CN116217547B - Substituted isatin-8-hydroxyquinoline derivative and preparation method and application thereof - Google Patents
Substituted isatin-8-hydroxyquinoline derivative and preparation method and application thereof Download PDFInfo
- Publication number
- CN116217547B CN116217547B CN202310140658.1A CN202310140658A CN116217547B CN 116217547 B CN116217547 B CN 116217547B CN 202310140658 A CN202310140658 A CN 202310140658A CN 116217547 B CN116217547 B CN 116217547B
- Authority
- CN
- China
- Prior art keywords
- isatin
- hydroxyquinoline derivative
- substituted isatin
- hydroxyquinoline
- substituted
- 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
- -1 isatin-8-hydroxyquinoline derivative Chemical class 0.000 title claims abstract description 97
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 239000003814 drug Substances 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims description 35
- 238000006467 substitution reaction Methods 0.000 claims description 8
- 230000003078 antioxidant effect Effects 0.000 claims description 6
- 229910052751 metal Inorganic materials 0.000 claims description 6
- 239000002184 metal Substances 0.000 claims description 6
- CTQMJYWDVABFRZ-UHFFFAOYSA-N cloxiquine Chemical compound C1=CN=C2C(O)=CC=C(Cl)C2=C1 CTQMJYWDVABFRZ-UHFFFAOYSA-N 0.000 claims description 5
- 239000003963 antioxidant agent Substances 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 239000008139 complexing agent Substances 0.000 claims description 2
- 229940052764 dopaminergic anti-parkinson drug mao b inhibitors Drugs 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 25
- 208000024827 Alzheimer disease Diseases 0.000 abstract description 24
- 102000010909 Monoamine Oxidase Human genes 0.000 abstract description 21
- 108010062431 Monoamine oxidase Proteins 0.000 abstract description 21
- 230000005764 inhibitory process Effects 0.000 abstract description 15
- 238000006243 chemical reaction Methods 0.000 abstract description 12
- 229940079593 drug Drugs 0.000 abstract description 12
- 229910021645 metal ion Inorganic materials 0.000 abstract description 11
- 201000010099 disease Diseases 0.000 abstract description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 5
- 238000011160 research Methods 0.000 abstract description 5
- 230000001225 therapeutic effect Effects 0.000 abstract description 5
- 230000007246 mechanism Effects 0.000 abstract description 4
- 230000003647 oxidation Effects 0.000 abstract description 4
- 238000007254 oxidation reaction Methods 0.000 abstract description 4
- 230000009920 chelation Effects 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 239000000203 mixture Substances 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 68
- JXDYKVIHCLTXOP-UHFFFAOYSA-N isatin Chemical compound C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 0.000 description 34
- 239000000243 solution Substances 0.000 description 32
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 17
- 238000005160 1H NMR spectroscopy Methods 0.000 description 17
- 230000015572 biosynthetic process Effects 0.000 description 17
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 17
- 238000003786 synthesis reaction Methods 0.000 description 17
- SJALPCXFOSGNST-UHFFFAOYSA-N 1-(2-bromoethyl)indole-2,3-dione Chemical compound C1=CC=C2N(CCBr)C(=O)C(=O)C2=C1 SJALPCXFOSGNST-UHFFFAOYSA-N 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- 239000000523 sample Substances 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- GLEVLJDDWXEYCO-UHFFFAOYSA-N Trolox Chemical compound O1C(C)(C(O)=O)CCC2=C1C(C)=C(C)C(O)=C2C GLEVLJDDWXEYCO-UHFFFAOYSA-N 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- 238000012360 testing method Methods 0.000 description 7
- 239000012498 ultrapure water Substances 0.000 description 7
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- 239000008055 phosphate buffer solution Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 229910021642 ultra pure water Inorganic materials 0.000 description 6
- LXEKPEMOWBOYRF-QDBORUFSSA-N AAPH Chemical compound Cl.Cl.NC(=N)C(C)(C)\N=N\C(C)(C)C(N)=N LXEKPEMOWBOYRF-QDBORUFSSA-N 0.000 description 5
- 230000007131 anti Alzheimer effect Effects 0.000 description 5
- 230000003064 anti-oxidating effect Effects 0.000 description 5
- 238000011161 development Methods 0.000 description 5
- 230000018109 developmental process Effects 0.000 description 5
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 5
- 210000002569 neuron Anatomy 0.000 description 5
- RLFWWDJHLFCNIJ-UHFFFAOYSA-N 4-aminoantipyrine Chemical compound CN1C(C)=C(N)C(=O)N1C1=CC=CC=C1 RLFWWDJHLFCNIJ-UHFFFAOYSA-N 0.000 description 4
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000001963 growth medium Substances 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000012488 sample solution Substances 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- LHXOCOHMBFOVJS-OAHLLOKOSA-N Ladostigil Chemical compound CCN(C)C(=O)OC1=CC=C2CC[C@@H](NCC#C)C2=C1 LHXOCOHMBFOVJS-OAHLLOKOSA-N 0.000 description 3
- 238000002835 absorbance Methods 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 239000001110 calcium chloride Substances 0.000 description 3
- 229910001628 calcium chloride Inorganic materials 0.000 description 3
- 239000000544 cholinesterase inhibitor Substances 0.000 description 3
- 238000010668 complexation reaction Methods 0.000 description 3
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 3
- 229910000366 copper(II) sulfate Inorganic materials 0.000 description 3
- NJDNXYGOVLYJHP-UHFFFAOYSA-L disodium;2-(3-oxido-6-oxoxanthen-9-yl)benzoate Chemical compound [Na+].[Na+].[O-]C(=O)C1=CC=CC=C1C1=C2C=CC(=O)C=C2OC2=CC([O-])=CC=C21 NJDNXYGOVLYJHP-UHFFFAOYSA-L 0.000 description 3
- 229940088598 enzyme Drugs 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 229950008812 ladostigil Drugs 0.000 description 3
- 239000008363 phosphate buffer Substances 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 239000011550 stock solution Substances 0.000 description 3
- 102000013498 tau Proteins Human genes 0.000 description 3
- 108010026424 tau Proteins Proteins 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 description 3
- 229910000368 zinc sulfate Inorganic materials 0.000 description 3
- 239000011686 zinc sulphate Substances 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 2
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- DZGWFCGJZKJUFP-UHFFFAOYSA-N Tyramine Natural products NCCC1=CC=C(O)C=C1 DZGWFCGJZKJUFP-UHFFFAOYSA-N 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 238000004220 aggregation Methods 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- 230000001713 cholinergic effect Effects 0.000 description 2
- 230000000536 complexating effect Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 210000003061 neural cell Anatomy 0.000 description 2
- 230000016273 neuron death Effects 0.000 description 2
- 230000008506 pathogenesis Effects 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- YQUVCSBJEUQKSH-UHFFFAOYSA-N protochatechuic acid Natural products OC(=O)C1=CC=C(O)C(O)=C1 YQUVCSBJEUQKSH-UHFFFAOYSA-N 0.000 description 2
- 239000003642 reactive oxygen metabolite Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 229960003732 tyramine Drugs 0.000 description 2
- DZGWFCGJZKJUFP-UHFFFAOYSA-O tyraminium Chemical compound [NH3+]CCC1=CC=C(O)C=C1 DZGWFCGJZKJUFP-UHFFFAOYSA-O 0.000 description 2
- WKOLLVMJNQIZCI-UHFFFAOYSA-N vanillic acid Chemical compound COC1=CC(C(O)=O)=CC=C1O WKOLLVMJNQIZCI-UHFFFAOYSA-N 0.000 description 2
- TUUBOHWZSQXCSW-UHFFFAOYSA-N vanillic acid Natural products COC1=CC(O)=CC(C(O)=O)=C1 TUUBOHWZSQXCSW-UHFFFAOYSA-N 0.000 description 2
- PPYSLDNXRTVLAJ-UHFFFAOYSA-N 1-(2-bromoethyl)-5-methoxyindole-2,3-dione Chemical compound COC1=CC=C2N(CCBr)C(=O)C(=O)C2=C1 PPYSLDNXRTVLAJ-UHFFFAOYSA-N 0.000 description 1
