CN117327140B - 一种具备抑制细菌用途的白桦脂酸衍生物 - Google Patents
一种具备抑制细菌用途的白桦脂酸衍生物 Download PDFInfo
- Publication number
- CN117327140B CN117327140B CN202311575224.0A CN202311575224A CN117327140B CN 117327140 B CN117327140 B CN 117327140B CN 202311575224 A CN202311575224 A CN 202311575224A CN 117327140 B CN117327140 B CN 117327140B
- Authority
- CN
- China
- Prior art keywords
- compound
- acid derivative
- bacteria
- betulinic acid
- ynyl
- 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
- 241000894006 Bacteria Species 0.000 title claims abstract description 34
- QGJZLNKBHJESQX-FZFNOLFKSA-N betulinic acid Chemical class C1C[C@H](O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CC[C@@H](C(=C)C)[C@@H]5[C@H]4CC[C@@H]3[C@]21C QGJZLNKBHJESQX-FZFNOLFKSA-N 0.000 title claims abstract description 21
- 230000002401 inhibitory effect Effects 0.000 title claims description 14
- 230000001580 bacterial effect Effects 0.000 claims abstract description 14
- 230000005764 inhibitory process Effects 0.000 claims abstract description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 72
- 125000004432 carbon atom Chemical group C* 0.000 claims description 23
- 241000607142 Salmonella Species 0.000 claims description 7
- 241000191967 Staphylococcus aureus Species 0.000 claims description 6
- 241000588724 Escherichia coli Species 0.000 claims description 4
- 241000192125 Firmicutes Species 0.000 claims description 3
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 11
- 229910052731 fluorine Inorganic materials 0.000 abstract description 9
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 9
- 238000000034 method Methods 0.000 abstract description 9
- 229940124350 antibacterial drug Drugs 0.000 abstract description 2
- -1 Substituted- Chemical class 0.000 description 97
- 125000000217 alkyl group Chemical group 0.000 description 30
- 125000003118 aryl group Chemical group 0.000 description 23
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 125000000623 heterocyclic group Chemical group 0.000 description 21
- 239000000243 solution Substances 0.000 description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 17
- 125000001072 heteroaryl group Chemical group 0.000 description 15
- 239000007787 solid Substances 0.000 description 15
- 229910052736 halogen Inorganic materials 0.000 description 13
- 150000002367 halogens Chemical class 0.000 description 13
- 238000012360 testing method Methods 0.000 description 12
- 229910052799 carbon Inorganic materials 0.000 description 11
- 201000010099 disease Diseases 0.000 description 11
- 150000003839 salts Chemical class 0.000 description 11
- 125000002619 bicyclic group Chemical group 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- 229910052760 oxygen Inorganic materials 0.000 description 10
- 125000003545 alkoxy group Chemical group 0.000 description 9
- 238000012512 characterization method Methods 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- 150000002430 hydrocarbons Chemical group 0.000 description 8
- 229910052717 sulfur Inorganic materials 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 230000006870 function Effects 0.000 description 7
- 239000001963 growth medium Substances 0.000 description 7
- 125000002950 monocyclic group Chemical group 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 229920001817 Agar Polymers 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000008272 agar Substances 0.000 description 6
- 125000000304 alkynyl group Chemical group 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 208000035475 disorder Diseases 0.000 description 6
- 125000005842 heteroatom Chemical group 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 125000006651 (C3-C20) cycloalkyl group Chemical group 0.000 description 5
- 239000004215 Carbon black (E152) Substances 0.000 description 5
- 206010020751 Hypersensitivity Diseases 0.000 description 5
- 125000003342 alkenyl group Chemical group 0.000 description 5
- 229940125904 compound 1 Drugs 0.000 description 5
- 229940125898 compound 5 Drugs 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 229930195733 hydrocarbon Natural products 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 230000007170 pathology Effects 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 238000006467 substitution reaction Methods 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 150000001721 carbon Chemical group 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 238000012650 click reaction Methods 0.000 description 4
- 150000001924 cycloalkanes Chemical class 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 125000005844 heterocyclyloxy group Chemical group 0.000 description 4
- HSZCZNFXUDYRKD-UHFFFAOYSA-M lithium iodide Chemical compound [Li+].[I-] HSZCZNFXUDYRKD-UHFFFAOYSA-M 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 238000004879 turbidimetry Methods 0.000 description 4
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 3
- 125000006708 (C5-C14) heteroaryl group Chemical group 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 125000004104 aryloxy group Chemical group 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 125000005605 benzo group Chemical group 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 125000005553 heteroaryloxy group Chemical group 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000002777 nucleoside Substances 0.000 description 3
- 125000004193 piperazinyl group Chemical group 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 125000006413 ring segment Chemical group 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 230000001954 sterilising effect Effects 0.000 description 3
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 3
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 description 2
- XXFUZSHTIOFGNV-UHFFFAOYSA-N 1-bromoprop-1-yne Chemical compound CC#CBr XXFUZSHTIOFGNV-UHFFFAOYSA-N 0.000 description 2
- QGJZLNKBHJESQX-UHFFFAOYSA-N 3-Epi-Betulin-Saeure Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C(=C)C)C5C4CCC3C21C QGJZLNKBHJESQX-UHFFFAOYSA-N 0.000 description 2
- CLOUCVRNYSHRCF-UHFFFAOYSA-N 3beta-Hydroxy-20(29)-Lupen-3,27-oic acid Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C(O)=O)CCC5(C)CCC(C(=C)C)C5C4CCC3C21C CLOUCVRNYSHRCF-UHFFFAOYSA-N 0.000 description 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 208000035143 Bacterial infection Diseases 0.000 description 2
