CN113754595A - Preparation method and application of 6-fluoroquinazoline derivatives containing disulfide structures - Google Patents
Preparation method and application of 6-fluoroquinazoline derivatives containing disulfide structures Download PDFInfo
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- CN113754595A CN113754595A CN202111079410.6A CN202111079410A CN113754595A CN 113754595 A CN113754595 A CN 113754595A CN 202111079410 A CN202111079410 A CN 202111079410A CN 113754595 A CN113754595 A CN 113754595A
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- CN
- China
- Prior art keywords
- fluoroquinazoline
- disulfide
- substituted
- preparation
- unsubstituted
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims abstract description 49
- JFMDVMJEMZLFKV-UHFFFAOYSA-N 6-fluoroquinazoline Chemical class N1=CN=CC2=CC(F)=CC=C21 JFMDVMJEMZLFKV-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 125000002228 disulfide group Chemical group 0.000 title claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 49
- 230000001580 bacterial effect Effects 0.000 claims abstract description 17
- 235000007164 Oryza sativa Nutrition 0.000 claims abstract description 10
- 235000009566 rice Nutrition 0.000 claims abstract description 10
- 241000207199 Citrus Species 0.000 claims abstract description 8
- 235000020971 citrus fruits Nutrition 0.000 claims abstract description 8
- 244000298697 Actinidia deliciosa Species 0.000 claims abstract description 7
- 235000009436 Actinidia deliciosa Nutrition 0.000 claims abstract description 7
- 235000009434 Actinidia chinensis Nutrition 0.000 claims abstract description 6
- 240000007594 Oryza sativa Species 0.000 claims abstract 2
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- -1 amino, hydroxyl Chemical group 0.000 claims description 13
- 241000196324 Embryophyta Species 0.000 claims description 12
- 238000006467 substitution reaction Methods 0.000 claims description 11
- 241000607479 Yersinia pestis Species 0.000 claims description 9
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 4
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 208000035143 Bacterial infection Diseases 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 201000010099 disease Diseases 0.000 claims description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 3
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 239000002671 adjuvant Substances 0.000 claims 1
- 208000022362 bacterial infectious disease Diseases 0.000 claims 1
- 230000000855 fungicidal effect Effects 0.000 claims 1
- 239000000417 fungicide Substances 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 24
- 230000005764 inhibitory process Effects 0.000 abstract description 12
- 241000589771 Ralstonia solanacearum Species 0.000 abstract description 7
- 244000000005 bacterial plant pathogen Species 0.000 abstract description 7
- 125000000107 disulfanyl group Chemical group [*]SS[H] 0.000 abstract 1
- 125000000623 heterocyclic group Chemical group 0.000 abstract 1
- WMPSQXLZNFEYEP-UHFFFAOYSA-N 6-fluoro-1h-quinazoline-4-thione Chemical group N1=CNC(=S)C2=CC(F)=CC=C21 WMPSQXLZNFEYEP-UHFFFAOYSA-N 0.000 description 24
- 230000015572 biosynthetic process Effects 0.000 description 24
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 24
- 238000003786 synthesis reaction Methods 0.000 description 24
- 230000000844 anti-bacterial effect Effects 0.000 description 15
- 125000001424 substituent group Chemical group 0.000 description 11
- 241000191967 Staphylococcus aureus Species 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 241000209094 Oryza Species 0.000 description 8
- 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 8
- 230000002401 inhibitory effect Effects 0.000 description 8
- 238000011160 research Methods 0.000 description 8
- 239000000575 pesticide Substances 0.000 description 7
- 230000004071 biological effect Effects 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 6
- 244000052616 bacterial pathogen Species 0.000 description 5
- 239000002609 medium Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- ONJROLGQWMBXAP-UHFFFAOYSA-N 2-methyl-1-(2-methylpropyldisulfanyl)propane Chemical compound CC(C)CSSCC(C)C ONJROLGQWMBXAP-UHFFFAOYSA-N 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 229960003405 ciprofloxacin Drugs 0.000 description 4
- GVPWHKZIJBODOX-UHFFFAOYSA-N dibenzyl disulfide Chemical compound C=1C=CC=CC=1CSSCC1=CC=CC=C1 GVPWHKZIJBODOX-UHFFFAOYSA-N 0.000 description 4
- 150000002019 disulfides Chemical class 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000001963 growth medium Substances 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 241000894006 Bacteria Species 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229960003180 glutathione Drugs 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- 229960003085 meticillin Drugs 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000005556 structure-activity relationship Methods 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical group SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 3
- UYKWEIJSRNJHQD-UHFFFAOYSA-N (ethyldisulfanyl)benzene Chemical compound CCSSC1=CC=CC=C1 UYKWEIJSRNJHQD-UHFFFAOYSA-N 0.000 description 2
- IDJPKRIELSFBPE-UHFFFAOYSA-N 1-(decyldisulfanyl)decane Chemical compound CCCCCCCCCCSSCCCCCCCCCC IDJPKRIELSFBPE-UHFFFAOYSA-N 0.000 description 2
