CN117304097A - 一种杂芳基吡啶碘鎓盐类化合物及其制备方法和作为抗菌剂的应用 - Google Patents
一种杂芳基吡啶碘鎓盐类化合物及其制备方法和作为抗菌剂的应用 Download PDFInfo
- Publication number
- CN117304097A CN117304097A CN202311142921.7A CN202311142921A CN117304097A CN 117304097 A CN117304097 A CN 117304097A CN 202311142921 A CN202311142921 A CN 202311142921A CN 117304097 A CN117304097 A CN 117304097A
- Authority
- CN
- China
- Prior art keywords
- heteroaryl
- pyridinium
- compound
- iodonium salt
- iodopyridine
- 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.)
- Pending
Links
- -1 Heteroaryl pyridinium iodonium salt compound Chemical class 0.000 title claims abstract description 50
- 239000003242 anti bacterial agent Substances 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 22
- 150000001875 compounds Chemical class 0.000 claims abstract description 16
- 150000002367 halogens Chemical group 0.000 claims abstract description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 12
- 239000001257 hydrogen Substances 0.000 claims abstract description 12
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 10
- 150000002431 hydrogen Chemical group 0.000 claims abstract description 9
- 238000000034 method Methods 0.000 claims abstract description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 8
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 5
- 125000004185 ester group Chemical group 0.000 claims abstract description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims abstract description 4
- 150000001450 anions Chemical class 0.000 claims abstract description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 42
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 14
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical group OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 12
- XDELKSRGBLWMBA-UHFFFAOYSA-N 3-iodopyridine Chemical compound IC1=CC=CN=C1 XDELKSRGBLWMBA-UHFFFAOYSA-N 0.000 claims description 11
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 claims description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- 150000001555 benzenes Chemical group 0.000 claims description 8
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 claims description 8
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 8
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 8
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N ethyl benzoate Chemical compound CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 claims description 8
- 241000894006 Bacteria Species 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical group CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- QWLGCWXSNYKKDO-UHFFFAOYSA-N 2-chloro-5-iodopyridine Chemical compound ClC1=CC=C(I)C=N1 QWLGCWXSNYKKDO-UHFFFAOYSA-N 0.000 claims description 4
- CCZWSTFVHJPCEM-UHFFFAOYSA-N 2-iodopyridine Chemical compound IC1=CC=CC=N1 CCZWSTFVHJPCEM-UHFFFAOYSA-N 0.000 claims description 4
- 239000004305 biphenyl Substances 0.000 claims description 4
- 235000010290 biphenyl Nutrition 0.000 claims description 4
- KBPLFHHGFOOTCA-UHFFFAOYSA-N caprylic alcohol Natural products CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 claims description 4
- 229940125904 compound 1 Drugs 0.000 claims description 4
