CN107827852B - Patchoulenone derivative and preparation method and application thereof - Google Patents
Patchoulenone derivative and preparation method and application thereof Download PDFInfo
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- CN107827852B CN107827852B CN201711184338.7A CN201711184338A CN107827852B CN 107827852 B CN107827852 B CN 107827852B CN 201711184338 A CN201711184338 A CN 201711184338A CN 107827852 B CN107827852 B CN 107827852B
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- patchoulenone
- dehydroacetic acid
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- JAWSHISYWRRQQQ-HFAKWTLXSA-N patchoulenone Chemical class C[C@@H]1CC[C@@H]2C(=O)C3=C(C)CC[C@]13C2(C)C JAWSHISYWRRQQQ-HFAKWTLXSA-N 0.000 title claims abstract description 38
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 239000003814 drug Substances 0.000 claims abstract description 22
- 229940079593 drug Drugs 0.000 claims abstract description 15
- 241000894006 Bacteria Species 0.000 claims abstract description 9
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 claims abstract description 8
- 229960003085 meticillin Drugs 0.000 claims abstract description 8
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 72
- 238000006243 chemical reaction Methods 0.000 claims description 39
- 239000004287 Dehydroacetic acid Substances 0.000 claims description 29
- JEQRBTDTEKWZBW-UHFFFAOYSA-N dehydroacetic acid Chemical compound CC(=O)C1=C(O)OC(C)=CC1=O JEQRBTDTEKWZBW-UHFFFAOYSA-N 0.000 claims description 29
- 229940061632 dehydroacetic acid Drugs 0.000 claims description 29
- 235000019258 dehydroacetic acid Nutrition 0.000 claims description 29
- PGRHXDWITVMQBC-UHFFFAOYSA-N dehydroacetic acid Natural products CC(=O)C1C(=O)OC(C)=CC1=O PGRHXDWITVMQBC-UHFFFAOYSA-N 0.000 claims description 29
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 24
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 15
- 241000191967 Staphylococcus aureus Species 0.000 claims description 13
- 239000003480 eluent Substances 0.000 claims description 13
- UQEAIHBTYFGYIE-UHFFFAOYSA-N hexamethyldisiloxane Chemical compound C[Si](C)(C)O[Si](C)(C)C UQEAIHBTYFGYIE-UHFFFAOYSA-N 0.000 claims description 13
- 229960000583 acetic acid Drugs 0.000 claims description 12
- 239000012362 glacial acetic acid Substances 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 12
- 238000001816 cooling Methods 0.000 claims description 11
- 239000003208 petroleum Substances 0.000 claims description 11
- 238000010898 silica gel chromatography Methods 0.000 claims description 11
- 150000001299 aldehydes Chemical class 0.000 claims description 10
- 239000003054 catalyst Substances 0.000 claims description 9
- 150000007524 organic acids Chemical class 0.000 claims description 9
- 150000003335 secondary amines Chemical class 0.000 claims description 9
- 241000191963 Staphylococcus epidermidis Species 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 5
- XYRAWLRFGKLUMW-OWOJBTEDSA-N (e)-3-(4-bromophenyl)prop-2-enal Chemical compound BrC1=CC=C(\C=C\C=O)C=C1 XYRAWLRFGKLUMW-OWOJBTEDSA-N 0.000 claims description 3
- HONRSHHPFBMLBT-OWOJBTEDSA-N (e)-3-(4-chlorophenyl)prop-2-enal Chemical compound ClC1=CC=C(\C=C\C=O)C=C1 HONRSHHPFBMLBT-OWOJBTEDSA-N 0.000 claims description 3
- DKOUYOVAEBQFHU-NSCUHMNNSA-N 3-(4-Methylphenyl)-2-propenal Chemical compound CC1=CC=C(\C=C\C=O)C=C1 DKOUYOVAEBQFHU-NSCUHMNNSA-N 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- YSIYEWBILJZDQH-OWOJBTEDSA-N (e)-3-(4-fluorophenyl)prop-2-enal Chemical group FC1=CC=C(\C=C\C=O)C=C1 YSIYEWBILJZDQH-OWOJBTEDSA-N 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 239000004615 ingredient Substances 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000012046 mixed solvent Substances 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 abstract description 5
- 239000012453 solvate Substances 0.000 abstract description 4
- 241000191940 Staphylococcus Species 0.000 abstract description 3
- 244000052616 bacterial pathogen Species 0.000 abstract description 3
- 208000022362 bacterial infectious disease Diseases 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 36
- 150000001875 compounds Chemical class 0.000 description 33
- 238000002844 melting Methods 0.000 description 19
- 230000008018 melting Effects 0.000 description 19
- 238000010828 elution Methods 0.000 description 18
- 230000000844 anti-bacterial effect Effects 0.000 description 15
- 239000000243 solution Substances 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- 239000004305 biphenyl Substances 0.000 description 9
- 239000012295 chemical reaction liquid Substances 0.000 description 9
- 239000011734 sodium Substances 0.000 description 9
- 238000001291 vacuum drying Methods 0.000 description 9
- KJPRLNWUNMBNBZ-QPJJXVBHSA-N (E)-cinnamaldehyde Chemical group O=C\C=C\C1=CC=CC=C1 KJPRLNWUNMBNBZ-QPJJXVBHSA-N 0.000 description 6
- KJPRLNWUNMBNBZ-UHFFFAOYSA-N cinnamic aldehyde Natural products O=CC=CC1=CC=CC=C1 KJPRLNWUNMBNBZ-UHFFFAOYSA-N 0.000 description 6
- 230000001580 bacterial effect Effects 0.000 description 5
