CN110496126B - Application of dihydroartemisinin and quinolone conjugate in preparation of hypolipidemic drugs - Google Patents
Application of dihydroartemisinin and quinolone conjugate in preparation of hypolipidemic drugs Download PDFInfo
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- CN110496126B CN110496126B CN201910786500.5A CN201910786500A CN110496126B CN 110496126 B CN110496126 B CN 110496126B CN 201910786500 A CN201910786500 A CN 201910786500A CN 110496126 B CN110496126 B CN 110496126B
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- dihydroartemisinin
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- 229960002521 artenimol Drugs 0.000 title claims abstract description 19
- BJDCWCLMFKKGEE-ISOSDAIHSA-N artenimol Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2O[C@H](O)[C@@H]4C BJDCWCLMFKKGEE-ISOSDAIHSA-N 0.000 title claims abstract description 19
- 229930016266 dihydroartemisinin Natural products 0.000 title claims abstract description 19
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 title claims abstract description 16
- 239000003524 antilipemic agent Substances 0.000 title claims abstract description 10
- 238000002360 preparation method Methods 0.000 title abstract description 12
- 229940122392 PCSK9 inhibitor Drugs 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 description 29
- 238000005481 NMR spectroscopy Methods 0.000 description 15
- 230000015572 biosynthetic process Effects 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 12
- 101001098868 Homo sapiens Proprotein convertase subtilisin/kexin type 9 Proteins 0.000 description 11
- 102100038955 Proprotein convertase subtilisin/kexin type 9 Human genes 0.000 description 11
- 238000000034 method Methods 0.000 description 11
- 238000012360 testing method Methods 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 229940079593 drug Drugs 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- 238000004896 high resolution mass spectrometry Methods 0.000 description 8
- 230000005764 inhibitory process Effects 0.000 description 8
- 238000001035 drying Methods 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N ethyl acetate Substances CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 5
- 229910052736 halogen Inorganic materials 0.000 description 5
- 150000002367 halogens Chemical class 0.000 description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 5
- -1 hydroxy, amino Chemical group 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 150000007660 quinolones Chemical class 0.000 description 5
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 230000003248 secreting effect Effects 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 108010028554 LDL Cholesterol Proteins 0.000 description 3
- 102000000853 LDL receptors Human genes 0.000 description 3
- 108010001831 LDL receptors Proteins 0.000 description 3
- 241000187479 Mycobacterium tuberculosis Species 0.000 description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 238000012512 characterization method Methods 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 229960003405 ciprofloxacin Drugs 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 3
- 231100000053 low toxicity Toxicity 0.000 description 3
- DHRLEVQXOMLTIM-UHFFFAOYSA-N phosphoric acid;trioxomolybdenum Chemical compound O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.OP(O)(O)=O DHRLEVQXOMLTIM-UHFFFAOYSA-N 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 description 2
- XUBOMFCQGDBHNK-JTQLQIEISA-N (S)-gatifloxacin Chemical compound FC1=CC(C(C(C(O)=O)=CN2C3CC3)=O)=C2C(OC)=C1N1CCN[C@@H](C)C1 XUBOMFCQGDBHNK-JTQLQIEISA-N 0.000 description 2
- XBHBWNFJWIASRO-UHFFFAOYSA-N 6-fluoro-1-(4-fluorophenyl)-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1=CC=C(F)C=C1 XBHBWNFJWIASRO-UHFFFAOYSA-N 0.000 description 2
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 2
- 101000600434 Homo sapiens Putative uncharacterized protein encoded by MIR7-3HG Proteins 0.000 description 2
- 102100037401 Putative uncharacterized protein encoded by MIR7-3HG Human genes 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 229950001320 clinafloxacin Drugs 0.000 description 2
- QGPKADBNRMWEQR-UHFFFAOYSA-N clinafloxacin Chemical compound C1C(N)CCN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN(C3CC3)C2=C1Cl QGPKADBNRMWEQR-UHFFFAOYSA-N 0.000 description 2
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 2
- 229940072185 drug for treatment of tuberculosis Drugs 0.000 description 2
- 235000019439 ethyl acetate Nutrition 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 229960003923 gatifloxacin Drugs 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 229960002422 lomefloxacin Drugs 0.000 description 2
