CN114874152B - Synephrine benzoxazole sulfonamide derivative, intermediate, preparation method and application thereof - Google Patents
Synephrine benzoxazole sulfonamide derivative, intermediate, preparation method and application thereof Download PDFInfo
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- CN114874152B CN114874152B CN202210579020.3A CN202210579020A CN114874152B CN 114874152 B CN114874152 B CN 114874152B CN 202210579020 A CN202210579020 A CN 202210579020A CN 114874152 B CN114874152 B CN 114874152B
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- YRCWQPVGYLYSOX-UHFFFAOYSA-N Synephrin-oxalat Natural products CNCC(O)C1=CC=C(O)C=C1 YRCWQPVGYLYSOX-UHFFFAOYSA-N 0.000 title claims abstract description 80
- 229960003684 oxedrine Drugs 0.000 title claims abstract description 52
- -1 Synephrine benzoxazole sulfonamide derivative Chemical class 0.000 title claims abstract description 35
- 238000002360 preparation method Methods 0.000 title claims description 8
- 230000000844 anti-bacterial effect Effects 0.000 claims abstract description 17
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 8
- 238000000034 method Methods 0.000 claims abstract description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 38
- 150000001875 compounds Chemical class 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 19
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 18
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 241000222122 Candida albicans Species 0.000 claims description 11
- 229940095731 candida albicans Drugs 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 11
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 10
- BOBIZYYFYLLRAH-UHFFFAOYSA-N 5-chloro-3h-1,3-benzoxazole-2-thione Chemical compound ClC1=CC=C2OC(S)=NC2=C1 BOBIZYYFYLLRAH-UHFFFAOYSA-N 0.000 claims description 10
- 241001225321 Aspergillus fumigatus Species 0.000 claims description 10
- 241000222173 Candida parapsilosis Species 0.000 claims description 10
- 241000191938 Micrococcus luteus Species 0.000 claims description 10
- 229940091771 aspergillus fumigatus Drugs 0.000 claims description 10
- 229940055022 candida parapsilosis Drugs 0.000 claims description 10
- ULTHEAFYOOPTTB-UHFFFAOYSA-N 1,4-dibromobutane Chemical compound BrCCCCBr ULTHEAFYOOPTTB-UHFFFAOYSA-N 0.000 claims description 8
- 241000588626 Acinetobacter baumannii Species 0.000 claims description 8
- 241000222178 Candida tropicalis Species 0.000 claims description 8
- 241000233866 Fungi Species 0.000 claims description 7
- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical compound Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 claims description 7
- 241000589517 Pseudomonas aeruginosa Species 0.000 claims description 6
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims description 6
- 241000894006 Bacteria Species 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- 241000235058 Komagataella pastoris Species 0.000 claims description 4
- 241000607142 Salmonella Species 0.000 claims description 4
- 241000191967 Staphylococcus aureus Species 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 3
- 241001354013 Salmonella enterica subsp. enterica serovar Enteritidis Species 0.000 claims description 2
- 239000011230 binding agent Substances 0.000 claims description 2
- 239000003429 antifungal agent Substances 0.000 claims 2
- QHZVYZZRMVDSRK-UHFFFAOYSA-N 1,3-oxazole-2-sulfonamide Chemical class NS(=O)(=O)C1=NC=CO1 QHZVYZZRMVDSRK-UHFFFAOYSA-N 0.000 claims 1
- CPHXLFKIUVVIOQ-UHFFFAOYSA-N 2-(trifluoromethoxy)benzaldehyde Chemical group FC(F)(F)OC1=CC=CC=C1C=O CPHXLFKIUVVIOQ-UHFFFAOYSA-N 0.000 claims 1
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims 1
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 claims 1
- 241000222120 Candida <Saccharomycetales> Species 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 67
- 230000000694 effects Effects 0.000 abstract description 34
- 239000003814 drug Substances 0.000 abstract description 25
- 229940079593 drug Drugs 0.000 abstract description 22
- 229960004884 fluconazole Drugs 0.000 abstract description 19
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 abstract description 19
- 230000000843 anti-fungal effect Effects 0.000 abstract description 12
- 238000012360 testing method Methods 0.000 abstract description 11
- 229910052736 halogen Inorganic materials 0.000 abstract description 7
- 150000002367 halogens Chemical class 0.000 abstract description 7
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 abstract description 4
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 abstract description 4
- 229940121375 antifungal agent Drugs 0.000 abstract description 4
- 230000004071 biological effect Effects 0.000 abstract description 4
- 239000013641 positive control Substances 0.000 abstract description 4
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 abstract description 2
- 125000005236 alkanoylamino group Chemical group 0.000 abstract description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 abstract description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 66
- 239000007787 solid Substances 0.000 description 36
- 238000004896 high resolution mass spectrometry Methods 0.000 description 31
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 26
- 230000002401 inhibitory effect Effects 0.000 description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 14
- 229960003405 ciprofloxacin Drugs 0.000 description 13
- 230000015572 biosynthetic process Effects 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 12
- 238000003756 stirring Methods 0.000 description 11
- OGJPXUAPXNRGGI-UHFFFAOYSA-N norfloxacin Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 OGJPXUAPXNRGGI-UHFFFAOYSA-N 0.000 description 9
- 229960001180 norfloxacin Drugs 0.000 description 9
- SPFYMRJSYKOXGV-UHFFFAOYSA-N Baytril Chemical compound C1CN(CC)CCN1C(C(=C1)F)=CC2=C1C(=O)C(C(O)=O)=CN2C1CC1 SPFYMRJSYKOXGV-UHFFFAOYSA-N 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 229960000740 enrofloxacin Drugs 0.000 description 8
- ZEKZLJVOYLTDKK-UHFFFAOYSA-N lomefloxacin Chemical compound FC1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNC(C)C1 ZEKZLJVOYLTDKK-UHFFFAOYSA-N 0.000 description 8
- 229960002422 lomefloxacin Drugs 0.000 description 8
- XUBOMFCQGDBHNK-JTQLQIEISA-N (S)-gatifloxacin Chemical compound FC1=CC(C(C(C(O)=O)=CN2C3CC3)=O)=C2C(OC)=C1N1CCN[C@@H](C)C1 XUBOMFCQGDBHNK-JTQLQIEISA-N 0.000 description 7
- 229960003923 gatifloxacin Drugs 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 238000004809 thin layer chromatography Methods 0.000 description 7
- 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 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 229950007734 sarafloxacin Drugs 0.000 description 6
- 150000003457 sulfones Chemical class 0.000 description 6
- MGQLHRYJBWGORO-LLVKDONJSA-N Balofloxacin Chemical compound C1[C@H](NC)CCCN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN(C3CC3)C2=C1OC MGQLHRYJBWGORO-LLVKDONJSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 229950000805 balofloxacin Drugs 0.000 description 5
- 238000013461 design Methods 0.000 description 5
- 244000000008 fungal human pathogen Species 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- 150000003568 thioethers Chemical class 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 244000000007 bacterial human pathogen Species 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 3
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 2
- 230000000845 anti-microbial effect Effects 0.000 description 2
- 235000013361 beverage Nutrition 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 244000052637 human pathogen Species 0.000 description 2
- 125000005647 linker group Chemical group 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- XOHZHMUQBFJTNH-UHFFFAOYSA-N 1-methyl-2h-tetrazole-5-thione Chemical compound CN1N=NN=C1S XOHZHMUQBFJTNH-UHFFFAOYSA-N 0.000 description 1
- HFFXLYHRNRKAPM-UHFFFAOYSA-N 2,4,5-trichloro-n-(5-methyl-1,2-oxazol-3-yl)benzenesulfonamide Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C(=CC(Cl)=C(Cl)C=2)Cl)=N1 HFFXLYHRNRKAPM-UHFFFAOYSA-N 0.000 description 1
- PVJZBZSCGJAWNG-UHFFFAOYSA-N 2,4,6-trimethylbenzenesulfonyl chloride Chemical compound CC1=CC(C)=C(S(Cl)(=O)=O)C(C)=C1 PVJZBZSCGJAWNG-UHFFFAOYSA-N 0.000 description 1
- QXWAUQMMMIMLTO-UHFFFAOYSA-N 2,6-difluorobenzenesulfonyl chloride Chemical compound FC1=CC=CC(F)=C1S(Cl)(=O)=O QXWAUQMMMIMLTO-UHFFFAOYSA-N 0.000 description 1
- VKPQLZPZPYQFOK-UHFFFAOYSA-N 2-acetamidobenzenesulfonyl chloride Chemical compound CC(=O)NC1=CC=CC=C1S(Cl)(=O)=O VKPQLZPZPYQFOK-UHFFFAOYSA-N 0.000 description 1
- VFPWGZNNRSQPBT-UHFFFAOYSA-N 2-bromobenzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1Br VFPWGZNNRSQPBT-UHFFFAOYSA-N 0.000 description 1
- ZSZKAQCISWFDCQ-UHFFFAOYSA-N 2-fluorobenzenesulfonyl chloride Chemical compound FC1=CC=CC=C1S(Cl)(=O)=O ZSZKAQCISWFDCQ-UHFFFAOYSA-N 0.000 description 1
- DODDSXTWDSJCDN-UHFFFAOYSA-N 3-(trifluoromethoxy)benzenesulfonyl chloride Chemical compound FC(F)(F)OC1=CC=CC(S(Cl)(=O)=O)=C1 DODDSXTWDSJCDN-UHFFFAOYSA-N 0.000 description 1
- PJGOLCXVWIYXRQ-UHFFFAOYSA-N 3-bromobenzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC(Br)=C1 PJGOLCXVWIYXRQ-UHFFFAOYSA-N 0.000 description 1
- OKYSUJVCDXZGKE-UHFFFAOYSA-N 3-fluorobenzenesulfonyl chloride Chemical compound FC1=CC=CC(S(Cl)(=O)=O)=C1 OKYSUJVCDXZGKE-UHFFFAOYSA-N 0.000 description 1
- UHCDBMIOLNKDHG-UHFFFAOYSA-N 4-(trifluoromethoxy)benzenesulfonyl chloride Chemical compound FC(F)(F)OC1=CC=C(S(Cl)(=O)=O)C=C1 UHCDBMIOLNKDHG-UHFFFAOYSA-N 0.000 description 1
- OZDCZHDOIBUGAJ-UHFFFAOYSA-N 4-(trifluoromethyl)benzenesulfonyl chloride Chemical compound FC(F)(F)C1=CC=C(S(Cl)(=O)=O)C=C1 OZDCZHDOIBUGAJ-UHFFFAOYSA-N 0.000 description 1
- BFXHJFKKRGVUMU-UHFFFAOYSA-N 4-fluorobenzenesulfonyl chloride Chemical compound FC1=CC=C(S(Cl)(=O)=O)C=C1 BFXHJFKKRGVUMU-UHFFFAOYSA-N 0.000 description 1
- JXRGUPLJCCDGKG-UHFFFAOYSA-N 4-nitrobenzenesulfonyl chloride Chemical compound [O-][N+](=O)C1=CC=C(S(Cl)(=O)=O)C=C1 JXRGUPLJCCDGKG-UHFFFAOYSA-N 0.000 description 1
- QJFGYXVRZBGDOB-UHFFFAOYSA-N 5-sulfonyltetrazole Chemical compound O=S(=O)=C1N=NN=N1 QJFGYXVRZBGDOB-UHFFFAOYSA-N 0.000 description 1
- 241001232615 Acinetobacter baumannii ATCC 19606 = CIP 70.34 = JCM 6841 Species 0.000 description 1
- 201000004384 Alopecia Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 241000207199 Citrus Species 0.000 description 1
- 244000183685 Citrus aurantium Species 0.000 description 1
- 235000007716 Citrus aurantium Nutrition 0.000 description 1
- 241000235646 Cyberlindnera jadinii Species 0.000 description 1
- 241001360526 Escherichia coli ATCC 25922 Species 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 241001506991 Komagataella phaffii GS115 Species 0.000 description 1
- 206010047139 Vasoconstriction Diseases 0.000 description 1
- 150000008043 acidic salts Chemical class 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 231100000360 alopecia Toxicity 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 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
- 230000032677 cell aging Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 235000020971 citrus fruits Nutrition 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 238000005142 microbroth dilution method Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 238000000643 oven drying Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- CDRNYKLYADJTMN-UHFFFAOYSA-N pyridine-3-sulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CN=C1 CDRNYKLYADJTMN-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000004576 sand Substances 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 230000025033 vasoconstriction Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
- C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
- C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles 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 in position 2
-
- 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
-
- 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
- A61P31/10—Antimycotics
-
- 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)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a synephrine benzoxazole sulfonamide derivative shown in a formula I, wherein X is S or SO 2 The method comprises the steps of carrying out a first treatment on the surface of the R is phenyl, substituted phenyl or 3-pyridyl; the phenyl substituent is one or more and is independently selected from halogen, hydroxy, amino, C1-C3 alkanoylamino, nitro, C1-C3 alkyl, halogen substituted C1-C3 alkyl, C1-C3 alkoxy or halogen substituted C1-C3 alkoxy; the biological activity test results show that the derivative molecules and intermediates have certain antibacterial and/or antifungal activity, are stronger than that of the parent nucleus synephrine, especially have partial high-activity and broad-spectrum molecules, have quite even stronger activity than that of positive control salcin marketed medicines or fluconazole, and have the potential of further developing and developing antibacterial and/or antifungal medicines.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and relates to a synephrine benzoxazole sulfonamide derivative, an intermediate, a preparation method and application thereof.