- DIZWSDNSTNAYHK-XGWVBXMLSA-N Betulinic acid Natural products CC(=C)[C@@H]1C[C@H]([C@H]2CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@@]34C)[C@@H]12)C(=O)O DIZWSDNSTNAYHK-XGWVBXMLSA-N 0.000 description 2
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- 241000233866 Fungi Species 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 239000003810 Jones reagent Substances 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- JYDNKGUBLIKNAM-UHFFFAOYSA-N Oxyallobutulin Natural products C1CC(=O)C(C)(C)C2CCC3(C)C4(C)CCC5(CO)CCC(C(=C)C)C5C4CCC3C21C JYDNKGUBLIKNAM-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 2
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 208000022362 bacterial infectious disease Diseases 0.000 description 2
- 230000003385 bacteriostatic effect Effects 0.000 description 2
- FVWJYYTZTCVBKE-ROUWMTJPSA-N betulin Chemical compound C1C[C@H](O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(CO)CC[C@@H](C(=C)C)[C@@H]5[C@H]4CC[C@@H]3[C@]21C FVWJYYTZTCVBKE-ROUWMTJPSA-N 0.000 description 2
- MVIRREHRVZLANQ-UHFFFAOYSA-N betulin Natural products CC(=O)OC1CCC2(C)C(CCC3(C)C2CC=C4C5C(CCC5(CO)CCC34C)C(=C)C)C1(C)C MVIRREHRVZLANQ-UHFFFAOYSA-N 0.000 description 2
- 238000007664 blowing Methods 0.000 description 2
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 2
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- PZXJOHSZQAEJFE-UHFFFAOYSA-N dihydrobetulinic acid Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C(C)C)C5C4CCC3C21C PZXJOHSZQAEJFE-UHFFFAOYSA-N 0.000 description 2
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- KWIUHFFTVRNATP-UHFFFAOYSA-N glycine betaine Chemical compound C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- MQYXUWHLBZFQQO-UHFFFAOYSA-N nepehinol Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C)CCC(C(=C)C)C5C4CCC3C21C MQYXUWHLBZFQQO-UHFFFAOYSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 125000005936 piperidyl group Chemical group 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 210000000582 semen Anatomy 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- YAPQBXQYLJRXSA-UHFFFAOYSA-N theobromine Chemical compound CN1C(=O)NC(=O)C2=C1N=CN2C YAPQBXQYLJRXSA-UHFFFAOYSA-N 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- DNISEZBAYYIQFB-PHDIDXHHSA-N (2r,3r)-2,3-diacetyloxybutanedioic acid Chemical compound CC(=O)O[C@@H](C(O)=O)[C@H](C(O)=O)OC(C)=O DNISEZBAYYIQFB-PHDIDXHHSA-N 0.000 description 1
- JUSWZYFYLXTMLJ-JTQLQIEISA-N (2s)-1-(benzenesulfonyl)pyrrolidine-2-carboxylic acid Chemical compound OC(=O)[C@@H]1CCCN1S(=O)(=O)C1=CC=CC=C1 JUSWZYFYLXTMLJ-JTQLQIEISA-N 0.000 description 1
- RQYKQWFHJOBBAO-JTQLQIEISA-N (2s)-1-benzoylpyrrolidine-2-carboxylic acid Chemical compound OC(=O)[C@@H]1CCCN1C(=O)C1=CC=CC=C1 RQYKQWFHJOBBAO-JTQLQIEISA-N 0.000 description 1
- 125000006593 (C2-C3) alkynyl group Chemical group 0.000 description 1
- 125000006714 (C3-C10) heterocyclyl group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- UWYVPFMHMJIBHE-OWOJBTEDSA-N (e)-2-hydroxybut-2-enedioic acid Chemical compound OC(=O)\C=C(\O)C(O)=O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- 125000005918 1,2-dimethylbutyl group Chemical group 0.000 description 1
- 125000004972 1-butynyl group Chemical group [H]C([H])([H])C([H])([H])C#C* 0.000 description 1
- 125000006218 1-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- GOCCREQJUBABAL-UHFFFAOYSA-N 2,2-dihydroxyacetic acid Chemical compound OC(O)C(O)=O GOCCREQJUBABAL-UHFFFAOYSA-N 0.000 description 1
- UZYQSNQJLWTICD-UHFFFAOYSA-N 2-(n-benzoylanilino)-2,2-dinitroacetic acid Chemical compound C=1C=CC=CC=1N(C(C(=O)O)([N+]([O-])=O)[N+]([O-])=O)C(=O)C1=CC=CC=C1 UZYQSNQJLWTICD-UHFFFAOYSA-N 0.000 description 1
- KMGUEILFFWDGFV-UHFFFAOYSA-N 2-benzoyl-2-benzoyloxy-3-hydroxybutanedioic acid Chemical compound C=1C=CC=CC=1C(=O)C(C(C(O)=O)O)(C(O)=O)OC(=O)C1=CC=CC=C1 KMGUEILFFWDGFV-UHFFFAOYSA-N 0.000 description 1
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000005916 2-methylpentyl group Chemical group 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- 229940080296 2-naphthalenesulfonate Drugs 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- ALKYHXVLJMQRLQ-UHFFFAOYSA-N 3-Hydroxy-2-naphthoate Chemical compound C1=CC=C2C=C(O)C(C(=O)O)=CC2=C1 ALKYHXVLJMQRLQ-UHFFFAOYSA-N 0.000 description 1
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 1
- 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005917 3-methylpentyl group Chemical group 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-M 3-phenylpropionate Chemical compound [O-]C(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-M 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 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 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- JBMKAUGHUNFTOL-UHFFFAOYSA-N Aldoclor Chemical class C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NC=NS2(=O)=O JBMKAUGHUNFTOL-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 235000018185 Betula X alpestris Nutrition 0.000 description 1
- 235000018212 Betula X uliginosa Nutrition 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 1
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 1
- 125000005914 C6-C14 aryloxy group Chemical group 0.000 description 1
- JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 240000006432 Carica papaya Species 0.000 description 1
- 235000009467 Carica papaya Nutrition 0.000 description 1
- 229920002284 Cellulose triacetate Polymers 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 1
- DSLZVSRJTYRBFB-LLEIAEIESA-L D-glucarate(2-) Chemical compound [O-]C(=O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O DSLZVSRJTYRBFB-LLEIAEIESA-L 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- RBNPOMFGQQGHHO-UWTATZPHSA-N D-glyceric acid Chemical compound OC[C@@H](O)C(O)=O RBNPOMFGQQGHHO-UWTATZPHSA-N 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 244000166124 Eucalyptus globulus Species 0.000 description 1
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 208000006877 Insect Bites and Stings Diseases 0.000 description 1