- ZEKZLJVOYLTDKK-UHFFFAOYSA-N lomefloxacin Chemical compound FC1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNC(C)C1 ZEKZLJVOYLTDKK-UHFFFAOYSA-N 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 229960003702 moxifloxacin Drugs 0.000 description 2
- FABPRXSRWADJSP-MEDUHNTESA-N moxifloxacin Chemical compound COC1=C(N2C[C@H]3NCCC[C@H]3C2)C(F)=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 FABPRXSRWADJSP-MEDUHNTESA-N 0.000 description 2
- 229960001180 norfloxacin Drugs 0.000 description 2
- OGJPXUAPXNRGGI-UHFFFAOYSA-N norfloxacin Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 OGJPXUAPXNRGGI-UHFFFAOYSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 229950007734 sarafloxacin Drugs 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 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
- GSDSWSVVBLHKDQ-UHFFFAOYSA-N 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)COC3=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-UHFFFAOYSA-N 0.000 description 1
- MGQLHRYJBWGORO-LLVKDONJSA-N Balofloxacin Chemical compound C1[C@H](NC)CCCN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN(C3CC3)C2=C1OC MGQLHRYJBWGORO-LLVKDONJSA-N 0.000 description 1
- BJDCWCLMFKKGEE-KDTBHNEXSA-N Dihydroartemisinin (DHA) Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2O[C@@H](O)[C@@H]4C BJDCWCLMFKKGEE-KDTBHNEXSA-N 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- GSDSWSVVBLHKDQ-JTQLQIEISA-N Levofloxacin Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-JTQLQIEISA-N 0.000 description 1
- 229940127355 PCSK9 Inhibitors Drugs 0.000 description 1
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 108010044159 Proprotein Convertases Proteins 0.000 description 1
- 102000006437 Proprotein Convertases Human genes 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 108090000787 Subtilisin Proteins 0.000 description 1
- 150000008043 acidic salts Chemical class 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000078 anti-malarial effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- BLUAFEHZUWYNDE-NNWCWBAJSA-N artemisinin Chemical class C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2OC(=O)[C@@H]4C BLUAFEHZUWYNDE-NNWCWBAJSA-N 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 238000005844 autocatalytic reaction Methods 0.000 description 1
- 229950000805 balofloxacin Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000012054 celltiter-glo Methods 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- HXGBXQDTNZMWGS-RUZDIDTESA-N darifenacin Chemical compound C=1C=CC=CC=1C([C@H]1CN(CCC=2C=C3CCOC3=CC=2)CC1)(C(=O)N)C1=CC=CC=C1 HXGBXQDTNZMWGS-RUZDIDTESA-N 0.000 description 1
- 229960002677 darifenacin Drugs 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 229960002549 enoxacin Drugs 0.000 description 1
- IDYZIJYBMGIQMJ-UHFFFAOYSA-N enoxacin Chemical compound N1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 IDYZIJYBMGIQMJ-UHFFFAOYSA-N 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 238000002114 high-resolution electrospray ionisation mass spectrometry Methods 0.000 description 1
- 230000000260 hypercholesteremic effect Effects 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 229960003376 levofloxacin Drugs 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 229960001699 ofloxacin Drugs 0.000 description 1
- 239000005416 organic matter Substances 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Obesity (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
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- Diabetes (AREA)
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Abstract
The invention discloses application of a dihydroartemisinin and quinolone conjugate shown in a formula I in preparation of a hypolipidemic drug, and widens pharmaceutical application thereof.
Description
Technical Field
The invention belongs to the technical field of medical application of compounds, and relates to application of dihydroartemisinin and quinolone conjugates in preparation of hypolipidemic drugs.
Background
Dihydroartemisinin is an artemisinin derivative and has high-efficiency and low-toxicity antimalarial activity. In recent years, research shows that dihydroartemisinin and its derivatives have various biological activities such as anti-tumor, anti-inflammatory and anti-tissue fibrosis.
Quinolone drugs (such as ciprofloxacin, ofloxacin, levofloxacin, moxifloxacin and gatifloxacin) are the first drugs for treating widely-tolerated multi-drug tuberculosis (MDR-TB) at present, have good inhibition or killing effects on mycobacterium tuberculosis, do not generate obvious cross resistance with non-quinolone antituberculosis drugs, have no inhibition effect on the activity of the drugs when combined administration is carried out, but the long-term use of the quinolone drugs can promote the generation of mycobacterium tuberculosis resistant to the quinolone drugs on the market.