Background
The design strategy of the multi-target medicine is a new idea for solving the problem of complex diseases, especially multi-target diseases. The pharmacophore connection method can introduce medicines with multiple action targets into a single molecule, so as to realize the design of the medicines with multiple targets.
Synephrine (synephrine) is a natural small-molecule alkaloid, which exists in the peel and pulp of citrus, and is one of the main components of traditional Chinese medicine immature bitter orange. Synephrine has biological activities of vasoconstriction, weight loss, cell aging delay, asthma resistance, depression resistance, alopecia resistance, inflammation resistance, stomach illness resistance, bacteria resistance, fungus resistance and the like, is currently carried in the northern Europe and the German pharmacopoeia, is used in the industries of medicines, food and beverage and the like in European and American countries, and is the most widely applied as a weight-losing health-care product and beverage. The synephrine contains phenolic hydroxyl, alcoholic hydroxyl and secondary amino, and can be used as a linker (linker) of a multi-target drug and one of pharmacophores, thereby having potential research prospect.
In the previous researches in the laboratory, the inventor designs a synephrine sulfonyl tetrazole sulfonamide derivative by respectively introducing 1-methyl-5-mercapto-1H-tetrazole and sulfonyl on phenolic hydroxyl and amino of synephrine, and although the antibacterial activity of the obtained molecule is not satisfactory, a few molecules have good antifungal activity and have the potential of further researches.
Disclosure of Invention
In view of the above, the present invention aims to design and synthesize a new class of synephrine derivatives, and it is desirable to find new molecules with better antibacterial and/or antifungal activity.
Through researches, the invention provides the following technical scheme:
1. synephrine benzoxazole sulfonamide derivatives represented by formula I or pharmaceutically acceptable salts thereof:
in the formula I, the compound (I),
x is S or SO 2 ;
R is phenyl, substituted phenyl or 3-pyridyl; the phenyl substituent is one or more and is independently selected from halogen, hydroxy, amino, C1-C3 alkanoylamino, nitro, C1-C3 alkyl, halogen substituted C1-C3 alkyl, C1-C3 alkoxy or halogen substituted C1-C3 alkoxy.
Further, the phenyl substituent is one or more, independently selected from fluorine, bromine, amino, acetamido, nitro, methyl, trifluoromethyl, methoxy or trifluoromethoxy.
Further, the synephrine benzoxazole sulfonamide derivative shown in the formula I is any one of the following compounds:
2. an intermediate of formula II:
in formula II, Y is tert-butoxycarbonyl (Boc) or H.
3. The preparation method of the synephrine benzoxazole sulfonamide derivative or the pharmaceutically acceptable salt thereof in the formula I comprises the following steps:
i. the synephrine and di-tert-butyl dicarbonate, namely Boc 2 O reacts to prepare an intermediate IM1;
reacting the intermediate IM1 with 1, 4-dibromobutane to obtain an intermediate IM2;
reacting the intermediate IM2 with 5-chloro-2-mercaptobenzoxazole to obtain an intermediate IM3, namely an intermediate shown in a formula II, wherein Y is Boc;
reacting the intermediate IM3 with HCl-ethyl acetate (HCl-EA) to obtain an intermediate IM4, namely an intermediate hydrochloride shown in a formula II, wherein Y is H;
v. intermediate IM4 is combined with compound RSO 2 Cl reacts to prepare a compound TM1, namely a synephrine benzoxazole sulfonamide derivative shown in a formula I, wherein X in the formula I is S;
reacting compound TM1 with m-chloroperoxybenzoic acid (mCPBA) to obtain compound TM2, namely synephrine benzoxazole sulfonamide derivative shown in formula I, wherein X is SO 2 ;
Compound RSO 2 And R in the structural formulas of Cl, TM1 and TM2 is the same as the definition in the synephrine benzoxazole sulfonamide derivative shown in the formula I.
Further, the preparation method of the synephrine benzoxazole sulfonamide derivative or the pharmaceutically acceptable salt thereof comprises the following steps:
i. the synephrine and Boc are combined 2 O reacts in ethanol solvent at 0-35 ℃ to prepare an intermediate IM1;
ii. intermediate IM1 and 1, 4-dibromobutane in base K 2 CO 3 Reacting in solvent N, N-Dimethylformamide (DMF) at 45 ℃ in the presence of the solvent to prepare an intermediate IM2;
intermediate IM2 and 5-chloro-2-mercaptobenzoxazole in base K 2 CO 3 Reacting in DMF at 45 ℃ in the presence of a solvent to obtain an intermediate IM3, namely an intermediate shown in a formula II, wherein Y is Boc;
reacting the intermediate IM3 with HCl-EA at 0-5 ℃ to obtain an intermediate IM4, namely an intermediate hydrochloride shown in a formula II, wherein Y is H;
v. intermediate IM4 is combined with compound RSO 2 Cl reacts in DMF at-15-25 ℃ in the presence of an acid-binding agent N, N-Diisopropylethylamine (DIPEA) to prepare a compound TM1, namely a synephrine benzoxazole sulfonamide derivative shown in a formula I, wherein X is S;
reacting compound TM1 with mCPBA in Dichloromethane (DCM) at 30deg.C to obtain compound TM2, namely synephrine benzoxazole sulfonamide derivative shown in formula I, wherein X is SO 2 。
4. Application of synephrine benzoxazole sulfonamide derivatives shown in formula I or pharmaceutically acceptable salts thereof in preparation of antibacterial and/or antifungal drugs.
5. The application of the intermediate shown in the formula II or pharmaceutically acceptable salt thereof in preparing antibacterial and/or antifungal medicines.
The term "pharmaceutically acceptable salt" in the present invention may be an acidic salt or a basic salt, such as an inorganic acid salt, an organic acid salt, an inorganic base salt or an organic base salt, unless otherwise specified. The term "halogen" refers to F, cl, br and I.
The invention has the beneficial effects that: the invention respectively introduces benzoxazolyl and sulfonyl on phenolic hydroxyl and amino of a synephrine mother nucleus, designs and synthesizes a synephrine benzoxazole sulfonamide derivative, and biological activity test results show that derivative molecules and intermediates have certain antibacterial and/or antifungal activity, which is stronger than that of synephrine, especially has partial high-activity and broad-spectrum molecules, has quite even stronger activity than that of positive control sarcin marketed drugs or fluconazole, and has the potential of further developing and developing antibacterial and/or antifungal drugs.
Detailed Description
In order to make the objects, technical solutions and advantageous effects of the present invention more apparent, preferred embodiments of the present invention will be described in detail below.
Main chemical reagent and instrument
Synephrine (Mianyang Di Australia pharmaceutical Co., ltd.); 1, 4-dibromobutane, di-tert-butyl dicarbonate (Boc) 2 O), 5-chloro-2-mercaptobenzoxazole, m-chloroperoxybenzoic acid (mCPBA) (Shanghai darey fine chemical Co., ltd., AR); n, N-diisopropylethylamine (DIPEA, new De chemical Co., ltd., AR); potassium carbonate (AR, new chemical industry limited of Chongqing city, before use, mortar for grinding, oven drying), p-nitrobenzenesulfonyl chloride, o-fluorobenzenesulfonyl chloride, p-fluorobenzenesulfonyl chloride, m-fluorobenzenesulfonyl chloride, o-bromobenzenesulfonyl chloride, m-bromobenzenesulfonyl chloride, p-trifluoromethoxybenzenesulfonyl chloride, m-trifluoromethoxybenzenesulfonyl chloride, p-trifluoromethylbenzenesulfonyl chloride, p-toluenesulfonyl chloride, 2, 6-difluorobenzenesulfonyl chloride, 2,4, 6-trimethylbenzenesulfonyl chloride, 3-pyridinesulfonyl chloride and acetamidobenzenesulfonyl chloride (AR, shanghai medical technology limited), the remaining reagents are all commercially pure or analytically pure products, the reaction solvent is dried, and the rest is directly used without purification.
Nuclear magnetic resonance equipment (Bruker ADVANCE III) TM 600MHz, switzerland, TMSAn internal standard); high resolution mass spectrometer (QTOF-MS, bruker Impact II, bremen, germany); automatic polarimeter (WZZ-2S, shanghai precision scientific instruments Co., ltd.); melting point tester (X-6, beijing Fukai instruments Co., ltd.); ultraviolet analyzer (ZF-1, shanghai Gu Cun electro-optical instruments).
1 Synthesis of target molecule TM
The synthetic route is as follows:
i. synthesis of intermediate IM1
The synephrine and Boc are combined 2 O reacts in ethanol solvent at 0-35 ℃ to prepare the intermediate IM1.
Operation example: into a 100mL round bottom flask was added synephrine (8.458 g,50 mmol) and ethanol (EtOH) (10 mL), and after rapid stirring at room temperature (30 ℃ C.) for 5min, boc was slowly added dropwise 2 O (12.874 g,55 mmol), after the dropwise addition, stirring rapidly at room temperature was continued and the progress of the reaction was monitored by Thin Layer Chromatography (TLC). After the reaction is finished, removing EtOH by rotation, adding a proper amount of Petroleum Ether (PE), stirring by ultrasound until white solid is separated out, adding a proper amount of PE, stirring for 0.5h, filtering, drying, weighing to obtain 13.258g of white solid IM1 (pure product), and obtaining the yield of 99.2%, m.p.88.5-90.1 ℃.