- PEIZUEQKUGACKB-UHFFFAOYSA-N 1-(3-bromopropyl)indole-2,3-dione Chemical compound C1=CC=C2N(CCCBr)C(=O)C(=O)C2=C1 PEIZUEQKUGACKB-UHFFFAOYSA-N 0.000 description 1
- FPIVKSNMTRBVNP-UHFFFAOYSA-N 1-(4-bromobutyl)-5-chloroindole-2,3-dione Chemical compound ClC1=CC=C2N(CCCCBr)C(=O)C(=O)C2=C1 FPIVKSNMTRBVNP-UHFFFAOYSA-N 0.000 description 1
- YVKQIZORCPVLTC-UHFFFAOYSA-N 1-(4-bromobutyl)indole-2,3-dione Chemical compound C1=CC=C2N(CCCCBr)C(=O)C(=O)C2=C1 YVKQIZORCPVLTC-UHFFFAOYSA-N 0.000 description 1
- MRJNZXQDDUJUER-UHFFFAOYSA-N 1-(5-bromopentyl)-5-methoxyindole-2,3-dione Chemical compound COC1=CC=C2N(CCCCCBr)C(=O)C(=O)C2=C1 MRJNZXQDDUJUER-UHFFFAOYSA-N 0.000 description 1
- BVBQSSIJIDHTIG-UHFFFAOYSA-N 1-(5-bromopentyl)indole-2,3-dione Chemical compound C1=CC=C2N(CCCCCBr)C(=O)C(=O)C2=C1 BVBQSSIJIDHTIG-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- SEOLJSWXRCEQBJ-UHFFFAOYSA-N 5-bromo-1-(3-bromopropyl)indole-2,3-dione Chemical compound BrC1=CC=C2N(CCCBr)C(=O)C(=O)C2=C1 SEOLJSWXRCEQBJ-UHFFFAOYSA-N 0.000 description 1
- OPQMFMSDHIAPMG-UHFFFAOYSA-N 5-bromo-1-(4-bromobutyl)indole-2,3-dione Chemical compound BrC1=CC=C2N(CCCCBr)C(=O)C(=O)C2=C1 OPQMFMSDHIAPMG-UHFFFAOYSA-N 0.000 description 1
- VFVFTDNTEZOZRZ-UHFFFAOYSA-N 5-bromo-1-(5-bromopentyl)indole-2,3-dione Chemical compound BrC1=CC=C2N(CCCCCBr)C(=O)C(=O)C2=C1 VFVFTDNTEZOZRZ-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 208000037259 Amyloid Plaque Diseases 0.000 description 1
- 102000013455 Amyloid beta-Peptides Human genes 0.000 description 1
- 108010090849 Amyloid beta-Peptides Proteins 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 208000023105 Huntington disease Diseases 0.000 description 1
- 208000036110 Neuroinflammatory disease Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000006933 amyloid-beta aggregation Effects 0.000 description 1
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 210000003710 cerebral cortex Anatomy 0.000 description 1
- 208000013677 cerebrovascular dementia Diseases 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 150000004696 coordination complex Chemical class 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000002888 effect on disease Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000003090 exacerbative effect Effects 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000003269 fluorescent indicator Substances 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 210000001320 hippocampus Anatomy 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 206010028417 myasthenia gravis Diseases 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 230000003959 neuroinflammation Effects 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000004792 oxidative damage Effects 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 238000005375 photometry Methods 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000010453 quartz Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 231100000041 toxicology testing Toxicity 0.000 description 1
- 238000002211 ultraviolet spectrum Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- 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
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Neurology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- Life Sciences & Earth Sciences (AREA)
- Neurosurgery (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Biomedical Technology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Psychology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of biological medicines, and particularly relates to a substituted isatin-8-hydroxyquinoline derivative, and a preparation method and application thereof. The composition has remarkable monoamine oxidase-B activity inhibition, oxidation resistance and metal ion chelation effects, and has therapeutic effects on diseases related to the mechanisms; particularly has remarkable treatment effect on a plurality of treatment targets of Alzheimer's disease, and has lower biotoxicity, high safety and higher medical research and market application value. On the other hand, the raw materials for the production are low, the reaction steps are few, the preparation method is simple, and the method is very suitable for large-scale industrial production.
Description
Technical Field
The invention belongs to the technical field of biological medicine. More particularly relates to a substituted isatin-8-hydroxyquinoline derivative, a preparation method and application thereof.
Background
Alzheimer's Disease (AD), commonly known as "senile dementia", is a chronic progressive degenerative disease of the central nervous system. With the development of society and the improvement of living standard of people, the world population is gradually aged, so the incidence rate of AD is gradually increased year by year, and the AD has become one of main diseases seriously threatening the life health and quality of life of the aged.
Current studies indicate that the main pathological feature of AD patients is the aggregation of β -amyloid (aβ) to senile plaques, abnormal aggregation of intracellular Tau protein to Neuronal Fiber Tangles (NFT) and neuronal death. However, the cause of the onset of AD has not been clarified so far, and it has been suggested that the cause of AD involves various causative factors; various relevant hypotheses have been proposed during the study in an attempt to explain the occurrence and development of the disease, including cholinergic hypothesis, amyloid cascade hypothesis, tau protein hypothesis, oxidative stress hypothesis, metal ion hypothesis, neuroinflammation hypothesis, and the like. For the different hypotheses described above, the prior art discloses a number of corresponding therapeutic strategies: for example, the development of cholinesterase inhibitors (ChEI) (CN 110627767 a) has been proposed to achieve therapeutic objectives by preventing excessive degradation of cholinergic neurotransmitters, and 3 of the drugs currently marketed for the treatment of AD belong to ChEI, indicating that this site is of great significance for the treatment of AD; the development of aβ aggregation inhibitors (CN 108926565A), antioxidants and anti-AD drugs targeting Tau protein (CN 110691594A) is also one of the important directions of current research; metal ion chelators developed based on the metal ion hypothesis (CN 115040514 a) are also considered as a potential therapeutic approach for AD. In addition, monoamine oxidase (MAO), and in particular monoamine oxidase B, has been found in recent years to be an important causative factor of AD, and numerous studies have shown that AD patients have significantly increased activity of MAO-B in the cerebral cortex and hippocampus, accompanied by increased production of hydrogen peroxide and Reactive Oxygen Species (ROS), exacerbating oxidative damage to nerve cells and leading to neuronal death; thus, inhibitors of MAO-B have also proven to be of great value in the treatment of AD, and related inhibitors of MAO-B have been developed for use in the treatment of AD (CN 113307806A).
Based on the complicated and closely related pathogenesis of AD, the current single-target drug treatment effect is not ideal, and more researches show that the drug which simultaneously acts on a plurality of targets related to diseases, namely the multi-target drug (MTDLs), can have better treatment effect and good treatment prospect. Thus, there is an urgent need to provide a multi-target therapeutic drug for AD.
Disclosure of Invention
The invention aims to overcome the defect and the defect of unsatisfactory curative effect of the existing single-target drug for treating AD, and provides a substituted isatin-8-hydroxyquinoline derivative with multi-target curative effect on AD.
The invention aims to provide a preparation method of the substituted isatin-8-hydroxyquinoline derivative.