- 229940117916 cinnamic aldehyde Drugs 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- AJFJTORMMHWKFW-UHFFFAOYSA-N Dhelwangin Chemical compound CC(C)CCC(=O)C1=C(O)C=C(C)OC1=O AJFJTORMMHWKFW-UHFFFAOYSA-N 0.000 description 4
- 235000011751 Pogostemon cablin Nutrition 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 150000002367 halogens Chemical class 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- KKVZAVRSVHUSPL-UHFFFAOYSA-N o-methoxycinnamic aldehyde Natural products COC1=CC=CC=C1C=CC=O KKVZAVRSVHUSPL-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 241000222666 Boerhavia diffusa Species 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 229940126214 compound 3 Drugs 0.000 description 3
- 229940125898 compound 5 Drugs 0.000 description 3
- 239000002504 physiological saline solution Substances 0.000 description 3
- HGBCDXOKFIDHNS-HWKANZROSA-N (e)-3-(2-chlorophenyl)prop-2-enal Chemical compound ClC1=CC=CC=C1\C=C\C=O HGBCDXOKFIDHNS-HWKANZROSA-N 0.000 description 2
- WMSYHZMJKDCFAK-HWKANZROSA-N (e)-3-(2-fluorophenyl)prop-2-enal Chemical compound FC1=CC=CC=C1\C=C\C=O WMSYHZMJKDCFAK-HWKANZROSA-N 0.000 description 2
- DWPBUTPTXDAJJX-DUXPYHPUSA-N (e)-3-(3-fluorophenyl)prop-2-enal Chemical compound FC1=CC=CC(\C=C\C=O)=C1 DWPBUTPTXDAJJX-DUXPYHPUSA-N 0.000 description 2
- KPNHONAEPLEAJL-UHFFFAOYSA-N 2-methoxy-3-phenylprop-2-enal Chemical compound COC(C=O)=CC1=CC=CC=C1 KPNHONAEPLEAJL-UHFFFAOYSA-N 0.000 description 2
- VLUMOWNVWOXZAU-UHFFFAOYSA-N 2-methyl-3-phenylprop-2-enal Chemical compound O=CC(C)=CC1=CC=CC=C1 VLUMOWNVWOXZAU-UHFFFAOYSA-N 0.000 description 2
- KKVZAVRSVHUSPL-GQCTYLIASA-N Cassiastearoptene Chemical compound COC1=CC=CC=C1\C=C\C=O KKVZAVRSVHUSPL-GQCTYLIASA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- -1 hydroxy, carboxy Chemical group 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000003908 quality control method Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- BOCRJYUZWIOMOJ-UHFFFAOYSA-N 2-benzylidenebutanal Chemical compound CCC(C=O)=CC1=CC=CC=C1 BOCRJYUZWIOMOJ-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- STEAYQWRQSSBRN-ZDUSSCGKSA-N C[Si](C)(C)OC[C@H]1N(CCC1)C1=CC(=CC(=C1)C(F)(F)F)C(F)(F)F Chemical compound C[Si](C)(C)OC[C@H]1N(CCC1)C1=CC(=CC(=C1)C(F)(F)F)C(F)(F)F STEAYQWRQSSBRN-ZDUSSCGKSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- 229930182821 L-proline Natural products 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- TZRXHJWUDPFEEY-UHFFFAOYSA-N Pentaerythritol Tetranitrate Chemical compound [O-][N+](=O)OCC(CO[N+]([O-])=O)(CO[N+]([O-])=O)CO[N+]([O-])=O TZRXHJWUDPFEEY-UHFFFAOYSA-N 0.000 description 1
- 240000002505 Pogostemon cablin Species 0.000 description 1
- 206010036790 Productive cough Diseases 0.000 description 1
- 238000005411 Van der Waals force Methods 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 229940124350 antibacterial drug Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229910000437 dibromine pentoxide Inorganic materials 0.000 description 1
- 238000003113 dilution method Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005485 electric heating Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 210000004349 growth plate Anatomy 0.000 description 1
- CAOOISJXWZMLBN-PPHPATTJSA-N htn0d03vrz Chemical compound Cl.C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 CAOOISJXWZMLBN-PPHPATTJSA-N 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 238000007031 hydroxymethylation reaction Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 229940030980 inova Drugs 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 230000002906 microbiologic effect Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 239000006916 nutrient agar Substances 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 229940100688 oral solution Drugs 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 229960004321 pentaerithrityl tetranitrate Drugs 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 229960002429 proline Drugs 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 210000003802 sputum Anatomy 0.000 description 1
- 208000024794 sputum Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 239000000341 volatile oil Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/34—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D309/36—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a patchoulenone derivative shown as a formula I, or a solvate thereof, or a pharmaceutically acceptable salt thereof, and also provides a patchoulenone derivative, a preparation method and application thereof. Experimental results show that the patchoulenone derivative provided by the invention has good inhibitory activity on pathogenic bacteria such as staphylococcus and the like, can effectively inhibit the growth of the bacteria, can also effectively resist methicillin-resistant bacteria, can be used for medicines for treating bacterial infectious diseases, and provides a new idea and selection for clinical medication.
Description
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to patchoulenone, and a preparation method and an antibacterial application thereof.