Synthesis of intermediate IM2
Intermediate IM1 and 1, 4-dibromobutane in base K 2 CO 3 Reacting in DMF at 45 deg.C to obtain intermediate IM2.
Operation example: to a 100mL round bottom flask was added intermediate IM1 (4.013 g,20 mmol), DMF (2 mL), triturated K 2 CO 3 After stirring the powder (3.112 g,22.5 mmol) in an oil bath at 45℃for 0.5h, 1, 4-dibromobutane (6.432 g,30 mmol) was added dropwise and the reaction was stirred rapidly in an oil bath at 45℃and monitored by TLC (DCM: meOH=10:1). After the reaction is finished, adding proper amount of saturated Na 2 CO 3 The solution was stirred with an appropriate amount of Dichloromethane (DCM) at room temperature for 0.5h, the organic phase was collected, washed with saturated NaCl solution (10 mL. Times.3), anhydrous Na 2 SO 4 Drying, spin-removing solvent to obtain yellowish liquid, addingAdding a proper amount of PE, rapidly stirring until white solid is separated out, filtering, collecting the white solid, washing the PE until the PE has no 1, 4-dibromobutane smell, drying, and weighing to obtain a crude product. The crude product was purified by column chromatography with PE: EA (ethyl acetate) =10:1-5:1 (v/v) to give 5.423g of white solid IM 2.4% in 67.4% yield, m.p.92.8-94 ℃.
Synthesis of intermediate IM3
Intermediate IM2 and 5-chloro-2-mercaptobenzoxazole are reacted in the presence of base K 2 CO 3 Reacting in DMF at 45 deg.C to obtain intermediate IM3.
Operation example: to a 100mL round bottom flask was added 5-chloro-2-mercaptobenzoxazole (9.288 g,50 mmol), DMF (4 mL), stirred to dissolve, and anhydrous K was added 2 CO 3 (6.911 g,50 mmol), stirring rapidly at room temperature (32 ℃) for 0.5h, adding intermediate IM2 (8.051 g,20 mmol), stirring rapidly at 45℃in an oil bath, and monitoring the progress of the reaction by TLC (PE: EA=5:1, DCM: meOH=10:1). After the completion of the reaction, the reaction mixture was cooled to room temperature, and ice-cooled saturated Na was added thereto 2 CO 3 The solution (10 mL), stirred for 10min, DCM (20 mL) was added, stirred for 10min, the organic phase was collected, washed with saturated NaCl solution (10 mL. Times.3), anhydrous Na 2 SO 4 Drying and spin-off of the solvent gave a pink solid IM 3.079 g, yield 99.4%, m.p.151.2-153.7deg.C.
Synthesis of intermediate IM4
Intermediate IM3 is reacted with HCl-Ethyl Acetate (EA) at a temperature of between-15 and 25 ℃ to prepare intermediate IM4.
Operation example to a 100mL round bottom flask was added intermediate IM3 (7.605 g,15 mmol), 3mol/LHCl-EA (30 mL,90 mmol) was added dropwise, the reaction was stirred rapidly with an ice water bath (0-5 ℃ C.) and TLC monitored for progress. After the reaction, the solvent is removed by rotating, adding an appropriate amount of EA, stirring for a few minutes, removing the solvent again by rotating, adding an appropriate amount of PE, stirring for a few minutes, removing the solvent again, adding diethyl ether (20 mL), stirring for dispersion, and carrying out suction filtration to obtain pink solid IM4 6.058g, with the yield of 91.1%, m.p.168.9-169.8 ℃.
Synthesis of target molecule TM1
Intermediate IM4 and compound RSO 2 Cl is subjected to ice water bath (0-5 ℃) reaction in DMF solvent in the presence of DIPEA serving as an acid binding agentAccordingly, the target molecule TM1 was produced.
Operation example: into a 100mL round bottom flask was added intermediate IM4 (1 mmol), DMF (1.5 mL), DIPEA (0.5 mL,3 mmol) was added dropwise, and the mixture was stirred rapidly in an ice water bath (0-5 ℃ C.) for 30min, followed by RSO 2 Cl (2 mmol), ice-water bath (0-5 ℃ C.) and TLC monitored the progress of the reaction. After the reaction was completed, water (10 mL) and DCM (10 mL) were added, stirred for 10min, the organic phase was collected, washed with saturated NaCl solution, and dried Na 2 SO 4 Drying, spin-removing solvent, purifying by column chromatography (PE: EA=12:1-8:1, v/v) to obtain TM1, drying, weighing, and calculating the yield. The synthesis results are shown in Table 1.
TABLE 1 Synthesis of TM1
Synthesis of target molecule TM2
Target molecule TM1 was reacted with mCPBA in solvent DCM at 30℃to give target molecule TM2.
Operation example: to a 100mL round bottom flask were added the target molecule TM1 (0.5 mmol), DCM (1.5 mL) and mCPBA (1.25 mmol), the reaction was stirred rapidly at 30deg.C and TLC monitored the progress of the reaction. After the reaction was completed, ice-cold saturated NaHCO was added 3 The solution (5 mL) and DCM (5 mL) were stirred for 5min, the organic phase was collected, washed with water (10 mL. Times.3), anhydrous Na 2 SO 4 Drying, spin-removing solvent, column chromatography (PE: ea=5:1-2:1, v/v) purification to give TM2, drying, weighing, and calculating the yield. The synthesis results are shown in Table 2.
TABLE 2 Synthesis of TM2
The structural formula and structural characterization data of the intermediate IM3 and the target molecules TM1 and TM2 are as follows:
IM3:Pink solid,m.p.151.2-153.7℃,(2mg/mL,DMSO). 1 H NMR(600MHz,DMSO-d6)δ7.74(s,1H,H-1),7.67(d,J=8.6Hz,1H,H-2),7.36(dd,J=8.6,1.9Hz,1H,H-3),7.19(d,J=8.2Hz,2H,H-4),6.88(d,J=7.5Hz,2H,H-5),5.29(d,J=32.1Hz,1H,H-6),4.64(d,J=27.8Hz,1H,H-7),4.04–3.93(m,2H,H-8),3.41(t,J=7.0Hz,2H,H-9),3.32(s,3H,H-10),3.24(dd,J=29.0,17.8Hz,1H,H-11),3.14(dd,J=13.7,7.2Hz,1H,H-12),1.94(dd,J=14.1,7.0Hz,2H,H-13),1.90–1.80(m,2H,H-14),1.37(s,3H,H-15),1.29(s,6H,H-16).
IM4:Pink solid,m.p.169.7.2-172.3℃,(2mg/mL,DMSO). 1 H NMR(600MHz,DMSO-d6)δ7.72(s,1H,H-1),7.67(d,J=8.8Hz,1H,H-2),7.40(dd,J=8.9,1.9Hz,1H,H-3),7.19(d,J=7.8Hz,2H,H-4),6.84(d,J=8.2Hz,2H,H-5),5.79(d,J=4.8Hz,1H,H-6),4.75(q,J=4.3Hz,1H,H-7),4.06–4.01(m,1H,H-8),4.01(t,J=5.8Hz,2H,,H-9),3.14(t,J=8.4Hz,2H,H-10),3.04(dd,J=6.1,4.3Hz,1H,H-11),3.00(dd,J=6.0,4.4Hz,1H,H-12),2.51(s,3H,H-13),1.90–1.80(m,2H,H-14),1.75–1.60(m,2H,H-15).
TM1a:White solid,m.p.82.3-83.5℃,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ7.66(d,J=7.4Hz,2H,H-1),7.54(s,1H,H-2),7.33(d,J=8.6Hz,1H,H-3),7.29(d,J=7.8Hz,2H,H-4),7.28(d,J=7.8Hz,2H,H-5),7.20(d,J=8.6Hz,1H,H-6),6.87(d,J=7.5Hz,2H,H-7),4.86(d,J=8.6Hz,1H,H-8),4.01(t,J=5.7Hz,1H,H-9),3.38(t,J=6.9Hz,2H,H-10),3.26(dd,J=13.9,8.9Hz,1H,H-11),2.99(d,J=14.1Hz,1H,H-12),2.79(s,3H,H-13),2.41(s,2H,H-14),2.08–2.01(m,2H,H-15),2.01–1.92(m,2H,H-16). 13 C NMR(151MHz,CDCl 3 )δ166.75,159.06,158.71,150.43,143.63,143.06,134.39,133.31,129.78,127.43,127.28,123.97,118.43,114.57,110.45,71.79,67.17,58.29,36.76,28.18,26.13,21.49.HR MS calcd for C 27 H 29 ClN 2 O 5 S 2 ,[M+H] + :561.1279,found:561.1280;[M+Na] + :583.1099,found:583.1099.
TM1b:yellow solid,m.p.115.1-116.9℃,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ8.36(d,J=8.5Hz,2H,H-1),7.98(d,J=8.5Hz,2H,H-2),7.56(s,1H,H-3),7.36(d,J=8.6Hz,1H,H-4),7.30(s,2H,H-5),7.23(d,J=8.3Hz,1H,H-6),6.90(d,J=8.3Hz,2H,H-7),4.93(dd,J=8.3,3.1Hz,1H,H-8),4.05(t,J=5.9Hz,2H,H-9),3.41(t,J=7.1Hz,2H,H-10),3.36(dd,J=14.2,8.6Hz,1H,H-11),3.20(dd,J=14.2,3.2Hz,1H,H-12),2.91(s,3H,H-13),2.08(dd,J=14.4,7.2H,2H,H-14),2.01(dd,J=13.3,6.3Hz,2H,H-15). 13 C NMR(151MHz,CDCl 3 )δ166.73,158.94,150.43,150.09,143.84,143.06,133.08,129.82,128.49,127.24,124.36,123.98,118.42,114.70,110.46,72.34,67.20,57.80,36.61,32.02,28.15,26.12.HR MS calcd for C 26 H 26 ClN 3 O 7 S 2 ,[M+H] + :592.0973,found:592.0983.
TM1c:yellow solid,m.p.105.9-108.2℃,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ7.99(d,J=7.6Hz,1H,H-1),7.68(p,J=7.5Hz,2H,H-2),7.61(d,J=7.5Hz,1H,H-3),7.53(s,1,H-4),7.33(d,J=8.6Hz,1H,H-5),7.28(d,J=8.0Hz,2H,H-6),7.20(d,J=8.6Hz,1H,H-7),6.87(d,J=7.9Hz,2H,H-8),4.92(dd,J=8.6,2.7Hz,1H,H-9),4.01(t,J=5.9Hz,2H,H-10),3.45(dd,J=14.7,8.9Hz,2H,H-11),3.38(t,J=7.1Hz,1H,,H-12),3.35(dd,J=14.8,2.9Hz,1H,H-13),2.99(s,3H,H-14),2.04(dt,J=14.5,7.1Hz,2H,H-15),2.00–1.93(m,2H,H-16). 13 C NMR(151MHz,CDCl 3 )δ166.75,158.81,150.43,148.23,143.06,133.61,133.28,132.22,131.61,130.98,127.25,124.17,123.97,118.42,114.67,110.46,72.23,67.18,57.61,36.35,32.04,28.17,26.13.HR MS calcd for C 26 H 26 ClN 3 O 7 S 2 ,[M+H] + :592.0973,found:592.0979.