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 1
- 235000006550 Liquidambar Nutrition 0.000 description 1
- 241000208682 Liquidambar Species 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-M Methacrylate Chemical compound CC(=C)C([O-])=O CERQOIWHTDAKMF-UHFFFAOYSA-M 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- BAVYZALUXZFZLV-UHFFFAOYSA-O Methylammonium ion Chemical compound [NH3+]C BAVYZALUXZFZLV-UHFFFAOYSA-O 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- BPQQTUXANYXVAA-UHFFFAOYSA-N Orthosilicate Chemical compound [O-][Si]([O-])([O-])[O-] BPQQTUXANYXVAA-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 239000001888 Peptone Substances 0.000 description 1
- 108010080698 Peptones Proteins 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 206010070834 Sensitisation Diseases 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- ULUAUXLGCMPNKK-UHFFFAOYSA-N Sulfobutanedioic acid Chemical compound OC(=O)CC(C(O)=O)S(O)(=O)=O ULUAUXLGCMPNKK-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 206010048245 Yellow skin Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- NNLVGZFZQQXQNW-ADJNRHBOSA-N [(2r,3r,4s,5r,6s)-4,5-diacetyloxy-3-[(2s,3r,4s,5r,6r)-3,4,5-triacetyloxy-6-(acetyloxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6s)-4,5,6-triacetyloxy-2-(acetyloxymethyl)oxan-3-yl]oxyoxan-2-yl]methyl acetate Chemical compound O([C@@H]1O[C@@H]([C@H]([C@H](OC(C)=O)[C@H]1OC(C)=O)O[C@H]1[C@@H]([C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](COC(C)=O)O1)OC(C)=O)COC(=O)C)[C@@H]1[C@@H](COC(C)=O)O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O NNLVGZFZQQXQNW-ADJNRHBOSA-N 0.000 description 1
- WDJHALXBUFZDSR-UHFFFAOYSA-M acetoacetate Chemical compound CC(=O)CC([O-])=O WDJHALXBUFZDSR-UHFFFAOYSA-M 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 1
- 239000001361 adipic acid Substances 0.000 description 1
- 235000011037 adipic acid Nutrition 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000003302 alkenyloxy group Chemical group 0.000 description 1
- 125000005108 alkenylthio group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 125000005133 alkynyloxy group Chemical group 0.000 description 1
- 125000005109 alkynylthio group Chemical group 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 125000005110 aryl thio group Chemical group 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 229910052788 barium Inorganic materials 0.000 description 1
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- 239000012964 benzotriazole Substances 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- WGQKYBSKWIADBV-UHFFFAOYSA-O benzylaminium Chemical compound [NH3+]CC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-O 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N beta-phenylpropanoic acid Natural products OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- 229960003237 betaine Drugs 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 1
- 229960001948 caffeine Drugs 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229940041514 candida albicans extract Drugs 0.000 description 1
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- 150000001719 carbohydrate derivatives Chemical class 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- VDANGULDQQJODZ-UHFFFAOYSA-N chloroprocaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1Cl VDANGULDQQJODZ-UHFFFAOYSA-N 0.000 description 1
- 229960002023 chloroprocaine Drugs 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 229940114081 cinnamate Drugs 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- LBJNMUFDOHXDFG-UHFFFAOYSA-N copper;hydrate Chemical compound O.[Cu].[Cu] LBJNMUFDOHXDFG-UHFFFAOYSA-N 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- 125000004465 cycloalkenyloxy group Chemical group 0.000 description 1
- 125000000000 cycloalkoxy group Chemical group 0.000 description 1
- 125000005366 cycloalkylthio group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000006547 cyclononyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- JBDSSBMEKXHSJF-UHFFFAOYSA-N cyclopentanecarboxylic acid Chemical compound OC(=O)C1CCCC1 JBDSSBMEKXHSJF-UHFFFAOYSA-N 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000004855 decalinyl group Chemical group C1(CCCC2CCCCC12)* 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000001335 demethylating effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 125000005959 diazepanyl group Chemical group 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-O dicyclohexylazanium Chemical compound C1CCCCC1[NH2+]C1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-O 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-O diethylammonium Chemical compound CC[NH2+]CC HPNMFZURTQLUMO-UHFFFAOYSA-O 0.000 description 1
- 125000005045 dihydroisoquinolinyl group Chemical group C1(NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000005046 dihydronaphthyl group Chemical group 0.000 description 1
- 231100000676 disease causative agent Toxicity 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 125000005883 dithianyl group Chemical group 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 229940043264 dodecyl sulfate Drugs 0.000 description 1
- 239000012154 double-distilled water Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000005187 foaming Methods 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 1
- 125000005549 heteroarylene group Chemical group 0.000 description 1
- 125000005368 heteroarylthio group Chemical group 0.000 description 1
- 125000004468 heterocyclylthio group Chemical group 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-M hexanoate Chemical compound CCCCCC([O-])=O FUZZWVXGSFPDMH-UHFFFAOYSA-M 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000002054 inoculum Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-O isopropylaminium Chemical compound CC(C)[NH3+] JJWLVOIRVHMVIS-UHFFFAOYSA-O 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- LVHBHZANLOWSRM-UHFFFAOYSA-N itaconic acid Chemical compound OC(=O)CC(=C)C(O)=O LVHBHZANLOWSRM-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229960004194 lidocaine Drugs 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-M lysinate Chemical compound NCCCCC(N)C([O-])=O KDXKERNSBIXSRK-UHFFFAOYSA-M 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-M naphthalene-2-sulfonate Chemical compound C1=CC=CC2=CC(S(=O)(=O)[O-])=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-M 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 238000011017 operating method Methods 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 229940039748 oxalate Drugs 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 235000019319 peptone Nutrition 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 238000000053 physical method Methods 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-M pivalate Chemical compound CC(C)(C)C([O-])=O IUGYQRQAERSCNH-UHFFFAOYSA-M 0.000 description 1