- IFGAFLQUAVLERP-UHFFFAOYSA-N 1-(heptyldisulfanyl)heptane Chemical compound CCCCCCCSSCCCCCCC IFGAFLQUAVLERP-UHFFFAOYSA-N 0.000 description 2
- GJPDBURPGLWRPW-UHFFFAOYSA-N 1-(hexyldisulfanyl)hexane Chemical compound CCCCCCSSCCCCCC GJPDBURPGLWRPW-UHFFFAOYSA-N 0.000 description 2
- AVWMIWJCGFMMNP-UHFFFAOYSA-N 1-(nonyldisulfanyl)nonane Chemical compound CCCCCCCCCSSCCCCCCCCC AVWMIWJCGFMMNP-UHFFFAOYSA-N 0.000 description 2
- AROCLDYPZXMJPW-UHFFFAOYSA-N 1-(octyldisulfanyl)octane Chemical compound CCCCCCCCSSCCCCCCCC AROCLDYPZXMJPW-UHFFFAOYSA-N 0.000 description 2
- YSQZSPCQDXHJDJ-UHFFFAOYSA-N 1-(pentyldisulfanyl)pentane Chemical compound CCCCCSSCCCCC YSQZSPCQDXHJDJ-UHFFFAOYSA-N 0.000 description 2
- PMBXCGGQNSVESQ-UHFFFAOYSA-N 1-Hexanethiol Chemical compound CCCCCCS PMBXCGGQNSVESQ-UHFFFAOYSA-N 0.000 description 2
- SGCNNRITIDAACO-UHFFFAOYSA-N 1-bromo-2-[(2-bromophenyl)disulfanyl]benzene Chemical compound BrC1=CC=CC=C1SSC1=CC=CC=C1Br SGCNNRITIDAACO-UHFFFAOYSA-N 0.000 description 2
- PEHGERSYFVVLQN-UHFFFAOYSA-N 1-bromo-3-[(3-bromophenyl)disulfanyl]benzene Chemical compound BrC1=CC=CC(SSC=2C=C(Br)C=CC=2)=C1 PEHGERSYFVVLQN-UHFFFAOYSA-N 0.000 description 2
- VZQVHIINDXJOQK-UHFFFAOYSA-N 1-bromo-4-[(4-bromophenyl)disulfanyl]benzene Chemical compound C1=CC(Br)=CC=C1SSC1=CC=C(Br)C=C1 VZQVHIINDXJOQK-UHFFFAOYSA-N 0.000 description 2
- IQCDDWQDDMUOCQ-UHFFFAOYSA-N 1-chloro-2-[(2-chlorophenyl)disulfanyl]benzene Chemical compound ClC1=CC=CC=C1SSC1=CC=CC=C1Cl IQCDDWQDDMUOCQ-UHFFFAOYSA-N 0.000 description 2
- ZIXXRXGPBFMPFD-UHFFFAOYSA-N 1-chloro-4-[(4-chlorophenyl)disulfanyl]benzene Chemical compound C1=CC(Cl)=CC=C1SSC1=CC=C(Cl)C=C1 ZIXXRXGPBFMPFD-UHFFFAOYSA-N 0.000 description 2
- BSLPHWROVJBMHX-UHFFFAOYSA-N 1-fluoro-2-[(2-fluorophenyl)disulfanyl]benzene Chemical compound FC1=CC=CC=C1SSC1=CC=CC=C1F BSLPHWROVJBMHX-UHFFFAOYSA-N 0.000 description 2
- LFVFHTBHAIVNJQ-UHFFFAOYSA-N 1-fluoro-3-[(3-fluorophenyl)disulfanyl]benzene Chemical compound FC1=CC=CC(SSC=2C=C(F)C=CC=2)=C1 LFVFHTBHAIVNJQ-UHFFFAOYSA-N 0.000 description 2
- PZQGLCGLPMWYBT-UHFFFAOYSA-N 1-methoxy-4-[(4-methoxyphenyl)disulfanyl]benzene Chemical compound C1=CC(OC)=CC=C1SSC1=CC=C(OC)C=C1 PZQGLCGLPMWYBT-UHFFFAOYSA-N 0.000 description 2
- TZOVOULUMXXLOJ-UHFFFAOYSA-N 1-methyl-4-[(4-methylphenyl)disulfanyl]benzene Chemical compound C1=CC(C)=CC=C1SSC1=CC=C(C)C=C1 TZOVOULUMXXLOJ-UHFFFAOYSA-N 0.000 description 2
- NXURYLWXQQBBPT-UHFFFAOYSA-N 2-methyl-3-(3-methylbutan-2-yldisulfanyl)butane Chemical compound CC(C)C(C)SSC(C)C(C)C NXURYLWXQQBBPT-UHFFFAOYSA-N 0.000 description 2
- MPYGLNNTOXLWOB-UHFFFAOYSA-N 3-methyl-1-(3-methylbutyldisulfanyl)butane Chemical compound CC(C)CCSSCCC(C)C MPYGLNNTOXLWOB-UHFFFAOYSA-N 0.000 description 2
- RSNWORHVUOZYLT-UHFFFAOYSA-N 5-[[(2-sulfanylidene-3h-1,3,4-thiadiazol-5-yl)amino]methylamino]-3h-1,3,4-thiadiazole-2-thione Chemical compound S1C(=S)NN=C1NCNC1=NNC(=S)S1 RSNWORHVUOZYLT-UHFFFAOYSA-N 0.000 description 2
- JDLKFOPOAOFWQN-VIFPVBQESA-N Allicin Natural products C=CCS[S@](=O)CC=C JDLKFOPOAOFWQN-VIFPVBQESA-N 0.000 description 2
- CUDSBWGCGSUXDB-UHFFFAOYSA-N Dibutyl disulfide Chemical compound CCCCSSCCCC CUDSBWGCGSUXDB-UHFFFAOYSA-N 0.000 description 2
- ODHAQPXNQDBHSH-UHFFFAOYSA-N Dicyclohexyl disulfide Chemical compound C1CCCCC1SSC1CCCCC1 ODHAQPXNQDBHSH-UHFFFAOYSA-N 0.000 description 2
- CETBSQOFQKLHHZ-UHFFFAOYSA-N Diethyl disulfide Chemical compound CCSSCC CETBSQOFQKLHHZ-UHFFFAOYSA-N 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 244000061176 Nicotiana tabacum Species 0.000 description 2
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 241000589634 Xanthomonas Species 0.000 description 2
- 241000589652 Xanthomonas oryzae Species 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- JDLKFOPOAOFWQN-UHFFFAOYSA-N allicin Chemical compound C=CCSS(=O)CC=C JDLKFOPOAOFWQN-UHFFFAOYSA-N 0.000 description 2
- 235000010081 allicin Nutrition 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- ALVPFGSHPUPROW-UHFFFAOYSA-N dipropyl disulfide Chemical compound CCCSSCCC ALVPFGSHPUPROW-UHFFFAOYSA-N 0.000 description 2
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethanethiol Chemical compound CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 125000001072 heteroaryl group Chemical group 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 150000003568 thioethers Chemical class 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- CXBJCROZMWLGAU-UHFFFAOYSA-N (2-bromophenyl) thiohypochlorite Chemical compound ClSC1=CC=CC=C1Br CXBJCROZMWLGAU-UHFFFAOYSA-N 0.000 description 1
- HGKUXIBLMFZDRP-UHFFFAOYSA-N (2-chlorophenyl) thiohypochlorite Chemical compound ClSC1=CC=CC=C1Cl HGKUXIBLMFZDRP-UHFFFAOYSA-N 0.000 description 1
- QEZKMMSPCIMRFE-UHFFFAOYSA-N (2-fluorophenyl) thiohypochlorite Chemical compound FC1=CC=CC=C1SCl QEZKMMSPCIMRFE-UHFFFAOYSA-N 0.000 description 1
- IVROYWCOKRUUCV-UHFFFAOYSA-N (3-bromophenyl) thiohypochlorite Chemical compound ClSC1=CC=CC(Br)=C1 IVROYWCOKRUUCV-UHFFFAOYSA-N 0.000 description 1
- YMOKCENTGQEDSA-UHFFFAOYSA-N (3-fluorophenyl) thiohypochlorite Chemical compound FC1=CC=CC(SCl)=C1 YMOKCENTGQEDSA-UHFFFAOYSA-N 0.000 description 1
- STDOUHHCZSZDME-UHFFFAOYSA-N (4-bromophenyl) thiohypochlorite Chemical compound ClSC1=CC=C(Br)C=C1 STDOUHHCZSZDME-UHFFFAOYSA-N 0.000 description 1
- WVTOJNFZIVWNIY-UHFFFAOYSA-N (4-chlorophenyl) thiohypochlorite Chemical compound ClSC1=CC=C(Cl)C=C1 WVTOJNFZIVWNIY-UHFFFAOYSA-N 0.000 description 1