Background
The traditional Chinese medicine patchouli has various physiological activities of regulating gastrointestinal tract function, resisting bacteria, resisting inflammation, relieving pain, clearing heat and the like, wherein the antibacterial action is concerned. Patchouli ketone (pogostone) is one of the main components in the patchouli volatile oil extract, and in vitro and in vivo tests show that the patchouli ketone has good antibacterial performance.
Tetranitropentaerythritol reductase (sc PDB database number: P71278) is a key target in the patchoulenone antibacterial action network. The dehydroacetic acid mother nucleus part of the patchoulenone is well combined with the target protein through the actions of hydrogen bonds, pi-pi bonds, van der waals force and the like; however, the side chain of the patchoulenone is in a larger hydrophobic cavity, and the part of the drug molecule is not tightly combined with a target, so that the antibacterial performance of the patchoulenone is influenced.
Modification of the side chains of patchoulenone is one way to increase its antibacterial activity (see Zheng-wei Tang, et al, cytoxic and antibacterial activities of the organisms of pogostone. Fitoteapaia 106(2015) 41-45.). Currently, the antibacterial activity of patchoulenone derivatives is yet to be further improved.
Disclosure of Invention
The invention aims to improve the antibacterial activity of patchoulenone by modifying the side chain of the patchoulenone.
A patchoulenone derivative represented by formula I, or a solvate thereof, or a pharmaceutically acceptable salt thereof:
wherein R is
R1、R2Respectively represent0-1 substitution on the benzene ring, R1、R2Each independently selected from hydrogen, halogen, C1～C4Alkyl radical, C1～C4Alkoxy, hydroxy, carboxy or halogen.
Further, R1、R2Selected from hydrogen, halogen, methyl or methoxy.
Further, R1、R2Are the same group or different groups.
Further, the compound is:
furthermore, the melting point of the compound 1 is 121-124 ℃, the melting point of the compound 2 is 185-188 ℃, the melting point of the compound 3 is 227-230 ℃, the melting point of the compound 4 is 132-135 ℃, the melting point of the compound 5 is 89-92 ℃, the melting point of the compound 6 is 115-119 ℃, the melting point of the compound 7 is 123-125 ℃, the melting point of the compound 8 is 108-112 ℃, and the melting point of the compound 9 is more than 230 ℃.
A process for the preparation of the above compound, characterized in that: the method comprises the following steps: adding dehydroacetic acid, alpha, beta unsaturated aldehyde, a secondary amine catalyst and organic acid into an organic solvent, stirring and reacting at 50-70 ℃, reacting for 10-12 h, cooling to room temperature after the thin-layer chromatography detection and complete reaction, carrying out silica gel chromatography, eluting with eluent, removing the solvent, recrystallizing and drying.
Further, the α, β unsaturated aldehyde is selected from cinnamaldehyde, halogenated cinnamaldehyde, methylcinnamaldehyde, ethylcinnamaldehyde, methoxycinnamaldehyde.
The halogenated cinnamaldehyde, the methyl cinnamaldehyde, the ethyl cinnamaldehyde and the methoxy cinnamaldehyde refer to that one or more hydrogen in the cinnamaldehyde is respectively substituted by halogen, methyl, ethyl and methoxy.
Further, the α, β unsaturated aldehyde is selected from the group consisting of cinnamaldehyde, 2-fluorocinnamaldehyde, 2-chlorocinnamaldehyde, 2-methoxycinnamaldehyde, 3-fluorocinnamaldehyde, 4-chlorocinnamaldehyde, 4-bromocinnamaldehyde, and 4-methylcinnamaldehyde.
Further, the molar ratio of the alpha, beta unsaturated aldehyde to the dehydroacetic acid is 2-3: 1.
Further, the molar ratio of the alpha, beta unsaturated aldehyde to dehydroacetic acid is in the range of 2.2: 1.
Further, the secondary amine catalyst is selected from the group consisting of L-proline, α -diphenylprolinol trimethylsilyl ether, α -diphenylprolinol t-butyldimethylsilyl ether, α -bis (3, 5-bis (trifluoromethyl)) phenylprolinol trimethylsilyl ether.
Further, the secondary amine catalyst is alpha, alpha-diphenyl prolinol trimethylsilyl ether.
Further, the mass ratio of the secondary amine catalyst to the dehydroacetic acid is 0.0.2-0.5: 1.
Further, the mass ratio of the secondary amine catalyst to dehydroacetic acid was 0.387: 1.
Further, the organic acid is selected from benzoic acid and glacial acetic acid.
Further, the organic acid is glacial acetic acid.
Further, the mass ratio of the organic acid to the dehydroacetic acid is 0.1-0.2: 1.
Further, the mass ratio of the organic acid to the dehydroacetic acid is 0.143: 1.
Further, the organic solvent is selected from acetonitrile, toluene, dichloromethane and tetrahydrofuran.
Further, the organic solvent is toluene.
Further, the volume-to-mass ratio of the solvent to the dehydroacetic acid is 56.1-112.2 mg:1 mL.
Further, the volume mass ratio of the solvent to the dehydroacetic acid is 100 mg:1 ml.
Further, the reaction temperature is 60-65 ℃.
Further, the eluent is petroleum ether/ethyl acetate, and the volume ratio is 7: 1-3: 1.
Further, the recrystallization is carried out by adopting a mixed solution of n-hexane and ethyl acetate, wherein the ratio of n-hexane to ethyl acetate is 7: 1.