The subject group of the inventor synthesizes conjugates of dihydroartemisinin and quinolones (clinafloxacin, ciprofloxacin, norfloxacin and sarafloxacin) in the past researches, and discovers that the conjugates have good antibacterial effects on standard sensitive strains, clinical isolated sensitive strains and clinical isolated drug-resistant strains of mycobacterium tuberculosis and can be used for preparing antituberculosis drugs.
Proprotein convertase subtilisin 9 (PCSK 9) is a protease synthesized by the liver and secreted into the blood after intramolecular autocatalysis cleavage, binds to hepatocyte surface low density lipoprotein receptor (LDL-R), promotes LDL-R degradation, and causes the elevation of low density lipoprotein cholesterol (LDL-C) levels. PCSK9 inhibitors are considered to be a new generation of lipid lowering drugs following statin therapy, with the greatest benefit being high risk coronary heart disease patients whose LDL-C is still not up to standard after intensive lipid lowering therapy and hypercholesterolemic patients who are not tolerant to high doses of statin therapy.
Disclosure of Invention
The invention aims to examine the activity of the dihydroartemisinin and quinolone conjugate in reducing blood fat so as to widen the pharmaceutical application of the dihydroartemisinin and quinolone conjugate.
Through researches, the invention provides the following technical scheme:
the application of dihydroartemisinin and quinolone conjugate shown in formula I or racemate, stereoisomer, nitrogen oxide and pharmaceutically acceptable salt thereof in preparing hypolipidemic drugs:
in the formula I, the compound (I),
the linker is selected from: - (CH) 2 ) n -or-CO (CH) 2 ) n CO-, n is selected from 2,3 or 4;
x is selected from: C1-C3 alkyl; a cyclopropyl group; a substituted or unsubstituted phenyl group, wherein the substituents on the phenyl group are one or more and are independently selected from halogen, hydroxy, amino, C1-C3 alkoxy or C1-C3 alkyl;
z is selected from: n or C-R 1 ；R 1 Selected from H, halogen or C1-C3 alkoxy;
y is selected from:
r' is selected from hydrogen or C1-C3 alkyl; r is R 2 Selected from hydrogen, halogen or C1-C3 alkyl; m is selected from 1 or 2; * Representing the connection end with the linker; # represents a linking end with an aromatic ring.
Further, in the formula I,
the linker is selected from: - (CH) 2 ) n -or-CO (CH) 2 ) n CO-, n is selected from 2 or 3;
x is selected from: methyl, ethyl, cyclopropyl, phenyl or halo substituted phenyl;
z is selected from: n or C-R 1 ；R 1 Selected from H, halogen, methoxy or ethoxy;
y is selected from:
r' is selected from hydrogen or methyl; r is R 2 Selected from hydrogen, halogen or methyl; m is selected from 1 or 2; * Representing the connection end with the linker; # represents a linking end with an aromatic ring.
Further, in the formula I,
the linker is selected from: -CH 2 CH 2 -、-CH 2 CH 2 CH 2 -or-COCH 2 CH 2 CO-；
X is selected from: ethyl, cyclopropyl or 4-fluorophenyl;
z is selected from: n or C-R 1 ；R 1 Selected from H, fluoro, chloro or methoxy;
y is selected from
R' is selected from hydrogen or methyl; r is R 2 Selected from hydrogen or methyl; m is selected from 1 or 2; * Representing the connection end with the linker; # represents a linking end with an aromatic ring.
Further, the dihydroartemisinin and quinolone conjugate shown in the formula I is any one of the following compounds:
further, the hypolipidemic agent is a PCSK9 inhibitor.
The term "racemate" in the present invention refers to an optically inactive organic substance consisting of equal amounts of enantiomers, unless otherwise indicated. "stereoisomers" refer to molecules in which the atomic composition and bonds are the same, but the atoms are different in three-dimensional space arrangement. "Nitrogen oxides" refer to tertiary nitrogen-linked oxygen atom formation + N-O - Organic matter of the structural unit. The "pharmaceutically acceptable salt" may be an acidic salt or a basic salt, such as an inorganic acid salt, an organic acid salt, an inorganic base salt, or an organic base salt.