- GTGOJSDZGAPFDW-UHFFFAOYSA-N (4-methoxyphenyl) thiohypochlorite Chemical compound COC1=CC=C(SCl)C=C1 GTGOJSDZGAPFDW-UHFFFAOYSA-N 0.000 description 1
- RSGBMGFQNOGIPC-UHFFFAOYSA-N (4-methylphenyl) thiohypochlorite Chemical compound CC1=CC=C(SCl)C=C1 RSGBMGFQNOGIPC-UHFFFAOYSA-N 0.000 description 1
- WHTVZRBIWZFKQO-AWEZNQCLSA-N (S)-chloroquine Chemical compound ClC1=CC=C2C(N[C@@H](C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-AWEZNQCLSA-N 0.000 description 1
- HGLVZPHZLRMRFW-UHFFFAOYSA-N 1-sulfidoquinazolin-1-ium Chemical class [N+]1(=CN=CC2=CC=CC=C12)[S-] HGLVZPHZLRMRFW-UHFFFAOYSA-N 0.000 description 1
- YUQUNWNSQDULTI-UHFFFAOYSA-N 2-bromobenzenethiol Chemical compound SC1=CC=CC=C1Br YUQUNWNSQDULTI-UHFFFAOYSA-N 0.000 description 1
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 description 1
- PWOBDMNCYMQTCE-UHFFFAOYSA-N 2-chlorobenzenethiol Chemical compound SC1=CC=CC=C1Cl PWOBDMNCYMQTCE-UHFFFAOYSA-N 0.000 description 1
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 1
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 1
- 125000002927 2-methoxybenzyl group Chemical group [H]C1=C([H])C([H])=C(C(OC([H])([H])[H])=C1[H])C([H])([H])* 0.000 description 1
- 125000006179 2-methyl benzyl group Chemical group [H]C1=C([H])C(=C(C([H])=C1[H])C([H])([H])*)C([H])([H])[H] 0.000 description 1
- BDFAOUQQXJIZDG-UHFFFAOYSA-N 2-methylpropane-1-thiol Chemical compound CC(C)CS BDFAOUQQXJIZDG-UHFFFAOYSA-N 0.000 description 1
- AGYVLJKQIZOYBJ-UHFFFAOYSA-N 2-methylpropyl thiohypochlorite Chemical compound CC(C)CSCl AGYVLJKQIZOYBJ-UHFFFAOYSA-N 0.000 description 1
- ZMRFRBHYXOQLDK-UHFFFAOYSA-N 2-phenylethanethiol Chemical compound SCCC1=CC=CC=C1 ZMRFRBHYXOQLDK-UHFFFAOYSA-N 0.000 description 1
- BFLXFRNPNMTTAA-UHFFFAOYSA-N 3-Methyl-2-butanethiol Chemical compound CC(C)C(C)S BFLXFRNPNMTTAA-UHFFFAOYSA-N 0.000 description 1
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 description 1
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 1
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- 125000006497 3-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1[H])C([H])([H])* 0.000 description 1
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- SUVIGLJNEAMWEG-UHFFFAOYSA-N propane-1-thiol Chemical compound CCCS SUVIGLJNEAMWEG-UHFFFAOYSA-N 0.000 description 1
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- XELRMPRLCPFTBH-UHFFFAOYSA-N quinazoline-2,4-diamine Chemical class C1=CC=CC2=NC(N)=NC(N)=C21 XELRMPRLCPFTBH-UHFFFAOYSA-N 0.000 description 1
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- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/93—Sulfur atoms
-
- 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
- A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
- A01N43/54—1,3-Diazines; Hydrogenated 1,3-diazines
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Agronomy & Crop Science (AREA)
- Pest Control & Pesticides (AREA)
- Plant Pathology (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Dentistry (AREA)
- General Health & Medical Sciences (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Environmental Sciences (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention relates to a preparation method and application of 6-fluoroquinazoline derivatives containing disulfide structures. The compound has a structure shown as a general formula (I):
Description
Technical Field
The invention relates to the technical field of agricultural pharmacy, in particular to a preparation method and application of 6-fluoroquinazoline derivatives containing disulfide structures.
Background
Plant pathogenic bacteria seriously affect the yield and quality of agricultural products all over the world, and more pathogenic bacteria species are discovered year by year, but pathogenic bacteria causing the yield and quality reduction of main crops, such as Ralstonia solanacearum (Rs), the host of which relates to more than 200 plants, including important crops such as potatoes, tobacco, tomatoes, eggplants, peanuts and the like, need to be considered preferentially. Xanthomonas is also a large pathogenic genus, comprising 27 plant pathogenic bacteria, which host about 400 plants (both monocotyledonous and dicotyledonous plants), and the colony morphology is yellow, and the bacteria protect themselves from light by secreting xanthosine. Xanthomonas campestris survives for a period of time after leaving the host, and thus both deciduous leaves and soil can serve as infectious sources, and seeds, deciduous leaves, insects, wind, rain, humans, farming machines, and the like can serve as vectors for the outward diffusion of germs, such as Xanthomonas oryzae (xoma oryzae, Xoo), citrus canker (Xac), bacterial streak germ (xanthomas oryzae, orazacola, Xoc), and the like.
Chemical pesticide is used as an economic and effective control means and is applied to control of various plant diseases for a long time, but with the repeated stimulation of the pesticide for a long time, plant pathogenic bacteria gradually form various drug resistance mechanisms, so that the drug effect of a plurality of existing pesticides is reduced, and therefore, new high-activity and low-resistance compounds for plant pathogenic bacteria are urgently needed to be searched, and a green new pesticide with independent intellectual property rights is created on the basis, so that candidate drugs are provided for the control of the bacterial diseases of crops.