- 229940125782 compound 2 Drugs 0.000 claims description 4
- 229940126214 compound 3 Drugs 0.000 claims description 4
- MWKFXSUHUHTGQN-UHFFFAOYSA-N decan-1-ol Chemical compound CCCCCCCCCCO MWKFXSUHUHTGQN-UHFFFAOYSA-N 0.000 claims description 4
- LQZZUXJYWNFBMV-UHFFFAOYSA-N dodecan-1-ol Chemical compound CCCCCCCCCCCCO LQZZUXJYWNFBMV-UHFFFAOYSA-N 0.000 claims description 4
- KWKXNDCHNDYVRT-UHFFFAOYSA-N dodecylbenzene Chemical compound CCCCCCCCCCCCC1=CC=CC=C1 KWKXNDCHNDYVRT-UHFFFAOYSA-N 0.000 claims description 4
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 claims description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- 229940006460 bromide ion Drugs 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 239000007800 oxidant agent Substances 0.000 claims description 3
- 230000001590 oxidative effect Effects 0.000 claims description 3
- FZBHCYSESMFQJL-UHFFFAOYSA-N 2-bromo-3-iodopyridine Chemical compound BrC1=NC=CC=C1I FZBHCYSESMFQJL-UHFFFAOYSA-N 0.000 claims description 2
- OHWSWGXNZDSHLM-UHFFFAOYSA-N 2-chloro-3-iodopyridine Chemical compound ClC1=NC=CC=C1I OHWSWGXNZDSHLM-UHFFFAOYSA-N 0.000 claims description 2
- WCDCAXVNBOLWNO-UHFFFAOYSA-N 2-fluoro-3-iodopyridine Chemical compound FC1=NC=CC=C1I WCDCAXVNBOLWNO-UHFFFAOYSA-N 0.000 claims description 2
- GYZNHUNWABYAPO-UHFFFAOYSA-N 2-fluoro-5-iodopyridine Chemical compound FC1=CC=C(I)C=N1 GYZNHUNWABYAPO-UHFFFAOYSA-N 0.000 claims description 2
- NQAHWRGOUDATCK-UHFFFAOYSA-N 2-nitroethyl formate Chemical compound [O-][N+](=O)CCOC=O NQAHWRGOUDATCK-UHFFFAOYSA-N 0.000 claims description 2
- AOOZLVWDZUPEHT-UHFFFAOYSA-N 3-bromo-5-iodopyridine Chemical compound BrC1=CN=CC(I)=C1 AOOZLVWDZUPEHT-UHFFFAOYSA-N 0.000 claims description 2
- MMJSSIRVEYQWMU-UHFFFAOYSA-N 3-fluoro-5-iodopyridine Chemical compound FC1=CN=CC(I)=C1 MMJSSIRVEYQWMU-UHFFFAOYSA-N 0.000 claims description 2
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 239000012445 acidic reagent Substances 0.000 claims description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 claims description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 claims description 2
- 229940006461 iodide ion Drugs 0.000 claims description 2
- 150000002500 ions Chemical class 0.000 claims description 2
- AUHZEENZYGFFBQ-UHFFFAOYSA-N mesitylene Substances CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 claims description 2
- 125000001827 mesitylenyl group Chemical group [H]C1=C(C(*)=C(C([H])=C1C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- TVMXDCGIABBOFY-UHFFFAOYSA-N n-Octanol Natural products CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims description 2
- HLZKNKRTKFSKGZ-UHFFFAOYSA-N tetradecan-1-ol Chemical compound CCCCCCCCCCCCCCO HLZKNKRTKFSKGZ-UHFFFAOYSA-N 0.000 claims 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 claims description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 claims 2
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 23
- 230000001954 sterilising effect Effects 0.000 abstract description 4
- 238000004659 sterilization and disinfection Methods 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 239000008346 aqueous phase Substances 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 229930002839 ionone Natural products 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 30