It is another object of the present invention to provide the use of said substituted isatin-8-hydroxyquinoline derivatives.
The above object of the present invention is achieved by the following technical scheme:
A substituted isatin-8-hydroxyquinoline derivative having the structure of formula (I):
Wherein R is selected from one or more of hydrogen, halogen and C 1～5 alkoxy; n is a positive integer of 2 to 5.
Preferably, R is selected from one or more of hydrogen, halogen, methoxy; n is a positive integer of 2 to 5.
More preferably, the substituted isatin-8-hydroxyquinoline derivative has any one of the following structures:
further, pharmaceutically acceptable salts, solvates, enantiomers, diastereomers, and tautomers of the substituted isatin-8-hydroxyquinoline derivatives are also included.
In addition, the invention also provides a preparation method of the substituted isatin-8-hydroxyquinoline derivative, and the synthetic route is as follows:
The method specifically comprises the following steps:
s1, carrying out substitution reaction on a compound of the formula (II) and Br- (CH 2)n -Br) in an alkaline environment to obtain a compound of the formula (III);
S2, carrying out substitution reaction on the compound of the formula (III) obtained in the step S1 and 5-chloro-8-hydroxyquinoline under an alkaline condition to obtain a compound of the formula (I);
Wherein R, n is defined as above.
Further, in step S1, the alkaline environment is formed by adding one or more alkaline reagents selected from sodium hydroxide, cesium carbonate and potassium carbonate.
Further, in the step S1, the substitution reaction is carried out at 25-60 ℃ for 2-8 hours.
Further, in step S2, the alkaline environment is formed by adding one or more alkaline reagents selected from sodium hydroxide, cesium carbonate and potassium carbonate.
Further, in the step S2, the substitution reaction is carried out at 25-60 ℃ for 2-8 hours.
Further, in step S2, the substitution reaction is followed by column chromatography or recrystallization purification.
Experiments are carried out on the obtained substituted isatin-8-hydroxyquinoline derivative, and the result proves that the obtained substituted isatin-8-hydroxyquinoline derivative has remarkable monoamine oxidase-B activity inhibition, oxidation resistance and metal ion chelation effects.
The invention therefore claims the use of said substituted isatin-8-hydroxyquinoline derivatives for the preparation of monoamine oxidase-B inhibitors.
In addition, the invention also claims the use of said substituted isatin-8-hydroxyquinoline derivatives for the preparation of antioxidants.
In addition, the invention claims the application of the substituted isatin-8-hydroxyquinoline derivative in preparing metal complexing agents.
Based on the treatment principle of monoamine oxidase-B and metal ion complexation and antioxidation, the substituted isatin-8-hydroxyquinoline derivative provided by the invention has treatment effect on diseases related to the mechanism.
Thus, the invention also claims the use of said substituted isatin-8-hydroxyquinoline derivatives for the preparation of a medicament for the treatment of Alzheimer's disease, cerebrovascular dementia, myasthenia gravis, parkinson's disease, huntington's disease or amyotrophic lateral sclerosis.
Further, the application of the substituted isatin-8-hydroxyquinoline derivative in preparing medicines for treating Alzheimer's disease. Based on the mechanisms of oxidation stress hypothesis, metal ion hypothesis, monoamine oxidase-B hypothesis and the like of Alzheimer disease pathogenesis factors, the substituted isatin-8-hydroxyquinoline derivative provided by the invention has remarkable treatment effect on a plurality of treatment targets, and has the advantages of low biotoxicity, high safety and high medical research and market application value.
In addition, the invention also claims a pharmaceutical preparation comprising the substituted isatin-8-hydroxyquinoline derivative.
Further, the dosage form of the pharmaceutical preparation is tablets, pills, capsules, injections, suspending agents or emulsions.
The invention has the following beneficial effects:
The invention provides a substituted isatin-8-hydroxyquinoline derivative which has remarkable monoamine oxidase-B activity inhibition, oxidation resistance and metal ion chelation effects and has therapeutic effects on diseases related to the mechanisms; particularly has remarkable treatment effect on a plurality of treatment targets of Alzheimer's disease, and has lower biotoxicity, high safety and higher medical research and market application value. On the other hand, the raw materials for the production are low, the reaction steps are few, the preparation method is simple, and the method is very suitable for large-scale industrial production.
Drawings
FIG. 1 is a UV spectrum showing the effect of substituted isatin-8-hydroxyquinoline derivative P7 and metal ions in experimental example 3.
Detailed Description
The invention is further illustrated in the following drawings and specific examples, which are not intended to limit the invention in any way. Unless specifically stated otherwise, the reagents, methods and apparatus employed in the present invention are those conventional in the art.
Reagents and materials used in the following examples are commercially available unless otherwise specified.
EXAMPLE 1 Synthesis of substituted isatin-8-hydroxyquinoline derivative P1
In a 25mL round bottom flask was added 5mL MeCN, 5-chloro-8-hydroxyquinoline (0.14 g,0.787 mmol) and Cs 2CO3 (0.38 g,1.181 mmol), and after stirring at 60℃for 30min, isatin intermediate N- (2-bromoethyl) isatin (0.2 g,0.787 mmol) was added and the progress of the reaction was monitored by TLC; after the reaction is finished, the reaction solution is decompressed and spin-dried, water is added and stirred for 30min at room temperature, so that the solid is fully precipitated, suction filtration is carried out, the obtained solid is dried, and the substituted isatin-8-hydroxyquinoline derivative P1 is obtained through silica gel column chromatography separation, and the yield is: 48.7%.
1H NMR(500MHz,CDCl3)δ8.96(dd,J＝4.2,1.7Hz,1H),8.54(dd,J＝8.6,1.7Hz,1H),7.64–7.50(m,5H),7.11(td,J＝7.5,0.9Hz,1H),7.03(d,J＝8.4Hz,1H),4.54(t,J＝5.5Hz,2H),4.35(t,J＝5.5Hz,2H).13C NMR(126MHz,CDCl3)δ183.11,158.70,153.21,151.07,149.78,140.84,138.48,133.03,127.24,126.33,125.17,123.88,123.37,122.51,117.59,112.11,109.55,67.00,40.04.ESI-MS m/z:353.5[M+H]+.
EXAMPLE 2 Synthesis of substituted isatin-8-hydroxyquinoline derivative P2
In a 25mL round bottom flask were added 5mL DMF, 5-chloro-8-hydroxyquinoline (0.13 g,0.704 mmol) and K 2CO3 (0.19 g,1.408 mmol), after stirring at 45℃for 30min, isatin intermediate N- (2-bromoethyl) -5-methoxy-isatin (0.2 g,0.704 mmol) was added and the reaction was continued at 45℃with stirring, monitoring the progress of the reaction by TLC; after the reaction was completed, the reaction solution was poured into 100mL of ice water, stirred at room temperature for 30min, extracted with DCM (30 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, and separated by silica gel column chromatography to give substituted isatin-8-hydroxyquinoline derivative P2, yield: 52.4%.
1H NMR(500MHz,CDCl3)δ8.96(dd,J＝4.2,1.7Hz,1H),8.53(dd,J＝8.6,1.7Hz,1H),7.56(dd,J＝8.5,4.2Hz,1H),7.51(dd,J＝8.5,4.2Hz,2H),7.14(dd,J＝8.6,2.7Hz,1H),7.09(d,J＝2.7Hz,1H),7.01(d,J＝8.4Hz,1H),4.51(t,J＝5.4Hz,2H),4.31(t,J＝5.4Hz,2H),3.79(s,3H).13C NMR(126MHz,CDCl3)δ183.47,158.82,156.53,153.23,149.77,145.14,140.81,133.02,127.22,126.34,125.06,123.28,122.52,117.92,113.43,109.39,108.88,67.18,55.95,40.12.ESI-MS m/z:383.8[M+H]+.