In recent years, a plurality of compounds with better biological activity, such as antimalarial and antibacterial, are discovered by deriving a quinazoline as a parent structure, wherein the antibacterial activity of a 6-fluoroquinazoline compound is more remarkable; in addition, disulfide derivatives have a wide range of biological activities, such as antibacterial and antitumor activities, and among them, the unique bactericidal action mode of disulfide antibacterial compound allicin (allicin) has attracted extensive attention and research.
In order to search for efficient and resistant bactericidal active compounds, the 6-fluoroquinazoline is used as a parent structure, a disulfide bond with biological activity is introduced into the system, a series of 6-fluoro-quinazoline-4-disulfide derivatives are synthesized, the bactericidal biological activity of the derivatives is investigated, and a certain scientific basis is provided for the research, development and creation of new pesticides.
The research on the biological activity of quinazoline derivatives has been advanced as follows:
in 2011, Pierre [ Pierre Verhaeghe, Aur Lelien Dum tre, Caroline Castera-Ducros, et al.4-Thiophenoxy-2-trichloromethyl quinazolines display in video selective active ingredient acquisition aid the human mammalian parasiteplasia falciparum [ J ] J].Bioorganic&Medicinal Chemistry Letters.2011,21:6003-6006.]Introducing a diphenyl sulfide structure at the 4 th position of quinazoline to obtain 20 quinazoline monosulfide compounds, wherein the in vitro activity shows that: and control drug chloroquine (IC)500.5 μ M) and doxycycline hydrochloride (IC)505.0 muM), most compounds in the series have better inhibition effect on plasmodium and IC (integrated circuit) thereof500.9-15 mu M, and the preliminary structure-activity relationship shows that the activity is better when the para position of thiophenol is substituted by an electron-withdrawing group.
In 2014, 73 2,4 Disubstituted diamine Quinazoline derivatives were synthesized from Kurt [ Kurt S.Van Horn, Whitney N.Burda, Rene Fleeman, et al.Antibacter Activity of a Series of N2, N4-disubstuted Quinazoline-2,4-diamines [ J ]. Journal of Medicinal chemistry.2014,57:3075-3093 ], and the like, and the in vitro inhibitory effect of the Series of compounds on methicillin-resistant Staphylococcus aureus was determined, and the in vivo antibacterial Activity of the Series of compounds was also studied in mice, wherein the protective effect of the highly active compounds on mice infected with Staphylococcus aureus was superior to that of the lethal control vancomycin. The structure-activity relationship shows that: the amino group at the 2, 4-positions is essential for the resistance to Staphylococcus aureus, and in addition, when the 6/7/8-position of the benzene ring is substituted with chlorine, the antibacterial activity is lower than that of the unsubstituted compound.
In 2020, Shao [ Wu-Bin Shao, Yu-Tao Zheng, Jia-Min Liu, et alibacterial activities against Ralstonia solanacearum and Xanthomonasoryzaepv.oryzae of 6-chloro-4-(4-substituted piperazinyl)quinazolinederivatives[J].Bioorganic&Medicinal Chemistry Letters.2020,30:126912.]Introducing piperazine group into 4-position of quinazoline mother ring to obtain a series of piperazine quinazoline derivatives, and in-vitro primary activity determination shows that the series of compounds have good inhibitory activity on Ralstonia solanacearum and rice bacterial blight, wherein EC of the compounds with optimal RS inhibitory effect50EC for compound with value of 2.72. mu.g/mL and best inhibition of Xoo50The value was 8.46. mu.g/mL.
The research on the biological activity of disulfide compounds has progressed as follows:
in 2008, a series of asymmetric disulfide derivatives were synthesized by Turos [ Turos E, Revell K D, Ramaraju P, et al, asymmetric methyl aryl-alkyl sulfate growth inhibition of methicillin-resistant Staphylococcus aureus and Bacillus anthracnose [ J ]. Bioorganic & medicinal chemistry.2008,16(13):6501 and 6508 ], etc., and the series of compounds were found to have different degrees of inhibition on Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, Bacillus anthracis and Escherichia coli, and the structure-activity relationship of the first three pathogenic bacteria was found: when the aromatic ring has an electron-withdrawing substituent, the activity is better, wherein the activity of meta-substitution and para-substitution is better than that of ortho-substitution; if a carbon atom is inserted between the substituted benzene ring and the sulfur atom, the activity is reduced; in addition, if there is a hydrophilic substituent on the aromatic ring, the activity decreases; the chain length of the linear chain is increased, the activity is increased, and the activity of the branched chain substitution is better than that of the linear chain substitution. In Escherichia coli, the activity is better when the alkyl group is methyl or ethyl. These results show that: the method is favorable for reducing the charge density of sulfur in the disulfide bond, namely, the substituent group for increasing the nucleophilic substitution reaction activity is favorable for increasing the antibacterial activity, and meanwhile, in order to ensure the activity of the compound, a lipophilic group needs to be introduced into the molecular structure, so that the compound can conveniently permeate cell membranes.
In 2018, a series of disulfide derivatives containing pyridyl groups were designed and synthesized by Shepard [ Shepard J G, McAleer J P, Sarakar P, et al, Alicin-immobilized pyridine derivatives as anti-biotic agents for multidrug-resistant Staphylococcus aureus [ J ]. European journal of medical chemistry.2018,143:1185-1195 ], and the like, and the inhibitory activity of the target compound on multi-drug resistant Staphylococcus aureus was determined, under the physiological conditions of thalli, the pyridyl groups in the series of compounds would form quaternary ammonium salts, thereby reducing the electron cloud density of sulfur, facilitating the exchange reaction of disulfide bonds and free sulfydryl groups, which becomes a structural premise with improved activity. Researches show that part of target compounds not only have better antibacterial activity, but also realize the synergistic antibacterial action when being used together with vancomycin, thereby increasing the antibacterial effect of the compounds and showing low toxicity to normal cells of a human body. The preliminary action mechanism research finds that the compounds not only cause the damage of thallus membranes, but also reduce the metabolism level of bacteria and inhibit the growth of thallus.
In 2016, a series of N-alkylfluoroquinolone thioether derivatives were prepared by introducing thioether into the parent structure of Ciprofloxacin (CIP) by Shepard [ Shepard J G, Long T E. albumin-immobilized fluoroquinolones as antibiotics, ESKAPE pathway [ J ]. Bioorganic & medicinal chemistry letters, 26(22):5545-5549 ], et al, and the antibacterial activity and the activity of the target compound against ESKAPE (Enterococcus spp., Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterbacter spp.) were determined, and the results of the studies were consistent with the results of the primary inhibitory activity of the target compound against GSH-activated Staphylococcus aureus, MRGS-activated protein complex, MRS-activated protein complex, and MRS-activated protein complex Ionic fragment peaks of CIP and GSH, which preliminarily evidence that the mechanism of action of the active compound may be the binding of S-alkyl to glutathione. In addition, ciprofloxacin is released while the substitution exchange reaction is carried out, so that the antibacterial activity of the target compound is further enhanced.