The invention has the beneficial effects that: the invention discloses application of a dihydroartemisinin and quinolone conjugate shown in a formula I in preparation of a hypolipidemic drug, and widens pharmaceutical application thereof.
Detailed Description
In order to make the objects, technical solutions and advantageous effects of the present invention more apparent, preferred embodiments of the present invention will be described in detail below.
The main reagents and specifications used in the preferred embodiment are clinafloxacin, sarafloxacin (zheng Keltem Biochemical technologies Co., ltd. > 95%); norfloxacin, ciprofloxacin, lomefloxacin, gatifloxacin, moxifloxacin (Dou Aisi te trade company, AR); enoxacin, balofloxacin (AR, shanghai darifenacin fine chemical limited); dihydroartemisinin (DHA) (Chongqing Hua Liwu Lingshan pharmaceutical Co., ltd., AR); the remaining reagents were commercially available chemically pure or analytically pure products, which were used without purification.
The main instrument used in the preferred embodiment is a melting point tester (X-6, beijing Fukai instruments Co., ltd.); nuclear magnetic resonance (AV-400, bruker, ΜSA;600DD2 type, 600MHz, agilent, ΜSA; TMS is an internal standard); high resolution mass spectrometer (HR ESI MS) (Varian 7.0t, varian, Μsa).
EXAMPLE 1 preparation of the target Compound
1. Synthesis of the TM1 series of target Compounds
The target compounds (TM 1-1 to TM 1-12) were prepared according to the method described in China patent 104418864B (conjugate of dihydroartemisinin and quinolone compounds, preparation method and application thereof).
2. Synthesis of the target Compound TM9 series
1) Synthesis of intermediate IM3
Intermediate IM3 was prepared according to the method described in chinese patent 104418864B (conjugate of dihydroartemisinin and quinolones, and methods of preparation and use thereof).
2) Synthesis of the target Compound TM9 series
IM3 (1 mmol) and 3mL of Dichloromethane (DCM) are added into a 100mL reaction flask, the mixture is stirred at-10 ℃ to 0 ℃ to be partially dissolved, N' -diisopropylethylamine (DIPEA, 1.5 mmol) and pivaloyl chloride (1.5 mmol) are sequentially added, the mixture is stirred at-10 ℃ to 0 ℃ to continue the reaction for about 0.5h, FQ (1 mmol) is added, and the reaction progress is monitored by Thin Layer Chromatography (TLC). After the reaction was completed, the mixture was filtered under reduced pressure, the cake was washed with DCM (2 mL. Times.3), the washings and filtrate were collected, and 10mL of DCM was added, followed by saturated NaHCO 3 Aqueous solution, 5% aqueous citric acid solution, saturated aqueous NaCl solution (10 mL. Times.2 each), and anhydrous Na 2 SO 4 Drying, suction filtering, evaporating filtrate under reduced pressure to obtain crude product, purifying by column chromatography (with Petroleum Ether (PE) -Ethyl Acetate (EA) mixed solvent as eluent with volume ratio of 1:1), collecting eluent, drying under reduced pressure, recrystallizing petroleum ether, checking purity by TLC-ultraviolet fluorescence and phosphomolybdic acid color development method, and vacuum drying to obtain TM9. Specific synthesis conditions and results are shown in Table 1.
TABLE 1 experimental results for the preparation of TM9
The broken lines in the HY and X formulas each represent a connecting bond.