- 229950010765 pivalate Drugs 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- WGYKZJWCGVVSQN-UHFFFAOYSA-O propan-1-aminium Chemical compound CCC[NH3+] WGYKZJWCGVVSQN-UHFFFAOYSA-O 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000004353 pyrazol-1-yl group Chemical group [H]C1=NN(*)C([H])=C1[H] 0.000 description 1
- 125000004289 pyrazol-3-yl group Chemical group [H]N1N=C(*)C([H])=C1[H] 0.000 description 1
- 125000004497 pyrazol-5-yl group Chemical group N1N=CC=C1* 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 229950007734 sarafloxacin Drugs 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-M sulfamate Chemical compound NS([O-])(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-M 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 239000003451 thiazide diuretic agent Substances 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000005556 thienylene group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M trans-cinnamate Chemical compound [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-O triethylammonium ion Chemical compound CC[NH+](CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-O 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 150000003648 triterpenes Chemical class 0.000 description 1
- 125000005455 trithianyl group Chemical group 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 239000012137 tryptone Substances 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000012138 yeast extract Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
- C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Communicable Diseases (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及抗菌衍生物技术领域,提供一种具备抑制细菌用途的白桦脂酸衍生物,具有如下式(Ⅰ‑5)所示的结构:,X选自O;Y选自OH或NH2;R0选自H、F、Cl、Br或OH;R1选自H或甲基。该白桦脂酸衍生物具有抗菌活性,对多种细菌均表现出较好的抑菌效果,可用于制备抗菌药物。
Description
技术领域
本发明属于抗菌衍生物技术领域,尤其涉及一种具备抑制细菌用途的白桦脂酸衍生物。
背景技术
细菌属于细菌域,也是所有生物中数量最多的一类。细菌是许多疾病的病原体,可以通过各种方式,例如接触、消化道、呼吸道以及昆虫叮咬等在正常人体间传播疾病,具有较强的传染性,对社会危害极大。
白桦脂酸属于羽扇豆烷型的五环三萜,主要存在于白桦树皮中,在皱皮木瓜、齿叶黄皮叶、丹皮、桑白皮、酸枣仁、桉树球、胡芦巴、鸡脚参、藤山柳、大枣以及魔芋等多种中药材中也含有此成分,是一种非常有价值的天然产物。
因此,开发白桦脂酸及其衍生物的新的药物用途具有重要意义。目前,尚未发现有文献对此类衍生物的抗细菌活性进行研究和报道。
发明内容
针对现有技术中的缺陷,本发明提供了一种对多种细菌表现出较好抑菌效果的具备抑制细菌用途的白桦脂酸衍生物。
本发明所提供的技术方案是:一种具备抑制细菌用途的白桦脂酸衍生物,所述白桦脂酸衍生物具有如下式(Ⅰ-5)所示的结构:
其中,X选自O;
Y选自OH或NH2;
R0选自H、F、Cl、Br或OH;
R1选自H或甲基。
作为一种改进的方案,当R0选自F、Cl、Br或OH时,与R0相连接的碳原子选自R构型或S构型。
作为一种改进的方案,式(Ⅰ-5)所述的白桦脂酸衍生物选自如下化合物:
。
作为一种改进的方案,所述细菌选自革兰氏阴性菌,包括沙门氏菌、大肠杆菌;
或选自革兰氏阳性菌,包括金黄色葡萄球菌。
本发明提供的白桦脂酸衍生物具有抗菌活性,对多种细菌均表现出较好的抑菌效果,可用于制备抗菌药物。
具体实施方式
下面对本发明技术方案的实施例进行详细的描述。以下实施例仅用于更加清楚地说明本发明的技术方案,因此只作为示例,而不能以此来限制本发明的保护范围。
在本发明实施例中,具备抑制细菌用途的白桦脂酸衍生物具有如下式(Ⅰ)所示的结构:
其中,X选自O、无取代或任选被一个、两个或更多个Ra取代的基团;
R1选自H、无取代或任选被一个、两个或更多个Rb取代的基团;
Het1选自被1个、2个或更多个Rm取代的5-6元杂环基,例如;Het2选自被1个、2个或更多个Rn取代的或,Y选自H、卤素、OH、SH、CN、NO2,无取代或任选被一个、两个或更多个Rc取代的基团;
Z选自O、S、卤素、OH、SH、CN、无取代或任选被一个、两个或更多个Rd取代的基团;
Rm、Rn相同或不同,彼此独立地选自H、卤素、OH、SH、CN,无取代或任选被一个、两个或更多个Rf取代的基团。
在该实施例中,X选自O、无取代或任选被一个、两个或更多个Ra取代的下列基团:C1-40烷基、NH;
R1选自H、无取代或任选被一个、两个或更多个Rb取代的下列基团:C1-40烷基、C3-20环烷基、3-20元杂环基、C6-20芳基或5-20元杂芳基;
Y选自H、卤素、OH、SH、CN、NO2,无取代或任选被一个、两个或更多个Rc取代的下列基团:C1-40烷基、C3-20环烷基、C1-40烷氧基、3-20元杂环基、C6-20芳基、5-20元杂芳基、3-20元杂环基氧基、C6-20芳基氧基、5-20元杂芳基氧基、NH2、-C(O)OR3、-OC(O)R4、-OP(O)(OR5)2、-OS(O)2R6;
Z选自O、S、卤素、OH、SH、CN、无取代或任选被一个、两个或更多个Rd取代的下列基团:C1-40烷基、C3-20环烷基、C1-40烷氧基、3-20元杂环基、C6-20芳基、5-20元杂芳基、3-20元杂环基氧基、C6-20芳基氧基、5-20元杂芳基氧基、NH2、-C(O)OR2、-OC(O)R3、-OP(O)(OR4)2、-OS(O)2R5;其中,当“”为双键时,Z选自O或S;当“”为单键时,Z选自定义的除O和S之外的其他基团;
每一个R2、R3、R4、R5、R6相同或不同,彼此独立地选自H、无取代或任选被一个、两个或更多个Re取代的下列基团:C1-40烷基、C3-20环烷基、3-20元杂环基、C6-20芳基、5-20元杂芳基;
Rm、Rn选自H、卤素、OH、SH、CN,无取代或任选被一个、两个或更多个Rf取代的下列基团:C1-40烷基或C1-40烷氧基;
Ra、Rb、Rc、Rd、Re、Rf相同或不同,彼此独立地选自卤素、OH、CN、NO2、氧代(=O)、硫代(=S)、C1-40烷基、C2-40烯基、C2-40炔基、C3-40环烷基、C3-40环烯基、C3-40环炔基、C6-20芳基、5-20元杂芳基、3-20元杂环基、C1-40烷基氧基、C2-40烯基氧基、C2-40炔基氧基、C3-40环烷基氧基、C3-40环烯基氧基、C3-40环炔基氧基、C6-20芳基氧基、5-20元杂芳基氧基、3-20元杂环基氧基、C1-40烷基硫基、C2-40烯基硫基、C2-40炔基硫基、C3-40环烷基硫基、C3-40环烯基硫基、C3-40环炔基硫基、C6-20芳基硫基、5-20元杂芳基硫基、3-20元杂环基硫基、NH2、-C(O)C1-40烷基、-C(O)NH2、-C(O)NHC1-40烷基、-C(O)-NH-OH、-COOC1-40烷基、-COOH、-OC(O)C1-40烷基、-OC(O)H、-S(O)2C1-40烷基、S(O)2H、-S(O)2OC1-40烷基、-OS(O)2C1-40烷基、-P(O)(OH)2、-B(OH)2。
在本发明实施例中,具备抑制细菌用途的白桦脂酸衍生物具有如下式(Ⅰ-1)或(Ⅰ-2)所示的结构:
其中,X选自O、无取代或任选被一个、两个或更多个Ra取代的NH或CH2;
Y选自H、卤素、OH、SH、CN、NO2,无取代或任选被一个、两个或更多个Rc取代的NH或CH3;
R选自H、C1-6烷基、C3-8环烷基;
R0选自H、卤素、OH、SH、CN、C1-6烷基或C1-6烷氧基;
R1选自H、无取代或任选被一个、两个或更多个Rb取代的下列基团:C1-6烷基、C3-8环烷基、3-8元杂环基、C6-14芳基或5-14元杂芳基;
R2选自H、卤素、OH、SH、CN,无取代或任选被一个、两个或更多个Rf取代的下列基团:C1-6烷基或C1-6烷氧基;
Z选自O、卤素、OH、SH、CN、无取代或任选被一个、两个或更多个Rd取代的C1-6烷基或C1-6烷氧基,当“”为双键时,Z选自O;当“”为单键时,Z选自定义的除O之外的其他基团;
Ra选自C1-6烷基;
Rb、Rc、Rf相同或不同,彼此独立地选自卤素、OH、CN、NO2、C1-6烷基、C3-8环烷基、C1-6烷氧基、3-8元杂环基、C6-14芳基、5-14元杂芳基、3-8元杂环基氧基、C6-14芳基氧基或5-14元杂芳基氧基。
具备抑制细菌用途的白桦脂酸衍生物具有如下式(Ⅰ-3)或(Ⅰ-4)所示的结构:
其中, X选自O;
Y选自OH或NH2;
R选自H、C1-6烷基;
R0选自H、OH、F或CH3;
R1选自H或C1-6烷基;
R2选自H、F、Cl、Br、OH、SH、CN或CH3;
Z选自O、F、Cl、Br、OH、CN、C1-6烷基或C1-6烷氧基,当“”为双键时,Z为O;当“”为单键时,Z选自 F、Cl、Br、OH、CN、C1-6烷基或C1-6烷氧基。
在本发明实施例中,具备抑制细菌用途的白桦脂酸衍生物具有如下式(Ⅰ-5)所示的结构:
其中,X选自O;
Y选自OH或NH2;
R0选自H、F、Cl、Br或OH;
R1选自H或甲基。
其中,当R0选自F、Cl、Br或OH时,与R0相连接的碳原子选自R构型或S构型。
在该实施例中,式(Ⅰ-5)所述的白桦脂酸衍生物选自如下化合物:
。
其中,该细菌选自革兰氏阴性菌,包括沙门氏菌、大肠杆菌;
或选自革兰氏阳性菌,包括金黄色葡萄球菌。
在本发明实施例中,化合物的制备如下:
该实施例中,所涉及的化合物2-9的制备参考化合物1的制备例所示:
(1)先用Jones试剂将白桦醇a氧化为路路通酸b。
(2)用碳酸二甲酯回流将步骤(1)中制备的化合物b甲酯化得到化合物c。
(3)使用溴代丙炔与步骤(2)中制备的化合物c反应得到化合物d。
(4)采用硼氢化钠将步骤(3)中制备的化合物d中的羰基还原成羟基,制备得到化合物e。
(5)用碘化锂加热回流脱甲基得到化合物f。
(6)通过click反应将2’-氟-4’-叠氮尿苷加入到步骤(5)中制备的化合物f中合成化合物1。
具体合成路线如下:
化合物b的合成:将白桦脂醇(化合物a,20.0g,45.2 mmol)溶于400 mL丙酮,0℃下滴加新制备的Jones试剂(200 mL)。滴加完毕后0℃反应20分钟,撤掉冰浴继续搅拌反应2小时(TLC监测)。反应完毕后,加入300mL甲醇,搅拌20分,再加入300 mL水,搅拌20分钟。蒸去溶剂后,乙酸乙酯萃取(3 × 200 mL),柱层析分离得到白色固体化合物b(12.2g, 26.8mmol, 59.3%)。1H NMR (DMSO-d6, 400MHz) δ:12.10 (s, 1H), 4.69(s, 1H), 4.57 (s,1H), 2.95 (td, J=11.1, 5.2Hz, 1H), 2.48-2.30 (m, 2H), 2.26 (td, J=12.6, 3.2Hz, 1H), 2.15-2.06 (m, 1H), 1.89-1.73 (m, 3H), 1.65 (s, 3H), 1.67-1.60 (m,1H), 1.54 (t, J=11.3Hz, 1H), 1.48-1.00 (m, 14H), 1.02-0.96 (m, 1H), 0.98(s,3H), 0.95(s, 3H), 0.93(s, 3H), 0.90(s, 3H), 0.85(s, 3H). 13C NMR (DMSO-d6,100MHz) δ:218.5, 177.2, 150.3, 109.7, 55.4, 53.8, 49.0, 48.4, 46.6, 46.5,42.1, 40.1, 38.8, 37.7, 36.4, 36.3, 33.6, 33.1, 31.6, 30.1, 29.2, 26.4, 25.1,21.0, 20.7, 19.2, 19.0, 15.7, 15.4, 14.3。
化合物c的合成:将化合物c(4.54 g,10.0 mmol)溶于碳酸二甲酯(40 mL),加入DBU(6.0 mL,40 mmol),加热回流24小时(TLC监测)。反应完毕后蒸干溶剂后溶于乙酸乙酯,10%盐酸洗涤两次,饱和碳酸氢钠洗涤一次。蒸干溶剂后柱层析得到白色固体化合物c(3.36g, 7.2 mmol, 72.0%)。1H NMR (CDCl3, 400MHz) δ: 4.74 (d, J=1.8 Hz, 1H), 4.60 (s,1H), 3.67 (s, 3H), 3.00 (td, J=10.8, 4.3Hz, 1H), 2.55-2.34 (m, 2H), 2.30-2.17(m, 2H), 1.95-1.83 (m, 3H), 1.77-1.70 (m, 1H), 1.69 (s, 3H), 1.60 (t, J=11.5Hz, 1H), 1.50-1.24 (m, 13H), 1.20-1.14 (m, 1H), 1.07 (s, 3H), 1.05-0.99 (m,1H), 1.02 (s, 3H), 0.97 (s, 3H), 0.95 (s, 3H), 0.92 (s, 3H). 13C NMR ( CDCl3,100MHz) δ:218.2, 176.6, 150.5, 109.6, 56.5, 54.9, 51.3, 49.9, 49.3, 47.3,46.9, 42.4, 40.6, 39.6, 38.3, 36.9, 36.9, 34.1, 33.6, 32.1, 30.5, 29.6, 26.6,25.5, 21.4, 21.0, 19.6, 19.3, 15.9, 15.7, 14.6。
化合物d的合成:将化合物c (2.54 g,5.4 mmol)溶于乙二醇二甲醚(DME, 135mL),加入双(三甲基硅烷基)氨基钾的四氢呋喃溶液(KN(SiMe3)2, 32 mL,32 mmol),搅拌30min后加入1mol/L Et3B的四氢呋喃溶液(40mL, 40 mmol),继续搅拌1.5h后加入溴代丙炔(4.0 mL, 48mmol),搅拌过夜。TLC检测反应完毕后,加入稀盐酸将溶液调至酸性,反应液用乙酸乙酯萃取(3 × 150 mL),收集有机相并用饱和碳酸氢钠溶液洗,无水Na2SO4干燥,柱色谱分离(乙酸乙酯:石油醚=1:20),得到暗黄色化合物d (2.32g, 4.58 mmol, 84.8%)。1HNMR (DMSO-d6, 400MHz) δ:4.73-4.68 (m, 1H), 4.57 (s, 1H), 3.60 (s, 3H), 2.98-2.82 (m, 2H), 2.72 (t, J=2.5Hz, 1H), 2.42 (ddd, J = 16.7, 4.3, 2.7 Hz, 1H),2.25-2.07 (m, 4H), 1.85-1.73 (m, 2H), 1.71-1.62 (m, 1H), 1.65 (s, 3H), 1.56(t, J = 11.4 Hz, 1H), 1.52-1.20 (m, 11H), 1.14-1.00 (m, 4H), 1.06 (s, 3H),0.97 (s, 3H), 0.97 (s, 3H), 0.93 (s, 3H), 0.91 (s, 3H). 13C NMR (DMSO-d6,100MHz) d 214.4, 175.6, 150.0, 109.8, 83.0, 72.0, 56.3, 55.8, 51.2, 49.2,48.7, 47.5, 46.6, 45.4, 42.1, 40.4, 40.1, 37.6, 36.8, 36.1, 33.5, 31.4, 29.9,29.1, 24.9, 24.8, 21.3, 20.7, 19.0, 18.8, 18.8, 15.7, 15.6, 14.3。
化合物e的合成:将化合物d (1.89 g, 3.7 mmol)溶于120 mL异丙醇,加入NaBH4(2.8 g, 7.4 mmol),室温搅拌过夜。反应完毕后滴加稀盐酸中和NaBH4,减压蒸馏除去异丙醇,乙酸乙酯萃取(3 × 100 mL),合并有机相用饱和碳酸氢钠溶液洗,无水Na2SO4干燥,过滤,减压除去溶剂。柱色谱分离(乙酸乙酯:石油醚=1:15)得到白色固体化合物e (0.98 g,1.9 mmol, 51.4%)。1H NMR (DMSO-d6, 400MHz) δ:4.70 (d, J = 2.1 Hz, 1H), 4.59-4.54 (m, 1H), 4.43 (d, J = 6.7 Hz, 1H), 3.60 (s, 3H), 2.92 (td, J = 10.7, 5.3Hz, 1H), 2.73-2.65 (m, 2H), 2.43 (dt, J = 16.5, 3.0 Hz, 1H), 2.22 – 1.98 (m,3H), 1.86-1.73 (m, 3H), 1.69-1.60 (m, 1H), 1.65 (s, 3H), 1.60-1.52 (m, 2H),1.51-0.96 (m, 13H), 0.94 (s, 3H), 0.87 (s, 3H), 0.85 (s, 3H), 0.79 (s, 3H),0.73-0.62 (m, 2H), 0.66 (s, 3H). 13C NMR (DMSO-d6, 100MHz) d 175.6, 150.0,109.7, 83.5, 79.2, 72.0, 55.8, 55.0, 51.2, 49.9, 48.7, 46.6, 44.1, 42.0,40.2, 38.8, 37.7, 36.7, 36.1, 34.4, 33.8, 31.4, 29.9, 29.1, 28.4, 24.9, 21.7,20.5, 18.8, 18.1, 16.6, 16.5, 15.6, 14.4。
化合物f的合成:将化合物e(508 mg, 1 mmol)溶于15 mLDMF,加入碘化锂(2.10g,15 mmol),加热回流24h(TLC监测)。反应完毕后加入10 mL水,10%盐酸中和后用乙酸乙酯萃取(3 × 30 mL)。柱分离得到白色固体化合物f(386 mg, 0.78 mmol, 78.0%)。1H NMR (CDCl3, 400MHz) δ:4.77-4.71 (m 1H), 4.63-4.57 (m, 1H), 3.07-2.95 (m, 2H),2.45-2.30 (m, 2H), 2.27 (dt, J=12.6, 2.9 Hz, 1H), 2.24-2.14 (m, 1H), 2.00-1.95 (m, 2H), 1.83 (dd, J=12.8, 3.6 Hz, 1H), 1.79-1.69 (m, 2H), 1.69 (s, 3H),1.66-1.16 (m, 13H), 1.12-1.02 (m, 1H), 0.98 (s, 6H), 0.94 (s, 3H), 0.87 (s,3H),0.85-0.80 (m, 1H), 0.78(s, 3H), 0.76-0.70 (m, 1H). 13C NMR ( CDCl3,100MHz) d 180.2, 150.3, 109.8, 82.9, 81.5, 70.0, 56.2, 55.4, 50.4, 49.2,46.9, 44.8, 42.5, 40.7, 39.1, 38.4, 37.3, 37.0, 34.8, 34.2, 32.1, 30.5, 29.6,28.3, 25.5, 22.4, 20.9, 19.3, 18.5, 16.99, 16.2, 16.0, 14.7。
化合物1的合成:将化合物f在50 mL圆底烧瓶中, 将化合物e(120 mg,0.24mmol)、叠氮核苷化合物2’-氟-4’-叠氮尿苷(57.0 mg, 0.20 mmol)、DIPEA(50 uL, 0.3mmol)溶于4 mL的叔丁醇/水混合溶剂中(V/V=1/1),搅拌15分钟后,加入碘化亚铜(4 mg,0.02 mmol,1mL乙腈悬浮液),室温搅拌直至反应完毕(TLC监测)。蒸干溶剂后直接柱层析分离,二氯甲烷/甲醇(6:1)分离得到白色固体化合物1 (76.5 mg,0.10mmol,产率48.8%)。1HNMR (DMSO-d6, 400MHz) δ: 12.03 (brs, 1H), 11.56 (s, 1H), 7.92 (s, 1H), 7.84(d, J=8.3Hz, 1H), 6.73 (t, J=7.0Hz, 1H), 6.30 (d, J=5.6 Hz, 1H), 5.94 (t, J=5.5 Hz, 1H), 5.75 (dd, J=8.1, 1.5 Hz, 1H), 5.42 (dt, J=55.4, 6.0 Hz, 1H),4.78 (dt, J=25.8, 5.7Hz, 1H), 4.67 (s, 1H), 4.57 (d, J=6.2 Hz, 1H), 4.55 (s,1H), 4.16 (ddd, J=31.0, 12.3, 5.8Hz, 2H), 3.21-3.08 (m, 1H), 2.99-2.85 (m,1H), 2.69 (dd, J=9.8, 6.3Hz, 1H), 2.32-2.04 (m, 3H), 1.90-1.71 (m, 3H), 1.68-1.54 (m, 2H), 1.63 (s, 3H), 1.54-1.20 (m,11H), 1.14-1.01 (m, 2H), 1.01-0.88(m, 1H), 0.91 (s, 3H), 0.91 (s, 3H), 0.84 (s, 3H), 0.71 (s, 3H), 0.71 (s,3H), 0.73-0.63 (m, 1H), 0.50 (t, J=12.4 Hz, 1H). 13C NMR (DMSO-d6, 100 MHz) δ:177.2, 162.8, 150.2, 145.1, 141.2, 122.2, 109.6, 101.8, 95.3 (d, J=10.9Hz),94.7 (d, J=192.3 Hz), 82.2 (d, J=16.0 Hz), 80.3, 74.0 (d, J=24.3 Hz), 60.6,55.4, 55.0, 49.9, 48.5, 46.6, 44.3, 42.0, 40.2, 38.9, 37.5, 36.7, 36.3, 35.5,33.8, 31.7, 30.0, 29.1, 28.5, 28.5, 25.0, 20.3, 18.9, 18.2, 16.7, 16.6, 16.6,15.7, 14.3。
参考上述化合物1的方法合成了化合物2-9,不同之处在于将步骤(3)中得到的化合物d与相应的叠氮核苷进行步骤(6)的click反应,或者将步骤(4)中得到的化合物e与相应的叠氮核苷进行步骤(6)的click反应,或者将步骤(5)中得到的化合物f与相应的叠氮核苷进行步骤(6)的click反应,所得化合物(化合物2、化合物3、化合物4、化合物5、化合物6、化合物7、化合物8以及化合物9)的表征数据如下:
(1)化合物2
表征数据:白色固体,收率77.1%.1H NMR (MeOH-d4, 400 MHz) δ: 8.02 (d, J =8.0 Hz, 1H), 8.25-7.76 (m, 1H), 6.34 (d, J = 4.7 Hz, 1H), 5.79 (d, J = 8.2Hz, 1H), 4.70 (s, 1H), 4.65-4.53 (m, 3H), 4.45 (d, J = 11.6 Hz, 1H), 3.98 (d,J = 11.2 Hz, 1H), 3.64 (s, 3H), 3.22-3.05 (m, 1H), 3.03-2.71 (m, 2H), 2.69-2.38 (m, 1H), 2.29-2.12 (m, 2H), 2.10-1.78 (m, 3H), 1.68 (s, 3H), 0.98 (s,6H), 0.90 (s, 3H), 0.81 (s, 6H), 0.75-0.68 (m, 1H), 0.68-0.55 (m, 1H). 13C NMR(MeOH-d4, 100 MHz) δ: 178.2, 165.9, 152.6, 151.7, 142.9, 110.5, 103.7, 101.9,101.4, 91.5, 82.9, 74.5, 73.9, 65.9, 57.9, 57.1, 54.9, 51.9, 50.7, 48.5,46.3, 43.6, 42.0, 39.7, 38.5, 38.0, 35.6, 33.2, 31.7, 30.9, 29.1, 26.8, 22.1,19.8, 19.7, 17.6, 17.2, 16.7, 15.3。
(2)化合物3