Disclosure of Invention
The invention provides 6-fluoroquinazoline derivatives containing disulfide structures.
The invention also provides a preparation method of the compound and a preparation method thereof.
It is also an object of the present invention to provide the use of the above compound or the composition.
The invention also aims to provide a method for controlling agricultural pests by using the compound or the composition.
In order to realize the purpose, the invention adopts the following technical scheme:
6-fluoroquinazoline derivatives containing disulfide structures, wherein the compounds have a structure shown as a general formula (I):
wherein,
r is selected from any substituted or unsubstituted alkyl, any substituted or unsubstituted cycloalkyl and any substituted or unsubstituted aryl.
Further preferably, R is selected from alkyl, cycloalkyl, substituted or unsubstituted aryl;
preferably, R is selected from C2-C10Alkyl radical, C5-C6Cycloalkyl, substituted or unsubstituted C6-C7Aryl, wherein said substitution is by C1-C10Alkyl radical, C1-C10One or more of alkoxy, amino, hydroxyl, halogen, nitro and trifluoromethyl;
more preferably, R is selected from ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, cyclopentyl, cyclohexyl, hexyl, heptyl, octyl, nonyl, decyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, wherein said substitution is by C1-C10Alkyl radical, C1-C10One or more of alkoxy, amino, hydroxyl, halogen, nitro and trifluoromethyl;
most preferably, R is selected from the group consisting of ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, cyclopentyl, cyclohexyl, hexyl, heptyl, octyl, nonyl, decyl, phenyl, 4-methylphenyl, 4-methoxyphenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, benzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl.
The 6-fluoroquinazoline derivative containing the disulfide structure comprises the following compounds:
the invention also provides a preparation method of the 6-fluoroquinazoline derivative containing the disulfide structure, which comprises the following steps:
the compound or the composition can be used for controlling agricultural pests, preferably, the agricultural pests are plant bacterial diseases; more preferably, the agricultural pests are plant leaf blight, plant canker and plant bacterial wilt; most preferably, the agricultural pests are rice bacterial blight, bacterial wilt, citrus canker, kiwi canker.
The term "alkyl" as used herein is intended to include both branched and straight chain saturated hydrocarbon radicals having the specified number of carbon atoms. E.g. "C2-10Alkyl "(or alkylene) groups are intended to be C2, C3, C4, C5, C6, C7, C8, C9 and C10 alkyl groups. In addition, for example "C2-10Alkyl "denotes an alkyl group having 2 to 10 carbon atoms. Alkyl groups may be unsubstituted or substituted such that one or more of its hydrogen atoms are replaced with another chemical group. Examples of alkyl groups include, but are not limited to, ethyl (Et),Propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl) and the like. And, when reference is made to hexyl, heptyl, octyl, all isomers thereof are included in addition to n-hexyl, n-heptyl, n-octyl.
The term "substituted" as used herein means that any one or more hydrogen atoms on the designated atom or group is replaced with the designated group of choice, provided that the general valence of the designated atom is not exceeded. If not otherwise stated, substituents are named to the central structure. For example, it is understood that when (cycloalkyl) alkyl is a possible substituent, the point of attachment of the substituent to the central structure is in the alkyl moiety. When referring to substitution, especially polysubstitution, it is meant that the various substituents are substituted at various positions on the indicated group, e.g. dichlorophenyl means 1, 2-dichlorophenyl, 1, 3-dichlorophenyl and 1, 4-dichlorophenyl.
Combinations of substituents and or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable compound or stable structure implies that the compound is sufficiently stable to be isolated in useful purity from the reaction mixture and subsequently formulated to form an effective therapeutic agent.
The term "aryl" refers to a monocyclic aromatic hydrocarbon group having 6 carbon atoms in the ring portion, such as phenyl.
The term "halogen" or "halogen atom" refers to chlorine, bromine, fluorine.
Preferably, C2-C10Alkyl refers to ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and isomers thereof;
when substituents are mentioned, such as alkenyl, alkynyl, alkyl, halo, aryl, heteroaryl, alkoxy, cycloalkyl, hydroxy, amino, mercapto, phosphino, or when these substituents are specifically alkenyl, alkynyl, alkyl, halo, aryl, heteroaryl, alkoxy, cycloalkyl, hydroxy, amino, mercapto, phosphino, one to three of the above substituents are meant. Such as methylphenyl refers to phenyl substituted with one to three methyl groups.
By adopting the technical scheme, the 6-fluoroquinazoline derivatives containing disulfide structures are synthesized on the basis of 6-fluoroquinazoline structures, and the compounds are found to have good inhibition effects on part of plant pathogenic bacteria, such as rice bacterial blight (Xanthomonas oryzae v.oryzae, Xoo), Ralstonia solanacearum (Rs), citrus canker (Xanthomonas axopodis v.citri, Xac), kiwi canker (Pseudomonas ringiana, Actinidiae) and the like, which all show good inhibition effects, and provide a certain scientific basis for research and development of new pesticides.
Detailed Description
The invention is further illustrated by the following examples. It should be understood that the method described in the examples is only for illustrating the present invention and not for limiting the present invention, and that simple modifications of the preparation method of the present invention based on the concept of the present invention are within the scope of the claimed invention. All the starting materials and solvents used in the examples are commercially available products.
Example 1:synthesis of 4- (ethyldisulfide) -6-fluoroquinazoline
(1) Preparation of 6-fluoroquinazoline-4-sulfydryl
Adding 2-amino 5-fluorobenzoic acid 30g and formamide 60mL into a round bottom flask 150mL in sequence, heating to 120 ℃ under stirring, carrying out reflux reaction for about 5 hours, tracking by TLC, cooling to room temperature after the reaction is finished, pouring a proper amount of ice water, adjusting the pH to be alkalescent by using an aqueous solution of sodium bicarbonate, and filtering to obtain a crude product of 5-fluoroquinazolinone. Taking 3.8g (23.15mmol) of the crude product, adding thionyl chloride (16.79mL, 231.51mmol) into a 100mL round-bottom flask under stirring, heating to 84 ℃ for reflux reaction, dropwise adding a catalytic amount of DMF in the heating process, stopping heating after reacting for about 4 hours, removing most of solvent by rotation, adding water in batches for quenching, separating out a white solid, and filtering to obtain 4-chloro-6-fluoroquinolizoline. Taking tetrahydrofuran as a solvent, taking 4g (21.91mmol) of 4-chloro-6-fluoroquinazoline in a 100mL round-bottom flask, adding 2.67g (35.05mmol) of thiourea, stirring at normal temperature, tracing the reaction by TLC, finishing the reaction for about 2h, removing the solvent by rotation, adding a sodium hydroxide aqueous solution to be alkaline, filtering, adjusting the filtrate to be acidic by sulfuric acid, precipitating a light yellow solid, filtering, and drying to obtain 6-fluoroquinazoline-4-sulfydryl, wherein the yield is 70.79%.