Characterization data for TM9 series compounds are as follows:
TM9-1: pale yellow solid, m.p.:141-143 ℃. 1 H NMR(600MHz,CDCl 3 )δ:14.59(1H,s),8.63(1H,s),8.01-7.99(1H,d,J＝11.4Hz),5.82-5.79(1H,dd,J＝2.4and 9.6Hz),5.45(1H,s),4.8-4.73(1H,m),4.49-4.48(2H,q),4.30-4.10(1H,m),3.75-3.17(5H,m),2.88-2.58(5H,m),2.40-2.35(1H,td,J＝2.4,13.8and 27.6Hz),2.05-2.02(2H,m),1.91-1.88(1H,m),1.80-1.77(1H,m),1.73-1.62(4H,m),1.59-1.57(3H,t,J＝6.6Hz),1.49-1.48(3H,m),1.43(3H,s),1.37-1.35(2H,m),0.97-0.96(3H,d,J＝5.4Hz),0.91-0.88(3H,q). 13 C NMR(151MHz,CDCl 3 )δ:176.41,171.98,169.90,166.67,156.29,150.33,128.45,125.73,122.38,108.45,104.64,96.58,94.79,92.27,87.94,80.31,55.69,54.86,52.68,51.75,51.17,45.42,44.50,37.47,36.40,34.27,32.02,29.70,26.14,24.75,22.19,20.39,16.56,16.52,13.36,12.88,12.24.HR MS:C 36 H 45 F 2 N 3 O 10 [M+Na] + Calculated 740.2965, measured 740.29460.
TM9-2: pale yellow solid, m.p.:164-166 ℃. 1 H NMR(600MHz,CDCl 3 )δ:14.99(1H,s),8.79-8.77(1H,d,J＝7.8Hz),7.82-7.78(1H,t,J＝9.6Hz),5.82-5.77(1H,m),5.44-5.42(1H,d,J＝11.4Hz),5.26-5.22(1H,q),4.62-4.60(1H,m),4.17-3.99(2H,m),3.90-3.81(1H,m),3.61-3.57(3H,d,J＝8.4Hz),3.50-3.42(1H,m),3.26-3.25(1H,d,J＝10.2Hz),3.21-3.17(1H,t,J＝12Hz),2.85-2.57(5H,m),2.40-2.35(1H,m),2.32-2.26(1H,m),2.05-2.02(1H,m),1.88-1.71(5H,m),1.63-1.20(10H,m)(3H,m),1.14-1.05(2H,m),0.97-0.96(3H,d,J＝6Hz),0.88-0.87(3H,d,J＝6.6Hz). 13 C NMR(151MHz,CDCl 3 )δ:176.92,171.94,171.25,167.18,153.06,149.86,141.21,137.29,134.54,127.99,119.00,108.23,104.63,92.23,91.68,80.30,61.35,56.63,54.45,51.73,50.55,48.31,45.39,41.17,40.59,37.45,36.38,35.66,34.24,32.02,29.61,28.60,26.12,25.36,24.73,22.18,20.37,12.25,10.71,8.70.HR MS:C 40 H 50 FN 3 O 11 [M+Na] + Calculated 790.3321, measured 790.33000.
TM9-3 pale yellow solid, m.p. 146-148 ℃. 1 H NMR(600MHz,CDCl 3 )δ:14.70(1H,s),8.83(1H,s,),7.91-7.89(1H,d,J＝12Hz),5.82-5.80(1H,dd,J＝1.8and 10.2Hz),5.45(1H,s),4.89(1H,s),4.03-4.02(1H,t,J＝3.6Hz),3.74-3.61(4H,m),3.52-3.21(5H,m),2.89-2.63(4H,m),2.61-2.59(1H,m),2.40-2.35(1H,td,J＝3.6,14.4and 28.2Hz),2.05-2.02(1H,m),1.91-1.61(5H,m),1.52-1.44(6H,m),1.39-1.20(6H,m),1.05-1.00(2H,m),0.97-0.96(3H,d,J＝6Hz),0.89-0.88(3H,q). 13 C NMR(151MHz,CDCl 3 )δ:177.16,172.00,169.91,166.80,166.74,157.01,155.34,150.25,145.82,140.04,134.19,128.00,108.17,104.64,92.27,87.95,80.31,63.65,55.48,51.74,51.07,45.42,40.56,37.47,36.40,34.26,32.03,30.95,29.70,29.63,27.25,26.14,24.75,22.19,20.38,16.55,12.26,9.84.HR MS:C 38 H 48 FN 3 O 11 [M+Na] + Calculated 764.3165, measured 764.31428.