表征数据:白色固体,收率74.8%. 1H NMR( CDCl3, 400MHz) δ:9.73 (s, 1H),7.56 (s, 2H), 6.29 (t, J = 6.4 Hz, 1H), 5.47-5.34 (m, 1H), 4.72 (s, 1H), 4.58(s, 1H), 4.45-4.34 (m, 1H), 4.11-3.94 (m, 2H), 3.88-3.74 (m, 1H), 3.67 (s,3H), 3.24-3.12 (m, 1H), 3.09 (dd, J=14.4, 6.9 Hz, 1H), 3.03-2.83 (m, 3H),2.60 (dd, J = 14.4, 4.2 Hz, 1H), 2.27-2.08 (m, 3H), 1.94-1.83 (m, 2H), 1.90(s, 3H), 1.76-1.65 (m, 1H), 1.67 (s, 3H), 1.60-1.51 (m, 2H),1.48-1.23 (m,10H), 1.16-1.06 (m, 3H), 1.12 (s, 3H), 1.03 (s, 3H), 1.02 (s, 3H), 0.96 (s,3H), 0.94 (s, 3H).13C NMR ( CDCl3, 100MHz)δ:217.4, 176.6, 164.1, 150.5, 150.3,146.8, 137.7, 122.4, 111.0, 109.7, 87.9, 85.2, 61.3, 58.9, 57.5, 56.4, 51.2,50.0, 49.3, 48.5, 47.9, 46.9, 42.4, 42.2, 40.7, 38.1, 37.6, 37.5, 36.9, 34.0,32.1, 30.4, 29.5, 26.4, 25.3, 24.9, 21.4, 21.1, 19.2, 19.2, 16.1, 16.0, 14.6,12.4。
(3)化合物4
表征数据:白色固体,收率72.6%.1H NMR (MeOH-d4, 400 MHz) δ: 7.98 (d, J =7.5 Hz, 1H), 7.94 (s, 1H), 6.29 (d, J = 5.5 Hz, 1H), 5.97 (brs, 1H), 4.70 (s,1H), 4.66-4.53 (m, 3H), 4.41 (d, J = 12.0 Hz, 1H), 3.99 (d, J = 11.9 Hz, 1H),3.66 (s, 3H), 3.24-3.09 (m, 2H), 2.98 (td, J = 10.6, 4.5 Hz, 1H), 2.59 (dd, J= 14.1, 6.8 Hz, 1H), 2.30-2.16 (m, 2H), 2.06 (dd, J = 12.6, 5.2Hz, 1H), 1.93-1.78 (m, 2H), 1.68 (s, 3H), 1.12 (s, 3H), 1.07 (s, 3H), 1.04 (s, 3H), 0.99(s, 3H), 0.98 (s, 3H). 13C NMR (MeOH-d4, 100MHz) δ: 218.6, 178.2, 167.9,158.6, 151.8, 146.2, 143.8, 124.1, 110.5, 100.9, 96.9, 93.5, 74.8, 73.9,66.0, 58.9, 58.0, 51.9, 51.5, 50.7, 49.6, 48.6, 48.3, 43.7, 43.6, 42.1, 39.7,38.8, 37.9, 35.4, 33.2, 31.7, 30.9, 27.1, 26.8, 25.7, 22.3, 22.1, 20.5, 19.6,16.8, 16.6, 15.2。
(4)化合物5
表征数据:白色固体,收率55.4%.1H NMR (MeOH-d4, 400 MHz) δ: 8.00 (d, J =7.6 Hz, 1H), 7.96 (s, 1H), 6.32 (d, J = 5.2 Hz, 1H), 5.98 (d, J = 6.7 Hz,1H), 4.69 (d, J = 1.7 Hz, 1H), 4.63-4.55 (m, 3H), 4.43 (d, J = 11.9 Hz, 1H),3.99 (d, J = 11.9 Hz, 1H), 3.13 (dd, J = 14.4, 2.7 Hz, 1H), 3.00 (td, J =10.7, 4.5 Hz, 1H), 2.82 (d, J = 10.5 Hz, 1H), 2.54 (dd, J = 14.0, 8.8 Hz,1H), 2.32-2.18 (m, 2H), 1.99-1.84 (m, 3H), 1.68 (s, 3H), 0.98 (s, 3H), 0.97(s, 3H), 0.93 (s, 3H), 0.81 (s, 3H), 0.80 (s, 3H), 0.75-0.68 (m, 1H), 0.60(t, J = 12.8 Hz, 1H). 13C NMR (MeOH-d4, 100 MHz) δ: 180.1, 167.7, 158.3,152.0, 146.2, 143.9, 124.0, 110.3, 101.0, 93.3, 91.4, 82.9, 74.8, 73.9, 66.0,57.5, 57.1, 52.0, 50.5, 48.6, 46.2, 43.7, 42.0, 40.5, 39.7, 38.5, 38.2, 37.3,35.6, 33.4, 31.8, 30.9, 29.7, 29.1, 26.9, 22.1, 19.8, 19.7, 17.5, 17.1, 16.7,15.2。
(5)化合物6
表征数据:白色固体,收率60.4%. 1H NMR (DMSO-d6, 400MHz) δ:7.90 (s, 1H),7.77 (d, J = 7.5 Hz, 1H), 7.33 (br, 1H), 7.29 (br, 1H), 6.83-6.68 (m, 1H),6.22 (d, J = 5.4 Hz, 1H), 5.85 (t, J = 4.8 Hz, 1H), 5.80 (d, J = 7.3 Hz, 1H),5.32 (dt, J = 55.5, 5.6 Hz, 1H), 4.79-4.64 (m, 2H), 4.61-4.51 (m, 2H), 4.21-4.07 (m, 2H), 3.58 (s, 3H), 3.14 (d, J = 13.4 Hz, 1H), 2.89 (td, J=10.4, 5.0Hz, 1H), 2.68 (dd, J = 10.3, 6.5 Hz, 1H), 2.26 (dd, J = 14.2, 9.7 Hz, 1H),2.18-2.04 (m, 2H), 1.86-1.72 (m, 3H), 1.64 (s, 3H), 1.62-1.53 (m, 3H), 1.47-1.03 (m, 13H), 0.91 (s, 3H), 0.90 (s, 3H), 0.81 (s, 3H), 0.71 (s, 3H), 0.70(s, 3H), 0.73-0.63 (m, 1H), 0.49 (t, J = 12.7 Hz, 1H). 13C NMR (DMSO-d6,400MHz) δ:175.6, 165.6, 154.7, 150.0, 144.9, 141.8, 122.0, 109.8, 94.7 (d, J=191.6 Hz), 95.4 (d, J = 10.3 Hz), 94.1, 82.9, 80.3, 74.2 (d, J = 24.5 Hz),60.8, 55.8, 55.0, 51.2, 49.8, 48.7, 46.6, 44.3, 41.9, 40.1, 38.9, 37.6, 36.7,36.1, 35.5, 33.8, 31.4, 30.0, 29.1, 28.5, 28.5, 25.0, 20.3, 18.9, 18.2, 16.6,16.6, 15.6, 14.4。
(6)化合物7
表征数据:白色固体,收率64.8%.1H NMR (MeOH-d4, 400 MHz) δ: 8.02 (d, J =8.0 Hz, 1H), 6.34 (d, J = 4.7 Hz, 1H), 5.79 (d, J = 8.2 Hz, 1H), 4.70 (s,1H), 4.65-4.53 (m, 2H), 4.47 (d, J = 11.2 Hz, 1H), 3.94 (d, J = 11.2 Hz, 1H),3.64 (s, 3H), 3.22-3.05 (m, 1H), 3.03-2.71 (m, 2H), 2.69-2.38 (m, 3H), 2.29-2.12 (m, 2H), 2.10-1.78 (m, 3H), 1.68 (s, 3H), 0.98 (s, 6H), 0.90 (s, 3H),0.81 (s, 6H), 0.75-0.68 (m, 1H), 0.68-0.55 (m, 1H). 13C NMR (MeOH-d4, 100 MHz)δ: 178.2, 165.9, 152.6, 151.7, 142.9, 110.5, 103.7, 101.9, 101.4, 91.5, 82.9,73.9, 65.9, 57.9, 57.1, 54.9, 51.9, 50.7, 48.5, 46.3, 43.6, 42.0, 39.7, 38.9,38.5, 38.0, 35.6, 33.2, 31.7, 30.9, 29.1, 26.8, 22.1, 19.8, 19.7, 17.6, 17.2,16.7, 15.3。
(7)化合物8
表征数据:白色固体,收率71.1%。1H NMR (MeOH-d4, 400 MHz) δ: 7.98 (d, J =7.5 Hz, 1H), 7.94 (s, 1H), 6.29 (d, J = 5.5 Hz, 1H), 5.97 (brs, 1H), 4.70 (s,1H), 4.66-4.53 (m, 2H), 4.41 (d, J = 12.0 Hz, 1H), 3.99 (d, J = 11.9 Hz, 1H),3.66 (s, 3H), 3.24-3.09 (m, 2H), 2.98 (td, J = 10.6, 4.5 Hz, 1H), 2.59 (dd, J= 14.1, 6.8 Hz, 1H), 2.40-2.16 (m, 4H), 2.06 (dd, J = 12.6, 5.2Hz, 1H), 1.93-1.78 (m, 2H), 1.68 (s, 3H), 1.12 (s, 3H), 1.07 (s, 3H), 1.04 (s, 3H), 0.99(s, 3H), 0.98 (s, 3H). 13C NMR (MeOH-d4, 100MHz) δ: 218.6, 178.2, 167.9,158.6, 151.8, 146.2, 143.8, 124.1, 110.5, 100.9, 96.9, 93.5, 73.9, 66.0,58.9, 58.0, 51.9, 51.5, 50.7, 49.6, 48.6, 48.3, 43.7, 43.6, 42.1, 39.7, 38.8,37.9, 36.8, 35.4, 33.2, 31.7, 30.9, 27.1, 26.8, 25.7, 22.3, 22.1, 20.5, 19.6,16.8, 16.6, 15.2。
(8)化合物9
表征数据:白色固体,收率66.2%。1H NMR (MeOH-d4, 400 MHz) δ: 8.03 (d, J =8.1 Hz, 1H), 5.94 (dd, J = 17.3, 1.5 Hz, 1H), 5.72 (d, J=8.1 Hz, 1H), 4.89-5.08 (m, 1H), 4.69 (d, J = 1.7 Hz, 1H), 4.59 (s, 1H), 4.43 (d, J = 11.9 Hz,1H), 4.31 (ddd, J=21.8, 8.2, 4.3 Hz, 1H), 4.00 (d, J = 11.9 Hz, 1H), 3.64 (s,3H), 3.13 (d, J = 11.7 Hz, 1H), 2.97 (td, J = 10.9, 4.8 Hz, 1H), 2.82 (d, J =10.7 Hz, 1H), 2.56 (dd, J = 14.1, 8.8 Hz, 1H), 2.28-2.14 (m, 2H), 2.01-1.80(m, 3H), 1.68 (s, 3H), 0.97 (s, 6H), 0.90 (s, 3H), 0.81 (s, 3H), 0.80 (s,3H), 0.75-0.65 (m, 1H), 0.61 (t, J = 12.6 Hz, 1H).13C NMR (MeOH-d4, 100 MHz)δ: 178.2, 167.6, 151.8, 146.3, 143.7, 124.0, 110.4, 95.3 (d, J=186.4 Hz),94.7, 90.6 (d, J=34.6 Hz), 82.9, 69.2 (d, J=16.7 Hz), 58.0, 57.0, 52.0, 51.9,50.7, 48.6, 46.2, 43.6, 42.0, 40.5, 39.7, 38.5, 38.0, 37.3, 35.6, 33.2, 31.7,30.9, 29.8, 29.1, 26.9, 22.1, 19.8, 19.7, 17.5, 17.1, 16.6, 15.3。
实施例1 抑菌活性测定
1 材料与方法
1.1 材料
离心管(2mL,15mL)、锥形瓶(250 mL)、牛津杯(内径6.0 mm,高10.0 mm,外径8.0mm)、比色皿。
1.2 试剂
蛋白胨、酵母粉、NaCl、琼脂粉、二甲基亚砜(DMSO)。
1.3 培养基配制
(1)LB液体培养基:胰蛋白胨10 g,酵母提取物5 g,氯化钠10 g,加入1000 mLddH2O完全溶解后,调pH值至7.3±0.1,121℃灭菌20 min,固体培养基加入1-2%的琼脂。
(2)素琼脂:称取1.6 g琼脂粉于100 mL蒸馏水中,121℃灭菌20 min,备用。
1.4 指示菌菌悬液的准备
(1)菌株:大肠杆菌CICC 10389、金黄色葡萄球菌 CICC 21600和沙门氏菌CICC21513。
(2)指示菌稀释:取斜面培养基新鲜培养物,吸取5.0 mL培养液加入斜面试管内,反复吹吸,洗下菌苔。随后将洗液移至另一无菌试管中,用电动混合器混合(振荡)20 s,以使细菌悬浮均匀。先用细菌浓度比浊测定法粗测其含菌浓度,然后以培养液稀释为0.5麦氏比浊标准。此时菌液浓度在1.5×108 CFU/mL左右。
1.5 待测样品前处理
将受试化合物分别用DMSO将稀释至200μg/mL待用,以200μg/mL沙拉沙星为阳性对照,DMSO溶液为阴性对照。
1.6抑菌试验
(1)于超净工作台内,向每个灭菌培养皿中倾注约10 mL的素琼脂进行铺底,每个培养皿厚度均一,待素琼脂冷却凝固,备用。
(2)吸取调制好的指示菌菌液1mL加入到100 mL恒温至50℃左右的LB固体培养基中,轻轻摇匀(避免起泡,此时指示菌在培养基中的浓度为106 CFU/mL),向每个培养皿倒10mL,将该层均匀铺平,待其冷却凝固。
(3)在平板背面做好浓度梯度标记,将灭菌好的牛津杯置于菌层培养基之上。
(4)吸取150 μL的样液加入到相应的牛津杯内。
(5)将加过样的培养皿放入4℃的冰箱中预扩散4小时。
(6)将上述培养皿移入培养箱中37℃过夜培养。