EXAMPLE 3 Synthesis of substituted isatin-8-hydroxyquinoline derivative P3
The difference from example 1 is that the isatin intermediate of this example replaces N- (2-bromoethyl) isatin with N- (3-bromopropyl) -5-chloroisatin, and the other parameters and operations are described in reference to example 1 to give the substituted isatin-8-hydroxyquinoline derivative P3 in the yield: 60.2%.
1H NMR(500MHz,CDCl3)δ8.91(d,J＝4.2Hz,1H),8.55(d,J＝8.5Hz,1H),7.57(dd,J＝8.5,4.2Hz,1H),7.55–7.46(m,2H),7.32(dd,J＝8.4,2.3Hz,1H),7.19(d,J＝8.4Hz,1H),6.92(d,J＝8.4Hz,1H),4.28(t,J＝5.7Hz,2H),4.08(t,J＝6.4Hz,2H),2.43(q,J＝6.1Hz,2H).13C NMR(126MHz,CDCl3)δ182.86,158.50,153.64,150.01,149.58,141.01,137.92,133.53,129.78,127.48,126.81,125.37,123.15,122.90,118.94,112.32,109.14,66.49,38.24,27.32.ESI-MS m/z:401.0[M+H]+.
EXAMPLE 4 Synthesis of substituted isatin-8-hydroxyquinoline derivative P4
In a 25mL round bottom flask were added 8mL MeCN, 5-chloro-8-hydroxyquinoline (0.13 g,0.746 mmol) and Cs 2CO3 (0.78 g,2.238 mmol), and after stirring at room temperature for 30min, isatin intermediate N- (3-bromopropyl) -isatin (0.2 g,0.746 mmol) was added and the progress of the reaction was monitored by TLC; after the reaction is finished, the reaction solution is decompressed and spin-dried, water is added and stirred for 30min at room temperature, so that the solid is fully precipitated, suction filtration is carried out, the obtained solid is dried, and the substituted isatin-8-hydroxyquinoline derivative P4 is obtained through silica gel column chromatography separation, and the yield is: 52.9%.
1H NMR(500MHz,CDCl3)δ8.94(t,J＝4.8Hz,1H),8.53(d,J＝8.4Hz,1H),7.65–7.32(m,4H),7.14(d,J＝7.7Hz,1H),7.08–6.89(m,2H),4.29(q,J＝5.8Hz,2H),4.08(q,J＝6.5Hz,2H),2.44(h,J＝6.1,5.6Hz,2H).13C NMR(126MHz,CDCl3)δ183.48,158.60,153.43,150.89,149.69,140.74,138.29,133.05,133.03,127.08,127.06,126.43,125.21,125.18,123.63,122.63,122.60,122.44,117.65,110.51,108.89,66.20,37.55,27.10.ESI-MS m/z:367.1[M+H]+.
EXAMPLE 5 Synthesis of substituted isatin-8-hydroxyquinoline derivative P5
The difference from example 1 is that the isatin intermediate of this example replaces N- (2-bromoethyl) -isatin with N- (3-bromopropyl) -5-methoxyisatin, and other parameters and operations are described in reference example 1 to give the substituted isatin-8-hydroxyquinoline derivative P5 in the yield: 58.1%.
1H NMR(500MHz,CDCl3)δ8.95(d,J＝4.1Hz,1H),8.53(d,J＝8.5Hz,1H),7.66–7.42(m,2H),7.14–6.85(m,4H),4.29(t,J＝6.1Hz,2H),3.96–3.68(m,5H),2.09(q,J＝6.7,6.2Hz,2H).13C NMR(126MHz,CDCl3)δ183.72,158.23,156.21,153.55,149.56,144.60,140.66,132.91,126.99,126.34,124.59,122.21,117.76,111.36,109.26,108.67,68.03,55.80,39.74,25.87.ESI-MS m/z:411.1[M+H]+.
EXAMPLE 6 Synthesis of substituted isatin-8-hydroxyquinoline derivative P6
The difference from example 1 is that the isatin intermediate of this example replaces N- (2-bromoethyl) -isatin with N- (3-bromopropyl) -5-bromoisatin, and other parameters and operations are described in reference example 1 to give the substituted isatin-8-hydroxyquinoline derivative P6 in the yield: 58.6%.
1H NMR(500MHz,CDCl3)δ8.91(d,J＝4.3Hz,1H),8.54(d,J＝8.6Hz,1H),7.68–7.42(m,4H),7.13(d,J＝8.4Hz,1H),6.92(d,J＝8.4Hz,1H),4.27(t,J＝5.8Hz,2H),4.08(t,J＝6.5Hz,2H),2.42(t,J＝6.2Hz,2H).13C NMR(126MHz,CDCl3)δ182.17,157.80,153.10,149.50,149.48,140.44,140.24,133.03,127.68,126.96,126.29,122.62,122.39,118.76,116.29,112.21,108.61,65.98,37.72,26.79.ESI-MS m/z:445.0[M+H]+.
EXAMPLE 7 Synthesis of substituted isatin-8-hydroxyquinoline derivative P7
The difference from example 1 is that the isatin intermediate of this example replaces N- (2-bromoethyl) -isatin with N- (3-bromopropyl) -6-chloroisatin, and other parameters and operations are described in reference example 1 to give the substituted isatin-8-hydroxyquinoline derivative P7 in the yield: 48.9%.
1H NMR(500MHz,CDCl3)δ8.98(d,J＝4.2Hz,1H),8.56(d,J＝8.5Hz,1H),7.67–7.44(m,3H),7.22(s,1H),7.07–6.85(m,2H),4.27(q,J＝6.1Hz,2H),4.11(t,J＝6.4Hz,2H),2.45(p,J＝6.1Hz,2H).13C NMR(126MHz,CDCl3)δ182.11,158.79,153.28,152.19,150.00,145.02,133.22,127.35,126.49,126.20,124.25,123.94,122.91,122.70,111.48,111.20,108.83,65.66,37.86,27.13.ESI-MS m/z:401.0[M+H]+.
EXAMPLE 8 Synthesis of substituted isatin-8-hydroxyquinoline derivative P8
The difference from example 1 is that the isatin intermediate of this example replaces N- (2-bromoethyl) -isatin with N- (4-bromobutyl) -5-chloroisatin, and other parameters and operations are described in reference example 1 to give the substituted isatin-8-hydroxyquinoline derivative P8 in the following yields: 56.8%.
1H NMR(500MHz,CDCl3)δ8.94(d,J＝4.2Hz,1H),8.54(d,J＝8.5Hz,1H),7.59–7.46(m,3H),7.41(dd,J＝8.4,2.3Hz,1H),6.99(dd,J＝21.8,8.4Hz,2H),4.29(t,J＝5.9Hz,2H),3.89(t,J＝7.0Hz,2H),2.13–2.00(m,4H).13C NMR(126MHz,CDCl3)δ182.46,157.76,153.60,149.71,149.10,140.75,137.61,133.11,129.42,128.04,127.13,126.47,125.20,122.46,122.40,118.27,108.81,68.14,40.11,29.72,25.89.ESI-MS m/z:415.1[M+H]+.
EXAMPLE 9 Synthesis of substituted isatin-8-hydroxyquinoline derivative P9
The difference from example 1 is that the isatin intermediate of this example replaces N- (2-bromoethyl) -isatin with N- (4-bromobutyl) -isatin, and the other parameters and operations are described in reference example 1 to give the substituted isatin-8-hydroxyquinoline derivative P9 in the following yields: 76.8%.