TM1d:White solid,m.p.126.2-127.8℃,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ7.92(t,J=7.4Hz,1H,H-1),7.63–7.51(m,2H,H-2),7.36(d,J=8.6Hz,1H,H-3),7.32(d,J=8.4Hz,2H,H-4),7.28–7.27(m,1H,H-5),7.22(dd,J=14.2,8.8Hz,1H,H-6),6.89(d,J=7.7Hz,2H,H-7),4.94(d,J=8.3Hz,1H,H-8),4.04(t,J=5.8Hz,2H,H-9),3.45–3.41(m,2H,H-10),3.40(d,J=7.8Hz,1H,H-11),3.26(d,J=14.5Hz,1H,H-12),2.94(s,3H,H-13),2.07(dt,J=14.2,7.1Hz,2H,H-14),2.04–1.95(m,2H,H-15). 13 C NMR(151MHz,CDCl 3 )δ166.74,158.82,150.43,143.07,139.64,135.80,133.20,130.66,130.15,127.28,125.87,123.97,118.43,114.65,110.45,72.14,67.18,58.01,36.75,32.04,28.17,26.13.HR MS calcd for C 26 H 26 ClFN 2 O 5 S 2 ,[M+H] + :565.1028,found:565.1035.
TM1e:White solid,m.p.97.6-98.5,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ7.60(d,J=7.8Hz,1H,H-1),7.57(s,1H,H-2),7.54(d,J=8.0Hz,1H,H-3),7.51(d,J=8.6Hz,1H,H-4),7.36(d,J=8.6Hz,1H,H-5),7.32(s,1H,H-6),7.31(s,1H,H-7),7.23(d,J=8.6Hz,1H,H-8),6.90(d,J=8.2Hz,2H,H-9),4.91(d,J=6.3Hz,1H,H-10),4.05(t,J=5.9Hz,2H,H-11),3.41(t,J=7.1Hz,2H,H-12),3.32(dd,J=14.1,8.7Hz,1H,H-13),3.11(d,J=12.4Hz,1H,H-14),2.86(s,3H,H-15),2.08(dt,J=14.3,7.1Hz,2H,H-16),2.04–1.95(m,2H,H-17). 13 C NMR(151MHz,CDCl 3 )δ166.73,163.34,161.67,158.82,150.44,143.08,133.19,130.97,129.83,127.26,123.96,123.10,123.08,120.03,119.89,118.44,114.79,114.65,110.45,72.11,67.18,58.08,36.74,32.03,28.17,26.13.HR MS calcd for C 26 H 26 ClFN 2 O 5 S 2 ,[M+H] + :565.1028,found:565.1033.
TM1f:White solid,m.p.112.8-114.5℃,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ7.92(t,J=7.4Hz,1H,H-1),7.59(d,J=7.1Hz,1H,H-2),7.57(s,1H,H-3),7.36(d,J=8.6Hz,1H,H-4),7.32(d,J=8.4Hz,2H,H-5),7.29–7.27(m,1H,H-6),7.23(d,J=8.4Hz,1H,H-7),7.21(d,J=9.3Hz,1H,H-8),6.89(d,J=7.7Hz,1H,H-9),4.94(d,J=8.3Hz,1H,H-10),4.04(t,J=5.8Hz,2H,H-11),3.43(d,J=7.1Hz,2H,H-12),3.40(d,J=7.8Hz,1H,H-13),3.26(d,J=14.5Hz,1H,H-14),2.94(s,3H,H-15),2.07(dt,J=14.2,7.1Hz,2H,H-16),2.04–1.94(m,2H,H-17). 13 C NMR(151MHz,CDCl 3 )δ166.73,158.74,150.44,143.09,134.98,134.92,133.36,131.37,129.82,127.26,124.47,124.45,123.96,118.44,117.16,114.61,110.44,72.20,67.17,57.85,36.43,36.41,32.04,28.17,26.13.HR MS calcd for C 26 H 26 ClFN 2 O 5 S 2 ,[M+H] + :565.1028,found:565.1015./>
TM1g:White solid,m.p.96.9-98.2℃,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ7.78(d,J=7.9Hz,2H,H-1),7.58(t,J=7.2Hz,1H,H-2),7.54(s,1H,H-3),7.33(d,J=8.6Hz,1H,H-4),7.28(d,J=8.0Hz,2H,H-5),7.20(d,J=8.6Hz,1H,H-6),6.87(d,J=8.1Hz,2H,H-7),4.88(d,J=8.4Hz,1H,H-8),4.01(t,J=5.9Hz,2H,H-9),3.38(t,J=7.0Hz,2H,H-10),3.34–3.24(m,1H,H-11),3.02(d,J=14.1Hz,1H,H-12),2.81(s,3H,H-13),2.10–2.00(m,2H,H-14),2.01–1.90(m,1H,H-15). 13 C NMR(151MHz,CDCl 3 )δ166.74,158.74,150.44,143.07,137.46,133.27,132.78,129.83,129.48,129.17,127.37,127.28,123.97,118.44,114.60,110.45,71.89,67.18,58.24,36.76,32.04,28.18,26.13.HR MS calcd for C 26 H 25 ClF 2 N 2 O 5 S 2 ,[M+H] + :583.0934,found:583.0933.
TM1h:White solid,m.p.70.2-71.6℃,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ7.57(s,1H,H-1),7.51(t,J=7.1Hz,1H,H-2),7.36(d,J=8.6Hz,1H,H-3),7.33(d,J=8.0Hz,2H,H-4),7.29(s,1H,H-5),7.23(d,J=8.5Hz,1H,H-6),7.04(d,J=9.1Hz,1H,H-7),7.02(d,J=9.1Hz,1H,H-8),6.90(d,J=7.9Hz,2H,H-9),4.98(dd,J=8.5,2.8Hz,1H,H-10),4.04(t,J=5.9Hz,2H,H-11),3.46(dd,J=14.6,8.7Hz,2H,H-12),3.41(t,J=7.1Hz,1H,H-13),3.34(dd,J=14.7,2.5Hz,1H,H-14),3.01(s,3H,H-15),2.07(dt,J=14.4,7.1Hz,2H,H-16),2.03–1.97(m,2H,H-7). 13 C NMR(151MHz,CDCl 3 )δ166.74,160.47,160.11,158.78,150.43,143.07,134.36,134.28,134.21,133.36,129.83,127.26,123.96,118.43,114.63,113.24,113.21,113.08,113.05,110.45,72.41,67.17,57.79,36.44,32.04,28.17,26.13.HR MS calcd for C 26 H 26 BrClN 2 O 5 S 2 ,[M+H] + :625.0228,found:625.0219.
TM1i:White solid,m.p.78.2-80.7℃,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ8.10(d,J=7.8Hz,1H,H-1),7.73(d,J=7.8Hz,1H,H-2),7.54(s,1H,H-3),7.44(t,J=7.6Hz,1H,H-4),7.38(t,J=7.6Hz,1H,H-5),7.33(d,J=8.6Hz,2H,H-6),7.27(d,J=11.0Hz,1H,H-7),7.20(d,J=8.6Hz,2H,H-8),4.92(d,J=8.0Hz,1H,H-9),4.01(t,J=5.8Hz,2H,H-10),3.46(dd,J=14.7,8.9Hz,2H,H-11),3.38(t,J=6.0Hz,1H,H-12),3.36(d,J=12.6Hz,1H,H-13),2.96(s,3H,H-14),2.04(dt,J=14.1,7.0Hz,2H,H-15),2.00–1.92(m,2H,H-16). 13 C NMR(151MHz,CDCl 3 )δ166.73,158.73,150.43,143.08,138.31,135.75,133.64,133.46,132.45,129.83,127.59,127.22,123.96,120.22,118.44,114.62,110.45,72.19,67.17,58.08,36.28,32.04,28.17,26.13.HR MS calcd for C 26 H 26 BrClN 2 O 5 S 2 ,[M+H] + :625.0228,found:625.0209./>
TM1j:White solid,m.p.107.8-109.6,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ7.93(d,J=7.9Hz,2H,H-1),7.80(d,J=7.9Hz,2H,H-2),7.56(s,1H,H-3),7.36(d,J=8.5Hz,1H,H-4),7.31(d,J=7.6Hz,2H,H-5),7.23(d,J=8.6Hz,1H,H-6),6.92(t,J=15.6Hz,2H,H-7),4.92(d,J=8.3Hz,1H,H-8),4.05(t,J=5.7Hz,2H,H-9),3.41(t,J=7.0Hz,2H,,H-10),3.33(dd,J=14.0,8.8Hz,1H,H-11),3.13(d,J=14.2Hz,1H,H-12),2.88(s,3H,H-13),2.07(dt,J=14.2,7.0Hz,2H,H-14),2.04–1.96(m,2H,H-15). 13 C NMR(151MHz,CDCl 3 )δ166.74,158.86,150.43,143.04,141.36,133.15,129.84,127.83,127.25,126.31,126.29,123.98,118.42,114.67,110.45,72.21,67.19,57.97,36.68,32.03,28.16,26.12.HR MS calcd for C 27 H 26 ClF 3 N 2 O 5 S 2 ,[M+H] + :615.0997,found:615.1005.
TM1k:White solid,m.p.81.3-82.9℃,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ7.86(d,J=8.4Hz,2H,H-1),7.57(s,1H,H-2),7.37(s,1H,H-3),7.35(s,2H,H-4),7.31(d,J=8.1Hz,2H,H-5),7.23(d,J=8.6Hz,1H,H-6),6.90(d,J=8.1Hz,2H,H-7),4.92(d,J=7.9Hz,1H,H-8),4.05(t,J=5.9Hz,2H,H-9),3.41(t,J=7.1Hz,2H,H-10),3.32(dd,J=14.1,8.8Hz,1H,H-11),3.10(d,J=14.0Hz,1H,H-12),2.86(s,3H,H-13),2.07(dd,J=14.2,7.0Hz,2H,H-14),2.01(dd,J=13.3,6.5Hz,2H,H-15). 13 C NMR(151MHz,CDCl 3 )δ166.72,158.84,152.23,150.44,143.08,136.06,133.18,129.83,129.47,127.26,123.97,121.01,118.44,114.65,110.45,72.10,67.19,58.05,36.69,32.03,28.17,26.12.HR MS calcd for C 27 H 26 ClF 3 N 2 O 6 S 2 ,[M+H] + :631.0946,found:631.0955
TM1l:White solid,m.p.75.3-77.1℃,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ7.95(s,1H,H-1),7.74(d,J=7.8Hz,2H,H-2),7.57(s,1H,H-13),7.41(t,J=8.0Hz,1H,H-4),7.36(d,J=8.6Hz,1H,H-5),7.31(d,J=7.7Hz,2H,H-6),7.24(d,J=8.6Hz,1H,H-7),6.91(d,J=7.6Hz,2H,H-8),4.91(d,J=8.2Hz,1H,H-9),4.05(t,J=5.8Hz,2H,H-10),3.42(t,J=7.0Hz,2H,H-11),3.33(dd,J=14.1,8.8Hz,1H,H-12),3.12(d,J=14.1Hz,1H,H-13),2.87(s,3H,H-14),2.08(dt,J=14.6,7.2Hz,2H,H-15),2.03–1.96(m,2H,H-16). 13 C NMR(151MHz,CDCl 3 )δ166.74,158.72,150.43,146.07,143.07,135.80,134.37,133.43,132.15,129.82,127.21,126.46,123.96,120.21,118.43,114.60,110.44,72.21,67.16,57.75,36.38,32.04,28.18,26.13.HR MS calcd for C 27 H 26 ClF 3 N 2 O 6 S 2 ,[M+H] + :631.0946,found:631.0954.
