为抗菌药发展的新方向，其中细菌群体感应抑制剂可以与抗生素联合用药，提高致病细菌对抗生素的敏感性，增强药物疗效，主要治疗多种革兰氏阴性菌引起的如腹泻、败血症等疾病。对高丝氨酸内酯的酰基侧链进行修饰，合成含苯并杂环类结构的衍生物，研究其群体感应抑制活性，对进一步研究新型抗细菌群体感应、抗菌增效剂、抗菌或抗肿瘤药物，开发自主知识产权药物具有重要意义，目前未见相关文献报道。
发明内容
本发明目的在于提供一类具有较好抗细菌群体感应活性的含苯并杂环取代的N-酰基高丝氨酸内酯类化合物。
本发明的另一个目的是提供其合成新方法。本发明再一个目的是提供所述化合物在制备抗细菌群体感应、抗菌增效剂、抗菌或抗肿瘤药物方面的应用。
为实现本发明目的,技术方案如下：
所述含苯并杂环取代的N-酰基高丝氨酸内酯类化合物具有如下结构通式：
其中n为含有1～12个碳原子的直链或支链烷基；
X为S、O、P、N或C；Y为S、O、P、N或C；R为P、N或C。
优选如下化合物：
n为含有1～6个碳原子的直链烷基；X为S或O；Y为S或O；R为N。
更优选如下化合物：
n为含有1～2个碳原子的直链烷基；X为S或O；Y为S或O；R为N。
优选如下具体化合物：
本发明提供的上述化合物的制备方法，通过以下反应路线实现：
将氯代酰化高丝氨酸内酯1溶于有机溶剂中，加热至40℃～120℃，加入化合物2和催化剂进行反应得到通式3所示的含苯并杂环类N-酰基高丝氨酸内酯类化合物。
所用的氯代酰化高丝氨酸内酯1为：n为含有1～12个碳原子的直链或支链烷基；
所用的化合物2为：X为S、O、P、N或C；Y为S、O、P、N或C；R为P、N或C。
所用的催化剂为碘化钾，碘化钠，溴化钾，溴化钠，碳酸钾，碳酸钠，碳酸氢钾，碳酸氢钠中的一种或两种；
所用的有机溶剂为甲醇、乙醇、乙腈、丙酮、甲酸甲酯、甲酸乙酯、乙酸乙酯、乙酸丁酯、二氯甲烷、二氯乙烷中的一种或两种；
投料摩尔比为氯代酰化高丝氨酸内酯1：化合物2：催化剂＝1：1.1～2：0.05～3；反应时间为2～40小时。
本发明提供的含苯并杂环取代的N-酰基高丝氨酸内酯类化合物的制备方法简单,条件温和,收率高,总收率达70％以上，可以方便地制备含苯并杂环取代的N-酰基高丝氨酸内酯类化合物。体外活性评价试验结果表明,本发明提供的含苯并杂环取代的N-酰基高丝氨酸内酯类化合物对细菌群体感应具有明显的抑制作用,因此可应用于制备抗细菌群体感应、抗菌增效剂、抗菌或抗肿瘤药物。
具体实施方式
下面结合实施例对本发明做进一步描述。
实施例1：制备通式3所示的衍生物(3-a)
将化合物(S)-2-氯-N-(2-羰基四氢呋喃-3-基)乙酰胺(150mg，0.84mmol)，碳酸钾(116mg，0.84mmol)溶于10mL乙腈中，加热至80℃后，加入2-巯基苯并噻唑(140mg，0.84mmol)，,恒温反应3h后，TLC跟踪反应完毕，抽滤，除去碳酸钾，减压蒸干溶剂，硅胶柱色谱分离(洗脱剂：乙酸乙酯/石油醚＝2/1)，得到类白色固体，即化合物(3-a)191mg，产率74％。
实施例2：制备通式3所示的衍生物(3-b)
将化合物(S)-2-氯-N-(2-羰基四氢呋喃-3-基)乙酰胺(150mg，0.84mmol)，碳酸钾(116mg，0.84mmol)溶于10mL乙腈中，加热至80℃后，加入2-巯基苯并恶唑(127mg，0.84mmol)，,恒温反应4h后，TLC跟踪反应完毕，抽滤，除去碳酸钾，减压蒸干溶剂，硅胶柱色谱分离(洗脱剂：乙酸乙酯/石油醚＝2/1)，得到类白色固体，即化合物(3-b)179mg，产率73％。
实施例3：制备通式3所示的衍生物(3-c、3-d、3-e、3-f)
采用2-羟基苯并噻唑替代2-巯基苯并噻唑，用实施例1同样的方法制备化合物3-c。
采用2-羟基苯并恶唑替代2-巯基苯并恶唑，用实施例1同样的方法制备化合物3-d。
采用化合物(S)-2-氯-N-(2-羰基四氢呋喃-3-基)丙酰胺替代化合物(S)-2-氯-N-(2-羰基四氢呋喃-3-基)乙酰胺，用实施例1同样的方法制备化合物3-e。
采用化合物(S)-2-氯-N-(2-羰基四氢呋喃-3-基)丙酰胺替代化合物(S)-2-氯-N-(2-羰基四氢呋喃-3-基)乙酰胺，，用实施例2同样的方法制备化合物3-f。
本发明合成的部分优选化合物的化学结构,核磁数据如下表1：
实施例4：本发明化合物体外抗群体感应筛选试验
利用铜绿假单胞菌LAS系统检测模型PAO MWI(QSIS-lasI)和PQS系统检测模型PQSI-pqsA，用呋喃酮C30和萘酚为试验的阳性对照,测得部分化合物抗铜绿假单胞菌群体感应的IC50值。见表2。
表2本发明化合物对铜绿假单胞菌LAS和PQS系统的活性(IC50)
注：a.NS表明没有显著抑制活性；b.呋喃酮C30作为LAS系统检测阳性对照,甲醇作为阴性对照；c.萘酚作为PQS系统检测的阳性对照，乙腈作为阴性对照。
实验结果表明：化合物3-a、3-e的LAS系统抑制活性优于对照药呋喃酮C30；化合物3-a、3-d、3-e的PQS系统抑制活性优于对照药萘酚。将这些化合物进一步开发，可作为活性成分或与其他药物组合，与制药中可以接受的辅助和/或添加成分混合后，按常规制药方法和工艺要求，可制成用于抗细菌群体感应、抗菌增效剂、抗菌或抗肿瘤的药物制剂。
Claims (10)