1H NMR(500MHz,CDCl3)δ8.95(dd,J＝4.3,1.7Hz,1H),8.53(dd,J＝8.5,1.7Hz,1H),7.61–7.45(m,4H),7.07(t,J＝7.5Hz,1H),6.99(dd,J＝11.1,8.2Hz,2H),4.30(t,J＝6.1Hz,2H),3.88(t,J＝7.1Hz,2H),2.25–1.96(m,4H).13C NMR(400MHz,CDCl3)δ183.50,158.28,153.72,150.85,149.69,140.79,138.34,133.05,127.12,126.47,125.39,123.65,122.35(2C),117.52,110.46,108.82,68.24,39.90,26.07,24.08.ESI-MS m/z:381.1[M+H]+.
EXAMPLE 10 Synthesis of substituted isatin-8-hydroxyquinoline derivative P10
The difference from example 1 is that the isatin intermediate of this example replaces N- (2-bromoethyl) -isatin with N- (4-bromobutyl) -5-methoxyisatin, and other parameters and operations are described in reference example 1 to give the substituted isatin-8-hydroxyquinoline derivative P10 in the yield: 69.4%.
1H NMR(500MHz,CDCl3)δ9.01–8.89(m,1H),8.52(dd,J＝8.5,1.7Hz,1H),7.60–7.45(m,2H),7.10–6.86(m,4H),4.29(t,J＝6.1Hz,2H),3.81(d,J＝30.8Hz,5H),2.06(dq,J＝31.1,7.2Hz,4H).13C NMR(126MHz,CDCl3)δ183.83,158.34,156.33,153.69,149.68,144.70,140.80,133.00,127.10,126.46,124.68,122.33,122.31,117.88,111.48,109.39,108.81,68.17,55.92,39.86,25.99,23.95.ESI-MS m/z:411.1[M+H]+.
EXAMPLE 11 Synthesis of substituted isatin-8-hydroxyquinoline derivative P11
The difference from example 1 is that the isatin intermediate of this example replaces N- (2-bromoethyl) -isatin with N- (4-bromobutyl) -5-bromoisatin, and other parameters and operations are described in reference example 1 to give the substituted isatin-8-hydroxyquinoline derivative P11, yield: 49.8%.
1H NMR(500MHz,CDCl3)δ8.94(dd,J＝4.2,1.6Hz,1H),8.54(dd,J＝8.5,1.7Hz,1H),7.62(d,J＝2.1Hz,1H),7.60–7.48(m,3H),6.96(dd,J＝8.4,2.3Hz,2H),4.29(t,J＝5.8Hz,2H),3.89(t,J＝6.9Hz,2H),2.13–1.98(m,4H).13C NMR(126MHz,CDCl3)δ182.28,157.58,153.59,149.71,149.54,140.73,140.46,133.16,128.05,127.14,126.48,122.48,122.41,118.63,116.46,112.30,108.82,68.13,40.11,25.89,23.95.ESI-MS m/z:459.0[M+H]+.
EXAMPLE 12 Synthesis of substituted isatin-8-hydroxyquinoline derivative P12
The difference from example 1 is that the isatin intermediate of this example replaces N- (2-bromoethyl) -isatin with N- (4-bromobutyl) -6-chloroisatin, and other parameters and operations are described in reference example 1 to give the substituted isatin-8-hydroxyquinoline derivative P12, yield: 52.9%.
1H NMR(500MHz,CDCl3)δ9.00–8.91(m,1H),8.53(dd,J＝7.0,3.2Hz,1H),7.60–7.44(m,3H),7.09–6.94(m,3H),4.29(t,J＝5.2Hz,2H),3.90(q,J＝6.2,4.5Hz,2H),2.15–1.99(m,4H).13C NMR(400MHz,CDCl3)δ181.96,158.28,153.66,151.88,149.80,144.92,140.90,133.05,127.12,126.43,126.31,123.83,122.41(2C),115.78,111.32,108.76,68.30,40.28,25.94,24.16.ESI-MS m/z:415.1[M+H]+.
EXAMPLE 13 Synthesis of substituted isatin 8-hydroxyquinoline derivative P13
The difference from example 1 is that the isatin intermediate of this example replaces N- (2-bromoethyl) -isatin with N- (5-bromopentyl) -5-chloroisatin, and other parameters and operations are described in reference example 1 to give the substituted isatin-8-hydroxyquinoline derivative P13, yield: 48.3%.
1H NMR(500MHz,CDCl3)δ8.96(dd,J＝4.3,1.7Hz,1H),8.54(dd,J＝8.5,1.7Hz,1H),7.59–7.45(m,4H),6.96(d,J＝8.4Hz,1H),6.85(d,J＝8.4Hz,1H),4.22(t,J＝6.5Hz,2H),3.76(t,J＝7.3Hz,2H),2.13–2.02(m,2H),1.82(p,J＝7.5Hz,2H),1.70–1.62(m,3H).13C NMR(126MHz,CDCl3)δ182.52,157.66,153.89,149.77,149.16,140.79,137.65,133.05,129.49,127.12,126.45,125.36,122.35,122.19,118.39,111.42,108.59,68.66,40.26,28.47,26.96,23.55.ESI-MS m/z:429.1[M+H]+.
EXAMPLE 14 Synthesis of substituted isatin 8-hydroxyquinoline derivative P14
The difference from example 1 is that the isatin intermediate of this example replaces N- (2-bromoethyl) -isatin with N- (5-bromopentyl) -isatin, and the other parameters and operations are described in reference to example 1 to give the substituted isatin-8-hydroxyquinoline derivative P14 in the yield: 54.0%.
1H NMR(500MHz,CDCl3)δ8.97(d,J＝4.2Hz,1H),8.53(d,J＝8.5Hz,1H),7.55(ddd,J＝16.7,13.7,7.9Hz,4H),7.10(t,J＝7.5Hz,1H),6.94(dd,J＝34.4,8.2Hz,2H),4.23(t,J＝6.7Hz,2H),3.77(t,J＝7.3Hz,2H),2.09(p,J＝7.0Hz,2H),1.84(p,J＝7.4Hz,2H),1.67(p,J＝8.0Hz,2H).13C NMR(126MHz,CDCl3)δ183.58,158.21,153.91,150.90,149.77,140.81,138.37,133.01,127.09,126.46,125.47,123.67,122.33,122.10,117.56,110.17,108.60,68.74,40.08,28.52,27.07,23.55.ESI-MS m/z:395.1[M+H]+.
EXAMPLE 15 Synthesis of substituted isatin 8-hydroxyquinoline derivative P15
The difference from example 1 is that the isatin intermediate of this example replaces N- (2-bromoethyl) -isatin with N- (5-bromopentyl) -5-methoxyisatin, and other parameters and operations are described in reference example 1 to give the substituted isatin-8-hydroxyquinoline derivative P15, yield: 76.5%.
1H NMR(500MHz,CDCl3)δ8.98(d,J＝4.2Hz,1H),8.54(d,J＝8.5Hz,1H),7.60–7.48(m,2H),7.18–7.03(m,2H),6.97(d,J＝8.4Hz,1H),6.81(d,J＝8.5Hz,1H),4.22(t,J＝6.6Hz,2H),3.80(s,3H),3.74(t,J＝7.2Hz,2H),2.07(q,J＝7.2Hz,2H),1.82(t,J＝7.7Hz,2H),1.67–1.63(m,2H).13C NMR(126MHz,CDCl3)δ183.93,158.26,156.39,153.91,149.76,144.78,140.81,133.02,127.10,126.45,124.62,122.31,122.11,117.99,111.14,109.64,108.59,68.73,55.97,40.07,29.71,27.05,23.52.ESI-MS m/z:425.1[M+H]+.