An application of patchoulenone derivative, or solvate thereof, or pharmaceutically acceptable salt thereof in preparing medicine for resisting drug-resistant bacteria is provided.
Further, the bacteria are methicillin-resistant staphylococcus aureus, staphylococcus aureus and staphylococcus epidermidis.
A pharmaceutical composition is prepared from patchoulenone derivative, or solvate thereof, or pharmaceutically acceptable salt thereof as active ingredient, and pharmaceutically acceptable adjuvants or auxiliary ingredients.
Furthermore, the preparation is injection, freeze-dried powder injection, tablet, powder, granule, capsule, pill, dripping pill or oral solution.
The patchoulenone derivative prepared by the invention has good antibacterial activity on drug-resistant bacteria, especially methicillin-resistant staphylococcus aureus.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
Detailed Description
The present invention will be described in further detail with reference to the following examples. It should not be understood that the scope of the above-described subject matter of the present invention is limited to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Dehydroacetic acid and various cinnamaldehydes are purchased from exploration platforms.
α, α -Diphenylprolinol trimethylsilyl ether, reference Robert K.Boeckman, and John R.Miller, et al, Organic enzymatic α -Hydroxymethylation of Aldehydes, mechanical applications and Optimization, The Journal of Organic Chemistry,2015,80(8), 4030-4045.
Nuclear magnetic resonance apparatus: VarianUNITY (Vatian corporation, INOVA 400MHz)
Mass spectrometry: SYNAPT-G2 (US Waters Corp. UCB-285)
The test method comprises the following steps: the measurement was carried out using a glass melting point tube.
Example 1 preparation of compound 1((1' S,2' S,3' S) -2' - (6-methyl-4-hydroxy-2-O-2H-3-pyrone) -1',2',3',6' -tetrahydro- [1,1':3',1 "-diphenyl ] -4' -aldehyde)):
dehydroacetic acid (200mg), cinnamaldehyde (186.6mg), α -diphenylprolinol trimethylsilylether (77.4mg) and glacial acetic acid (28.6mg) were added together to a reaction vessel containing 2mL of a toluene solvent, and the reaction was continued with stirring at 60 to 65 ℃ overnight. And cooling the reaction liquid after the reaction is completed. Separating and purifying the reaction solution by a silica gel chromatography method, and performing gradient elution, wherein an eluent is petroleum ether: ethyl acetate 7:1, 5:1, after elution, there were four fractions, and the third fraction containing the target compound was collected. Removing the solvent by adopting n-hexane: ethyl acetate 7:1, and vacuum drying to obtain the compound 1.
Melting point: 121-124 ℃.
1H NMR(400MHz,CDCl3):δ＝9.52(s,1H),7.41(d,J＝7.2Hz,2H),7.30(t,J＝7.6Hz, 2H),7.18(dd,J＝15.2,7.2Hz,4H),7.08(d,J＝7.2Hz,2H),5.86(s,1H),4.79(s,1H),4.26(s, 1H),3.37-3.31(m,2H),3.01-2.95(m,1H),2.22(s,3H)ppm.13C NMR(100MHz,CDCl3):δ＝ 207.6,192.7,181.7,169.1,160.8,152.8,141.5,141.3,139.9,128.6,128.4,128.3,127.6,126.8, 126.7,101.7,99.7,53.0,40.0,36.7,31.1,20.6ppm.
HRMS (ESI) m/z calculation C26H22O5+ Na 437.1365, found 437.1364.
Example 2 preparation of compound 2((1' S,2' S,3' S) -2,2 "-difluoro-2 ' - (6-methyl-4-hydroxy-2-O-2H-3-pyrone) -1',2',3',6' -tetrahydro- [1,1':3', 1" -diphenyl ] -4' -aldehyde)):
dehydroacetic acid (200mg), 2-fluorocinnamaldehyde (214.3mg), α -diphenylprolinol trimethylsilylether (77.4mg) and glacial acetic acid (28.6mg) were added together to a reaction vessel containing 2mL of a toluene solvent, and the reaction was continued with stirring at 60 to 65 ℃ overnight. And cooling the reaction liquid after the reaction is completed. Separating and purifying the reaction solution by a silica gel chromatography method, and performing gradient elution, wherein an eluent is petroleum ether: ethyl acetate 7:1, 5:1, after elution, there were four fractions, and the third fraction containing the target compound was collected. Removing the solvent by adopting n-hexane: ethyl acetate 7:1, and vacuum drying to obtain the compound 2.
Melting point: 185 ℃ and 188 ℃.
1H NMR(400MHz,CDCl3):δ＝15.84(s,1H),9.48(s,1H),7.21–6.89(m,9H),5.85(s, 1H),5.14(dd,J＝12.4,4.0Hz,1H),4.96(d,J＝4.4Hz,1H),3.79(d,J＝4.8Hz,1H),3.00(dt, J＝20.8,5.2Hz,1H),2.58(dd,J＝20.4,10.8Hz,1H),2.28(s,3H)ppm.
13C NMR(101MHz,CDCl3):δ＝205.7,191.4,180.9,169.0,161.2,161.0(d,JCF＝245.8 Hz),160.7(d,JCF＝245.5Hz),150.1,141.5,130.6(d,JCF＝1.5Hz),130.5,130.0(d,JCF＝3.6 Hz),129.0(d,JCF＝8.5Hz),128.00(d,JCF＝8.2Hz),125.4(d,JCF＝14.9Hz),124.5(d,JCF＝ 3.4Hz),123.8(d,JCF＝3.5Hz),115.6(d,JCF＝22.8Hz),115.2(d,JCF＝23.0Hz),101.5,100.5 (d,J＝2.5Hz),50.3,34.5,32.6,20.7ppm.