1.含苯并杂环取代的N-酰基高丝氨酸内酯类化合物，其特征在于：具有如下所示结构：
。
2.含苯并杂环取代的N-酰基高丝氨酸内酯类化合物，其特征在于：具有如下所示结构：
。
3.含苯并杂环取代的N-酰基高丝氨酸内酯类化合物，其特征在于：具有如下所示结构：
。
4.制备权利要求1所述的含苯并杂环取代的N-酰基高丝氨酸内酯类化合物的方法，其特征在于：通过以下步骤实现：
将(S)-2-氯-N-(2-羰基四氢呋喃-3-基)乙酰胺溶于有机溶剂中，加热至40℃~ 120℃，加入2-巯基苯并噻唑和催化剂进行反应得到；
所用的催化剂为碘化钾，碘化钠，溴化钾，溴化钠，碳酸钾，碳酸钠，碳酸氢钾，碳酸氢钠中的一种或两种；
所用的有机溶剂为甲醇、乙醇、乙腈、丙酮、甲酸甲酯、甲酸乙酯、乙酸乙酯、乙酸丁酯、二氯甲烷、二氯乙烷中的一种或两种。
5.根据权利要求4所述的制备含苯并杂环取代的N-酰基高丝氨酸内酯类化合物的方法，其特征在于：投料摩尔比为(S)-2-氯-N-(2-羰基四氢呋喃-3-基)乙酰胺：2-巯基苯并噻唑：催化剂=1：1.1 ~ 2：0.05 ~ 3。
6.制备权利要求2所述的含苯并杂环取代的N-酰基高丝氨酸内酯类化合物的方法，其特征在于：通过以下步骤实现：
将(S)-2-氯-N-(2-羰基四氢呋喃-3-基)乙酰胺溶于有机溶剂中，加热至40℃~ 120℃，加入2-羟基苯并恶唑和催化剂进行反应得到；
所用的催化剂为碘化钾，碘化钠，溴化钾，溴化钠，碳酸钾，碳酸钠，碳酸氢钾，碳酸氢钠中的一种或两种；
所用的有机溶剂为甲醇、乙醇、乙腈、丙酮、甲酸甲酯、甲酸乙酯、乙酸乙酯、乙酸丁酯、二氯甲烷、二氯乙烷中的一种或两种。
7.根据权利要求6所述的制备含苯并杂环取代的N-酰基高丝氨酸内酯类化合物的方法，其特征在于：投料摩尔比为(S)-2-氯-N-(2-羰基四氢呋喃-3-基)乙酰胺：2-羟基苯并恶唑：催化剂=1：1.1 ~ 2：0.05 ~ 3。
8.制备权利要求3所述的含苯并杂环取代的N-酰基高丝氨酸内酯类化合物的方法，其特征在于：通过以下步骤实现：
将(S)-2-氯-N-(2-羰基四氢呋喃-3-基)丙酰胺溶于有机溶剂中，加热至40℃~ 120℃，加入2-巯基苯并噻唑和催化剂进行反应得到；
所用的催化剂为碘化钾，碘化钠，溴化钾，溴化钠，碳酸钾，碳酸钠，碳酸氢钾，碳酸氢钠中的一种或两种；
所用的有机溶剂为甲醇、乙醇、乙腈、丙酮、甲酸甲酯、甲酸乙酯、乙酸乙酯、乙酸丁酯、二氯甲烷、二氯乙烷中的一种或两种。
9.根据权利要求8所述的制备含苯并杂环取代的N-酰基高丝氨酸内酯类化合物的方法，其特征在于：投料摩尔比为(S)-2-氯-N-(2-羰基四氢呋喃-3-基)丙酰胺：2-巯基苯并噻唑：催化剂=1：1.1 ~ 2：0.05 ~ 3。
10.根据权利要求1~3任一项所述的含苯并杂环取代的N-酰基高丝氨酸内酯类化合物在制备药物中的应用，其特征在于：将其作为活性成分或与其他药物组合，与药物中可接受的辅助和/或添加成分混合后，制成用于抗细菌群体感应、抗菌增效剂或抗菌的药物制剂。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610986981.0A CN106518861B (zh) | 2016-11-01 | 2016-11-01 | 含苯并杂环取代的n-酰基高丝氨酸内酯类化合物、其制备方法及应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610986981.0A CN106518861B (zh) | 2016-11-01 | 2016-11-01 | 含苯并杂环取代的n-酰基高丝氨酸内酯类化合物、其制备方法及应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106518861A CN106518861A (zh) | 2017-03-22 |
| CN106518861B true CN106518861B (zh) | 2019-03-26 |
Family
ID=58350988
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610986981.0A Active CN106518861B (zh) | 2016-11-01 | 2016-11-01 | 含苯并杂环取代的n-酰基高丝氨酸内酯类化合物、其制备方法及应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106518861B (zh) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107098874B (zh) * | 2017-06-21 | 2019-04-30 | 郑州大学 | 含苯基脲取代的n-硫代酰基高丝氨酸内酯类化合物、其制备方法及应用 |
| CN108513982B (zh) * | 2018-04-14 | 2020-10-23 | 华南农业大学 | Ahl分子作为化学农药杀菌增效剂在青枯病菌引起的病害防治中的应用 |
| CN108575999B (zh) * | 2018-04-14 | 2020-10-23 | 华南农业大学 | Ahl分子作为化学农药杀菌增效剂在洋葱伯克霍尔德氏菌引起的植物病害防治中的应用 |