TM1m:White solid,m.p.70.1-72.9℃,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ7.85–7.78(m,2H,H-1),7.56(s,1H,H-2),7.36(d,J=8.6Hz,1H,H-3),7.31(d,J=8.1Hz,2H,H-4),7.29(m,1H,H-5),7.23(d,J=9.0Hz,21H,,H-6),7.20(s,1H,H-7),6.90(d,J=8.2Hz,1H,H-8),4.91(d,J=8.5Hz,1H,H-9),4.04(t,J=5.9Hz,2H,H-10),3.41(t,J=7.1Hz,2H,H-11),3.31(dd,J=14.0,8.8Hz,1H,H-12),3.07(d,J=14.1Hz,1H,H-13),2.84(s,3H,H-14),2.13–2.04(m,2H,H-15),2.04–1.97(m,2H,H-14). 13 C NMR(151MHz,CDCl 3 )δ166.73,164.33,158.79,150.44,143.08,133.23,130.07,130.01,127.26,123.97,118.43,116.48,116.33,114.62,110.45,72.00,67.18,58.10,36.69,32.03,28.17,26.13.HR MS calcd for C 26 H 27 ClN 2 O 5 S 2 ,[M+H] + :547.1123,found:547.1120;[M+Na] + :569.0942,found:569.0939.
TM1n:yellow oil,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ9.02(s,1H,H-1),8.79(d,J=3.8Hz,1H,H-2),8.11(d,J=7.7Hz,1H,H-3),7.53(s,1H,H-4),7.51–7.46(m,1H,H-5),7.33(d,J=8.6Hz,1H,H-6),7.28(s,2H,H-7),7.20(d,J=8.6Hz,1H,H-8),6.87(d,J=7.9Hz,2H,H-9),4.89(d,J=7.7Hz,1H,H-10),4.02(t,J=5.8Hz,2H,H-11),3.38(t,J=6.7Hz,2H,H-12),3.36–3.31(m,1H,H-13),3.13(d,J=14.2Hz,1H,H-14),2.87(s,3H,H-15),2.08–2.01(m,2H,H-16),1.97(dd,J=13.5,6.3Hz,2H,H-17). 13 C NMR(151MHz,CDCl 3 )δ166.72,159.40,158.88,152.45,150.44,147.54,143.09,135.83,135.65,133.12,129.82,127.25,124.07,124.02,123.97,118.44,114.70,110.45,72.04,72.01,67.19,57.87,36.48,36.45,32.03,28.16,26.12.HR MS calcd for C 25 H 26 ClN 3 O 5 S 2 ,[M+H] + :548.1063,found:548.1075.
TM1o:White solid,m.p.116.7-118.0℃,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ7.54(s,1H,H-1),7.33(d,J=8.6Hz,1H,H-2),7.22(d,J=8.8Hz,2H,H-3),7.19(s,1H,H-4),6.94(s,2H,H-5),6.84(d,J=7.9Hz,2H,H-6),4.88(d,J=7.9Hz,1H,,H-7),4.01(t,J=5.8Hz,2H,H-8),3.38(t,J=7.3Hz,2H,H-9),3.36–3.29(m,1H,H-10),3.23(d,J=13.9Hz,1H,H-11),2.86(s,3H,H-12),2.59(s,6H,H-13),2.29(s,3H,H-14),2.04(dt,J=14.3,7.1Hz,2H,H-15),1.97(dd,J=13.1,6.4Hz,2H,H-16). 13 C NMR(151MHz,CDCl 3 )δ166.74,158.67,150.44,142.67,140.31,133.66,132.04,129.84,127.15,123.97,118.44,114.58,110.45,71.71,67.17,56.93,34.78,32.04,28.18,26.13,22.86,20.93.HR MS calcd for C 29 H 33 ClN 2 O 5 S 2 ,[M+H] + :589.1592,found:589.1601.
TM1p:Colorless liquid,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ10.30(s,1H,H-1),7.66(d,J=7.4Hz,2H,H-2),7.54(s,1H,H-3),7.33(d,J=8.6Hz,1H,H-1),7.29(d,J=7.8Hz,1H,H-5),7.28(d,J=7.8Hz,2H,H-6),7.20(d,J=8.6Hz,1H,H-7),6.87(d,J=7.5Hz,2H,H-8),4.86(d,J=8.6Hz,1H,H-9),4.01(t,J=5.7Hz,2H,H-10),3.38(t,J=6.9Hz,2H,H-11),3.26(dd,J=13.9,8.9Hz,1H,H-12),2.99(d,J=14.1Hz,1H,H-13),2.79(s,3H,H-14),2.41(s,3H,H-15),2.08–2.01(m,2H,H-16),2.01–1.92(m,2H,H-17). 13 C NMR(151MHz,CDCl 3 )δ166.75,159.06,158.71,150.43,143.63,143.06,134.39,133.31,129.78,127.43,127.28,123.97,118.43,114.57,110.45,71.79,67.17,58.29,36.76,28.18,26.13,21.49.HR MS calcd for C 28 H 30 ClN 3 O 6 S 2 ,[M+H] + :604.1337,found:604.1346.
TM2a:white solid,m.p.106.2-108.5℃,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ7.85(d,J=1.7Hz,1H,H-1),7.66(d,J=8.2Hz,2H,H-1),7.61(d,J=8.8Hz,1H,H-3),7.55–7.51(m,2H,H-4),7.31(s,1H,,H-5),7.29(d,J=5.9Hz,2H,H-6),6.82(d,J=8.6Hz,2H,H-7),4.87(dd,J=8.8,3.3Hz,1H,H-8),3.99(t,J=5.8Hz,2H,H-9),3.67–3.62(m,2H,H-10),3.26(dd,J=14.1,8.8Hz,1H,H-11),2.99(dd,J=14.1,3.4Hz,1H,H-12),2.79(s,3H,H-13),2.41(s,3H,H-14),2.19–2.10(m,2H,H-15),2.02–1.93(m,2H,H-16). 13 C NMR(151MHz,CDCl 3 )δ171.07,167.71,159.54,158.39,149.49,143.62,140.48,130.83,129.76,128.79,127.42,127.30,122.01,114.52,112.84,71.79,68.18,60.34,38.79,36.75,28.93,27.66,19.41,14.16.HRMS calcd for C 27 H 29 ClN 2 O 7 S 2 ,[M+Na] + :615.0997,found:615.0995.
TM2b:yellow solid,m.p.146.7-148.0℃,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ8.31(d,J=10.3Hz,2H,H-1),7.92(d,J=10.4Hz,2H,H-2),7.72(d,J=1.7Hz,1H,H-3),7.65(d,J=8.8Hz,1H,H-4),7.41(dd,J=8.9,1.9Hz,1H,H-5),7.20(d,J=8.2Hz,2H,H-6),6.84(d,J=8.2Hz,1H,H-7),4.91(q,J=5.4Hz,1H,H-8),4.00(dd,J=7.2,4.1Hz,2H,H-9),3.55(ddd,J=35.7,13.0,5.6Hz,1H,H-10,H-11),3.35–3.26(m,2H,H-12),2.67(s,3H,H-13),1.98–1.86(m,2H,H-14),1.86–1.79(m,2H,H-15). 13 C NMR(151MHz,CDCl 3 )δ161.35,158.63,149.81,149.46,142.69,139.65,133.63,131.15,127.88,127.28,126.09,124.44,118.72,115.43,112.57,69.67,67.88,57.39,51.64,36.71,28.04,21.29.HR MS calcd for C 26 H 26 ClN 3 O 9 S 2 ,[M+Na] + :646.0691,found:646.0685.
TM2c:yellow solid,m.p.137.6-138.9℃,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ7.85(d,J=1.7Hz,1H,H-1),7.66(d,J=8.2Hz,1H,H-2),7.61(d,J=8.8Hz,2H,H-3,4),7.55–7.51(m,1H,H-5,6),7.31(s,1H,H-7),7.29(d,J=5.9Hz,2H,H-8),6.82(d,J=8.6Hz,2H,H-9),4.87(dd,J=8.8,3.3Hz,1H,H-10),3.99(t,J=5.8Hz,2H,H-11),3.67–3.62(m,2H,H-12),3.26(dd,J=14.1,8.8Hz,1H,H-13),2.99(dd,J=14.1,3.4Hz,1H,H-14),2.79(s,3H,H-15),2.19–2.10(m,1H,H-16),2.02–1.93(m,1H,H-17). 13 C NMR(151MHz,CDCl 3 )δ158.50,149.49,140.48,133.60,132.02,131.57,131.02,129.12,127.27,124.17,122.03,114.62,112.85,72.21,69.45,66.79,57.61,54.38,36.33,27.65,19.41.HR MS calcd for C 26 H 26 ClN 3 O 9 S 2 ,[M+Na] + :646.0691,found:646.0688.
TM2d:white solid,m.p.122.3-124.8℃,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ7.92(s,1H,H-1),7.73–7.66(m,2H,H-2),7.53(d,J=1.8Hz,1H,H-3),7.38(t,J=7.9Hz,2H,H-4),7.33(d,J=8.6Hz,1H,H-5),7.28(d,J=8.5Hz,2H,H-6),7.20(dd,J=8.6,2.0Hz,1H,H-7),4.88(dd,J=8.6,3.6Hz,1H,H-8),4.02(t,J=6.0Hz,2H,H-9),3.38(t,J=7.1Hz,2H,H-10),3.29(dd,J=14.2,8.6Hz,1H,H-11),3.10(dd,J=14.2,3.7Hz,1H,H-12),2.83(s,3H,H-13),2.08–2.01(m,2H,H-14),2.01–1.92(m,2H,H-15). 13 C NMR(151MHz,CDCl 3 )δ166.71,158.85,150.46,143.12,139.79,138.81,135.76,130.62,130.16,129.84,127.26,125.85,123.95,123.23,118.46,114.69,110.42,72.19,67.22,58.02,36.73,32.05,28.18,26.15.HR MS calcd for C 26 H 26 ClFN 2 O 7 S 2 ,[M+Na] + :619.0746,found:619.0745.
TM2e:white solid,m.p.117.7-119.6℃,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ7.84(d,J=1.7Hz,1H,H-1),7.61(d,J=8.8Hz,1H,H-2),7.57(d,J=7.8Hz,1H,H-3),7.54(dd,J=8.8,1.9Hz,1H,H-4),7.52–7.45(m,2H,H-5,H-6),7.32–7.28(m,1H,H-7),7.28(d,J=8.6Hz,2H,H-8),6.83(d,J=8.6Hz,2H,H-9),4.88(dd,J=8.6,3.4Hz,1H,H-10),4.00(t,J=5.7Hz,2H,H-11),3.73–3.60(m,2H,H-12),3.29(dd,J=14.2,8.7Hz,1H,H-13),3.08(dd,J=14.2,3.5Hz,1H,H-14),2.84(s,3H,H-15),2.21–2.10(m,2H,H-16),2.02–1.95(m,2H,H-17). 13 C NMR(151MHz,CDCl 3 )δ163.35,161.68,159.53,158.51,149.49,140.48,133.49,132.03,130.97,129.12,127.30,123.07,122.03,119.89,114.78,114.60,112.84,72.07,66.79,58.07,54.38,36.74,27.67,19.41.HR MS calcd for C 26 H 26 ClFN 2 O 7 S 2 ,[M+H] + :597.0927,found:597.0935;[M+Na] + :619.0746,found:619.0749.