HRMS(ESI):m/z calculated for C26H20F2O5+Na 473.1176,found:473.1175.
Example 3 preparation of the compound 3((1' R,2' S,3' S) -2,2 "-dichloro-2 ' - (6-methyl-4-hydroxy-2-O-2H-3-pyrone) -1',2',3',6' -tetrahydro- [1,1':3', 1" -diphenyl ] -4' -aldehyde)):
dehydroacetic acid (200mg), 2-chlorocinnamaldehyde (237.8mg), α -diphenylprolinol trimethylsilylether (77.4mg) and glacial acetic acid (28.6mg) were added together to a reaction vessel containing 2mL of a toluene solvent, and the reaction was continued with stirring at 60-65 ℃ overnight. And cooling the reaction liquid after the reaction is completed. Separating and purifying the reaction solution by a silica gel chromatography method, and performing gradient elution, wherein an eluent is petroleum ether: ethyl acetate 7:1, 5:1, 3:1, after elution, there were four fractions, the fourth fraction containing the target compound was collected. Removing the solvent by adopting n-hexane: ethyl acetate 7:1, and vacuum drying to obtain a compound 3.
Melting point: 227-.
1H NMR(400MHz,CDCl3):δ＝15.82(s,1H),9.45(s,1H),7.30-7.04(m,9H),5.82(s, 1H),5.27-5.20(m,2H),4.18(br s,1H),3.08(dt,J＝20.8,5.2Hz,1H),2.43(br s,1H),2.27(s, 3H).13C NMR(100MHz,CDCl3):δ＝205.5,191.4,180.6,168.9,161.4,149.3,142.4,136.2, 135.0,130.1,129.7,129.7,128.4,127.6,127.5,126.3,101.6,101.4,49.9,36.0,20.7ppm.
HRMS(ESI):m/z calculated for C26H20Cl2O5+Na 505.0585,found:505.0586.
Example 4 preparation of compound 4((1' S,2' S,3' S) -3,3 "-difluoro-2 ' - (6-methyl-4-hydroxy-2-O-2H-3-pyrone) -1',2',3',6' -tetrahydro- [1,1':3', 1" -diphenyl ] -4' -aldehyde)):
dehydroacetic acid (200mg), 3-fluorocinnamaldehyde (214.3mg), α -diphenylprolinol trimethylsilylether (77.4mg) and glacial acetic acid (28.6mg) were added together to a reaction vessel containing 2mL of a toluene solvent, and the reaction was continued with stirring at 60 to 65 ℃ overnight. And cooling the reaction liquid after the reaction is completed. Separating and purifying the reaction solution by a silica gel chromatography method, and performing gradient elution, wherein an eluent is petroleum ether: ethyl acetate 7:1, 5:1, after elution, there were four fractions, and the third fraction containing the target compound was collected. Removing the solvent by adopting n-hexane: ethyl acetate 7:1, and vacuum drying to obtain a compound 4.
Melting point: 132 ℃ and 135 ℃.
1H NMR(400MHz,CDCl3):δ＝16.27(s,1H),9.53(s,1H),7.37–6.82(m,10H),5.90(s, 1H),4.72(t,J＝3.2Hz,1H),4.26(d,J＝2.8Hz,1H),3.40–3.29(m,2H),2.99–2.91(m,1H), 2.26(s,3H)ppm；13C NMR(100MHz,CDCl3):δ＝207.0,192.5,181.9,169.5,163.0(d,JCF＝ 245.5Hz),162.9(d,JCF＝245.7Hz),160.9,153.0,144.1(d,JCF＝6.9Hz),143.8(d,JCF＝7.0 Hz),139.5,130.0(d,JCF＝8.5Hz),130.0(d,JCF＝8.5Hz),124.4(d,JCF＝2.7Hz),123.5(d, JCF＝2.7Hz),115.6(d,JCF＝22.2Hz),114.7(d,JCF＝21.8Hz),114.0(d,JCF＝21.1Hz),113.8 (d,JCF＝21.0Hz),101.8,99.7,52.9,39.8,36.5,31.1,20.7ppm.
HRMS(ESI):m/z calculated for C26H20F2O5+Na 473.1176,found:473.1178.
Example 5 preparation of compound 5((1' S,2' S,3' S) -4,4 "-difluoro-2 ' - (6-methyl-4-hydroxy-2-O-2H-3-pyrone) -1',2',3',6' -tetrahydro- [1,1':3', 1" -diphenyl ] -4' -aldehyde)):
dehydroacetic acid (200mg), 4-fluorocinnamaldehyde (214.3mg), α -diphenylprolinol trimethylsilylether (77.4mg) and glacial acetic acid (28.6mg) were added together to a reaction vessel containing 2mL of a toluene solvent, and the reaction was continued overnight with stirring at 60-65 ℃. And cooling the reaction liquid after the reaction is completed. Separating and purifying the reaction solution by a silica gel chromatography method, and performing gradient elution, wherein an eluent is petroleum ether: ethyl acetate 7:1, 5:1, after elution, there were four fractions, and the third fraction containing the target compound was collected. Removing the solvent by adopting n-hexane: ethyl acetate 7:1, and vacuum drying to obtain the compound 5.