TM9-4 pale yellow solid, m.p. 171-173 ℃. 1 H NMR(600MHz,CDCl 3 )δ:14.92(1H,s),8.71(1H,s),8.16-8.13(1H,d,J＝13.2Hz),5.80-5.79(1H,d,J＝10.2Hz),5.44(1H,s),4.44-4.41(2H,q),3.93-3.82(6H,m),3.74-3.73(2H,m),2.90-2.54(5H,m),2.39-2.34(1H,m),2.05-2.02(1H,m),1.91-1.88(1H,m),1.80-1.60(3H,m),1.53-1.51(3H,t,J＝7.2Hz),1.43(3H,s),1.39-1.24(4H,m),1.05-1.00(1H,m),0.97-0.96(3H,d,J＝6Hz),0.88-0.87(3H,d,J＝7.2Hz). 13 C NMR(151MHz,CDCl 3 )δ:177.27,171.87,170.19,166.96,150.62,148.37,146.77,145.11,120.84,114.50,109.65,104.65,92.35,91.70,80.30,60.57,51.72,47.98,47.00,45.40,41.50,37.47,36.38,34.25,32.03,29.63,27.75,26.13,24.74,22.18,20.38,15.19,12.24.HR MS:C 34 H 43 FN 4 O 10 [M+Na] + Calculated 709.2855, measured 709.28255.
TM9-5 pale yellow solid, m.p. 135-137 ℃. 1 H NMR(600MHz,CDCl 3 )δ:14.80-14.76(1H,d,J＝27Hz),8.83-8.80(1H,t),7.88-7.82(1H,q),5.79-5.74(1H,m),5.43-5.41(1H,d,J＝11.4Hz),4.74-4.72(1H,m),4.06-4.04(1H,m),3.92-3.88(1H,m),3.84-3.80(3H,m),3.55-3.41(2H,td,J＝10.2,40.8and 70.8Hz),3.28-3.18(1H,m),3.07-2.91(3H,m),2.86-2.51(5H,m),2.39-2.35(1H,m),2.07-1.60(10H,m),1.60-1.12(9H,m),1.03-1.00(2H,m),0.97-0.96(3H,d,J＝5.4Hz),0.85-0.84(3H,d,J＝6Hz). 13 C NMR(151MHz,CDCl 3 )δ:177.16,171.96,171.32,166.93,155.50,149.98,139.62,133.89,128.41,125.68,107.76,104.57,92.15,91.62,80.25,62.44,58.55,54.19,53.24,51.69,50.88,45.34,40.77,37.42,36.34,34.20,31.96,30.58,29.59,28.75,28.16,27.70,26.08,24.70,22.14,20.34,12.18,9.83,9.45.HR MS:C 39 H 50 FN 3 O 11 [M+Na] + Calculated 778.3321, measured 778.33022.
3. Synthesis of the target Compound TM10 series
1) Synthesis of intermediate IM1
Intermediate IM1 was prepared according to the method described in chinese patent 104418864B (conjugate of dihydroartemisinin and quinolones, and methods of preparation and use thereof).
2) Synthesis of the target Compound TM10 series
FQ and anhydrous K are added into a 100mL round bottom flask in sequence 2 CO 3 And DMF,60 ℃ water bath stirring for 30min (FQ slight dissolution), adding IM1, controlling the temperature at 50-75 ℃ water bath stirring reaction, and TLC monitoring the reaction progress. After the completion of the reaction, water was added and stirred to precipitate a large amount of solid, ethyl acetate (EtOAc) was used for extraction (20 mL. Times.2), and the organic phases were combined, washed successively with 5% aqueous citric acid, saturated aqueous NaCl solution (20 mL. Times.2 each) and anhydrous Na 2 SO 4 Drying, evaporating under reduced pressure to obtain crude product, purifying by column chromatography, eluting with DCM-MeOH (volume ratio of 90:1), collecting eluate, and spinning under reduced pressureAnd (5) drying, recrystallizing by using diethyl ether, checking the purity by using TLC-ultraviolet fluorescence and phosphomolybdic acid chromogenic method, and drying in vacuum to obtain the TM10. Specific synthesis conditions and results are shown in Table 2.
TABLE 2 experimental results for the preparation of TM10
The broken lines in the HY and X formulas each represent a connecting bond.