- 239000000203 mixture Substances 0.000 description 14
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 10
- 229910052740 iodine Inorganic materials 0.000 description 10
- 239000011630 iodine Substances 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 10
- 239000002244 precipitate Substances 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 238000010992 reflux Methods 0.000 description 8
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 239000012528 membrane Substances 0.000 description 6
- GHXZTYHSJHQHIJ-UHFFFAOYSA-N Chlorhexidine Chemical compound C=1C=C(Cl)C=CC=1NC(N)=NC(N)=NCCCCCCN=C(N)N=C(N)NC1=CC=C(Cl)C=C1 GHXZTYHSJHQHIJ-UHFFFAOYSA-N 0.000 description 5
- 229960003260 chlorhexidine Drugs 0.000 description 5
- 241000192125 Firmicutes Species 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 235000014469 Bacillus subtilis Nutrition 0.000 description 3
- 239000004599 antimicrobial Substances 0.000 description 3
- 230000001580 bacterial effect Effects 0.000 description 3
- 210000002421 cell wall Anatomy 0.000 description 3
- DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical group I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 3
- 244000063299 Bacillus subtilis Species 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- WEVYAHXRMPXWCK-FIBGUPNXSA-N acetonitrile-d3 Chemical compound [2H]C([2H])([2H])C#N WEVYAHXRMPXWCK-FIBGUPNXSA-N 0.000 description 2
- 230000000845 anti-microbial effect Effects 0.000 description 2
- 230000000975 bioactive effect Effects 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 102000039446 nucleic acids Human genes 0.000 description 2
- 108020004707 nucleic acids Proteins 0.000 description 2
- 150000007523 nucleic acids Chemical class 0.000 description 2
- 239000012466 permeate Substances 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000013049 sediment Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- 125000005415 substituted alkoxy group Chemical group 0.000 description 2
- 125000000547 substituted alkyl group Chemical group 0.000 description 2
- 239000002344 surface layer Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- ORJDDOBAOGKRJV-CQSZACIVSA-N (2S)-Pinocembrin Natural products C1([C@H]2CC(=O)C3=C(O)C=C(C=C3O2)OC)=CC=CC=C1 ORJDDOBAOGKRJV-CQSZACIVSA-N 0.000 description 1
- 241000607534 Aeromonas Species 0.000 description 1
- RTIXKCRFFJGDFG-UHFFFAOYSA-N Chrysin Natural products C=1C(O)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=CC=C1 RTIXKCRFFJGDFG-UHFFFAOYSA-N 0.000 description 1
- ORJDDOBAOGKRJV-UHFFFAOYSA-N Dihydrotectochrysin Natural products O1C2=CC(OC)=CC(O)=C2C(=O)CC1C1=CC=CC=C1 ORJDDOBAOGKRJV-UHFFFAOYSA-N 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- FGUBFGWYEYFGRK-HNNXBMFYSA-N Pinocembrin Natural products Cc1cc(C)c2C(=O)C[C@H](Oc2c1)c3ccccc3 FGUBFGWYEYFGRK-HNNXBMFYSA-N 0.000 description 1
- 240000007263 Pinus koraiensis Species 0.000 description 1
- 235000011615 Pinus koraiensis Nutrition 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 238000002815 broth microdilution Methods 0.000 description 1