(7)培养结束后,用镊子去掉牛津杯,然后用游标卡尺测量抑菌圈直径,测量时通过圆心,并记录测量结果。
1.7 受试化合物的抑菌效果
由表1可知,沙门氏菌普遍对化合物1-4、6-9高敏;大肠杆菌对4种化合物高敏,对5种化合物中敏;金黄色葡萄球菌普遍对化合物中敏;三种细菌除对对照化合物5均为中敏外,至少一种细菌对其他化合物为高敏。表明化合物有广泛的抑菌活性,且活性优于对照化合物5。
表1 化合物1-9的抑菌圈直径(mm)
注:牛津杯直径8 mm,抑菌圈直径10mm以下为低敏,10-14mm为中敏,15-20mm为高敏,20mm以上为极敏。
实施例2 最低抑菌浓度(MIC)测定
1.1 试验菌株
大肠杆菌CICC 10389、金黄色葡萄球菌 CICC 21600和沙门氏菌CICC 21513。
1.2 操作步骤
(1)MIC板制备:将用培养液倍比稀释后不同浓度的抗菌药物溶液分别加到灭菌的96孔聚苯乙烯板中,第1至第11孔加药液,每孔100 μL,第12孔不加药作为生长对照。
(2)接种物制备:取斜面培养基新鲜培养物,吸取5.0 mL培养液加入斜面试管内,反复吹吸,洗下菌苔。随后将洗液移至另一无菌试管中,用电动混合器混合(振荡)20 s,以使细菌悬浮均匀。先用细菌浓度比浊测定法粗测其含菌浓度,然后以培养液稀释为0.5麦氏比浊标准。经培养液1∶1000稀释后,取100 μL菌悬液接种于含抗(抑)菌剂的MIC板,作为试验组样本。此时,第1孔至第11孔药物浓度分别为128、64、32、16、8、4、2、1、0.5、0.25、0.125μg/mL。
(3)细菌培养:将MIC板放置36 ℃培养箱中,培养24 h;观察结果。
1.3 受试化合物的测试结果
当阳性对照有微生物生长(混浊),阴性对照无菌生长(透明)时,试验组无菌生长的最高稀释度所对应的抗(抑)菌剂浓度,为该样品对受试菌的MIC。
由表2可知,受试化合物均有抑菌效果,对沙门氏菌的抑菌效果最好,大肠杆菌其次,且效果优于对照化合物5。
表2 最小抑菌浓度MIC (μg/mL)
本发明实施例还提供一种式(I)所示的化合物或其药学上可接受的盐作为抑制细菌药物的应用。
本发明还提供一种抑制细菌感染的方法,包括给予患者治疗有效量的式(I)所示的化合物或其药学上可接受的盐,从而治疗细菌感染。
本发明还提供一种式(I)所示的化合物或其药学上可接受的盐,其具有抑制细菌活性。
本发明还提供一种抑制细菌的药物组合物,包括式(I)所示的化合物或其药学上可接受的盐中的至少一种。
根据本发明的实施方案,所述药物组合物还包括至少一种药学上可接受的载体。
除非另有说明,本申请中记载的基团和术语定义,包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等,可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构,应当属于本申请说明书记载的范围内。
除非另有说明,本申请记载的数值范围相当于至少记载了其中每一个具体的整数数值。例如,数值范围“1-40”相当于记载了数值范围“1-10”中的每一个整数数值即1、2、3、4、5、6、7、8、9、10,以及数值范围“11-40”中的每一个整数数值即11、12、13、14、15、......、35、36、37、38、39、40。此外,当某些数值范围被定义为“数”时,应当理解为记载了该范围的两个端点、该范围内的每一个整数以及该范围内的每一个小数。例如,“0~10的数”应当理解为不仅记载了0、1、2、3、4、5、6、7、8、9和10的每一个整数,还至少记载了其中每一个整数分别与0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9的和。
应当理解,在描述1、2个或更多个中,“更多个”应当是指大于2,例如大于等于3的整数,例如3、4、5、6、7、8、9或10。
术语“卤素”表示氟、氯、溴和碘。
术语“C1-40烷基”应理解为表示具有1~40个碳原子的直链或支链饱和一价烃基。例如,“C1-6烷基”表示具有1、2、3、4、5或6个碳原子的直链和支链烷基。所述烷基是例如甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基等或它们的异构体。
术语“C2-40烯基”应理解为优选表示直连或支链的一价烃基,其包含一个或多个双键并且具有2~40个碳原子,优选“C2-10烯基”。“C2-10烯基”应理解为优选表示直连或支链的一价烃基,其包含一个或多个双键并且具有2、3、4、5、6、7、8、9或10个碳原子,例如,具有2、3、4、5或6个碳原子(即,C2-6烯基),具有2或3个碳原子(即,C2-3烯基)。应理解,在所述烯基包含多于一个双键的情况下,所述双键可相互分离或者共轭。所述烯基是例如乙烯基、烯丙基、(E)-2-甲基乙烯基、(Z)-2-甲基乙烯基、(E)-丁-2-烯基、(Z)-丁-2-烯基、(E)-丁-1-烯基、(Z)-丁-1-烯基、戊-4-烯基、(E)-戊-3-烯基、(Z)-戊-3-烯基、(E)-戊-2-烯基、(Z)-戊-2-烯基、(E)-戊-1-烯基、(Z)-戊-1-烯基、己-5-烯基、(E)-己-4-烯基、(Z)-己-4-烯基、(E)-己-3-烯基、(Z)-己-3-烯基、(E)-己-2-烯基、(Z)-己-2-烯基、(E)-己-1-烯基、(Z)-己-1-烯基、异丙烯基、2-甲基丙-2-烯基、1-甲基丙-2-烯基、2-甲基丙-1-烯基、(E)-1-甲基丙-1-烯基、(Z)-1-甲基丙-1-烯基、3-甲基丁-3-烯基、2-甲基丁-3-烯基、1-甲基丁-3-烯基、3-甲基丁-2-烯基、(E)-2-甲基丁-2-烯基、(Z)-2-甲基丁-2-烯基、(E)-1-甲基丁-2-烯基、(Z)-1-甲基丁-2-烯基、(E)-3-甲基丁-1-烯基、(Z)-3-甲基丁-1-烯基、(E)-2-甲基丁-1-烯基、(Z)-2-甲基丁-1-烯基、(E)-1-甲基丁-1-烯基、(Z)-1-甲基丁-1-烯基、1,1-二甲基丙-2-烯基、1-乙基丙-1-烯基、1-丙基乙烯基、1-异丙基乙烯基。
术语“C2-40炔基”应理解为表示直连或支链的一价烃基,其包含一个或多个三键并且具有2~40个碳原子,优选“C2-10炔基”。术语“C2-10炔基”应理解为优选表示直连或支链的一价烃基,其包含一个或多个三键并且具有2、3、4、5、6、7、8、9或10个碳原子,例如,具有2、3、4、5或6个碳原子(即,“C2-6炔基”),具有2或3个碳原子(“C2-3炔基”)。所述炔基是例如乙炔基、丙-1-炔基、丙-2-炔基、丁-1-炔基、丁-2-炔基、丁-3-炔基、戊-1-炔基、戊-2-炔基、戊-3-炔基、戊-4-炔基、己-1-炔基、己-2-炔基、己-3-炔基、己-4-炔基、己-5-炔基、1-甲基丙-2-炔基、2-甲基丁-3-炔基、1-甲基丁-3-炔基、1-甲基丁-2-炔基、3-甲基丁-1-炔基、1-乙基丙-2-炔基、3-甲基戊-4-炔基、2-甲基戊-4-炔基、1-甲基戊-4-炔基、2-甲基戊-3-炔基、1-甲基戊-3-炔基、4-甲基戊-2-炔基、1-甲基戊-2-炔基、4-甲基戊-1-炔基、3-甲基戊-1-炔基、2-乙基丁-3-炔基、1-乙基丁-3-炔基、1-乙基丁-2-炔基、1-丙基丙-2-炔基、1-异丙基丙-2-炔基、2,2-二甲基丁-3-炔基、1,1-二甲基丁-3-炔基、1,1-二甲基丁-2-炔基或3,3-二甲基丁-1-炔基。特别地,所述炔基是乙炔基、丙-1-炔基或丙-2-炔基。
术语“C3-20环烷基”应理解为表示饱和的一价单环、双环烃环或桥环烷烃,其具有3~20个碳原子,优选“C3-10环烷基”。术语“C3-10环烷基”应理解为表示饱和的一价单环、双环烃环或桥环烷烃,其具有3、4、5、6、7、8、9或10个碳原子。所述C3-10环烷基可以是单环烃基,如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基或环癸基,或者是双环烃基如十氢化萘环。
术语“3-20元杂环基”意指饱和的一价单环、双环烃环或桥环烷烃,其包含1-5个独立选自N、O和S的杂原子的总成环原子数为3-20(如原子数为3、4、5、6、7、8、9、10等)的非芳族环状基团,优选“3-10元杂环基”。术语“3-10元杂环基”意指饱和的一价单环、双环烃环或桥环烷烃,其包含1-5个,优选1-3个选自N、O和S的杂原子。所述杂环基可以通过所述碳原子中的任一个或氮原子(如果存在的话)与分子的其余部分连接。特别地,所述杂环基可以包括但不限于:4元环,如氮杂环丁烷基、氧杂环丁烷基;5元环,如四氢呋喃基、二氧杂环戊烯基、吡咯烷基、咪唑烷基、吡唑烷基、吡咯啉基;或6元环,如四氢吡喃基、哌啶基、吗啉基、二噻烷基、硫代吗啉基、哌嗪基或三噻烷基;或7元环,如二氮杂环庚烷基。任选地,所述杂环基可以是苯并稠合的。所述杂环基可以是双环的,例如但不限于5,5元环,如六氢环戊并[c]吡咯-2(1H)-基环,或者5,6元双环,如六氢吡咯并[1,2-a]吡嗪-2(1H)-基环。含氮原子的环可以是部分不饱和的,即它可以包含一个或多个双键,例如但不限于2,5-二氢-1H-吡咯基、4H-[1,3,4]噻二嗪基、4,5-二氢恶唑基或4H-[1,4]噻嗪基,或者,它可以是苯并稠合的,例如但不限于二氢异喹啉基。根据本发明,所述杂环基是无芳香性的。所述3-20元杂环基与其它基团相连构成本发明的化合物时,可以为3-20元杂环基上的碳原子与其它基团相连,也可以为3-20元杂环基环上杂环原子与其它基团相连。例如当3-20元杂环基选自哌嗪基时,可以为哌嗪基上的氮原子与其它基团相连。或当3-20元杂环基选自哌啶基时,可以为哌啶基环上的氮原子和其对位上的碳原子与其它基团相连。
术语“C6-20芳基”应理解为优选表示具有6~20个碳原子的一价芳香性或部分芳香性的单环、双环或三环烃环,优选“C6-14芳基”。术语“C6-14芳基”应理解为优选表示具有6、7、8、9、10、11、12、13或14个碳原子的一价芳香性或部分芳香性的单环、双环或三环烃环(“C6-14芳基”),特别是具有6个碳原子的环(“C6芳基”),例如苯基;或联苯基,或者是具有9个碳原子的环(“C9芳基”),例如茚满基或茚基,或者是具有10个碳原子的环(“C10芳基”),例如四氢化萘基、二氢萘基或萘基,或者是具有13个碳原子的环(“C13芳基”),例如芴基,或者是具有14个碳原子的环(“C14芳基”),例如蒽基。当所述C6-20芳基被取代时,其可以为单取代或者多取代。并且,对其取代位点没有限制,例如可以为邻位、对位或间位取代。
术语“5-20元杂芳基”应理解为包括这样的一价单环、双环或三环芳族环系:其具有5~20个环原子且包含1-5个独立选自N、O和S的杂原子,例如“5-14元杂芳基”。术语“5-14元杂芳基”应理解为包括这样的一价单环、双环或三环芳族环系:其具有5、6、7、8、9、10、11、12、13或14个环原子,特别是5或6或9或10个碳原子,且其包含1-5个,优选1-3各独立选自N、O和S的杂原子并且,另外在每一种情况下可为苯并稠合的。特别地,杂芳基选自噻吩基、呋喃基、吡咯基、恶唑基、噻唑基、咪唑基、吡唑基、异恶唑基、异噻唑基、恶二唑基、三唑基、噻二唑基、噻-4H-吡唑基等以及它们的苯并衍生物,例如苯并呋喃基、苯并噻吩基、苯并恶唑基、苯并异恶唑基、苯并咪唑基、苯并三唑基、吲唑基、吲哚基、异吲哚基等;或吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基等,以及它们的苯并衍生物,例如喹啉基、喹唑啉基、异喹啉基等;或吖辛因基、吲嗪基、嘌呤基等以及它们的苯并衍生物;或噌啉基、酞嗪基、喹唑啉基、喹喔啉基、萘啶基、蝶啶基、咔唑基、吖啶基、吩嗪基、吩噻嗪基、吩恶嗪基等。当所述5-20元杂芳基与其它基团相连构成本发明的化合物时,可以为5-20元杂芳基环上的碳原子与其它基团相连,也可以为5-20元杂芳基环上的杂原子与其它基团相连。当所述5-20元杂芳基被取代时,其可以为单取代或者多取代。并且,对其取代位点没有限制,例如可以为杂芳基环上与碳原子相连的氢被取代,或者杂芳基环上与杂原子相连的氢被取代。
除非另有说明,杂环基、杂芳基或亚杂芳基包括其所有可能的异构形式,例如其位置异构体。因此,对于一些说明性的非限制性实例,可以包括在其1-、2-、3-、4-、5-、6-、7-、8-、9-、10-、11-、12-位等(如果存在)中的一个、两个或更多个位置上取代或与其他基团键合的形式,包括吡啶-2-基、亚吡啶-2-基、吡啶-3-基、亚吡啶-3-基、吡啶-4-基和亚吡啶-4-基;噻吩基或亚噻吩基包括噻吩-2-基、亚噻吩-2-基、噻吩-3-基和亚噻吩-3-基;吡唑-1-基、吡唑-3-基、吡唑-4-基、吡唑-5-基。
除非另有说明,本文中术语的定义同样适用于包含该术语的基团,例如C1-40烷基的定义也适用于C1-40烷氧基等。
本领域技术人员可以理解,式I所示化合物可以以各种药学上可接受的盐的形式存在。如果这些化合物具有碱性中心,则其可以形成酸加成盐;如果这些化合物具有酸性中心,则其可以形成碱加成盐;如果这些化合物既包含酸性中心(例如羧基)又包含碱性中心(例如氨基),则其还可以形成内盐。酸加成盐包括但不限于:盐酸盐、氢氟酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、焦硫酸盐、磷酸盐、硝酸盐、甲磺酸盐、乙磺酸盐、2-羟基乙磺酸盐、苯磺酸盐、甲苯磺酸盐、氨基磺酸盐、2-萘磺酸盐、甲酸盐、乙酰乙酸、丙酮酸、月硅酸酯、肉桂酸酯、苯甲酸盐、醋酸盐、二羟乙酸盐、三氟乙酸盐、三甲基乙酸盐、丙酸盐、丁酸盐、己酸盐、庚酸盐、十一酸盐、硬脂酸盐、抗坏血酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、富马酸盐、苹果酸盐、马来酸盐、羟基马来酸盐、草酸盐、水杨酸盐、琥珀酸盐、葡萄糖酸盐、奎尼酸盐、双羟萘酸盐、甘醇酸盐、酒石酸盐、乳酸盐、2-(4-羟基苯甲酰基)苯甲酸盐、环戊烷丙酸盐、二葡糖酸盐、3-羟基-2-萘甲酸盐、烟酸盐、扑酸盐、果胶酯酸盐、3-苯基丙酸盐、苦味酸盐、特戊酸盐、衣康酸盐、三氟甲磺酸盐、十二烷基硫酸盐、对甲苯磺酸盐、萘二磺酸盐、丙二酸盐、己二酸盐、藻酸盐、扁桃酸盐、葡庚酸盐、甘油磷酸盐、磺基水杨酸盐、半硫酸或硫氰酸盐、天冬氨酸盐等;碱加成盐例如碱金属盐、碱土金属盐和铵盐等,具体包括但不限于:钠盐、锂盐、钾盐、铵盐、铝盐、镁盐、钙盐、钡盐、铁盐、亚铁盐、锰盐、亚锰盐、锌盐、铵盐(包括与NH3和有机胺形成的盐(NH4盐)、甲铵盐、三甲铵盐、二乙铵盐、三乙铵盐、丙铵盐、三丙铵盐、异丙铵盐、叔丁铵盐、N,N'-二苄基乙二铵盐、二环己铵盐、1,6-己二铵盐、苄铵盐、乙醇铵盐、N, N-二甲基乙醇铵盐、N,N-二乙基乙醇铵盐、三乙醇铵盐、氨丁三醇盐、赖氨酸盐、精氨酸盐、组氨酸盐、葡糖铵盐、N-甲基葡糖铵盐、二甲基葡糖铵盐、乙基葡糖铵盐、葡甲铵盐、甜菜碱盐、咖啡因盐、氯普鲁卡因盐、普鲁卡因盐、利多卡因盐、吡啶盐、甲基吡啶盐、哌啶盐、吗啉盐、哌嗪盐、嘌呤盐、可可碱盐、胆碱盐)等。