(2) Preparation of ethyl sulfur chloride
8mL of dichloromethane and 0.23g (3.7mmol) of ethyl mercaptan are added into a round-bottomed bottle, 0.6g (4.44mmol) of sulfonyl chloride is dropwise added under ice bath, the mixture reacts for 1h under ice bath conditions, the solvent is removed by rotary evaporation, and the mixture is dissolved by ether and then directly used for the next reaction.
(3) Preparation of 4- (ethyldisulfide) -6-fluoroquinazoline
40mL of diethyl ether and 0.5g (2.77mmol) of 6-fluoroquinazoline-4-sulfydryl are added into a 100mL round-bottom flask, the reaction product in the step (2) is dripped into the reaction system, stirred at normal temperature overnight, added with about 50mL of petroleum ether, stirred, filtered by suction, and filtered by an ethyl acetate/petroleum ether column to obtain a white solid with the yield of 56.99%.
Example 2:synthesis of 4- (propyldisulfide) -6-fluoroquinazoline
The 6-fluoroquinazoline-4-thiol group was prepared as described in example 1; preparation of propylthiochloride and preparation of 4- (propyldisulfide) -6-fluoroquinazoline reference is made to example 1, in which the molar ratio of the charged sulfonyl chloride, propylthiol and 6-fluoroquinazoline-4-mercapto group is 4: 2: 1.
example 3:synthesis of 4- (butyldisulfide) -6-fluoroquinazoline
The 6-fluoroquinazoline-4-thiol group was prepared as described in example 1; preparation of butylthiochloride and preparation of 4- (butyldisulfide) -6-fluoroquinazoline reference is made to example 1, in which the molar ratio of the feed of sulfonyl chloride, butylthiol and 6-fluoroquinazoline-4-mercapto group is 4: 2: 1.
example 4:synthesis of 4- (isobutyl disulfide) -6-fluoroquinazoline
The 6-fluoroquinazoline-4-thiol group was prepared as described in example 1; preparation of isobutylthiochloride and 4- (isobutyldisulfide) -6-fluoroquinazoline reference is made to example 1, in which the molar ratio of the charged sulfonyl chloride, isobutylthiol and 6-fluoroquinazoline-4-mercapto group is 4: 2: 1.
example 5:synthesis of 4- (3-methyl-2-butyldisulfide) -6-fluoroquinazoline
The 6-fluoroquinazoline-4-thiol group was prepared as described in example 1; preparation of 3-methyl-2-butylthiochloride and 4- (3-methyl-2-butyldisulfide) -6-fluoroquinolizoline reference is made to example 1, in which the charged molar ratio of sulfonyl chloride, 3-methyl-2-butylthiol and 6-fluoroquinolizoline-4-mercapto is 4: 2: 1.
example 6:synthesis of 4- (pentyldisulfide) -6-fluoroquinazoline
The 6-fluoroquinazoline-4-thiol group was prepared as described in example 1; preparation of pentylthiochloride and preparation of 4- (pentyldisulfide) -6-fluoroquinazoline reference is made to example 1, where the charged molar ratio of sulfonyl chloride, pentylthiol and 6-fluoroquinazoline-4-mercapto is 4: 2: 1.
example 7:synthesis of 4- (isopentyl disulfide) -6-fluoroquinazoline
The 6-fluoroquinazoline-4-thiol group was prepared as described in example 1; preparation of isopentyl sulfur chloride and preparation of 4- (isopentyl disulfide) -6-fluoroquinazoline reference is made to example 1, wherein the molar ratio of the feed of sulfonyl chloride, isopentyl thiol and 6-fluoroquinazoline-4-thiol is 4: 2: 1.
example 8:synthesis of 4- (cyclohexyl disulfide) -6-fluoroquinazoline
The 6-fluoroquinazoline-4-thiol group was prepared as described in example 1; preparation of cyclohexyl sulfur chloride and preparation of 4- (cyclohexyl disulfide) -6-fluoroquinazoline reference is made to example 1, wherein the charged molar ratio of sulfonyl chloride, cyclohexyl thiol and 6-fluoroquinazoline-4-mercapto is 4: 2: 1.
example 9:synthesis of 4- (hexyldisulfide) -6-fluoroquinazoline
The 6-fluoroquinazoline-4-thiol group was prepared as described in example 1; preparation of hexylthio chloride and 4- (hexyldisulfide) -6-fluoroquinazoline preparation reference is made to example 1, wherein the molar ratio of the charged sulfonyl chloride, hexylmercaptan and 6-fluoroquinazoline-4-mercapto group is 4: 2: 1. a
Example 10:synthesis of 4- (heptyl disulfide) -6-fluoroquinazoline
The 6-fluoroquinazoline-4-thiol group was prepared as described in example 1; preparation of heptylthiochloride and of 4- (heptyldisulfide) -6-fluoroquinazoline reference is made to example 1, wherein the charged molar ratio of sulfonyl chloride, heptylthiol and 6-fluoroquinazoline-4-mercapto is 4: 2: 1.
example 11:synthesis of 4- (octyl disulfide) -6-fluoroquinazoline
The 6-fluoroquinazoline-4-thiol group was prepared as described in example 1; preparation of octyl sulfur chloride and preparation of 4- (octyl disulfide) -6-fluoroquinazoline reference is made to example 1, wherein the molar ratio of the charged sulfonyl chloride, octyl mercaptan and 6-fluoroquinazoline-4-mercapto group is 4: 2: 1.
example 12:synthesis of 4- (nonyl disulfide) -6-fluoroquinazoline
The 6-fluoroquinazoline-4-thiol group was prepared as described in example 1; preparation of nonyl Sulfur chloride and preparation of 4- (nonyl disulfide) -6-fluoroquinazoline reference is made to example 1, where the molar ratios of the charged sulfonyl chloride, nonyl thiol and 6-fluoroquinazoline-4-mercapto group are 4: 2: 1.