- 230000022534 cell killing Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229940125890 compound Ia Drugs 0.000 description 1
- 239000000645 desinfectant Substances 0.000 description 1
- 125000005520 diaryliodonium group Chemical group 0.000 description 1
- KCFYHBSOLOXZIF-UHFFFAOYSA-N dihydrochrysin Natural products COC1=C(O)C(OC)=CC(C2OC3=CC(O)=CC(O)=C3C(=O)C2)=C1 KCFYHBSOLOXZIF-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 150000002497 iodine compounds Chemical class 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- YCWSUKQGVSGXJO-NTUHNPAUSA-N nifuroxazide Chemical group C1=CC(O)=CC=C1C(=O)N\N=C\C1=CC=C([N+]([O-])=O)O1 YCWSUKQGVSGXJO-NTUHNPAUSA-N 0.000 description 1
- JPMIIZHYYWMHDT-UHFFFAOYSA-N octhilinone Chemical compound CCCCCCCCN1SC=CC1=O JPMIIZHYYWMHDT-UHFFFAOYSA-N 0.000 description 1
- NIEHEMAZEULEKB-UHFFFAOYSA-N ortho-ethylanisole Natural products CCC1=CC=CC=C1OC NIEHEMAZEULEKB-UHFFFAOYSA-N 0.000 description 1
- URFCJEUYXNAHFI-ZDUSSCGKSA-N pinocembrin Chemical compound C1([C@@H]2CC(=O)C3=C(O)C=C(C=C3O2)O)=CC=CC=C1 URFCJEUYXNAHFI-ZDUSSCGKSA-N 0.000 description 1
- ORJDDOBAOGKRJV-AWEZNQCLSA-N pinostrobin Chemical compound C1([C@@H]2CC(=O)C3=C(O)C=C(C=C3O2)OC)=CC=CC=C1 ORJDDOBAOGKRJV-AWEZNQCLSA-N 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/61—Halogen atoms or nitro radicals
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
- A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
- A01P1/00—Disinfectants; Antimicrobial compounds or mixtures thereof
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
- A01P3/00—Fungicides
-
- 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
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Environmental Sciences (AREA)
- Zoology (AREA)
- Pest Control & Pesticides (AREA)
- Plant Pathology (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Wood Science & Technology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Dentistry (AREA)
- Agronomy & Crop Science (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Pyridine Compounds (AREA)
Abstract
本发明属于有机合成及抗菌应用领域,公开了一种杂芳基吡啶碘鎓盐类化合物及其制备方法和作为抗菌剂的应用,结构如下所示:其中,R1优选自氢、烷基中一种,所指烷基链长为1‑18个碳;R2优选自氢、卤素、硝基、酯基、苯环、卤素取代的苯环、烷基、烷氧基、卤素取代的烷基、卤素取代的烷氧基中一种;X阴离子选自三氟甲磺酸根离子、溴离子、氯离子中一种。本发明提供的化合物合成工艺较简单,具有较高的产率,且具有高浓度杀菌,低浓度抑菌的性质,可作抗菌剂应用于抗菌领域,同时可稳定存在于水相中,增加应用范围。
Description
技术领域
本发明涉及有机合成和抗菌应用领域,具体地说,涉及一种杂芳基吡啶碘鎓盐化合物、其制备方法以及作为抗菌剂的应用。
背景技术
碘元素具有稳定而广谱的抗菌活性,长期以来被广泛应用于医用体表消毒杀菌剂中。含碘抗菌剂是一种广谱抗菌剂,能够对多种细菌、真菌、病毒等具有杀灭作用,其作用原理是通过破坏微生物的细胞膜和细胞壁,使其失去生存能力,从而达到抑制和杀灭细菌的效果。
含碘抗菌剂主要分为无机碘和有机碘两种类型。其中,无机碘是指碘元素本身,其杀菌效果较差,但价格低廉,使用方便;有机碘是通过将碘与有机物结合而产生的抗菌剂,其具有杀菌作用强、稳定性好、使用安全等特点。
目前对含碘化合物,特别是有机高价碘化合物在抗菌方面的开发研究仍然很少,缺乏深入的理论和实验探索。近年来,一些文献报道了二芳基碘盐类化合物在抗菌方面具有巨大潜力,并显示出低毒、高效、敏感等优点。本发明意图将具有生物活性的吡啶与二芳基高价(III)碘鎓盐结构相结合,设计了新型杂芳基吡啶碘鎓盐化合物分子结构,以期达到较好的抗菌效果,作为新型抗菌结构具有一定的市场开发前景。现有技术中并未涉及该类杂芳基吡啶碘鎓盐化合物及其作为抗菌剂的应用。
发明内容
本发明基于上述研究进行,目的在于提供一类新的有机碘抗菌剂--杂芳基吡啶碘鎓盐类化合物,并对其结构、合成方法以及抗菌功效进行描述。
为了实现上述目的,本发明采用的技术方案如下:
本发明的第一方面,提供了一种杂芳基吡啶碘鎓盐化合物,其结构通式如下式I或式II所示:
其中,R1选自氢、烷基;R2选自氢、卤素、硝基、酯基、苯环、卤素取代的苯环、烷基、烷氧基、卤素取代的烷基、卤素取代的烷氧基;X代表阴离子选自选自三氟甲磺酸离子、四氟硼酸离子、对甲苯磺酸阴离子、溴离子、氯离子、碘离子中的任一种。
优选的,R1独立选自氢、甲基、正癸烷基;R2独立选自氢、卤素、硝基、1-8个碳的酯基、苯环、卤素取代的苯环、碳链为1-12个碳的烷基、1-8个碳的烷氧基、卤素取代的1-12个碳的烷基、卤素取代的1-8个碳的烷氧基;X代表阴离子选自三氟甲磺酸根离子(-CF3SO3,对应通式II中的-OTf)、溴离子、氯离子。