| CN108947928B (zh) * | 2018-07-03 | 2022-05-20 | 江苏大学 | 含氮、氧、氧三取代六元环内脂化合物及制备方法和用途 |
| CN111303073B (zh) * | 2020-03-07 | 2022-03-29 | 内蒙古工业大学 | 利用苯并噻唑酮与2-卤代-n-甲基-n-苯基乙酰胺制备农药苯噻草胺的方法 |
| CN112043697B (zh) * | 2020-08-05 | 2022-02-22 | 华南农业大学 | 苯并噻唑化合物作为群体感应抑制剂在治疗细菌病害中的应用 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104356099B (zh) * | 2014-11-19 | 2016-05-11 | 郑州大学 | 高丝氨酸内酯类化合物、其制备方法及其应用 |
-
2016
- 2016-11-01 CN CN201610986981.0A patent/CN106518861B/zh active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104356099B (zh) * | 2014-11-19 | 2016-05-11 | 郑州大学 | 高丝氨酸内酯类化合物、其制备方法及其应用 |
Non-Patent Citations (5)
| Title |
|---|
| Margrith E. Mattmann，等.Small Molecules That Modulate Quorum Sensing and Control Virulence in Pseudomonas aeruginosa.《J. Org. Chem.》.2010,第75卷第6737–6746页. * |
| RN：1008479-88-6;CHEMICAL ABSTRACTS SERVICE;《CHEMICAL ABSTRACTS》;20080317 * |
| RN：1024719-10-5;CHEMICAL ABSTRACTS SERVICE;《CHEMICAL ABSTRACTS》;20080602 * |
| Small Molecules That Modulate Quorum Sensing and Control Virulence in Pseudomonas aeruginosa;Margrith E. Mattmann，等;《J. Org. Chem.》;20100730;第75卷;第6737–6746页 * |
| Thiolactone modulators of quorum sensing revealed through library design and screening;Christine E. McInnis,等;《Bioorganic & Medicinal Chemistry》;20110815;第19卷(第16期);第4820–4828页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106518861A (zh) | 2017-03-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106518861B (zh) | 含苯并杂环取代的n-酰基高丝氨酸内酯类化合物、其制备方法及应用 | |
| Teng et al. | Facilely accessible quinoline derivatives as potent antibacterial agents | |
| Chimenti et al. | Synthesis, selective anti-Helicobacter pylori activity, and cytotoxicity of novel N-substituted-2-oxo-2H-1-benzopyran-3-carboxamides | |
| Joao Matos et al. | Looking for new targets: simple coumarins as antibacterial agents | |
| Scopel et al. | Dipeptide cis-cyclo (Leucyl-Tyrosyl) produced by sponge associated Penicillium sp. F37 inhibits biofilm formation of the pathogenic Staphylococcus epidermidis | |
| Alper-Hayta et al. | Synthesis, antimicrobial activity, pharmacophore analysis of some new 2-(substitutedphenyl/benzyl)-5-[(2-benzofuryl) carboxamido] benzoxazoles | |