example 13:synthesis of 4- (decyl disulfide) -6-fluoroquinazoline
The 6-fluoroquinazoline-4-thiol group was prepared as described in example 1; preparation of decyl sulfur chloride and 4- (decyl disulfide) -6-fluoroquinazoline reference is made to example 1, where the molar ratios of sulfonyl chloride, decyl thiol and 6-fluoroquinazoline-4-mercapto fed are 4: 2: 1.
example 14:synthesis of 4- (benzyl disulfide) -6-fluoroquinazoline
The 6-fluoroquinazoline-4-thiol group was prepared as described in example 1; preparation of benzylthio chloride and preparation of 4- (benzyldisulfide) -6-fluoroquinazoline reference is made to example 1, in which the molar ratios of the feed of sulfonyl chloride, benzylthiol and 6-fluoroquinazoline-4-mercapto are 4: 2: 1.
example 15:synthesis of 4- (4-methoxyphenyl disulfide) -6-fluoroquinazoline
The 6-fluoroquinazoline-4-thiol group was prepared as described in example 1; preparation of 4-methoxyphenyl thiochloride and preparation of 4- (4-methoxyphenyl disulfide) -6-fluoroquinazoline reference example 1, in which the molar ratio of the charged sulfonyl chloride, 4-methoxythiophenol and 6-fluoroquinazoline-4-mercapto group was 4: 2: 1.
example 16:synthesis of 4- (4-methylphenyl disulfide) -6-fluoroquinazoline
The 6-fluoroquinazoline-4-thiol group was prepared as described in example 1; preparation of 4-methylphenylthiochloride and 4- (4-methylphenyldisulfide) -6-fluoroquinazoline reference example 1, wherein the molar ratio of the charged sulfonyl chloride, 4-methylphenylthiol and 6-fluoroquinazoline-4-mercapto group was 4: 2: 1.
example 17:synthesis of 4- (2-bromophenyl disulfide) -6-fluoroquinazoline
The 6-fluoroquinazoline-4-thiol group was prepared as described in example 1; preparation of 2-bromophenyl thiochloride and 4- (2-bromophenyl disulfide) -6-fluoroquinazoline reference example 1, in which the molar ratio of charged sulfonyl chloride, 2-bromophenylthiol and 6-fluoroquinazoline-4-mercapto group was 4: 2: 1.
example 18:synthesis of 4- (3-bromophenyl disulfide) -6-fluoroquinazoline
The 6-fluoroquinazoline-4-thiol group was prepared as described in example 1; preparation of 3-bromophenyl thiochloride and 4- (3-bromophenyl disulfide) -6-fluoroquinazoline reference example 1, in which the charged molar ratio of sulfonyl chloride, 3-bromophenylthiol and 6-fluoroquinazoline-4-mercapto group was 4: 2: 1.
example 19:synthesis of 4- (4-bromophenyl disulfide) -6-fluoroquinazoline
The 6-fluoroquinazoline-4-thiol group was prepared as described in example 1; preparation of 4-bromophenyl thiochloride and preparation of 4- (4-bromophenyl disulfide) -6-fluoroquinazoline reference example 1, in which the molar ratio of charged sulfonyl chloride, 4-bromophenylthiol and 6-fluoroquinazoline-4-mercapto group was 4: 2: 1.
example 20:synthesis of 4- (2-fluorophenyl disulfide) -6-fluoroquinazoline
The 6-fluoroquinazoline-4-thiol group was prepared as described in example 1; preparation of 2-fluorophenylthiochloride and 4- (2-fluorophenyldisulfide) -6-fluoroquinazoline reference is made to example 1, in which the molar ratios of charged sulfonyl chloride, 2-fluorophenylthiol and 6-fluoroquinazoline-4-mercapto group are 4: 2: 1.
example 21:synthesis of 4- (2-chlorophenyl disulfide) -6-fluoroquinazoline
The 6-fluoroquinazoline-4-thiol group was prepared as described in example 1; preparation of 2-chlorophenyl thiochloride and preparation of 4- (2-chlorophenyl disulfide) -6-fluoroquinazoline reference is made to example 1, in which the molar ratios of charged sulfonyl chloride, 2-chlorobenzenethiol and 6-fluoroquinazoline-4-mercapto group are 4: 2: 1.
example 22:synthesis of 4- (3-fluorophenyl disulfide) -6-fluoroquinazoline
The 6-fluoroquinazoline-4-thiol group was prepared as described in example 1; preparation of 3-fluorophenylthiochloride and 4- (3-fluorophenyldisulfide) -6-fluoroquinazoline reference is made to example 1, in which the molar ratios of charged sulfonyl chloride, 3-fluorophenylthiol and 6-fluoroquinazoline-4-mercapto group are 4: 2: 1.
example 23:synthesis of 4- (4-chlorophenyl disulfide) -6-fluoroquinazoline
The 6-fluoroquinazoline-4-thiol group was prepared as described in example 1; preparation of 4-chlorophenyl thiochloride and preparation of 4- (4-chlorophenyl disulfide) -6-fluoroquinazoline reference is made to example 1, in which the molar ratios of charged sulfonyl chloride, 4-chlorobenzenethiol and 6-fluoroquinazoline-4-mercapto group are 4: 2: 1.
example 24:synthesis of 4- (phenethyl disulfide) -6-fluoroquinazoline
The 6-fluoroquinazoline-4-thiol group was prepared as described in example 1; preparation of phenethyl thio chloride and preparation of 4- (phenethyldisulfide) -6-fluoroquinazoline reference is made to example 1, wherein the molar ratio of the charged sulfonyl chloride, phenethyl thiol and 6-fluoroquinazoline-4-mercapto group is 4: 2: 1.
TABLE 1 NMR and high resolution mass spectral data for some of the compounds
Table 2 physicochemical properties of the target compounds
Pharmacological example 1:
the inhibition rate of a target compound on plant pathogenic bacteria is tested by adopting a turbidity method, the test objects are rice bacterial blight (Xoo), kiwi fruit canker (Psa), ralstonia solanacearum (Rs) and citrus canker (Xac), the culture medium is added with an equal volume of DMSO (dimethyl sulfoxide) as a blank control, and bismerthazol (90%) and Shenqinmycin (99.3%) are used as positive control drugs. Picking a proper amount of rice bacterial blight, citrus canker and kiwi canker on an NA solid culture medium, putting the rice bacterial blight, citrus canker and kiwi canker into an NB culture medium, and carrying out shake culture in a constant-temperature shaking table at 28 ℃ and 250rpm until the logarithmic phase is reserved; 4mL of NB-containing liquid medium (compound or drug) at various concentrations (e.g., 100, 50. mu.g/mL) were prepared in sterilized test tubes, and 40. mu.L of the cultured pathogenic bacteria were added to each of these test tubes, and the tubes were shaken in a shaker at 28 ℃ and 250rpm for about 12-24 hours. 200. mu.L of each of the bacterial solutions was removed from each test tube and used for OD measurement595Value, simultaneously determining the OD of the sterilized NB-containing liquid medium at the corresponding concentration595The value is obtained.