Melting point: 89-92 ℃.
1H NMR(400MHz,CDCl3)δ 16.34(s,1H),9.52(s,1H),7.38-7.34(m,3H),7.07-6.97(m, 4H),6.92-6.88(m,2H),5.90(d,J＝0.8Hz,1H),4.67(t,J＝3.6Hz,1H),4.22(d,J＝2.8Hz, 1H),3.37-3.29(m,2H),2.99-2.89(m,1H),2.26(s,3H)ppm.13C NMR(101MHz,CDCl3):δ＝ 207.4,192.7,181.8,169.5,161.9(d,JCF＝245.2Hz),161.7(d,JCF＝245.5Hz),161.0,152.9, 140.0,137.1(d,JCF＝3.2Hz),137.0(d,JCF＝3.1Hz),129.8(d,JCF＝90.0Hz),129.7(d,JCF＝ 89.8Hz),115.4(d,JCF＝21.3Hz),115.3(d,JCF＝21.1Hz),101.9,99.8,53.4,39.4,36.1,31.3, 20.8ppm.
HRMS(ESI):m/z calculated for C26H20F2O5+Na 473.1176,found:473.1177.
Example 6 preparation of compound 6((1' S,2' S,3' S) -4,4 "-dichloro-2 ' - (6-methyl-4-hydroxy-2-O-2H-3-pyrone) -1',2',3',6' -tetrahydro- [1,1':3', 1" -diphenyl ] -4' -aldehyde)):
dehydroacetic acid (200mg), 4-chlorocinnamaldehyde (237.8mg), α -diphenylprolinol trimethylsilylether (77.4mg) and glacial acetic acid (28.6mg) were added together to a reaction vessel containing 2mL of a toluene solvent, and the reaction was continued with stirring at 60-65 ℃ overnight. And cooling the reaction liquid after the reaction is completed. Separating and purifying the reaction solution by a silica gel chromatography method, and performing gradient elution, wherein an eluent is petroleum ether: ethyl acetate 7:1, 5:1, after elution, there were four fractions, and the third fraction containing the target compound was collected. Removing the solvent by adopting n-hexane: ethyl acetate 7:1, and vacuum drying to obtain the compound 6.
The melting point is: 115 ℃ and 119 ℃.
1H NMR(400MHz,CDCl3):δ＝15.89(s,1H),9.46(s,1H),7.33–7.03(m,8H),6.90(br s,2H),5.88(s,1H),4.93(d,J＝6.4Hz,1H),4.50(s,1H),3.40(s,1H),2.94(d,J＝18.8Hz, 1H),2.52(dd,J＝18.8,9.2Hz,1H),2.28(s,3H)ppm.13C NMR(101MHz,CDCl3):δ＝205.6, 191.7,181.3,169.6,161.0,149.6,142.5,141.7,137.4,133.3,132.3,130.0,128.9,128.8,128.5, 101.8,100.4,52.1,39.8,36.0,35.7,20.8ppm.
HRMS (ESI) m/z calculation C26H20Cl2O5+ Na 505.0585, found 505.0582.
Example 7 preparation of compound 7((1'S,2' S,3'S) -4,4' -dibromo-2 '- (6-methyl-4-hydroxy-2-O-2H-3-pyrone) -1',2',3',6 '-tetrahydro- [1,1':3',1 "-diphenyl ] -4' -aldehyde)):
dehydroacetic acid (200mg), 4-bromocinnamaldehyde (301.3mg), α -diphenylprolinol trimethylsilylether (77.4mg) and glacial acetic acid (28.6mg) were added together to a reaction vessel containing 2mL of a toluene solvent, and the reaction was continued with stirring at 60-65 ℃ overnight. And cooling the reaction liquid after the reaction is completed. Separating and purifying the reaction solution by a silica gel chromatography method, wherein an eluent is petroleum ether: the gradient elution is carried out at a ratio of ethyl acetate to 7:1 and 5:1, and after the elution, four fractions are obtained, and a third fraction containing the target compound is collected. Removing the solvent by adopting n-hexane: ethyl acetate 7:1, and vacuum drying to obtain a compound 7.
Melting point: 123 ℃ and 125 ℃.
1H NMR(400MHz,CDCl3):δ＝16.26(s,1H),9.50(s,1H),7.44–7.29(m,7H),6.96(d, J＝8.4Hz,2H),5.91(s,1H),4.65(t,J＝3.6Hz,1H),4.18(d,J＝3.2Hz,1H),3.36–3.25(m, 2H),2.97–2.91(m,1H),2.26(s,3H)ppm.13C NMR(100MHz,CDCl3):δ＝206.83,192.41, 181.69,169.45,160.85,152.77,140.24,140.20,139.55,131.59,131.47,130.29,129.44,120.96, 120.66,101.72,99.60,52.95,39.31,36.21,31.58,30.83,20.67ppm.