TM2f:white solid,m.p.129.4-131.2℃,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ7.91(t,J=7.2Hz,1H,H-1),7.58(dd,J=10.9,4.9Hz,1H,H-2),7.56(d,J=1.4Hz,1H,H-3),7.35(d,J=8.6Hz,1H,H-4),7.31(d,J=8.5Hz,2H,H-5),7.27(d,J=6.4Hz 1H,H-6),7.22(ddd,J=15.7,7.8,5.0Hz,1H,H-7,H-8),6.89(d,J=8.6Hz,2H,H-9),4.93(dd,J=8.7,3.5Hz,1H,H-10),4.04(t,J=6.0Hz,2H,H-11),3.44–3.38(m,2H,H-12),3.42–3.39(m,1H,H-13),3.26(dd,J=14.5,3.5Hz,1H,H-14),2.94(s,3H,H-15),2.11–2.03(m,2H,H-16),2.03–1.95(m,2H,H-17). 13 C NMR(151MHz,CDCl 3 )δ166.72,158.76,157.96,150.45,143.11,134.92,134.86,133.46,131.34,129.84,127.24,124.44,124.41,123.95,118.45,117.28,117.13,114.65,110.41,72.25,67.21,57.86,57.85,36.41,36.39,32.05,28.18,26.15.HR MS calcd for C 26 H 26 ClFN 2 O 7 S 2 ,[M+Na] + :619.0746,found:619.0742./>
TM2g:white solid,m.p.119.2-122.4℃,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ7.45(d,J=1.7Hz,1H,H-1),7.43–7.36(m,1H,H-2),7.25(d,J=8.6Hz,1H,H-3),7.22(d,J=8.5Hz,2H,H-4),7.11(dt,J=12.2,6.1Hz,1H,H-5),6.92(t,J=8.8Hz,2H,H-6),6.79(d,J=8.6Hz,2H,H-7),4.86(dd,J=8.6,3.6Hz,1H,H-8),3.93(t,J=6.0Hz,2H,H-9),3.36(dd,J=14.6,8.7Hz,1H,H-10),3.30(t,J=7.1Hz,1H,H-11),3.24(dd,J=14.6,3.6Hz,1H,H-12),2.90(s,3H,H-13),2.00–1.93(m,1H,H-14),1.92–1.84(m,1H,H-15). 13 C NMR(151MHz,CDCl 3 )δ166.73,160.45,158.79,158.74,150.45,143.10,133.45,129.83,128.80,127.25,123.95,118.44,117.13,114.67,113.21,113.18,113.05,113.02,110.42,72.43,67.21,57.78,36.41,32.05,28.18,26.15.HR MS calcd for C 26 H 26 ClF 2 N 2 O 7 S 2 ,[M+Na] + :637.0652,found:637.0649.
TM2h:yellow solid,m.p.144.6-146.7℃,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ7.94(s,1H,H-1),7.76–7.69(m,2H,H-2,H-3),7.55(d,J=1.7Hz,1H,H-4),7.40(t,J=7.9Hz,1H,H-5),7.35(d,J=8.6Hz,1H,H-6),7.30(d,J=8.5Hz,2H,H-7),7.22(dd,J=8.6,1.9Hz,1H,H-8),6.90(d,J=8.2Hz,1H,H-9),4.90(dd,J=8.6,3.6Hz,1H,H-10),4.04(t,J=6.0Hz,2H,H-11),3.41(t,J=7.1Hz,2H,H-12),3.32(dd,J=14.2,8.6Hz,1H,H-13),3.13(dd,J=14.2,3.7Hz,1H,H-14),2.86(s,3H,H-15),2.10–2.04(m,2H,H-16),2.00(dt,J=12.6,6.1Hz,2H,H-17). 13 C NMR(151MHz,CDCl 3 )δ166.72,158.84,150.45,143.10,139.79,135.76,133.28,130.62,130.15,129.84,127.26,125.85,123.96,123.22,118.45,114.69,110.42,72.19,67.22,58.01,36.72,32.05,28.18,26.15.HR MS calcd for C 26 H 26 BrClN 2 O 7 S 2 ,[M+Na] + :678.9946,found:678.9945.
TM2i:yellow solid,m.p.151.0-153.4℃,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ7.76(dd,J=8.5,1.4Hz,1H,H-1),7.72(d,J=1.7Hz,1H,H-2),7.70(dd,J=8.0,1.3Hz,1H,H-3),7.65(d,J=8.8Hz,1H,H-4),7.56(ddd,J=8.4,7.2,1.3Hz,1H,H-5),7.40(ddd,J=8.1,5.1,1.7Hz,2H,H-6,H-7),7.20(d,J=8.6Hz,2H,H-1),6.84(d,J=8.2Hz,2H,H-9),4.91(q,J=5.4Hz,1H,H-10),4.00(dd,J=7.2,4.1Hz,2H,H-11),3.64–3.51(m,1H,H-12,H-13),3.36–3.24(m,4H,H-14),2.72(s,3H,H-15),1.97–1.86(m,2H,H-16),1.86–1.79(m,2H,H-17). 13 C NMR(151MHz,CDCl 3 )δ161.35,158.63,149.46,139.65,137.61,135.08,134.81,133.65,131.15,129.41,129.00,127.28,126.09,122.25,118.72,115.43,112.57,69.67,67.88,57.34,51.64,36.86,28.04,21.29.HR MS calcd for C 26 H 26 BrClN 2 O 7 S 2 ,[M+Na] + :678.9946,found:678.9949./>
TM2j:white solid,m.p.109.7-111.0℃,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ7.83(d,J=8.1Hz,2H,H-1),7.77(d,J=1.5Hz,1H,H-2),7.70(d,J=8.2Hz,2H,H-3),7.54(d,J=8.8Hz,1H,H-4),7.47(dd,J=8.9,1.6Hz,1H,H-5),7.21(s,2H,H-6),6.76(d,J=8.5Hz,2H,H-7),4.82(dd,J=8.5,3.5Hz,1H,H-8),3.93(t,J=5.7Hz,2H,H-9),3.69–3.50(m,2H,H-10),3.23(dd,J=14.2,8.7Hz,1H,H-11),3.03(dd,J=14.2,3.5Hz,1H,H-12),2.78(s,3H,H-13),2.12–2.04(m,2H,H-14),1.95–1.87(m,2H,H-15). 13 C NMR(151MHz,CDCl 3 )δ158.56,149.49,140.48,133.45,132.03,130.84,129.12,128.80,127.82,127.28,126.31,122.02,114.62,112.84,72.16,66.81,57.98,54.37,36.68,27.67,19.40.HR MS calcd for C 27 H 26 ClF 3 N 2 O 7 S 2 ,[M+Na] + :669.0714,found:669.0710.
TM2k:white solid,m.p.132.6-134.1℃,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ7.84(dd,J=7.3,5.3Hz,2H,H-1,H-2),7.61(d,J=8.8Hz,1H,H-3),7.54(dd,J=8.8,1.9Hz,1H,H-4),7.33(d,J=8.4Hz,2H,H-5),7.28(d,J=8.5Hz,2H,H-6),6.83(d,J=8.5Hz,2H,H-7),4.89(dd,J=8.6,3.5Hz,1H,H-8),4.00(t,J=5.8Hz,2H,H-9),3.78–3.56(m,2H,H-10),3.29(dd,J=14.1,8.7Hz,1H,H-11),3.07(dd,J=14.2,3.5Hz,1H,H-12),2.83(s,3H,H-13),2.21–2.08(m,2H,H-14),2.01–1.95(m,2H,H-15). 13 C NMR(151MHz,CDCl 3 )δ158.54,154.86,149.49,142.38,130.16,129.58,129.46,129.13,127.30,122.76,122.03,121.02,114.62,112.84,111.00,110.35,72.06,66.81,58.04,54.38,36.69,27.67,19.40.HR MS calcd for C 27 H 26 ClF 3 N 2 O 8 S 2 ,[M+Na] + :685.0663,found:685.0662.
TM2l:white solid,m.p.115.4-117.6℃,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ8.05(d,J=7.9Hz,1H,H-1),7.62(t,J=7.9Hz,1H,H-2),7.56(d,J=1.7Hz,1H,H-3),7.41(t,J=7.7Hz,2H,H-4,H-5),7.35(d,J=8.6Hz,1H,H-6),7.30(d,J=8.5Hz,2H,H-7),7.22(dd,J=8.6,1.8Hz,1H,H-8),6.89(d,J=8.5Hz,1H,H-9),4.93(dd,J=8.7,3.5Hz,2H,H-10),4.03(t,J=6.0Hz,2H,H-11),3.41(dd,J=14.5,7.7Hz,2H,H-12),3.40(t,J=7.2Hz,1H,H-13),3.28(dd,J=14.7,3.6Hz,1H,H-14),2.95(s,3H,H-15),2.11–2.03(m,2H,H-16),1.99(dt,J=12.8,6.2Hz,2H,H-17). 13 C NMR(151MHz,CDCl 3 )δ166.73,163.37,158.74,150.45,146.08,143.11,134.31,133.51,132.12,131.11,129.84,127.20,126.43,123.94,120.21,118.44,114.65,110.41,72.25,67.20,57.75,36.35,32.05,28.18,26.15.HR MS calcd for C 27 H 26 ClF 3 N 2 O 8 S 2 ,[M+Na] + :685.0663,found:685.0636.
TM2m:Colorless liquid,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ7.79–7.74(m,1H,H-1),7.72(d,J=2.0Hz,1H,H-2),7.72–7.69(m,2H,H-3),7.65(dd,J=5.2,3.5Hz,1H,H-4),7.64–7.60(m,2H,H-5),7.41(dd,J=8.9,1.9Hz,1H,H-6),7.20(d,J=8.2Hz,2H,H-7),6.84(d,J=8.2Hz,2H,H-8),4.91(q,J=5.4Hz,1H,H-9),4.00(dd,J=7.2,4.1Hz,1H),H-10,3.55(ddd,J=36.1,13.0,5.5Hz,1H,H-11,12),3.35–3.26(m,2H,H-13),2.67(s,3H,H-14),1.98–1.86(m,2H,H-15),1.86–1.79(m,2H,H-16). 13 C NMR(151MHz,CDCl 3 )δ166.73,164.31,158.79,150.44,143.10,133.38,130.05,129.99,127.25,123.95,118.43,116.43,116.28,114.66,110.43,72.07,67.23,58.06,36.66,32.05,28.18,26.15.HR MS calcd for C 26 H 27 ClN 2 O 7 S 2 ,[M+Na] + :643.1310,found:643.1309.