Correcting OD value, namely OD value of the bacteria-containing culture medium-OD value of the sterile culture medium;
percent inhibition is [ (OD value of control medium liquid OD value after correction-OD value of medium containing toxin corrected)/OD value of control medium liquid OD value after correction ] × 100
The examples of the present invention are given to illustrate the technical solution of the present invention, but the contents of the examples are not limited thereto, and some experimental results of the target compounds are shown in the following table.
TABLE 3 inhibitory Activity of 6-fluoroquinazoline derivatives containing disulfide Structure on Paddy Rice Blakeslea blight fungus
——:lowactivity
TABLE 4 inhibitory Activity of 6-fluoroquinazoline derivatives containing disulfide Structure on Ralstonia solanacearum
——:lowactivity
The results of the in vitro experiments show that: compared with the control drugs of bismerthiazol and shenqinmycin, the series of compounds have better inhibitory activity on rice bacterial blight and tobacco bacterial wilt under the test concentration; taking the experimental data of a series of compounds for resisting rice bacterial blight as an example, the compounds 1-6, 8-10, 13 and 17 can still realize the inhibition effect of more than 90% under the condition of lower concentration of 25ppm, the inhibition effect is equivalent to that of shenqinmycin, the compounds 12, 23 and 24 realize the inhibition effect of more than 80%, and the inhibition rate of bismerthiazol under the same concentration is only about 30%. The preliminary in vitro activity data provides better support for further research, and the series of compounds can be further subjected to in vivo experiments, structure optimization and preliminary action mechanism research so as to provide a certain basis for creating new pesticides.
Claims (10)
1. 6-fluoroquinazoline derivatives containing disulfide structures are characterized in that: the compound has a structure shown as a general formula (I):
wherein,
r is selected from any substituted or unsubstituted alkyl, any substituted or unsubstituted cycloalkyl and any substituted or unsubstituted aryl.
2. The disulfide structure-containing 6-fluoroquinazoline derivative according to claim 1, characterized in that: r is selected from alkyl, cycloalkyl, and substituted or unsubstituted aryl.
3. The disulfide structure-containing 6-fluoroquinazoline derivative according to claim 1, characterized in that: r is selected from C2-C10Alkyl radical, C5-C6Cycloalkyl, substituted or unsubstituted C6-C7Aryl, wherein said substitution is by C1-C10Alkyl radical, C1-C10One or more of alkoxy, amino, hydroxyl, halogen, nitro and trifluoromethyl.
4. The dithioether structure-containing 6-fluoroquinazoline derivative according to claim 3, characterized in that: r is selected from ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, cyclopentyl, cyclohexyl, hexyl, heptyl, octyl, nonyl, decyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, wherein said substitution is by C1-C10Alkyl radical, C1-C10One or more of alkoxy, amino, hydroxyl, halogen, nitro and trifluoromethyl.
5. The preparation method of 6-fluoroquinazoline derivatives containing disulfide structures as claimed in any one of claims 1 to 4, characterized by comprising the following steps:
6. a composition comprising a compound according to any one of claims 1 to 4 and an agriculturally acceptable adjuvant or fungicide.
7. Use of a compound as claimed in any one of claims 1 to 4, or a composition as claimed in claim 6, in the manufacture of a medicament for use in the control of an agricultural pest.
8. Use according to claim 7, characterized in that: the agricultural pest is plant bacterial disease.
9. Use according to claim 7, characterized in that: the agricultural pests and diseases are plant leaf blight, plant canker and plant bacterial wilt.
10. Use according to claim 7, characterized in that: the agricultural pests and diseases are rice bacterial leaf blight, citrus canker, kiwi canker and bacterial wilt.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115521261A (en) * | 2022-11-02 | 2022-12-27 | 贵州理工学院 | Preparation method of sulfhydryl-containing quinazolinone and composition thereof and application of sulfhydryl-containing quinazolinone in resisting kiwifruit canker |
| CN115636795A (en) * | 2022-11-02 | 2023-01-24 | 贵州理工学院 | Quinazolinone derivative containing thiobenzamide structure, composition and application of quinazolinone derivative in prevention and treatment of kiwifruit canker |
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| CN109721554A (en) * | 2019-01-08 | 2019-05-07 | 贵州大学 | A kind of 4- amino-quinazoline compound and its preparation method and application |
| CN111285860A (en) * | 2020-03-25 | 2020-06-16 | 贵州大学 | Indole derivatives containing disulfanyl heterocyclic structure or stereoisomer thereof, or salt or solvate thereof |
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| CN109721554A (en) * | 2019-01-08 | 2019-05-07 | 贵州大学 | A kind of 4- amino-quinazoline compound and its preparation method and application |
| CN111285860A (en) * | 2020-03-25 | 2020-06-16 | 贵州大学 | Indole derivatives containing disulfanyl heterocyclic structure or stereoisomer thereof, or salt or solvate thereof |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115521261A (en) * | 2022-11-02 | 2022-12-27 | 贵州理工学院 | Preparation method of sulfhydryl-containing quinazolinone and composition thereof and application of sulfhydryl-containing quinazolinone in resisting kiwifruit canker |
| CN115636795A (en) * | 2022-11-02 | 2023-01-24 | 贵州理工学院 | Quinazolinone derivative containing thiobenzamide structure, composition and application of quinazolinone derivative in prevention and treatment of kiwifruit canker |
| CN115636795B (en) * | 2022-11-02 | 2024-04-05 | 贵州理工学院 | Preparation method of quinazolinone derivative containing thiobenzamide structure and composition thereof, and application of quinazolinone derivative and composition thereof in preventing and treating kiwi fruit canker |
| CN115521261B (en) * | 2022-11-02 | 2024-04-05 | 贵州理工学院 | Preparation method of mercapto-containing quinazolinone and composition thereof, and application of mercapto-containing quinazolinone in resisting kiwi fruit canker |
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Application publication date: 20211207 |