EXAMPLE 16 Synthesis of substituted isatin 8-hydroxyquinoline derivative P16
The difference from example 1 is that the isatin intermediate of this example replaces N- (2-bromoethyl) -isatin with N- (5-bromopentyl) -5-bromoisatin, and other parameters and operations are described in reference example 1 to give the substituted isatin-8-hydroxyquinoline derivative P16, yield: 65.8%.
1H NMR(500MHz,CDCl3)δ8.96(dd,J＝4.2,1.7Hz,1H),8.54(dd,J＝8.5,1.7Hz,1H),7.67(d,J＝2.0Hz,1H),7.63(dd,J＝8.4,2.1Hz,1H),7.58–7.49(m,2H),6.96(d,J＝8.4Hz,1H),6.80(d,J＝8.3Hz,1H),4.22(t,J＝6.6Hz,2H),3.76(t,J＝7.2Hz,2H),2.08(dt,J＝14.2,6.8Hz,2H),1.82(p,J＝7.4Hz,2H),1.27(d,J＝15.7Hz,2H).13C NMR(126MHz,CDCl3)δ182.35,157.48,153.90,149.80,149.60,140.83,140.51,133.03,128.22,127.13,126.44,122.35,122.20,118.74,116.48,111.84,108.59,68.66,40.25,28.47,26.96,23.56.ESI-MS m/z:473.0[M+H]+.
EXAMPLE 17 Synthesis of substituted isatin 8-hydroxyquinoline derivative P17
The difference from example 1 is that the isatin intermediate of this example replaces N- (2-bromoethyl) -isatin with N- (5-bromopentyl) -6-chloroisatin, and other parameters and operations are described in reference example 1 to give a substituted isatin-8-hydroxyquinoline derivative P17 in yield ：66.6％.1H NMR(500MHz,CDCl3)δ8.97(dd,J＝4.2,1.7Hz,1H),8.53(dd,J＝8.5,1.7Hz,1H),7.53(ddd,J＝12.7,8.2,3.5Hz,3H),7.07(dd,J＝8.0,1.7Hz,1H),6.97(d,J＝8.4Hz,1H),6.89(d,J＝1.6Hz,1H),4.23(t,J＝6.6Hz,2H),3.75(t,J＝7.3Hz,2H),2.09(p,J＝6.8Hz,2H),1.83(p,J＝7.5Hz,2H),1.67(q,J＝8.0Hz,2H).13C NMR(126MHz,CDCl3)δ181.99,158.17,153.94,151.90,149.82,144.82,140.87,132.98,127.13,126.47,126.43,123.87,122.34,122.18,115.87,110.92,108.62,68.70,40.33,28.48,27.00,23.55.ESI-MS m/z:429.1[M+H]+.
Experimental example 1 inhibition of monoamine oxidase-B by substituted isatin-8-hydroxyquinoline derivatives
The inhibitory activity of the substituted isatin-8-hydroxyquinoline derivatives obtained in examples 1 to 17 on monoamine oxidase-B (MAO-B) was measured by a fluorescence photometry method. The experimental results are expressed in terms of inhibition rate, ladostigil being used as a positive control. All tests were performed on a full wavelength microplate reader model PowerWave XS and absorbance was measured at 490 nm. The test concentration of the compound was 40 μm and the inhibition was calculated according to the following formula: inhibition (%) = [1- (sample-sample background)/(blank-blank background) ]x100%. Wherein, the blank set replaced 10 μl of sample solution with 10 μl of PBS (ph=7.6), the blank background set replaced 30 μl of substrate with 30 μl of PBS (ph=7.6), 10 μl of sample solution with 10 μl of PBS (ph=7.6), and the sample background set replaced 30 μl of substrate with 30 μl of PBS (ph=7.6).
(1) Preparing a sample solution:
The samples are respectively weighed and dissolved in dimethyl sulfoxide (DMSO) to prepare 10mM concentration, the samples are preserved in a refrigerator at the low temperature of minus 20 ℃, and the samples are diluted to the required concentration by phosphate buffer solution (0.2 mol/L, pH 7.6) when in use, so that the final concentration of the DMSO is less than or equal to 0.5% (v/v).
(2) Preparation of enzyme stock solution:
Monoamine oxidase B was purchased from Sigma; a certain amount of monoamine oxidase B is weighed and diluted with deionized water to a proper activity range.
(3) Preparing a substrate stock solution:
tyramine was purchased from Sigma; a certain amount of tyramine was weighed and prepared into a 2.5mM solution by using a phosphate buffer solution (0.2 mol/L, pH 7.6), and the solution was stored at 4℃under shade.
(4) Preparing a color-developing agent stock solution:
Weighing a certain amount of vanillic acid, 4-aminoantipyrine and horseradish peroxidase, preparing a color development solution (1 mM vanillic acid, 0.5mM 4-aminoantipyrine and 4U/mL horseradish peroxidase) by using a phosphate buffer solution (0.2 mol/L, pH 7.6), and performing shading preservation at 4 ℃.
(5) And (3) testing:
In a 96-well plate, 10. Mu.L of an enzyme solution and 10. Mu.L of a sample solution were added, respectively, incubated at 37℃for 20 minutes, 30. Mu.L of a substrate and 10. Mu.L of a color-developing solution were immediately added, and after incubation at 37℃for 60 minutes, absorbance values thereof were measured at λ=490 nm using an enzyme-labeled instrument, and experimental results are shown in Table 1.
TABLE 1 inhibitory Activity of substituted isatin-8-hydroxyquinoline derivatives on MAO-B
| Compounds of formula (I) | Residual Activity(％) | Compounds of formula (I) | Residual Activity(％) |
| P1 | 35.6±1.3 | P10 | 41.5±1.0 |
| P2 | 23.8±1.0 | P11 | 49.3±1.4 |
| P3 | 67.4±1.6 | P12 | 59.2±1.2 |
| P4 | 48.9±0.8 | P13 | 32.1±0.8 |
| P5 | 45.8±1.1 | P14 | 28.4±0.9 |
| P6 | 63.5±0.5 | P15 | 25.6±1.1 |
| P7 | 75.2±0.9 | P16 | 36.2±1.3 |
| P8 | 58.7±1.6 | P17 | 39.7±1.2 |
| P9 | 45.6±1.2 | Ladostigil | 59.1±1.1 |
As can be seen from the table, the compounds obtained by the invention all have different degrees of inhibition on MAO-B, wherein the inhibition of the compound P7 is strongest and reaches 75.2%, and the activity is even stronger than that of the positive control ladostigil. The substituted isatin-8-hydroxyquinoline derivative obtained by the invention can be used for preparing anti-Alzheimer disease medicines based on MAO-B inhibition.
Experimental example 2 in vitro antioxidant Activity experiment of substituted isatin-8-hydroxyquinoline derivative
The in vitro antioxidant activity of the substituted isatin-8-hydroxyquinoline derivatives obtained in examples 1 to 17 was measured by ORAC method, and the antioxidant capacity of a part of the compounds was evaluated by taking AAPH as a source of peroxy radicals and sodium Fluorescein (FL) as a fluorescent indicator, and the experimental result was expressed as the equivalents of Trolox. The method specifically comprises the following steps:
(1) Phosphate Buffer (PBS) is prepared by weighing a proper amount of phosphoric acid, and diluting with ultrapure water to obtain 75mM phosphoric acid solution; 8.56g of dipotassium hydrogen phosphate is weighed and dissolved in 500mL of ultrapure water, and the pH value is adjusted to 7.4 by using a phosphoric acid solution, so that 75mM of phosphate buffer solution with the pH value of 7.4 is obtained.
(2) AAPH solution (ready-to-use): AAPH 0.0588g was weighed precisely, dissolved in 5.42mL of phosphate buffer solution, and the volume was fixed to prepare an AAPH solution having a concentration of 40.0 mM.
