CN115108997A - 一类具抑菌活性的磺酰脲类化合物的合成与应用 - Google Patents
一类具抑菌活性的磺酰脲类化合物的合成与应用 Download PDFInfo
- Publication number
- CN115108997A CN115108997A CN202110299808.4A CN202110299808A CN115108997A CN 115108997 A CN115108997 A CN 115108997A CN 202110299808 A CN202110299808 A CN 202110299808A CN 115108997 A CN115108997 A CN 115108997A
- Authority
- CN
- China
- Prior art keywords
- halo
- alkyl
- carbon
- group
- straight
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 title claims abstract description 16
- 230000015572 biosynthetic process Effects 0.000 title claims description 8
- 238000003786 synthesis reaction Methods 0.000 title claims description 8
- 230000000844 anti-bacterial effect Effects 0.000 title description 9
- 241000191967 Staphylococcus aureus Species 0.000 claims abstract description 16
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 claims abstract description 15
- 229960003085 meticillin Drugs 0.000 claims abstract description 15
- 108010059993 Vancomycin Proteins 0.000 claims abstract description 10
- 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 claims abstract description 10
- 229960003165 vancomycin Drugs 0.000 claims abstract description 10
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 claims abstract description 10
- 244000063299 Bacillus subtilis Species 0.000 claims abstract description 7
- 235000014469 Bacillus subtilis Nutrition 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims description 32
- -1 monofluoromethyl Chemical group 0.000 claims description 17
- 125000005843 halogen group Chemical group 0.000 claims description 16
- 125000004432 carbon atom Chemical group C* 0.000 claims description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 239000003242 anti bacterial agent Substances 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 4
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 4
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 125000004185 ester group Chemical group 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 3
- 125000003544 oxime group Chemical group 0.000 claims description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 2
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 101150065749 Churc1 gene Proteins 0.000 claims description 2
- 102100038239 Protein Churchill Human genes 0.000 claims description 2
- 150000004982 aromatic amines Chemical class 0.000 claims description 2
- 150000001555 benzenes Chemical group 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- 229940125782 compound 2 Drugs 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 2
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 125000000623 heterocyclic group Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 239000011630 iodine Substances 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 229940124530 sulfonamide Drugs 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 238000010521 absorption reaction Methods 0.000 claims 1
- 239000000853 adhesive Substances 0.000 claims 1
- 230000001070 adhesive effect Effects 0.000 claims 1
- 150000008331 benzenesulfonamides Chemical class 0.000 claims 1
- 239000002775 capsule Substances 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 239000000839 emulsion Substances 0.000 claims 1
- 239000003623 enhancer Substances 0.000 claims 1
- 239000000945 filler Substances 0.000 claims 1
- 125000001153 fluoro group Chemical group F* 0.000 claims 1
- 125000001841 imino group Chemical group [H]N=* 0.000 claims 1