更优选的,R1独立选自甲基、正癸烷基;R2选自卤素、硝基、甲酸乙酯基、苯环、正十二烷基;X选自三氟甲磺酸根离子。
最优选的,所述杂芳基吡啶碘鎓盐类化合物为以下结构中的一种:
根据上述结构可知,本发明的杂芳基吡啶碘鎓盐化合物作为高价(III)碘化物,具有一个I+核心,可静电吸附作用吸附在细菌细胞壁表层,缓慢渗透进入膜内,与其中的蛋白质、核酸反应导致其内部组织工作程序紊乱,最终导致外壁的破裂,膜内溶质溶出,从而达到一定的抗菌效果。
本发明的第二方面,提供了上述杂芳基吡啶碘鎓盐化合物的制备方法,包括以下步骤:
(1)将1当量的邻碘吡啶类化合物1溶解于溶剂中,加入适宜的酸试剂,在冰浴中搅拌1小时,撤去冰浴后加入1~1.5当量的取代苯类化合物2,以及1.5当量的氧化剂间氯过氧苯甲酸充分搅拌,并置于1~80℃充分反应1~10小时,得化合物I;
优选的,邻碘吡啶类化合物1选自3-碘吡啶、2-溴-3-碘吡啶、3-溴-5-碘吡啶、2-氯-3-碘吡啶、2-氯-5-碘吡啶、2-氟-3-碘吡啶、2-氟-5-碘吡啶或3-氟-5-碘吡啶;
所述溶剂选自二氯甲烷、乙腈、丙酮、乙酸乙酯中的至少一种;
所述取代苯类化合物2选自甲苯、正十二烷基苯、氟苯、氯苯、溴苯、联苯、均三甲苯、苯甲酸乙酯或苯甲醚。
(2)将1当量的直链醇类化合物3溶解于溶剂中,在-78℃下,逐滴加入1~1.5当量的催化剂N,N-二异丙基乙胺充分搅拌,再逐滴加入1~1.5当量的三氟甲磺酸酐,反应1~2小时,得到化合物4;
优选的,所述直链醇类化合物3选自甲醇、正辛醇、正癸醇、正十二醇、正十四醇、正十六醇、正十八醇中的任意一种。
(3)将1当量的化合物I与1~1.5当量的化合物4在室温下充分反应1~24小时,可得化合物II。
本发明的第三方面,提供了杂芳基吡啶碘鎓盐类化合物在制备抗菌剂中的应用。
优选的,所述抗菌剂为抗革兰氏阳性菌和革兰氏阴性菌的抗菌剂。
进一步优选为抗革兰氏阳性菌的抗菌剂,可在较低的浓度范围(32μg/mL)内达到90%以上的杀菌率。
由于采用上述技术方案,本发明具有以下优点和有益效果:
合成方面,本发明制备的杂芳基吡啶碘鎓盐化合物合成简单,仅需2~3个步骤,产率最高可达96%,具有较高产率水平,且结构较稳定。
抗菌效果方面,本发明所涉及到的杂芳基吡啶碘鎓盐作为抗菌剂,与市售的广谱抗菌剂氯己定与卡松相比,对于革兰氏阳性菌的抗菌效果具有明显的优势,且对枯草芽孢杆菌更为敏感,可在较低的浓度范围(32μg/mL)内达到90%以上的杀菌率。本发明的杂芳基吡啶碘鎓盐在抗菌领域的应用具有稳定、高效等特点。
抗菌原理方面,本发明制备的杂芳基吡啶碘鎓盐化合物作为高价(III)碘化物,具有一个I+核心,可静电吸附作用吸附在细菌细胞壁表层,缓慢渗透进入膜内,与其中的蛋白质、核酸反应导致其内部组织工作程序紊乱,最终导致外壁的破裂,膜内溶质溶出,从而达到一定的抗菌效果。因此,本发明的杂芳基吡啶碘鎓盐结构作为抗菌剂开发,具有一定的研究意义,可作为新结构推动抗菌领域的发展。
具体实施方式
为了更清楚地说明本发明,下面将结合实施例对本发明的技术方案进行进一步说明。显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其它实施例,都属于本发明保护的范围。
下列实施例中未注明具体条件的实验方法,通常按照国家标准测定。若没有相应的国家标准,则按照通用的国际标准、常规条件、或按照制造厂商所建议的条件进行。除非另外说明,否则所有的份数为重量份,所有的百分比为重量百分比,所述的聚合物分子量为数均分子量。
除非另有定义或说明,本文所使用的所有专业与科学用语与本领域技术熟练人员所熟悉的意义相同。此外任何与所记载内容相似或均等的方法均可应用于本发明方法中。
本发明实施例所用试剂如下:3-碘吡啶(25g,AR)、2-氯-5-碘吡啶(20g,AR)购于上海皓鸿生物医药科技有限公司;3-氯过氧苯甲酸(100g,AR)、氯苯(100g,AR)、溴苯(50g,AR)、苯(100g,AR)、三氟甲磺酸(500g,AR)、三氟甲磺酸酐(25g,AR)购于上海麦克林生化科技有限公司;联苯(50g,AR)、氟苯(500mL,AR)、苯甲酸乙酯(100g,AR)、正十二烷基苯(100g,AR)购于上海毕得医药科技有限公司;二氯甲烷(5L,AR)、无水乙醚(500mL,AR)、丙酮(1L,AR)、氯己定(5g,AR)购于上海泰坦科技股份有限公司;卡松购于上海邦高化学有限公司。
实施例1:杂芳基吡啶碘鎓盐化合物Ia的制备
将3-碘吡啶(1.025g,5mmol)溶解于10mL二氯甲烷中充分溶解,在冰浴中,逐滴加入三氟甲磺酸(1.78mL,20mmol),酸化搅拌1小时,撤去冰浴,逐滴加入溴苯(0.57mL,5.5mmol)充分搅拌,缓慢加入间氯过氧苯甲酸(1.29g,7.5mmol)充分搅拌,并用置于60℃油浴回流反应8小时。反应结束后加入30mL乙醚充分搅拌反复3次,取沉淀,通过碱性氧化铝柱层析分离提纯并干燥,可得褐黄色固体Ia(产率为82%)。m.p.123.4-124.3℃.1H NMR(400MHz,DMSO-d6)δ9.31(d,J=2.2Hz,1H),8.84(dd,J=4.8,1.4Hz,1H),8.69(dt,J=8.3,1.8Hz,1H),8.24–8.20(m,2H),7.77(d,J=8.6Hz,2H),7.60(dd,J=8.3,4.8Hz,1H).
实施例2:杂芳基吡啶碘鎓盐化合物Ib的制备
将3-碘吡啶(1.025g,5mmol)溶解于10mL二氯甲烷中充分溶解,在冰浴中,逐滴加入三氟甲磺酸(1.78mL,20mmol),酸化搅拌1小时,撤去冰浴,缓慢加入联苯(0.85g,5.5mmol)充分搅拌,缓慢加入间氯过氧苯甲酸(1.29g,7.5mmol)充分搅拌,并用置于60℃油浴回流反应8小时。反应结束后加入30mL乙醚充分搅拌反复3次,取沉淀,通过碱性氧化铝柱层析分离提纯并干燥,可得黑色固体Ib(产率为87%)。m.p.57.5-58.7℃.1HNMR(400MHz,Acetonitrile-d3)δ9.32(d,J=2.1Hz,1H),8.93(d,J=5.4Hz,1H),8.88(dt,J=8.4,1.7Hz,1H),8.29–8.25(m,2H),7.90(dd,J=8.5,5.3Hz,1H),7.86–7.83(m,2H),7.69(dd,J=7.1,2.0Hz,2H),7.55(d,J=6.9Hz,1H),7.53–7.46(m,2H).
实施例3:杂芳基吡啶碘鎓盐化合物Ic的制备
将2-氯-5-碘吡啶(1.20g,5mmol)溶解于10mL二氯甲烷中充分溶解,在冰浴中,逐滴加入三氟甲磺酸(1.78mL,20mmol),酸化搅拌1小时,撤去冰浴,逐滴加入苯(0.49mL,5.5mmol)充分搅拌,缓慢加入间氯过氧苯甲酸(1.29g,7.5mmol)充分搅拌,并用置于60℃油浴回流反应8小时。反应结束后加入30mL乙醚充分搅拌反复3次,取沉淀,通过碱性氧化铝柱层析分离提纯并干燥,可得灰色固体Ic(产率为81%)。m.p.87.8-88.2℃.1H NMR(400MHz,DMSO-d6)δ9.18(d,J=2.4Hz,1H),8.71(dd,J=8.5,2.5Hz,1H),8.30–8.27(m,2H),7.75(d,J=8.5Hz,1H),7.70(t,J=7.5Hz,1H),7.56(t,J=7.8Hz,2H).