(3) Preparation of sodium fluorescein solution: 0.0650g of sodium Fluorescein (FL) was precisely weighed and dissolved in 50mL of high-purity water to prepare a 3.4mM FL solution, which was stored in a refrigerator at 4℃and 2. Mu.L of the solution was dissolved in 50mL of phosphate buffer solution at the time of use to obtain 136nM FL solution.
(4) Preparation of Trolox solution: precisely weighing Trolox 2.50mg, and measuring 1000 mu L of DMSO to dissolve by a pipette to obtain 10mM Trolox solution; the Trolox DMSO solution was precisely aspirated by a pipette and diluted to the test concentration with phosphate buffer.
(5) Preparation of compound solution: an appropriate amount of the compound was accurately weighed by a precision analytical balance, diluted with DMSO to a clear solution at a concentration of 1mM, and diluted with a phosphate buffer to the concentration used when used.
(6) Antioxidant Activity test: respectively sucking 20 mu L of compounds or Trolox with different concentrations, mixing 120 mu L of FL diluent with a black 96-well culture plate, incubating at 37 ℃ for 15min, rapidly adding 60 mu L of AAPH, measuring with a multifunctional enzyme-labeling instrument every 1min, recording fluorescence value, excitation wavelength of 485nm, emission wavelength of 535nm, and recording for 240min. The blank was tested with 20 μl PBS instead of compound. The area between the curve and the coordinates (AUC) was calculated by integral calculation of ORIGIN software, the protection area calculation formula for the sample: net AUC = AUC antioxidant-AUC blank, ORAC-FL value calculation: [ (AUC Sample-AUC blank)/(AUC Trolox-AUC blank) ]/[ Trolox concentration/Sample concentration) ], the Sample ORAC value being expressed in Trolox value equivalents.
TABLE 2 in vitro antioxidant Activity of substituted isatin-8-hydroxyquinoline derivatives
As can be seen from the table, the compounds obtained by the invention have better antioxidation in vitro, wherein the ORAC value of the compounds P7 and P13 is even higher than 5 at the concentration of 5 mu M, and the antioxidation is better. The substituted isatin-8-hydroxyquinoline derivative obtained by the invention can be used for preparing anti-Alzheimer disease medicines based on antioxidation.
Experimental example 3 Metal Complex experiment of substituted isatin-8-hydroxyquinoline derivative
The metal complexing ability of the substituted isatin-8-hydroxyquinoline derivative P7 obtained in the example was determined by the UV-vis method, and the specific steps are as follows:
1. preparing a solution:
(1) Compound P7 solution: a quantitative amount of the compound was weighed and formulated to 1mM with absolute ethanol.
(2) Metal ion solution: a certain amount NaCl, KCl, mgCl 2、CaCl2、ZnSO4、CuSO4 and FeSO 4 were weighed and prepared into 10mM with ultrapure water, and diluted to 1mM with absolute ethanol.
2. Effects of Compounds P7 and NaCl, KCl, mgCl 2、CaCl2、ZnSO4、CuSO4 and FeSO 4
7 Centrifuge tubes of 5mL were taken, 360. Mu.L of 1mM P7 compound solution was added, 360. Mu.L of 1mM NaCl, KCl, mgCl 2、CaCl2、ZnSO4、CuSO4 and FeSO 4 solution were added, respectively, and finally, absolute ethanol was added to a total volume of 3000. Mu.L, so that the final concentrations of both compound P7 and metal ions were 120. Mu.M. The blank was 360 μl of 1mM compound solution supplemented with absolute ethanol to the same concentration as the compound in the sample. After mixing, the mixture was left at room temperature for 30min, poured into a quartz cuvette and the absorption curve was scanned with an ultraviolet-visible spectrometer. The test temperature is room temperature, the test range is 250-700 nm, the wavelength interval is 1nm, the scanning speed is 200nm/min, each sample is tested three times, and the average value is obtained.
As a result, referring to fig. 1, it can be seen that the compound P7 of the present invention has a strong metal complexing ability and a good selectivity to Cu 2+ and Fe 2+; other substituted isatin-8-hydroxyquinoline with similar structures also have similar effects, and the substituted isatin-8-hydroxyquinoline derivative obtained by the invention can be proved to be based on metal complexation and used for preparing anti-Alzheimer disease medicines.
Experimental example 4 toxicity study of substituted isatin-8-hydroxyquinoline derivatives on nerve cells
The toxicity of the substituted isatin-8-hydroxyquinoline derivatives obtained in examples 1 to 17 on nerve cells (SH-SY 5Y) was determined by MTT method, and the specific steps are as follows:
1. solution preparation
(1) DMEM medium: dissolving the dry powder culture medium in 300mL of ultrapure water by using a 1000mL beaker, flushing the inner surface of the package twice by using 300mL of ultrapure water, combining the solutions, and magnetically stirring to completely dissolve the solution; 3.7g sodium bicarbonate and 2.38g HEPES were added and the mixture was completely dissolved by magnetic stirring; adjusting pH to 7.5 with 10M sodium hydroxide under stirring, sterilizing with 0.22 μm filter membrane in an ultra clean bench, and storing in a refrigerator at 4deg.C; antibiotics (final concentration of penicillin 100U/mL, streptomycin 100. Mu.g/mL) and fetal bovine serum (10%) were added for use.
(2) PBS buffer solution: accurately weighing 8g of NaCl, 0.2g of KH 2PO4 and 2.88g of Na 2HPO4·12H2 O, dissolving with ultrapure water, fixing the volume to 1L, autoclaving at 120 ℃ for 20min, and preserving in a refrigerator at 4 ℃.
(3) MTT solution: MTT was formulated as 5g/L with PBS, sterilized by filtration through a 0.22. Mu.M filter, and stored in a refrigerator at 4℃in the absence of light.
2. Culture of neural cells SH-SY5Y
The neural cell strain SH-SY5Y is taken and cultured in a DMEM culture medium in an incubator with the temperature of 37 ℃ and the humidity saturation and the environment of 5 percent CO 2 and 95 percent air for one passage for 2 to 3 days.
3. Neurocytotoxicity assays
(1) Cells in logarithmic growth phase were taken, digested with 0.25% pancreatin, washed twice with PBS, resuspended in DMEM medium, counted under a microscope with a cell counting plate and adjusted to a cell concentration of 5X 10 4 cells/mL, seeded in 96-well cell culture plates, 100. Mu.L/well and cultured for 24h to allow adherence of the cells.
(2) The original medium was aspirated, and compound solutions of different concentrations diluted with DMEM medium were added, 100 μl per well, with 5 multiplex wells. Adding culture medium to replace compound into blank and control group, and culturing in 5% CO 2 incubator at 37deg.C for 48 hr; culture medium containing 5mg/mL MTT was added to the sample and control groups at 4h before termination of the experiment, 100. Mu.L/well, and incubation was continued for 4h.
(3) Removing the supernatant, adding 100 mu L of DMSO into each well, oscillating to fully dissolve formazan, and measuring absorbance value (OD value) of each well on a full-wavelength microplate reader to obtain 570nm wavelength; cell viability (%) = (OD sample-OD blank)/(OD control-OD blank) ×100% in each sample; cell inhibition (%) =100% to cell survival (%) of each sample, and the concentration is plotted with the inhibition ratio, and the concentration with the inhibition ratio of 50% is the compound IC 50 value. The results are shown in Table 3.