根据其分子结构,本发明的化合物是手性的,因此可能存在各种对映异构体形式。因而这些化合物可以以消旋体形式或光学活性形式存在。本发明的化合物或其中间体可以通过本领域技术人员公知的化学或物理方法分离为对映异构体化合物,或者以此形式用于合成。在外消旋的胺的情况中,通过与光学活性的拆分试剂反应,从混合物制得非对映异构体。适当的拆分试剂的示例是光学活性的酸,例如R和S形式的酒石酸、二乙酰酒石酸、二苯甲酰酒石酸、扁桃酸、苹果酸、乳酸、适当的N-保护的氨基酸(例如N-苯甲酰脯氨酸或N-苯磺酰基脯氨酸)或各种光学活性的樟脑磺酸。借助光学活性的拆分试剂(例如固定在硅胶上的二硝基苯甲酰基苯基甘氨酸、三乙酸纤维素或其它碳水化合物的衍生物或手性衍生化的异丁烯酸酯聚合物),也可有利地进行色谱对映体拆分。用于此目的的适当的洗脱剂是含水或含醇的溶剂混合物,例如,己烷/异丙醇/乙腈。
术语“互变异构体”(tautomerism)包括本领域技术人员已知的那些互变异构形式,例如选自烯醇式-酮式、酰胺式-亚胺酸式、内酰胺式-内酰亚胺式、烯胺式-亚胺烯胺式-烯胺式等的互变异构体。
可以根据已知的方法,例如通过萃取、过滤或柱层析来分离相应的稳定异构体。
术语“患者”是指包括哺乳动物在内的任何动物,优选小鼠、大鼠、其它啮齿类动物、兔、狗、猫、猪、牛、羊、马或灵长类动物,最优选人。
使用的短语“治疗有效量”是指研究人员、兽医、医师或其它临床医师正在组织、系统、动物、个体或人中寻找的引起生物学或医学反应的活性化合物或药物的量,它包括以下一项或多项:(1)预防疾病:例如在易感染疾病、紊乱或病症但尚未经历或出现疾病病理或症状的个体中预防疾病、紊乱或病症。(2)抑制疾病:例如在正经历或出现疾病、紊乱或病症的病理或症状的个体中抑制疾病、紊乱或病症(即阻止病理和/或症状的进一步发展)。(3)缓解疾病:例如在正经历或出现疾病、紊乱或病症的病理或症状的个体中缓解疾病、紊乱或病症(即逆转病理和/或症状)。
以上各实施例仅用以说明本发明的技术方案,而非对其限制;尽管参照前述各实施例对本发明进行了详细的说明,本领域的普通技术人员应当理解:其依然可以对前述各实施例所记载的技术方案进行修改,或者对其中部分或者全部技术特征进行等同替换;而这些修改或者替换,并不使相应技术方案的本质脱离本发明各实施例技术方案的范围,其均应涵盖在本发明的权利要求和说明书的范围当中。
Claims (3)
1.一种具备抑制细菌用途的白桦脂酸衍生物,其特征在于,所述白桦脂酸衍生物具有如下式(Ⅰ-5)所示的结构:
其中,X选自O;
Y选自OH或NH2;
R0选自F、OH或H;
R1选自H或甲基;
其中,式(Ⅰ-5)所述的白桦脂酸衍生物选自如下化合物:
。
2.根据权利要求1所述的具备抑制细菌用途的白桦脂酸衍生物,其特征在于,当R0选自H时,与R0相连接的碳原子选自R构型或S构型。
3.根据权利要求1所述的具备抑制细菌用途的白桦脂酸衍生物,其特征在于,所述细菌选自革兰氏阴性菌,为沙门氏菌、大肠杆菌;
或选自革兰氏阳性菌,为金黄色葡萄球菌。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202311575224.0A CN117327140B (zh) | 2023-11-24 | 2023-11-24 | 一种具备抑制细菌用途的白桦脂酸衍生物 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202311575224.0A CN117327140B (zh) | 2023-11-24 | 2023-11-24 | 一种具备抑制细菌用途的白桦脂酸衍生物 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN117327140A CN117327140A (zh) | 2024-01-02 |
CN117327140B true CN117327140B (zh) | 2024-03-12 |
Family
ID=89283323
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202311575224.0A Active CN117327140B (zh) | 2023-11-24 | 2023-11-24 | 一种具备抑制细菌用途的白桦脂酸衍生物 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN117327140B (zh) |
Citations (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014031681A1 (en) * | 2012-08-20 | 2014-02-27 | The University Of Chicago | Inhibiting gram positive bacteria |
CN104940211A (zh) * | 2015-06-08 | 2015-09-30 | 曹晓宏 | 白桦脂酸在制备抗真菌生物被膜药物中的应用 |
US20150368291A1 (en) * | 2014-06-20 | 2015-12-24 | Northeast Forestry University | N-acetyl amino acid ESTER derivatives of Betulin and preparation method thereof |
CN108503681A (zh) * | 2018-05-19 | 2018-09-07 | 河南省医药科学研究院 | 白桦脂酸衍生物及其合成方法和应用 |
CN108727460A (zh) * | 2018-05-19 | 2018-11-02 | 河南省科学院高新技术研究中心 | 白桦脂酮酸衍生物及其合成方法和应用 |
CN112979743A (zh) * | 2019-12-02 | 2021-06-18 | 河南省医药科学研究院 | 白桦脂酸衍生物及其应用 |
CN113912663A (zh) * | 2020-07-07 | 2022-01-11 | 河南省生殖健康科学技术研究院(河南省出生缺陷干预工程技术研究中心) | 白桦脂酸衍生物,其制备方法、药物组合物和应用 |
CN114057823A (zh) * | 2020-08-06 | 2022-02-18 | 河南省生殖健康科学技术研究院(河南省出生缺陷干预工程技术研究中心) | 白桦脂酸衍生物,其制备方法、药物组合物和应用 |
CN114344313A (zh) * | 2022-01-28 | 2022-04-15 | 河南省科学院高新技术研究中心 | 用于预防或治疗神经系统退行性疾病的白桦脂酸衍生物 |
CN114392262A (zh) * | 2022-01-28 | 2022-04-26 | 河南省生殖健康科学技术研究院(河南省出生缺陷干预工程技术研究中心) | 抑制神经系统退行性疾病的白桦脂酸衍生物 |
CN115844903A (zh) * | 2023-01-17 | 2023-03-28 | 潍坊赛宝工业技术研究院有限公司 | 白桦醇衍生物在制备抑制细菌药物中的用途 |
CN115894600A (zh) * | 2021-09-30 | 2023-04-04 | 河南省科学院高新技术研究中心 | 别白桦醇衍生物及其制备方法、药物组合物和应用 |
-
2023
- 2023-11-24 CN CN202311575224.0A patent/CN117327140B/zh active Active
Patent Citations (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014031681A1 (en) * | 2012-08-20 | 2014-02-27 | The University Of Chicago | Inhibiting gram positive bacteria |
US20150368291A1 (en) * | 2014-06-20 | 2015-12-24 | Northeast Forestry University | N-acetyl amino acid ESTER derivatives of Betulin and preparation method thereof |
CN104940211A (zh) * | 2015-06-08 | 2015-09-30 | 曹晓宏 | 白桦脂酸在制备抗真菌生物被膜药物中的应用 |
CN108503681A (zh) * | 2018-05-19 | 2018-09-07 | 河南省医药科学研究院 | 白桦脂酸衍生物及其合成方法和应用 |
CN108727460A (zh) * | 2018-05-19 | 2018-11-02 | 河南省科学院高新技术研究中心 | 白桦脂酮酸衍生物及其合成方法和应用 |
CN112979743A (zh) * | 2019-12-02 | 2021-06-18 | 河南省医药科学研究院 | 白桦脂酸衍生物及其应用 |
CN113912663A (zh) * | 2020-07-07 | 2022-01-11 | 河南省生殖健康科学技术研究院(河南省出生缺陷干预工程技术研究中心) | 白桦脂酸衍生物,其制备方法、药物组合物和应用 |
CN114057823A (zh) * | 2020-08-06 | 2022-02-18 | 河南省生殖健康科学技术研究院(河南省出生缺陷干预工程技术研究中心) | 白桦脂酸衍生物,其制备方法、药物组合物和应用 |
CN115894600A (zh) * | 2021-09-30 | 2023-04-04 | 河南省科学院高新技术研究中心 | 别白桦醇衍生物及其制备方法、药物组合物和应用 |
CN114344313A (zh) * | 2022-01-28 | 2022-04-15 | 河南省科学院高新技术研究中心 | 用于预防或治疗神经系统退行性疾病的白桦脂酸衍生物 |
CN114392262A (zh) * | 2022-01-28 | 2022-04-26 | 河南省生殖健康科学技术研究院(河南省出生缺陷干预工程技术研究中心) | 抑制神经系统退行性疾病的白桦脂酸衍生物 |
CN115844903A (zh) * | 2023-01-17 | 2023-03-28 | 潍坊赛宝工业技术研究院有限公司 | 白桦醇衍生物在制备抑制细菌药物中的用途 |
Non-Patent Citations (2)
Title |
---|
23-羟基白桦脂酸的30位羟基衍生物的合成及其抗肿瘤活性;毕毅;徐进宜;吴晓明;叶文才;袁胜涛;张陆勇;;中国药科大学学报;20070425(02);第108-111页 * |
REGISTRY[online];Columbus,Ohio,US;《STN检索报告 US REGISTRY》;32 * |
Also Published As
Publication number | Publication date |
---|---|
CN117327140A (zh) | 2024-01-02 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2020239077A1 (zh) | 含氮杂环类衍生物调节剂、其制备方法和应用 | |
CN104411701A (zh) | 作为Bub1抑制剂的用于治疗癌症的取代的环烯并吡唑 | |
JP2010533729A (ja) | キナーゼ調節のための化合物と方法、及びそのための適応 | |
CN113912663B (zh) | 白桦脂酸衍生物,其制备方法、药物组合物和应用 | |
CN109384712B (zh) | 靶向nk1受体拮抗剂及其在化疗所致恶心、呕吐治疗中的应用 | |
CN105793262A (zh) | 二环炔衍生物及其用途 | |
CN115844903B (zh) | 白桦醇衍生物在制备抑制细菌药物中的用途 | |
US20230029009A1 (en) | Chemical compounds | |
WO2015074516A1 (zh) | 咪唑酮类衍生物、其药物组合物和用途 | |
CN103102349A (zh) | 蛋白激酶抑制剂及其组合物和用途 | |
CN115151541A (zh) | 新型化合物及其用途 | |
CN109369721B (zh) | 用于抑制激酶活性的芳基磷氧化物 | |
US20200148693A1 (en) | Chemical Compounds | |
JP2022501397A (ja) | Pd−l1拮抗薬化合物 | |
JP2023546742A (ja) | Lpa受容体活性に付随する症状を治療するための化合物および組成物 | |
CN113402543B (zh) | 丁苯酞开环衍生物及其制备方法和用途 | |
CN117327140B (zh) | 一种具备抑制细菌用途的白桦脂酸衍生物 | |
CN115894600B (zh) | 别白桦醇衍生物及其制备方法、药物组合物和应用 | |
CN114057823B (zh) | 白桦脂酸衍生物,其制备方法、药物组合物和应用 | |
CN113831342B (zh) | 一种酮咯酸衍生物、药物组合物及其制备方法和应用 | |
CN114344313A (zh) | 用于预防或治疗神经系统退行性疾病的白桦脂酸衍生物 | |
CN112759583B (zh) | 包含呋喃基的喹啉类衍生物及其制备方法和用途 | |
CN112625025B (zh) | 吡啶基取代的喹啉类衍生物及其制备方法和用途 | |
CN112694439B (zh) | 苯基丙烯酰胺基喹啉类衍生物及其制备方法和用途 | |
CN116621907A (zh) | 用于预防或治疗癌症的白桦脂酸核苷衍生物 |
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 |