实施例4:杂芳基吡啶碘鎓盐化合物Id的制备
将3-碘吡啶(1.025g,5mmol)溶解于10mL二氯甲烷中充分溶解,在冰浴中,逐滴加入三氟甲磺酸(1.78mL,20mmol),酸化搅拌1小时,撤去冰浴,逐滴加入氟苯(0.56mL,5.5mmol)充分搅拌,缓慢加入间氯过氧苯甲酸(1.29g,7.5mmol)充分搅拌,并用置于60℃油浴回流反应8小时。反应结束后加入30mL乙醚充分搅拌反复3次,取沉淀,通过碱性氧化铝柱层析分离提纯并干燥,可得白色固体Id(产率为96%)。m.p.142.8-143.2℃.1H NMR(400MHz,Acetonitrile-d3)δ9.34(d,J=2.1Hz,1H),9.08(ddd,J=8.5,2.1,1.3Hz,1H),8.94(d,J=5.8Hz,1H),8.31–8.20(m,2H),8.12(dd,J=8.5,5.8Hz,1H),7.40–7.30(m,2H).
实施例5:杂芳基吡啶碘鎓盐化合物Ie的制备
将3-碘吡啶(1.025g,5mmol)溶解于10mL二氯甲烷中充分溶解,在冰浴中,逐滴加入三氟甲磺酸(1.78mL,20mmol),酸化搅拌1小时,撤去冰浴,逐滴加入苯甲酸乙酯(0.79mL,5.5mmol)充分搅拌,缓慢加入间氯过氧苯甲酸(1.29g,7.5mmol)充分搅拌,并用置于60℃油浴回流反应8小时。反应结束后加入30mL乙醚充分搅拌反复3次,取沉淀,通过碱性氧化铝柱层析分离提纯并干燥,可得白色固体Ie(产率为74%)。m.p.122.5-123.0℃.1H NMR(400MHz,DMSO-d6)δ9.35(d,J=2.4Hz,1H),8.86–8.82(m,2H),8.74(dt,J=8.2,1.9Hz,1H),8.57–8.49(m,1H),8.22–8.16(m,1H),7.69(t,J=7.9Hz,1H),7.60(dd,J=8.3,4.7Hz,1H),4.34(q,J=7.1Hz,2H),1.32(t,J=7.1Hz,3H).
实施例6:杂芳基吡啶碘鎓盐化合物If的制备
将3-碘吡啶(1.025g,5mmol)溶解于10mL二氯甲烷中充分溶解,在冰浴中,逐滴加入三氟甲磺酸(1.78mL,20mmol),酸化搅拌1小时,撤去冰浴,逐滴加入正十二烷基苯(1.59mL,5.5mmol)充分搅拌,缓慢加入间氯过氧苯甲酸(1.29g,7.5mmol)充分搅拌,并用置于60℃油浴回流反应8小时。反应结束后加入30mL乙醚充分搅拌反复3次,取沉淀,通过碱性氧化铝柱层析分离提纯并干燥,可得白色固体If(产率为72%)。m.p.120.9-121.4℃.1HNMR(400MHz,DMSO-d6)δ9.31(d,J=2.3Hz,1H),8.82(d,J=4.7Hz,1H),8.71(d,J=8.3Hz,1H),8.20(d,J=8.2Hz,2H),7.60(dd,J=8.3,4.8Hz,1H),7.36(d,J=8.4Hz,2H),2.78–2.42(m,2H),1.53(d,J=27.7Hz,2H),1.27–0.81(m,18H),0.77–0.72(m,3H).
实施例7:杂芳基吡啶碘鎓盐化合物Ig的制备
将3-碘吡啶(1.025g,5mmol)溶解于10mL二氯甲烷中充分溶解,在冰浴中,逐滴加入三氟甲磺酸(1.78mL,20mmol),酸化搅拌1小时,撤去冰浴,逐滴加入氯苯(0.62mL,5.5mmol)充分搅拌,缓慢加入间氯过氧苯甲酸(1.29g,7.5mmol)充分搅拌,并用置于60℃油浴回流反应8小时。反应结束后加入30mL乙醚充分搅拌反复3次,取沉淀,通过碱性氧化铝柱层析分离提纯并干燥,可得淡黄色固体Ig(产率为83%)。m.p.130.8-131.1℃.1H NMR(400MHz,DMSO-d6)δ9.31(d,J=2.2Hz,1H),8.85(dd,J=4.8,1.4Hz,1H),8.70(ddd,J=8.2,2.3,1.4Hz,1H),8.34–8.26(m,2H),7.66–7.63(m,2H),7.62–7.59(m,1H).