TABLE 3 toxicity of substituted isatin-8-hydroxyquinoline derivatives on nerve cells (SH-SY 5Y)
| Compounds of formula (I) | IC50(μM) | Compounds of formula (I) | IC50(μM) |
| P1 | 89.5±0.8 | P10 | 105.1±0.3 |
| P2 | 95.9±0.4 | P11 | 115.9±0.3 |
| P3 | 153.4±0.8 | P12 | 143.6±0.2 |
| P4 | 122.6±0.8 | P13 | 138.5±0.8 |
| P5 | 128.2±0.5 | P14 | 118.7±0.4 |
| P6 | 171.8±0.3 | P15 | 112.2±0.8 |
| P7 | 168.4±0.6 | P16 | 119.3±0.5 |
| P8 | 150.7±0.5 | P17 | 121.6±0.2 |
| P9 | 102.6±0.9 |
As can be seen from the table, the IC 50 values of the substituted isatin-8-hydroxyquinoline derivatives obtained by the invention on SH-SY5Y cells are all more than 85 mu M, and the substituted isatin-8-hydroxyquinoline derivatives show lower nerve cytotoxicity; wherein the IC 50 value of the compound P7 with the strongest MAO-B inhibition activity is 168.4 mu M, and the compound P7 has better safety.
From the above, the substituted isatin-8-hydroxyquinoline derivative has better MAO-B inhibition activity, antioxidation activity and metal complexation activity, has smaller toxicity to nerve cells and high safety, and is very suitable for preparing the anti-Alzheimer disease drugs.
The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.
Claims (10)
1. A substituted isatin-8-hydroxyquinoline derivative, characterized by having the structure of formula (I):
Wherein R is selected from one of hydrogen, halogen and C 1~5 alkoxy; n is a positive integer of 2 to 5.
2. The substituted isatin-8-hydroxyquinoline derivative according to claim 1, wherein R is selected from one of hydrogen, halogen, methoxy; n is a positive integer of 2 to 5.
3. The substituted isatin-8-hydroxyquinoline derivative according to claim 2, wherein the substituted isatin-8-hydroxyquinoline derivative has any one of the following structures:
。
4. The substituted isatin-8-hydroxyquinoline derivative according to any one of claims 1 to 3, further comprising a pharmaceutically acceptable salt of the substituted isatin-8-hydroxyquinoline derivative.
5. The method for preparing the substituted isatin-8-hydroxyquinoline derivative according to any one of claims 1 to 4, which is characterized in that the synthetic route is as follows:
The method specifically comprises the following steps:
S1, carrying out substitution reaction on a compound of the formula (II) and Br- (CH 2)n -Br) in an alkaline environment to obtain a compound of the formula (III);
S2, carrying out substitution reaction on the compound of the formula (III) obtained in the step S1 and 5-chloro-8-hydroxyquinoline under an alkaline condition to obtain a compound of the formula (I);
wherein R, n is defined in accordance with any one of claims 1 to 4.
6. The use of a substituted isatin-8-hydroxyquinoline derivative according to any one of claims 1 to 4 for the preparation of monoamine oxidase-B inhibitors.
7. The use of a substituted isatin-8-hydroxyquinoline derivative according to any one of claims 1 to 4 for the preparation of an antioxidant.
8. The use of a substituted isatin-8-hydroxyquinoline derivative according to any one of claims 1 to 4 for the preparation of a metal complexing agent.
9. The use of a substituted isatin-8-hydroxyquinoline derivative according to any one of claims 1 to 4 in the preparation of a medicament for treating parkinson.
10. A pharmaceutical formulation comprising a substituted isatin-8-hydroxyquinoline derivative according to any one of claims 1 to 4.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310140658.1A CN116217547B (en) | 2023-02-17 | 2023-02-17 | Substituted isatin-8-hydroxyquinoline derivative and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310140658.1A CN116217547B (en) | 2023-02-17 | 2023-02-17 | Substituted isatin-8-hydroxyquinoline derivative and preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN116217547A CN116217547A (en) | 2023-06-06 |
| CN116217547B true CN116217547B (en) | 2024-10-22 |
Family
ID=86570921
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310140658.1A Active CN116217547B (en) | 2023-02-17 | 2023-02-17 | Substituted isatin-8-hydroxyquinoline derivative and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116217547B (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107337641A (en) * | 2017-07-01 | 2017-11-10 | 广东医科大学 | A kind of 4 flexible aromatic ethylene base quinoline derivatives of amido 2 and its preparation method and application |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106167461B (en) * | 2016-07-20 | 2020-08-07 | 天津科技大学 | Water-soluble isatin derivative and preparation method and application thereof |
-
2023
- 2023-02-17 CN CN202310140658.1A patent/CN116217547B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107337641A (en) * | 2017-07-01 | 2017-11-10 | 广东医科大学 | A kind of 4 flexible aromatic ethylene base quinoline derivatives of amido 2 and its preparation method and application |
Also Published As
| Publication number | Publication date |
|---|---|
| CN116217547A (en) | 2023-06-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105481706B (en) | The Hydroxylated Chalcones and Related compound of one class 2, preparation method and use | |
| UA123472C2 (en) | N-[4-fluoro-5-[[(2s,4s)-2-methyl-4-[(5-methyl-1,2,4-oxadiazol-3-yl)methoxy]-1-piperidyl]methyl]thiazol-2-yl]acetamide as oga inhibitor | |
| CN107698492B (en) | 2-hydroxy chalcone amine compounds and application thereof | |
| EP2417136B1 (en) | Imidazo [1,2-a] pyridine-6-carboxamide derivatives, their use for the treatment of colon cancer and their method of manufacture | |
| US7572923B2 (en) | Indirubin derivatives having anticancer property against human cancer cell line | |
| CN116217547B (en) | Substituted isatin-8-hydroxyquinoline derivative and preparation method and application thereof | |
| DE60220179T2 (en) | SUBSTITUTED BENZOPYRANEES AS SELECTIVE AGONISTS ON THE ESTROGEN RECEPTOR BETA | |
| CN109265362B (en) | 2, 5-dihydroxy terephthalamide compounds, preparation method and application thereof | |
| CN117624015B (en) | Substituted isatin-melatonin derivative and preparation method and application thereof | |
| CN116606251A (en) | Fluorescent probe and preparation method and application thereof | |
| CN107337641B (en) | 4-flexible amino-2-arylvinyl quinoline derivative and preparation method and application thereof | |
| CN113387867B (en) | Carbamate anthranilic tryptamine derivative and preparation and application thereof | |
| US5985887A (en) | Aza-anthracyclinone derivatives | |
| CN114890971A (en) | Eriocalyxin B derivative, pharmaceutical composition thereof and application of eriocalyxin B derivative in resisting neocoronary pneumonia | |
| CN110003033B (en) | Flurbiprofen chalcone Mannich base compound, and preparation method and application thereof | |
| CN110003034B (en) | Hydroxyflurbiprofen Mannich base compounds, and preparation method and application thereof | |
| US6103700A (en) | Fluoro labelled anthracyclinone and anthracycline derivatives | |
| CN114478318B (en) | Dinitrile isophorone derivative, preparation method and application thereof | |
| CN110698411B (en) | 4- (aminoalkyl) phthalazine-1-ketone compound, preparation method and application thereof | |
| CN107602518B (en) | Coumarin-dithiocarbamate derivative and synthesis method thereof | |
| CN113683604A (en) | Ratio type near-infrared fluorescent probe for detecting sulfur dioxide derivatives in crop mitochondria and preparation method and application thereof | |
| CN106632191B (en) | Homoisoflavone Mannich alkaloid compound, preparation method and use | |
| CN108424382B (en) | 3,3' -disubstituted bipyridine derivative and preparation method and application thereof | |
| CN116478143A (en) | Donepezil derivative, preparation method and application thereof | |
| CN108203423A (en) | Cumarin Mannich base and its purposes in neurodegenerative disease is prevented |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | 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 |