TM2n:yellow oil,m.p.156.7-158.5℃,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ8.90(d,J=35.7Hz,1H,H-1),8.71(d,J=4.2Hz,1H,H-2),8.05–7.96(m,1H,H-3),7.45(t,J=3.8Hz,1H,H-4),7.38(dt,J=14.6,7.3Hz,1H,H-5),7.24(t,J=13.7Hz,1H,H-6),7.20(d,J=7.1Hz,2H,H-7),7.12(dd,J=8.6,1.9Hz,1H,H-8),6.80(t,J=8.9Hz,2H,H-9),4.82(dd,J=8.6,3.5Hz,1H,H-10),3.94(t,J=6.0Hz,2H,H-11),3.31(t,J=7.1Hz,2H,H-12),3.26(dd,J=14.2,8.7Hz,1H,H-13),3.07(dd,J=14.2,3.6Hz,1H,H-14),2.79(s,3H,H-15),2.00–1.93(m,2H,H-16),1.90(dt,J=12.6,6.1Hz,2H,H-17). 13 C NMR(151MHz,CDCl 3 )δ166.71,158.87,152.85,150.45,147.83,143.10,135.25,134.97,133.27,129.84,127.23,123.95,123.84,118.44,114.73,110.42,72.20,67.23,57.86,36.55,32.04,28.17,26.14.HR MS calcd for C 25 H 26 ClN 3 O 7 S 2 ,[M+H] + :580.0971,found:580.0973;[M+Na] + :602.0793,found:602.0790.
TM2o:white solid,m.p.128.7.7-129.6℃,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ7.54(d,J=1.8Hz,1H,H-1),7.32(d,J=8.6Hz,1H,H-2),7.22(d,J=8.7Hz,2H,H-3),7.20–7.18(m,1H,H-4),6.94(s,1H,H-5),6.83(t,J=11.8Hz,2H,H-6),4.94–4.78(m,1H,H-7),4.01(t,J=6.0Hz,2H,H-8),3.38(t,J=7.1Hz,2H,H-9),3.36–3.30(m,1H,H-10),3.26–3.17(m,1H,H-11),2.86(s,3H,H-12),2.58(s,6H,H-13),2.29(s,3H,H-14),2.08–2.00(m,2H,H-15),1.97(dt,J=12.5,6.1Hz,2H,H-6). 13 C NMR(151MHz,CDCl 3 )δ166.72,158.70,150.45,143.10,142.61,140.31,133.74,132.01,129.85,127.13,123.95,118.45,114.62,110.41,71.76,67.21,56.94,34.78,32.06,28.18,26.15,22.81,20.89.HR MS calcd for C 29 H 33 ClN 2 O 7 S 2 ,[M+Na] + :601.0840,found:601.0837.
TM2p:Colorless liquid,(2mg/mL,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ7.85(s,1H,H-1),7.74–7.69(m,2H,H-2),7.67(d,J=8.6Hz,2H,H-3),7.55(d,J=1.1Hz,1H,H-4),7.34(t,J=8.4Hz,1H,H-5),7.28(d,J=5.8Hz,2H,H-6),7.22(dd,J=8.6,1.9Hz,1H,H-7),6.88(d,J=8.5Hz,2H,H-8),4.87(dd,J=8.6,3.4Hz,1H,H-9),4.03(t,J=6.0Hz,2H,H-10),3.40(t,J=7.1Hz,2H,H-11),3.29(dd,J=14.1,8.7Hz,1H,H-12),3.03(dd,J=14.2,3.3Hz,1H,H-13),2.80(s,3H,H-14),2.20(s,3H,H-15),2.09–2.03(m,2H,H-16),2.02–1.94(m,2H,H-17). 13 CNMR(151MHz,CDCl 3 )δ168.75,166.74,158.76,150.44,143.09,142.18,133.32,132.17,129.84,128.58,127.26,123.96,119.50,118.42,114.66,110.44,71.91,67.22,58.14,36.70,32.05,28.17,26.15,24.57.HR MS calcd for C 28 H 30 ClN 3 O 8 S 2 ,[M+Na] + :636.1236,found:636.1230.
2 target molecule and intermediate biological Activity test
2.1 antibacterial Activity
The test was performed according to the national clinical laboratory standardization committee (NCCLS) recommended microdilution method; test strain: gram positive bacteria: micrococcus luteus (Micrococcus luteus), staphylococcus aureus (Staphyloccocus aureus ATCC25129, ATCC 14125), gram negative bacteria: coli (Escherichia coli ATCC 25922), acinetobacter baumannii (Acinetobacter baumannii ATCC 19606), pseudomonas aeruginosa (Pseudomonas aeruginosa ATCC 27853) and salmonella (Salmonella Enteritidis ATCC 13076), and the test bacteria are all human pathogenic bacteria; positive controls were Ciprofloxacin (CLX), norfloxacin (NOR), ciprofloxacin (CIP), sarafloxacin (SAR), enrofloxacin (ENO), balofloxacin (BAL), lomefloxacin (LOM), gatifloxacin (GAT). The test results are shown in Table 3.
TABLE 3 inhibition of bacterial Activity of target molecules and intermediates
In general, most of the TM1 molecules show inhibitory activities with different intensities on Acinetobacter baumannii and are insensitive to other 6 human pathogenic bacteria; TM2 has inhibitory activity with different intensity on Acinetobacter baumannii and micrococcus luteus, and is insensitive to other 5 human pathogenic bacteria; the intermediate IM4 has the inhibitory activity on 5 human pathogens which is equivalent to or stronger than that of 8 kinds of drugs on the market.
For Acinetobacter baumannii, most of the TM1/TM2 target molecules have weaker inhibitory activity than CLX, CIP, SAR and BAL, but are comparable to GAT, LOM, ENO, NOR; wherein, TM2p (mic=0.404 μmol·ml) -1 The numerals in parentheses are MIC values) and TM1h/1i/1k/1l (0.406 to 0.409. Mu. Mol. ML) -1 ) Is equivalent to NOR (0.401. Mu. Mol. ML) -1 ) The ratio of TM2h/2i/2j/2k/2l (0.387-0.390. Mu. Mol.mL) -1 ) Even more active thanNOR; both TM2 (sulfone) and TM1 (thioether) have better active molecules, but overall TM2 is slightly more active than TM1. Inhibitory Activity of 3 intermediates (IM 2, IM3, IM 4) (0.145-0.318. Mu. Mol.mL) -1 ) And NOR, ENO, LOM, GAT (0.401, 0.356, 0.364, 0.341. Mu. Mol. ML) -1 ) Is equivalent or stronger than IM4 (0.145. Mu. Mol. ML) -1 ) Is only weaker than CIP and CLX, but is more than 2 times stronger than the activity of the other 6 sand drugs, even NOR, ENO, LOM and GAT. TM1 and TM2 all target molecules and all intermediates are more active than the parent synephrine.
For Micrococcus luteus, the inhibitory activity of TM1i and TM2h/2j/2l was stronger than that of synephrine and most intermediates, especially TM2l (0.048. Mu. Mol. ML -1 ) Is also stronger than ENO and NOR (0.089, 0.050 mu mol.mL) -1 ) With LOM, SAR (0.046, 0.042. Mu. Mol. ML) -1 ) Is equivalent in activity.
Notably, intermediate IM4 also showed superior antimicrobial activity against pseudomonas aeruginosa, micrococcus luteus, salmonella and staphylococcus aureus ATCC25129, indicating that the molecule has broad-spectrum antimicrobial properties with great research potential. For Pseudomonas aeruginosa, the inhibitory activity of IM4 (0.018. Mu. Mol. ML -1 ) Far stronger than CIP>0.768μmol·mL -1 ). For Micrococcus luteus, the inhibitory activity of IM4 (0.009. Mu. Mol. ML) -1 ) And CLX, CIP, BAL, GAT (0.005-0.006. Mu. Mol.mL) -1 ) Equivalent is SAR (0.042. Mu. Mol. ML) -1 ) Is 4.6 times that of LOM (0.046. Mu. Mol. ML) -1 ) Is 5 times that of NOR (0.050. Mu. Mol. ML) -1 ) Is 5.5 times that of ENO (0.089. Mu. Mol.mL) -1 ) 9.8 times of (3). For Salmonella, inhibitory Activity of IM4 (0.009. Mu. Mol. ML) -1 ) And 8 kinds of sarcin medicine (0.005-0.006 mu mol.mL) -1 ) Equivalent. Inhibitory Activity against Staphylococcus aureus ATCC25129, IM4 (0.009. Mu. Mol. ML -1 ) And NOR, CIP, SAR, ENO, BAL, LOM, GAT (0.005-0.006. Mu. Mol.mL) -1 ) Quite much stronger than CLX.
2.2 antifungal Activity
The test was performed using the NCCLS recommended micro-broth dilution method, testing the strain: human pathogenic fungi: candida tropicalis (Candida utilis) resistant strains, aspergillus fumigatus (Aspergillus fumigatus) resistant strains, candida parapsilosis (Candida parapsilosis) ATCC22019, candida albicans (Candida albicans) resistant strains, candida albicans ATCC 90023; non-human pathogenic fungi: pichia pastoris GS115; fluconazole (Fluconazole) was used as a positive control. The test results are shown in Table 4.
TABLE 4 inhibition Activity of target molecules and intermediates against fungi
Note that: -indicating no test.
In general, the target molecules TM1, TM2 and intermediates exhibit different levels of inhibitory activity against 5 human pathogenic fungi, and many molecules are sensitive to human pathogenic fungi. TM1 is insensitive to the non-human pathogen Pichia pastoris, but the intermediate IM4 has activity on Pichia pastoris (0.036. Mu. Mol.mL) -1 ) Is fluconazole (0.104 mu mol.mL) -1 ) Is 2.8 times as large as the above. As can also be seen from Table 4, IM4 shows high inhibitory activity against 5 strains of fungi, IM3 against 4 strains of fungi, TM2f/3f, TM2j/3j and TM2l against 3 strains of fungi, exhibiting broad spectrum.
For drug-resistant candida tropicalis, 2 intermediates (0.036. Mu. Mol.mL -1 ,0.126μmol·mL -1 ) 6 TM2 molecules (0.109-0.452. Mu. Mol.mL) -1 ) And 5 TM3 molecules (0.207-0.428. Mu. Mol.mL) -1 ) The inhibition activity is stronger than that of the parent synephrine>1.53μmol·mL -1 ). Intermediate IM4 (0.036. Mu. Mol. ML) -1 ) Is far more inhibitory than fluconazole (0.104 mu mol.mL) -1 ) And the activity sequence of the intermediate is IM4>IM3(0.126μmol·mL -1 )>IM2(≧0.636μmol·mL -1 ) It is shown that the introduction of 5-chloro-2-mercaptobenzoxazole into synephenol hydroxyl can improve the antifungal activity of the corresponding molecule, and even the activity can exceed that of fluconazole. Although TM 1-Most of the TM2 molecules have weak inhibitory activity on drug-resistant candida tropicalis, but TM1o has strong antibacterial activity (0.109 mu mol.mL) -1 ) Equivalent to fluconazole. As a whole, TM1 is more active than TM2. MIC value of sulfone type TM2o obtained by oxidizing thioether type TM1o was 0.207. Mu. Mol.mL -1 The activity is greatly reduced compared with TM1o; the activity is stronger than the number of molecules of the parent nucleus synephrine, the TM2 number is 5, the TM1 number is 6, and the part shows that the inhibition activity of the TM1 thioether type molecule on the drug-resistant candida tropicalis is stronger than the TM2 sulfone type molecule.