- 239000003112 inhibitor Substances 0.000 claims 1
- 238000002347 injection Methods 0.000 claims 1
- 239000007924 injection Substances 0.000 claims 1
- 239000000314 lubricant Substances 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 239000006187 pill Substances 0.000 claims 1
- 238000001179 sorption measurement Methods 0.000 claims 1
- 239000000725 suspension Substances 0.000 claims 1
- 239000003826 tablet Substances 0.000 claims 1
- 239000000080 wetting agent Substances 0.000 claims 1
- 229940100389 Sulfonylurea Drugs 0.000 abstract description 10
- 229940124350 antibacterial drug Drugs 0.000 abstract description 4
- 230000000694 effects Effects 0.000 abstract description 3
- 125000001424 substituent group Chemical group 0.000 abstract description 2
- 239000000022 bacteriostatic agent Substances 0.000 abstract 2
- 241001478240 Coccus Species 0.000 abstract 1
- 241000124008 Mammalia Species 0.000 abstract 1
- 230000005764 inhibitory process Effects 0.000 abstract 1
- 231100000252 nontoxic Toxicity 0.000 abstract 1
- 230000003000 nontoxic effect Effects 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 20
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- 230000002401 inhibitory effect Effects 0.000 description 11
- 239000000243 solution Substances 0.000 description 9
- 238000004113 cell culture Methods 0.000 description 8
- 241000894006 Bacteria Species 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 108010000700 Acetolactate synthase Proteins 0.000 description 5
- 241000194033 Enterococcus Species 0.000 description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- 230000001580 bacterial effect Effects 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000013641 positive control Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 230000002363 herbicidal effect Effects 0.000 description 3
- 230000036961 partial effect Effects 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 241000233866 Fungi Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 239000006142 Luria-Bertani Agar Substances 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 244000052616 bacterial pathogen Species 0.000 description 2
- 230000003385 bacteriostatic effect Effects 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 150000005693 branched-chain amino acids Chemical class 0.000 description 2
- 229940041514 candida albicans extract Drugs 0.000 description 2
- 239000013043 chemical agent Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 239000004009 herbicide Substances 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 239000012137 tryptone Substances 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 239000012138 yeast extract Substances 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 239000005496 Chlorsulfuron Substances 0.000 description 1
- HSFDAWKXHGTJHW-UHFFFAOYSA-N ClC1=C(C=C(C=C1)C=C)S(=O)(=O)N Chemical compound ClC1=C(C=C(C=C1)C=C)S(=O)(=O)N HSFDAWKXHGTJHW-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- WNDWKKPBLAKXMI-UHFFFAOYSA-N [5-(benzenesulfonyl)-2-nitrophenyl] 4-chlorobenzoate Chemical compound [O-][N+](=O)C1=CC=C(S(=O)(=O)C=2C=CC=CC=2)C=C1OC(=O)C1=CC=C(Cl)C=C1 WNDWKKPBLAKXMI-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- MYPYJXKWCTUITO-KIIOPKALSA-N chembl3301825 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(O)[C@H](C)O1 MYPYJXKWCTUITO-KIIOPKALSA-N 0.000 description 1