| Chakraborty et al. | Bacillibactin class of siderophore antibiotics from a marine symbiotic Bacillus as promising antibacterial agents | |
| Qu et al. | A new coumarin compound DCH combats methicillin-resistant Staphylococcus aureus biofilm by targeting arginine repressor | |
| Xu et al. | Discovery and development of DNA polymerase IIIC inhibitors to treat Gram-positive infections | |
| Vik et al. | (+)-Agelasine D: improved synthesis and evaluation of antibacterial and cytotoxic activities | |
| CN102229580B (zh) | 新型截短侧耳素衍生物、其制备方法及其医药用途 | |
| CN106749119B (zh) | 含苯环类取代的n-酰基高丝氨酸内酯类化合物、其制备方法及应用 | |
| PT1286998E (pt) | Derivados da oxazolidinona com actividade antibiotica | |
| CN101232884A (zh) | 作为抗菌剂的喹啉衍生物 | |
| CN104224775B (zh) | 一种包含四苯乙烯衍生物的药物组合物 | |
| JP2008528582A (ja) | １８員大環状化合物及びその類似化合物 | |
| Balasubramanian et al. | Synthesis and study of antibacterial and antifungal activities of novel 8-methyl-7, 9-diaryl-1, 2, 4, 8-tetraazaspiro [4.5] decan-3-thiones | |
| AU2014315045A1 (en) | Antimicrobial compounds and methods of making and using the same | |
| WO2011153310A1 (en) | Dihydrofolate reductase inhibitors | |
| Khan et al. | Synthesis, biological evaluations and computational studies of N-(3-(-2-(7-Chloroquinolin-2-yl) vinyl) benzylidene) anilines as fungal biofilm inhibitors | |
| CN106749213B (zh) | 一种具有1,2,4-恶二唑结构的吲哚衍生物及制备方法和在制备抗菌药物中的应用 | |
| Sulaiman et al. | Antimicrobial and biofilm-preventing activity of l-borneol possessing 2 (5 H)-furanone derivative F131 against S. aureus—C. albicans mixed cultures | |
| JP3274854B2 (ja) | 抗菌性ペネムエステル誘導体 | |
| Majed et al. | Structure-activity relationships of pyrazole-4-carbodithioates as antibacterials against methicillin–resistant Staphylococcus aureus | |
| CN107098874B (zh) | 含苯基脲取代的n-硫代酰基高丝氨酸内酯类化合物、其制备方法及应用 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20240429 Address after: Building 2, Chuangye Street, Zhengzhou University Science and Technology Park, No. 100 Cuizhu Street, High tech Zone, Zhengzhou City, Henan Province, 450001 Patentee after: Henan Qunbo Pharmaceutical Research Institute Co.,Ltd. Country or region after: China Address before: 450001 No. 100 science Avenue, hi tech Zone, Henan, Zhengzhou Patentee before: Zhengzhou University Country or region before: China |