HRMS(ESI):m/z calculated for C26H20Br2O5+Na 592.9575,found:592.9576。
EXAMPLE 8 Compound 8((1'S,2' S,3'S) -4,4 "-dimethyl-2' - (6-methyl-4-hydroxy-2-O-2H-3-pyrone)
-1',2',3',6' -tetrahydro- [1,1':3',1 "-diphenyl ] -4' -aldehyde)) by the following method:
dehydroacetic acid (200mg), 4-methylcinnamaldehyde (208.7mg), α -diphenylprolinol trimethylsilylether (77.4mg) and glacial acetic acid (28.6mg) were added together to a reaction vessel containing 2mL of a toluene solvent, and the reaction was continued with stirring at 60-65 ℃ overnight. And cooling the reaction liquid after the reaction is completed. Separating and purifying the reaction solution by a silica gel chromatography method, wherein an eluent is petroleum ether: the gradient elution is carried out at a ratio of ethyl acetate to 7:1 and 5:1, and after the elution, four fractions are obtained, and a third fraction containing the target compound is collected. Removing the solvent by adopting n-hexane: ethyl acetate 7:1, and vacuum drying to obtain the compound 8.
Melting point: 108 and 112 ℃.
1H NMR(400MHz,CDCl3):δ＝9.50(s,1H),7.33(d,J＝3.7Hz,1H),7.27(d,J＝12.4 Hz,2H),7.10(d,J＝8.0Hz,2H),6.99(dd,J＝14.8,8.0Hz,5H),5.87(s,1H),4.73(t,J＝3.6 Hz,1H),4.20(d,J＝2.8Hz,1H),3.37-3.26(m,2H),3.00-2.91(m,1H),2.30(s,3H),2.26(s, 3H),2.23(s,3H)ppm.13C NMR(100MHz,CDCl3):δ＝207.85,192.80,181.69,169.02, 160.81,152.75,140.15,138.54,138.31,136.29,136.18,129.16,129.03,128.45,127.54,101.71, 99.72,77.37,77.06,76.74,53.14,39.63,36.34,31.61,31.36,22.68,21.07,20.97,20.63,14.16.
HRMS(ESI):m/z calculated for C26H16O5+Na 465.1678,found:465.1676.
Example 9 preparation of compound 9((1' S,2' S,3' S) -2,2 "-dimethoxy-difluoro-2 ' - (6-methyl-4-hydroxy-2-O-2H-3-pyrone) -1',2',3',6' -tetrahydro- [1,1':3', 1" -diphenyl ] -4' -aldehyde)):
dehydroacetic acid (200mg), 2-methoxycinnamaldehyde (231.5mg), α -diphenylprolinol trimethylsilylether (77.4mg) and glacial acetic acid (28.6mg) were added together to a reaction vessel containing 2mL of a toluene solvent, and the reaction was continued with stirring at 60-65 ℃ overnight. And cooling the reaction liquid after the reaction is completed. Separating and purifying the reaction solution by a silica gel chromatography method, and performing gradient elution, wherein an eluent is petroleum ether: ethyl acetate 7:1, 5:1, 3:1, after elution, there were four fractions, and the third fraction containing the target compound was collected. Removing the solvent by adopting n-hexane: ethyl acetate 7:1, and vacuum drying to obtain the compound 9.
Melting point: is more than 230 ℃.
1H NMR(400MHz,CDCl3):δ＝16.21(s,1H),9.46(s,1H),7.19(t,J＝7.7Hz,1H),7.14 (br s,1H),7.10-7.01(m,3H),6.90(t,J＝7.6Hz,1H),6.79-6.70(m,3H),5.83(s,1H),5.24(br s,1H),5.04(d,J＝4.0Hz,1H),3.84-3.79(m,1H),3.74(s,3H),3.48(s,3H),2.96-2.91(m, 1H),2.55(br s,1H),2.28(s,3H)ppm.13C NMR(100MHz,CDCl3):δ＝206.7,192.0,180.2, 168.2,157.2,157.1,151.0,142.5,129.5,128.2,127.3,126.7,120.8,112.0,110.7,109.8,101.4, 100.9,55.4,54.4,49.6,32.9,20.7ppm.
HRMS(ESI):m/z calculated for C28H26O7+Na 497.1576,found:497.1578.
The advantageous effects of the present invention are described below in the form of test examples.
Test example 1 test for inhibitory Activity of the Compound of the present invention against Staphylococcus aureus
1 materials and instruments
1.1 Experimental instruments
A multi-point inoculation instrument (manufactured by Zuoju institute of Japan, SAKUMA MIT-P type), an electric heating constant temperature water bath (DSY-1-6 holes, Beijing Hokkihua medical instrument factory), a laboratory autoclave (SANYO, MLS-3780 type), CO2INCUBATOR (SANYO, MOC-15A), and an energy-saving purification workbench (Chengdu Xinguan non-Lante purification engineering Co., Ltd.).
1.2 test strains
Staphylococcus aureus ATCC 25923; methicillin-resistant staphylococcus aureus ATCC 43300. The standard quality control strains are all provided by Sichuan antibiotic industry research institute.
In addition to the commercially available bacteria, strains of pathogenic bacteria such as staphylococcus aureus, staphylococcus epidermidis, methicillin-resistant staphylococcus aureus and the like are all clinically isolated pathogenic bacteria collected in class A hospitals, such as Sichuan Chengdu areas, Beijing areas and the like, from 10 months to 1 month in 2013. The specimens are mainly from blood, sputum, urine, etc. The collection units were tested by automatic microbiological identification analyzers (VITEK-32, VITEK-60, Merriruk, France) and then re-tested by a laboratory Biolog bacterial identification instrument (USA) and API20E, 20NE, Staph series and conventional methods.