Characterization data for TM10 series compounds are as follows:
TM10-3 pale yellow solid, m.p. 160-162 ℃. 1 H NMR(600MHz,CDCl 3 )δ:13.10-13.01(1H,d,J＝55.8Hz),8.82-8.57(1H,m),7.89-7.82(1H,m),5.48-5.40(1H,m),4.90-4.87(1H,m),4.49-4.13(3H,m),4.07,4.02-4.00(1H,m),3.95-3.85(2H,m),3.83-3.75(3H,m),3.62-3.29(6H,m),2.74-2.72(1H,m,H-11),2.40-2.36(1H,m),2.07-2.03(1H,m),1.91-1.79(3H,m),1.64-1.47(5H,m),1.44-1.42(4H,m),1.34-1.17(4H,m),1.05-1.02(1H,m),1.01-0.89(6H,m),0.87-0.84(2H,m). 13 CNMR(151MHz,CDCl 3 )δ:176.96,172.44,166.45,164.80,156.14,154.49,150.31,145.69,134.18,133.20,110.11,108.24,104.59,102.17,88.09,81.30,66.18,63.56,61.51,58.56,52.50,47.55,45.16,44.07,40.68,39.51,37.32,36.42,34.58,31.00,26.19,24.80,20.44,14.71,13.17,9.72.HR MS:C 36 H 48 FN 3 O 9 [M+Na] + Calculated 708.3267, measured 708.32519.
TM10-4 pale yellow solid, m.p.:173-175 ℃. 1 H NMR(600MHz,CDCl 3 )δ:15.05(1H,s),8.68(1H,s),8.09-8.07(1H,d,J＝13.2Hz),5.49(1H,s),4.84-4.83(1H,d,J＝2.4Hz),4.43-4.39(2H,q),4.00-3.99(1H,m),3.89(4H,s),3.62(1H,s),2.72-2.65(7H,m),2.40-2.35(1H,td,J＝3.6,14.4and28.2Hz,),2.05-2.02(1H,m),1.91-1.74(4H,m),1.64-1.61(1H,m),1.52-1.46(5H,m),1.44(3H,s),1.34-1.32(1H,m),1.27-1.23(1H,m),0.96-0.95(3H,d,J＝6Hz),0.93-0.91(3H,d,J＝7.2Hz). 13 CNMR(151MHz,cdcl 3 )δ:177.18,167.12,150.60,148.39,146.50,145.24,120.40,113.91,109.42,104.28,102.23,88.13,81.23,65.84,57.96,53.38,52.70,47.94,47.29,44.54,37.79,36.57,34.84,30.99,29.86,26.35,24.93,24.62,20.53,15.13,13.25.HR MS:C 32 H 43 FN 4 O 8 [M+Na] + Calculated 653.2957, measured 653.29397.
4. Synthesis of target Compound TM11-1
1) Synthesis of intermediate IM2
Intermediate IM2 was prepared according to the method described in chinese patent 104418864B (conjugate of dihydroartemisinin and quinolones, and methods of preparation and use thereof).
2) Synthesis of target Compound TM11-1
Lomefloxacin (1.052 g/3.0 mmol), anhydrous K, were added sequentially to a 100mL round bottom flask 2 CO 3 And DMF,60℃water bath stirring for 30min, IM2 (1.456 g/3.6 mmol) was added, the reaction was continued to 60℃water bath stirring, and TLC monitored the progress of the reaction. After 9h the reaction was completed, water was added and stirred to precipitate a large amount of solids, etOAc was extracted (20 mL. Times.2), the organic phases were combined, washed sequentially with 5% aqueous citric acid, saturated aqueous NaCl (20 mL. Times.2 each), anhydrous Na 2 SO 4 Drying, evaporating under reduced pressure to obtain crude product, purifying by column chromatography, collecting eluent by using DCM-MeOH (volume ratio of 90:1) as eluent, spin-drying under reduced pressure, recrystallizing with diethyl ether, checking purity by TLC-ultraviolet fluorescence and phosphomolybdic acid color development method, and vacuum drying to obtain pure product 0.315g with 16% yield.