For drug-resistant Aspergillus fumigatus, the TM1/TM2 has 15 molecules with equivalent activity to fluconazole (0.404-0.468 mu mol.mL) -1 ) Activity of TM2l, TM2m (0.194, 0.222. Mu. Mol. ML) -1 ) Is more than fluconazole (0.418 mu mol.mL) -1 ). Intermediate IM4 (0.036. Mu. Mol. ML) -1 ) The antibacterial activity of the composition is 8 times that of fluconazole, and the composition shows excellent activity. 4 intermediates (0.036-0.985. Mu. Mol.mL) -1 ) 11 TM1 molecules (0.036-0.453. Mu. Mol.mL) -1 ) And 7 TM2 molecules (0.194-0.417. Mu. Mol.mL) -1 ) Is more inhibitory than the parent synephrine (1.531. Mu. Mol. ML) -1 ). Intermediate Activity IM4>IM3(0.505μmol·mL -1 )>IM2(0.636μmol·mL -1 )>IM1(0.958μmol·mL -1 ) It was further demonstrated that the introduction of 5-chloro-2-mercaptobenzoxazole onto the phenolic hydroxyl group of synephrine and sulfonyl onto the secondary amine can increase the inhibitory activity against aspergillus fumigatus. As a whole, TM2 is more active than TM1. Furthermore, sulfone type TM2l (0.194. Mu. Mol.mL) -1 ) The activity is far higher than that of thioether type TM1l (0.406 mu mol.mL) -1 ) The synephrine sulfone derivative is shown to be capable of improving the inhibitory activity on drug-resistant aspergillus fumigatus.
For Candida parapsilosis ATCC22019, all TM1 molecules (0.013-0.406. Mu. Mol.mL -1 ) TM2 molecule (0.006-0.442 mu mol/mL) -1 ) Intermediate (0.008-0.577 mu mol/mL) -1 ) Are all stronger than the parent synephrine (1.531 mu mol.mL) -1 ) The method comprises the steps of carrying out a first treatment on the surface of the The MIC of each of the TM1 and TM2 molecules is less than or equal to 0.113 mu mol.mL -1 The intensity of activity is not completely one-to-one, and may be related to the overall nature of the molecule; wherein, TM1g/1m/2f/2g/2j (0.025-0.029 mu mol.mL) -1 ) And TM1l/2m (0.013-0.014. Mu. Mol.mL) -1 ) Has strong inhibitory activity, and TM2l activity (0.006. Mu. Mol. ML) -1 ) Even stronger than fluconazole (0.007 mu mol.mL) -1 ). Activity of intermediate IM3 (0.008. Mu. Mol. ML) -1 ) And fluconazole (0.007. Mu. Mol.mL) -1 ) Quite, it is shown that the introduction of 5-chloro-2-mercaptobenzoxazole on synephenol hydroxyl can improve the antibacterial activity of molecules on candida parapsilosis. Overall activity analysis found that most TM2 was more active than the corresponding TM1, indicating that the synephrine sulfide derivatives after oxidation were able to increase antibacterial activity against candida parapsilosis.
For drug-resistant candida albicans, the activity of most target molecules and intermediates is stronger than that of parent synephrine; 7 TM1 molecules (0.007-0.108. Mu. Mol.mL) -1 ) 3 TM2 target molecules (0.048-0.215 mu mol.mL) -1 ) And 2 intermediates (0.072 to 0.126. Mu. Mol.mL) -1 ) Exhibits a strong antibacterial activity. Wherein the activity of TM2d/2g/2i/3l (0.048-0.057. Mu. Mol.mL) -1 ) Slightly weaker than fluconazole (0.014. Mu. Mol.mL) -1 ) Activity of TM2f (0.014. Mu. Mol. ML) -1 ) As with fluconazole, TM2l activity (0.007. Mu. Mol. ML) -1 ) Is stronger than fluconazole. Intermediate Activity IM4 (0.072. Mu. Mol.mL) -1 )>IM3(0.126μmol·mL -1 )>IM2(0.318μmol·mL -1 )>IM1(0.958μmol·mL -1 ) It was demonstrated that derivatization of synephrine at each step can increase antifungal activity. The activities of TM1 j-TM 1p and TM2 j-TM 2p are in one-to-one correspondence, which indicates that the activity of the synephrine sulfone type derivative TM2 is reduced compared with that of the thioether type derivative TM1 as a whole.
For Candida albicans ATCC90023, 3 intermediates, 10 TM1 molecules and 13 TM2 molecules were more active than the parent synephrine (1.531. Mu. Mol. ML -1 ) The method comprises the steps of carrying out a first treatment on the surface of the Has 2 intermediates (0.009-0.126. Mu. Mol.mL) -1 ) 5 TM1 molecules (0.004-0.052. Mu. Mol.mL) -1 ) And 5 TM2 molecules (0.006-0.107. Mu. Mol.mL) -1 ) Exhibits a strong antibacterial activity; wherein, TM1e/2e (0.013-0.014. Mu. Mol.mL) -1 ) Is weaker than fluconazole, intermediate IM4 (0.009. Mu. Mol. ML) -1 ) And TM2f (0.007. Mu. Mol. ML) -1 ) Is equivalent to fluconazole (0.007 mu mol.mL) -1 ) TM1f (0.004. Mu. Mol. ML) -1 )、TM1h(0.006μmol·mL -1 ) And TM2k (0.006. Mu. Mol. ML) -1 ) Is more active than fluconazole.
The TM1/TM2 activity data show that the antifungal activity rules of the synephrine thioether-type/sulfone-type derivatives are not uniform, and the thioether-type derivatives have stronger activity on drug-resistant aspergillus fumigatus and candida parapsilosis ATCC 22019; the sulfone derivative has stronger activity for drug-resistant candida tropicalis and drug-resistant candida albicans; for candida albicans ATCC90023, there is no rule. These data indicate that both sulfone/thioether structures are likely to increase inhibitory activity against certain human pathogenic fungi, possibly related to the overall nature of the molecule.
Finally, it is noted that the above-mentioned preferred embodiments are only intended to illustrate rather than limit the invention, and that, although the invention has been described in detail by means of the above-mentioned preferred embodiments, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention as defined by the appended claims.
Claims (6)
1. The synephrine benzoxazole sulfonamide derivative shown in the formula I or the pharmaceutically acceptable salt thereof is characterized in that,
in the formula I, X is S or SO 2 R is 2-fluorophenyl or 3-trifluoromethoxy, i.e., compound TM1f, TM2f, TM1l or TM2l;
or X is S, R is 3-bromophenyl or 2,4, 6-trimethyl, namely a compound TM1h or TM1o;
alternatively, X is SO 2 R is 4-trifluoromethoxy or phenyl, i.e. compound TM2k or TM2m;
2. an intermediate of formula II:
in formula II, Y is tert-butoxycarbonyl, i.e., boc or H.
3. The method for preparing the synephrine benzoxazole sulfonamide derivative or the pharmaceutically acceptable salt thereof according to claim 1, which is characterized by comprising the following steps:
i. the synephrine and di-tert-butyl dicarbonate, namely Boc 2 O reacts to prepare an intermediate IM1;
reacting the intermediate IM1 with 1, 4-dibromobutane to obtain an intermediate IM2;
reacting the intermediate IM2 with 5-chloro-2-mercaptobenzoxazole to obtain an intermediate IM3, namely an intermediate shown in a formula II, wherein Y is Boc;
reacting the intermediate IM3 with HCl-ethyl acetate, namely HCl-EA to prepare an intermediate IM4, namely hydrochloride of the intermediate shown in a formula II, wherein Y is H;
v. intermediate IM4 is combined with compound RSO 2 Cl reacts to prepare a compound TM1, namely a synephrine benzoxazole sulfonamide derivative shown in a formula I, wherein X in the formula I is S;
reacting compound TM1 with m-chloroperoxybenzoic acid (mCPBA) to obtain compound TM2 (synephrine benzoxazole sulfonamide derivative shown in formula I, wherein X is SO 2 ;
Compound RSO 2 R in the formulae Cl, TM1 and TM2 is as defined for R in the formula I as claimed in claim 1.
4. A process for the preparation of synephrine benzoxazole sulfonamide derivatives or pharmaceutically acceptable salts thereof according to claim 3, comprising the steps of:
i. the synephrine and Boc are combined 2 O reacts in ethanol solvent at 0-35 ℃ to prepare an intermediate IM1;
ii. intermediate IM1 and 1, 4-dibromobutane in base K 2 CO 3 Reacting in solvent N, N-Dimethylformamide (DMF) at 45 ℃ in the presence of the solvent to prepare an intermediate IM2;
intermediate IM2 and 5-chloro-2-mercaptobenzoxazole in base K 2 CO 3 Reacting in DMF at 45 ℃ in the presence of a solvent to obtain an intermediate IM3, namely an intermediate shown in a formula II, wherein Y is Boc;
reacting the intermediate IM3 with HCl-EA at 0-5 ℃ to obtain an intermediate IM4, namely an intermediate hydrochloride shown in a formula II, wherein Y is H;
v. intermediate IM4 is combined with compound RSO 2 Cl reacts in DMF at minus 15-25 ℃ in the presence of N, N-diisopropylethylamine, namely DIPEA, as acid-binding agent to prepare the compound TM1, namely synephenzene shown in formula IAnd oxazole sulfonamide derivatives, wherein X is S;
reacting compound TM1 with mCPBA in dichloromethane solvent (DCM) at 30deg.C to obtain compound TM2 (synephrine benzoxazole sulfonamide derivative shown in formula I), wherein X is SO 2 。
5. Use of a synephrine benzoxazole sulfonamide derivative of claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of an antibacterial and/or antifungal drug, wherein the bacterium is acinetobacter baumannii (Acinetobacter baumannii) and/or micrococcus luteus (Micrococcus luteus), and the fungus is one or more of Candida tropicalis (Candida tropicalis), aspergillus fumigatus (Aspergillus fumigatus), candida parapsilosis (Candida parapsilosis), and Candida albicans (Candida albicans).
6. Use of the intermediate of claim 2, or a pharmaceutically acceptable salt thereof, for the preparation of an antibacterial and/or antifungal drug, wherein the bacterium is one or more of acinetobacter baumannii (Acinetobacter baumannii), pseudomonas aeruginosa (Pseudomonas aeruginosa), micrococcus luteus (Micrococcus luteus), salmonella (Salmonella Enteritidis) and staphylococcus aureus (Staphyloccocus aureus), and the fungus is one or more of Candida tropicalis (Candida tropical), aspergillus fumigatus (Aspergillus fumigatus), candida parapsilosis (Candida parapsilosis), candida albicans (Candida albicans) and pichia pastoris (pichia pastoris).
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CN112079782A (en) * | 2020-09-25 | 2020-12-15 | 西南大学 | Synephrine azole derivatives, and preparation method and application thereof |
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KR20070006115A (en) * | 2005-07-07 | 2007-01-11 | 한국생명공학연구원 | Novel benzoxazole amide compound having lipoxygenase inhibitory activity, the preparation method thereof and a composition containing the same for preventing and treating asthma |
JP2007131584A (en) * | 2005-11-11 | 2007-05-31 | Sankyo Co Ltd | New benzoxazole derivative |
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