1.3 drugs
Test drugs: patchoulenone, patchoulenone derivatives (compounds 1-9, prepared in examples 1-9)
Positive drug: levofloxacin hydrochloride (Hainanpri pharmaceuticals, Inc., 1610081),
1.4 culture Medium, reagents and consumables
Mueller-Hinton agar (OXOID, batch No. 1376993), nutrient agar medium (Hangzhou microbial agents Co., Ltd., batch No. 20100831-02), sodium chloride (Tianjin MaoTao Chemicals Co., Ltd., batch No. L217030906), MILLEX-GP Filter Unit (0.22 μm), disposable sterile petri dishes (90mm, available from Jiangsu Kangsheng Co., Ltd.), Mcfarland Standard (bioMeri ux, Inc. batch No. 821772701), and the like.
2 test method
Preparing a drug-containing flat plate: diluting patchoulenone and patchoulenone derivative dissolved solution (solvent DMSO) by adopting a fold ratio dilution method, respectively adding 1mL of liquid medicine and 14mL of sterilized MH culture medium with different concentration gradients into a disposable sterile culture dish, diluting a test medicine into different concentration gradients, fully and uniformly mixing, drying for later use, and adding an equivalent amount of physiological saline into a plate to replace the medicine to prepare a positive control plate.
Preparing bacterial liquid: the tested strain and the drug sensitive quality control strain are adjusted to the concentration of the bacterial liquid of 10 by using sterile physiological saline6CFU/mL。
And (3) measuring in vivo antibacterial activity: the bacterial liquid of the experimental strain is added into the drug-containing flat plate and the positive control flat plate with different concentration gradients by adopting a multi-point inoculation instrument, and 5 mu L of physiological saline is used for replacing the bacterial liquid as negative control.
Incubating at 37 ℃ for 18-24h, and observing and recording the result.
And (4) judging a result: the Minimum Inhibitory Concentration (MIC) of the drug for this strain was the minimum concentration of the drug in the bacteria-free growth plate.
3 results of the test
The results are detailed in tables 1 and 2.
TABLE 1 test results of inhibitory Activity of the Compound of the present invention against Staphylococcus aureus (MIC, μ g/mL)
TABLE 2 inhibitory Activity test results (MIC, μ g/ml) of the inventive Compounds against Staphylococcus epidermidis
The results show that the compound prepared by the invention has good antibacterial activity on methicillin-resistant staphylococcus, staphylococcus aureus and staphylococcus epidermidis, is expected to be used as antibacterial drugs, and has especially good antibacterial effect on the compound 6 and the compound 7.
In conclusion, the invention provides a patchoulenone derivative, and a preparation method and application thereof. The patchoulenone derivative prepared by the invention has good antibacterial activity, and particularly has good antibacterial activity on methicillin-resistant staphylococcus, staphylococcus aureus and staphylococcus epidermidis.
Claims (7)
1. A patchoulenone derivative or a pharmaceutically acceptable salt thereof, which is characterized in that: the derivatives are:
2. a process for the preparation of patchoulenone derivatives according to claim 1, which comprises: the method comprises the following steps: adding dehydroacetic acid, alpha, beta unsaturated aldehyde, a secondary amine catalyst and organic acid into an organic solvent, stirring and reacting at the temperature of 50-70 ℃, reacting for 10-12 hours, cooling to room temperature after complete reaction, performing silica gel chromatography, eluting with eluent, removing the solvent, recrystallizing and drying; the alpha, beta unsaturated aldehyde is selected from 4-fluoro cinnamaldehyde, 4-chloro cinnamaldehyde, 4-bromo cinnamaldehyde, 4-methyl cinnamaldehyde; the secondary amine catalyst is alpha, alpha-diphenyl prolinol trimethylsilyl ether; the organic acid is glacial acetic acid; the organic solvent is toluene;
the molar ratio of the alpha, beta unsaturated aldehyde to the dehydroacetic acid is 2-3: 1; the mass ratio of the secondary amine catalyst to the dehydroacetic acid is 0.2-0.5: 1; the mass ratio of the organic acid to the dehydroacetic acid is 0.1-0.2: 1; the volume-mass ratio of the solvent to the dehydroacetic acid is 1mL: 56.1-112.2 mg.
3. The method of claim 2, wherein: the molar ratio of the alpha, beta unsaturated aldehyde to the dehydroacetic acid is 2.2: 1; and/or the mass ratio of the secondary amine catalyst to the dehydroacetic acid is 0.387: 1; and/or the mass ratio of the organic acid to the dehydroacetic acid is 0.143: 1; and/or the volume mass ratio of the solvent to the dehydroacetic acid is 1ml to 100 mg.
4. The production method according to claim 2 or 3, characterized in that: stirring and reacting at the temperature of 60-65 ℃; and/or the eluent is a petroleum ether/ethyl acetate mixed solvent with a volume ratio of 7: 1-3: 1; the recrystallization is carried out by adopting a mixed solution of normal hexane and ethyl acetate, wherein the ratio of the normal hexane to the ethyl acetate is 7: 1.
5. Use of the patchoulenone derivative of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament against drug-resistant bacteria.
6. Use according to claim 5, characterized in that: the bacteria are methicillin-resistant staphylococcus aureus, staphylococcus aureus and staphylococcus epidermidis.
7. A pharmaceutical composition characterized by: the patchoulenone derivative or pharmaceutically acceptable salt thereof as claimed in claim 1 is used as an active ingredient, and is added with pharmaceutically acceptable auxiliary materials or auxiliary ingredients to prepare a pharmaceutically common preparation.
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