Characterization data for TM11-1 are as follows: pale yellow solid, m.p.:161-163 ℃. 1 H NMR(600MHz,CDCl 3 )δ:14.45(1H,s),8.61-8.58(1H,m),7.99-7.93(1H,m),5.45-5.35(1H,m),4.82-4.80(1H,s),4.48-4.35(3H,m),4.11-4.00(2H,m),3.59-3.17(8H,m),2.67-2.62(1H,m,H-11),2.42-2.26(3H,m),2.1-2.03(3H,m),1.91-1.76(4H,m),1.71-1.66(2H,m),1.61-1.58(3H,m),1.55-1.53(2H,m),1.43-1.40(3H,m),1.28-1.24(2H,m),0.99-0.89(6H,m). 13 C NMR(151MHz,CDCl 3 )δ:176.17,171.72,166.29,150.40,135.12,127.21,108.44,104.42,102.22,91.37,88.09,81.00,80.52,65.39,62.48,59.12,54.96,52.60,51.83,50.88,47.84,45.16,44.32,37.52,36.49,34.64,30.89,29.22,26.26,24.82,23.24,20.48,16.62,14.32,13.25.HR MS:C 35 H 47 F 2 N 3 O 8 [M+Na] + Calculated 698.3223, measured 698.32102.
EXAMPLE 2 PCSK9 inhibitory Activity test of target Compounds
PCSK9 inhibitory Activity of the target compounds was tested by the American Gift company Open Innovation Drug Discovery (OIDD) program, first with a single concentration Primary screen (Primary SP), then with a multiple concentration test (Primary CRC) on the Primary screened potential molecules. The results of the PCSK9inhibition activity test for some compounds are shown in tables 3 and 4.
TABLE 3 results of PCSK9Inhibition (Eff-1) Activity test
Table 3 shows the inhibition rate of target compound TM1 series on human hepatoma cells HepG2 secreting PCSK9 and toxicity on HepG2 cells. Primary SP test results show that target compounds TM1 can inhibit HepG2 cells from secreting PCSK9, the inhibition rate of 10 compounds exceeds 90% and the inhibition rate of 6 compounds exceeds 100% and reaches 111.0% at the highest concentration of 20 mu M; at a test concentration of 2 μm, the inhibition rate of 7 compounds still exceeds 63%, and reaches 95.3% at the highest, showing strong inhibition activity; some compounds have low or little toxicity to HepG2 cells. Primary CRC test results showed that TM1-1 and TM1-5 IC on PCSK9 50 Cell Health IC for HepG2 cells with low value (strong indicator activity) 50 High value (low toxicity) and good drug development potential.
TABLE 4PCSK9Inhibition (Eff-2) Activity test results
Table 4 the inhibitory activity of the target compound against human hepatoma cell HuH7 secreting PCSK9 was tested using the AlphaLisa method, and the effect of the target compound on hepatoma cell HuH7 viability was tested using CellTiter-Glo reagent. The results show that the target compounds TM1, TM9, TM10 and TM11-1 can inhibit human liver cancer cells Huh7 from secreting PCSK9, wherein the inhibition rate of the PCSK9 of the TM1-4 under the test concentration of 5 mu M reaches 60.37 percent, relative to IC 50 (Rel IC 50 ) Has a value of 1.42 mu M, shows strong PCSK9 inhibitory activity, and has low toxicity to Huh7 cells, rel IC 50 Value of>40.0 mu M, with the potential for further development; at a test concentration of 40. Mu.M, 6 of the TM9, TM10 and TM11-1 compounds had PCSK9inhibition of over 74% and 3 compounds had PCSK9inhibition of over 90% up to 99.35%.
Based on the results of the PCSK9 inhibitory activity test of tables 3 and 4 and the common general knowledge in the art, the person skilled in the art can predict that the dihydroartemisinin and the quinolone conjugate shown in the formula I (including the compounds TM1, TM9, TM10, TM11-1 and the like) have more or less certain PCSK9 inhibitory activity, and can be used as a PCSK9 inhibitor for preparing the hypolipidemic drugs.
Finally, it is noted that the above-mentioned preferred embodiments are only intended to illustrate rather than limit the invention, and that, although the invention has been described in detail by means of the above-mentioned preferred embodiments, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention as defined by the appended claims.
Claims (1)
1. The application of dihydroartemisinin and quinolone conjugate or pharmaceutically acceptable salt thereof in preparing hypolipidemic drugs is characterized in that: the hypolipidemic drug is a PCSK9 inhibitor; the dihydroartemisinin and quinolone conjugate is TM1-1, TM1-4 or TM1-5, and the structure is shown as follows:
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