实施例8:杂芳基吡啶碘鎓盐化合物IIa的制备
将3-碘吡啶(1.025g,5mmol)溶解于10mL二氯甲烷中充分溶解,在冰浴中,逐滴加入三氟甲磺酸(1.78mL,20mmol),酸化搅拌1小时,撤去冰浴,逐滴加入氟苯(0.52mL,5.5mmol)充分搅拌,缓慢加入间氯过氧苯甲酸(1.29g,7.5mmol)充分搅拌,并用置于60℃油浴回流反应8小时。反应结束后加入30mL乙醚充分搅拌反复3次,取沉淀。
将甲醇(0.64mL,20mmol)溶解于10mL二氯甲烷中充分溶解,在-78℃下,逐滴加入N,N-二异丙基乙胺(4.35mL,25mmol)充分搅拌,再逐滴加入三氟甲磺酸酐(4.21mL,25mmol),反应1-2小时,加入上述沉淀(1.12g,2.5mmol),常温反应20小时,可得浅黄色固体IIa(产率为22%)。1H NMR(400MHz,DMSO-d6)δ9.31(d,J=2.2Hz,1H),8.84(d,J=4.8Hz,1H),8.69(dt,J=8.4,2.0Hz,1H),8.37(dd,J=8.8,5.1Hz,2H),7.61(dd,J=8.2,4.7Hz,1H),7.44(t,J=8.8Hz,2H),4.47(d,J=2.8Hz,3H).
实施例9:杂芳基吡啶碘鎓盐化合物IIb的制备
将3-碘吡啶(1.025g,5mmol)溶解于10mL二氯甲烷中充分溶解,在冰浴中,逐滴加入三氟甲磺酸(1.78mL,20mmol),酸化搅拌1小时,撤去冰浴,逐滴加入氟苯(0.52mL,5.5mmol)充分搅拌,缓慢加入间氯过氧苯甲酸(1.29g,7.5mmol)充分搅拌,并用置于60℃油浴回流反应8小时。反应结束后加入30mL乙醚充分搅拌反复3次,取沉淀。
将正癸烷醇(0.64mL,20mmol)溶解于10mL二氯甲烷中充分溶解,在-78℃下,逐滴加入N,N-二异丙基乙胺(4.35mL,25mmol)充分搅拌,再逐滴加入三氟甲磺酸酐(4.21mL,25mmol),反应1-2小时,加入上述沉淀(1.12g,2.5mmol),常温反应20小时,可得浅黄色固体IIa(产率为20%)。1H NMR(400MHz,DMSO-d6)δ=9.58(t,J=1.9,1H),9.28(dt,J=7.7,1.6,1H),9.11(dt,J=5.4,1.5,1H),8.21–8.12(m,2H),8.05–7.97(m,1H),7.35–7.26(m,2H),4.71(d,J=12.6,1H),1.99(tt,J=7.7,6.3,2H),1.64–1.37(m,6H),1.35–1.19(m,8H),0.95–0.84(m,3H).
实施例10:效果验证实验
采用最小抑菌浓度(MIC)测试衡量所合成的8种化合物的抗菌能力,同时将市售卡松与氯己定作为对比加入测试。本测试采用微量肉汤稀释法,测试方法如下:
分别将目标待测物以甲醇:水为1:9的比例充分溶解,在无菌环境中配置不同浓度梯度的抗菌液,浓度设置为:1280μg/mL、640μg/mL、320μg/mL、160μg/mL、80μg/mL、40μg/mL、20μg/mL、10μg/mL、5μg/mL、2.5μg/mL、1.25μg/mL、0.625μg/mL、0μg/mL。
本次测试采用了4种常用的测试菌种,包括:金黄色葡萄球菌(S.aureus)、枯草芽孢杆菌(B.subtilis)、大肠杆菌(E.coli)、铜绿假单胞菌(P.aeruginosa),分别作为革兰氏阳性菌(G+)和革兰氏阴性菌(G-)的代表测试菌种。将稀释后的细菌悬液(105CFU/mL)与不同浓度的抗菌液以1:9的比例在无菌的96孔板中混合,每孔添加的体积以微升计,充分混合并平放置于恒温生化培养箱中37℃下混合培育20小时取出并观察结果,如表1所示:
表1不同抗菌剂的MIC值
在实验测试条件下,所有测试化合物均可较稳定地存在于水相体系或甲醇与水的混合体系中,同时在20小时内,对4种测试菌种均具有一定的抗菌能力。
结果表明,本发明所涉及的杂芳基吡啶碘鎓盐化合物中,对于革兰氏阳性菌,化合物Ib的抗菌效果最佳,MIC低至2μg/mL,化合物If对4种细菌的抗菌效果均与卡松相当。化合物Ia与Ic对4种细菌的抗菌效果均与氯己定相当。目前,作为广谱抗菌剂的卡松因对人体产生刺激而被限制使用,并且较易使微生物产生抗性;氯己定作为广谱抗菌剂在一些研究数据中表现出了一定的人体体外细胞杀伤性。因此,本发明涉及的这一类生物活性结构相结合的杂芳基吡啶碘鎓盐化合物可作为一种新型抗菌剂,其结构具有进一步开发的潜力,且其抗菌效果在抗菌领域具有较好的市场前景,值得推动研究进展,并进一步得以开发利用。
以上所述仅是本发明的较佳实施例而已,并非对本发明作任何形式上的限制,虽然本发明已以较佳实施例揭露如上,然而并非用以限定本发明,任何熟悉本专利的技术人员在不脱离本发明技术方案范围内,当可利用上述提示的技术内容作出些许更动或修饰为等同变化的等效实施例,但凡是未脱离本发明技术方案的内容,依据本发明的技术实质对以上实施例所作的任何简单修改、等同变化与修饰,均仍属于本发明方案的范围内。
Claims (9)
1.一种杂芳基吡啶碘鎓盐类化合物,其特征在于:其结构如下式I或式II所示:
其中,R1选自氢、烷基中一种;
R2选自氢、卤素、硝基、酯基、苯环、烷基、烷氧基、卤素取代的苯环、卤素取代的烷基、卤素取代的烷氧中的任意一种;
X代表阴离子,选自三氟甲磺酸离子、四氟硼酸离子、对甲苯磺酸阴离子、溴离子、氯离子、碘离子中的任一种。
2.根据权利要求1所述的杂芳基吡啶碘鎓盐类化合物,其特征在于:
其中,R1独立选自氢、碳链为1-18个碳的烷基中一种;
R2独立选自氢、卤素、硝基、1-8个碳的酯基、苯环、卤素取代的苯环、碳链为1-12个碳的烷基、1-8个碳的烷氧基、卤素取代的1-12个碳的烷基、卤素取代的1-8个碳的烷氧基中一种。
3.根据权利要求1所述的杂芳基吡啶碘鎓盐类化合物,其特征在于:
其中,R1独立选自氢、甲基或正癸烷基;
R2选自氢、卤素、硝基、甲酸乙酯基、苯环或正十二烷基;
X选自三氟甲磺酸根离子。
4.根据权利要求1所述的杂芳基吡啶碘鎓盐类化合物,其特征在于,所述的杂芳基吡啶碘鎓盐类化合物为下列化合物中的任一种:
5.权利要求1-4中任一项所述的杂芳基吡啶碘鎓盐类化合物的制备方法,其特征在于,包括以下步骤:
(1)将1当量的邻碘吡啶类化合物1溶解于溶剂中,加入适宜的酸试剂,在冰浴中搅拌1小时后撤去冰浴,加入1~1.5当量的取代苯类化合物2,以及1.5当量的氧化剂充分搅拌,并置于1~80℃充分反应1-10小时,得化合物I;
(2)将1当量的直链醇类化合物3溶解于溶剂中,在-78℃下逐滴加入1~1.5当量的催化剂充分搅拌,再逐滴加入1-1.5当量的三氟甲磺酸酐,反应1-2小时,得到化合物4;
(3)将1当量的化合物I与1~1.5当量的化合物4在室温下充分反应1-24小时,得化合物II。
6.根据权利要求5所述的杂芳基吡啶碘鎓盐类化合物的制备方法,其特征在于:步骤(1)中,
所述邻碘吡啶类化合物1选自3-碘吡啶、2-溴-3-碘吡啶、3-溴-5-碘吡啶、2-氯-3-碘吡啶、2-氯-5-碘吡啶、2-氟-3-碘吡啶、2-氟-5-碘吡啶或3-氟-5-碘吡啶;
所述溶剂选自二氯甲烷、乙腈、丙酮、乙酸乙酯中的至少一种;
所述取代苯类化合物2选自甲苯、正十二烷基苯、硝基苯、氟苯、氯苯、溴苯、联苯、均三甲苯或苯甲酸乙酯;
所述氧化剂选自间氯过氧苯甲酸。
7.根据权利要求5所述的杂芳基吡啶碘鎓盐类化合物的制备方法,其特征在于:步骤(2)中,
所述直链醇类化合物3选自甲醇、正辛醇、正癸醇、正十二醇、正十四醇、正十六醇、正十八醇中的任意一种;
所述催化剂选自N,N-二异丙基乙胺。
8.权利要求1-4中任一项所述的杂芳基吡啶碘鎓盐类化合物在制备抗菌剂中的应用。
9.根据权利要求8所述的应用,其特征在于,所述抗菌剂为抗革兰氏阳性菌和革兰氏阴性菌的抗菌剂。
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