- VJYIFXVZLXQVHO-UHFFFAOYSA-N chlorsulfuron Chemical compound COC1=NC(C)=NC(NC(=O)NS(=O)(=O)C=2C(=CC=CC=2)Cl)=N1 VJYIFXVZLXQVHO-UHFFFAOYSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 238000005138 cryopreservation Methods 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000009088 enzymatic function Effects 0.000 description 1
- 230000000642 iatrogenic effect Effects 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 239000010413 mother solution Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
- 230000008023 solidification Effects 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及一类磺酰脲类抑菌剂的发现与应用,结构通式如I,式中个取代基团的定义见说明书。本发明的目的在于提供一类对人和哺乳动物安全无毒的新型磺酰脲类抑菌剂,该类化合物对耐甲氧西林金黄色葡萄球菌,金黄色葡萄球菌,耐万古霉素肠球菌,枯草杆菌有很好的抑制效果,可用于制备新型抗菌药物。
Description
技术领域
本发明涉及一类具抗菌活性的磺酰脲类化合物的合成及应用。
背景技术
20世纪70年代,美国杜邦公司的Levitt G.最早发现了磺酰脲类除草剂,1981年,第一个商品化品种氯磺隆问世,标志着除草剂发展进入了超高效时代,该类除草剂因为具有超高效、低毒、广谱、高选择性等特点受到广泛应用。该类化合物单一靶向乙酰乳酸合成酶(AHAS),AHAS除了在植物体内广泛存在外,也在各种细菌,真菌等物种体内存在,这使得磺酰脲类化合物通过抑制AHAS而表现出抑菌活性成为可能。可以推测,如果能够干扰微生物的AHAS酶功能,将能够阻断其自身合成支链氨基酸的途径,并且许多研究表明,大量的真菌和细菌不能从外界环境获取支链氨基酸或其前体来维持生存,因此开发高活性的微生物AHAS抑制剂对于新型抗菌药物的开发具有重要意义。因其除草活性和杀菌活性具有相似的作用机制,磺酰脲类化合物作为抗菌剂也具有的高效、低毒、高选择性等特点。
发明内容
本发明的目的在于提供一类具抗菌活性的磺酰脲类化合物的合成及应用。该类化合物具有很高的抑菌活性,为医用抗菌药物的发现提供了更多可能。
本发明提供的磺酰脲类新结构通式见式I:
式中:
R1选自H、卤素、酯基、硝基、氰基、三氟甲基、二氟代甲基、一氟代甲基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C1-C6烷硫基、卤代C1-C6烷硫基、C1-C6烷氧基羰基、卤代C3- C6环烷基或N,N-(C1-C6烷基)氨基甲酰基;
R2选自H、C1-C6烷氧基羰基、N,N-(C1-C6烷基)氨基甲酰基、C1-C6烷基、卤代C1-C6烷基、 C1-C6烷氧基、卤代C1-C6烷氧基、C1-C6烷硫基、卤代C1-C6烷硫基、氨基、C1-C6烷基氨基、C1-C6酰胺基、C1-C6磺酰胺基、C1-C6亚胺基、C2-C6烯基、卤代C2-C6烯基、C2-C6炔基、卤代C3-C6环烷基或卤代C2-C6炔基、C2-C6羰基、C2-C6酯基、C2-C6肟基;
R3和R4选H、F、Cl、CH3、OCH3、OC2H5、OCH2CH2CH3、CF3、OCF3、OCHF2、OCH2CF3、 NHCH3、N(CH3)2、SCH3、CH=CHCH3、4-卤素取代苯环,杂环。
在上述衍生物的定义中,所用术语不论单独使用还是用在复合词中,代表如下取代基:
卤素为氟、氯、溴或碘;
C1-C6烷基为直链或支链烷基
卤代C1-C6烷基为直链或支链烷基,卤代C1-C6烷基上的氢原子可以部分或全部被卤原子取代;“卤代C2-C6烯基”、“卤代C2-C6炔基”和“卤代C3-C6环烷基”的定义与术语“卤代C1-C6烷基”相同;
C2-C6亚胺基为有2-6个碳原子的直链或支链并可在任何位置上存在碳氮双键且为E构型;
C2-C6烯基为有2-6个碳原子的直链或支链并可在任何位置上存在碳碳双键且为E构型;
C2-C6炔基为有2-6个碳原子的直链或支链并可在任何位置上存在碳碳三键;
C2-C6羰基为有2-6个碳原子的直链或支链并可在任何位置上存在碳氧双键;
C2-C6酯基为有2-6个碳原子的直链或支链并可在任何位置上存在碳氧双键;
C2-C6肟基为有2-6个碳原子的直链或支链并可在任何位置上存在碳氮双键且为E构型。
本发明的磺酰脲类化合物I按Scheme-1所示的方法合成:
通式化合物1与碳酸钾溶于有机溶剂中,加热回流得到通式化合物2,然后与取代芳胺溶于有机溶剂中,加热回流制得通式化合物I。反应式中各基团如权利要求1中的定义。
如权利要求3所述的磺酰脲类衍生物的制备方法,其特征在于所述的有机溶剂选自丙酮、氯仿、四氯化碳、苯、甲苯、甲醇、乙醇、乙酸乙酯、四氢呋喃、乙腈、1,4-二氧六环、N,N-二甲基甲酰胺、二甲基亚砜,甲基叔丁基醚、乙醚或石油醚。
所述任何一种磺酰脲类衍生物均可用于制备抗菌剂,防除医源性致病菌。本发明提供的磺酰脲衍生物作为活性成分配以药物可以接受的助剂组成的药物组合物用于致病菌的防治。
本发明的技术效果是:提供了一类磺酰脲类抑菌剂的合成及应用技术。该类化合物具有较高的耐甲氧西林金黄色葡萄球菌,金黄色葡萄球菌,耐万古霉素肠球菌,枯草杆菌,为抗菌药物的发现提供了更多可能。
具体实施方式
以下结合实施例来进一步说明本发明,其目的是能更好的理解本发明的内容及体现本发明的实质性特点,因此所举之例不应视为对本发明保护范围的限制。
实施例1
2-氯-5-乙烯基苯磺酰胺甲酸乙酯的合成:
在100mL单口圆底烧瓶中,将2-氯-5-乙烯基苯磺酰胺(2.18g,0.01mol)、碳酸钾(2.76g, 0.02mol)溶到30mL丙酮中,然后加入氯甲酸乙酯(1.30g,0.012mol),加热回流6小时,减压浓缩除去溶剂丙酮,剩余物加入乙醚与水的混合溶剂(50mL,v/v=1∶1)溶解,分液去掉乙醚层,水层用盐酸调节pH至3左右,有固体析出,抽滤,干燥得到白色固体,直接用于下一步反应。
实施例2
1-(2-氯-5-乙烯基苯基磺酰基)-3-(4-噻吩-1,3-嘧啶-2-基)脲的合成:
在100mL单口圆底烧瓶中,将2-氯-5-乙烯基苯磺酰胺基甲酸乙酯(2.76g,0.01mol)、4-噻吩-2-氨基-1,3-嘧啶(1.77g,0.01mol)溶到40mL甲苯中,加热回流6小时,其间每2小时蒸出20 mL甲苯并补加20mL新甲苯。反应完毕后冷却至室温,将反应液脱溶,残余物经柱色谱纯化得到目标化合物。
现将根据实施例1~2的制备方法而采用不同的原料制备的该类衍生物1~468及部分衍生物的熔点列入表1,部分衍生物1H NMR和13C NMR(Bruker AV-400spectrometerusing tetramethylsilane as the internal standard)、高分辨质谱数据列入表2。
表1目标化合物I的结构
表2.部分化合物核磁和高分辨数据
实施例3.利用本发明所提供的磺酰脲类衍生物对耐甲氧西林金黄色葡萄球菌,金黄色葡萄球菌,耐万古霉素肠球菌及枯草杆菌抑制活性(最小抑菌浓度,MIC)的测定
实验材料
Mueller-Hinton Broth(北京奥博星生物技术有限责任公司),胰蛋白胨(英国OXOID公司),酵母浸出粉(英国OXOID公司),氯化钠(国药集团化学试剂有限公司),96孔细胞培养板(flatbottom) (美国康宁公司),阳性对照药物万古霉素和甲氧西林(美国Amresco公司),DMSO(国药集团化学试剂有限公司),MHB培养基(使用电子天平称取24gMueller-Hinton Broth干粉,溶解于1000mL蒸馏水,调节pH至7.2,使用高压蒸汽灭菌锅在121℃下灭菌20min制备所得)。耐甲氧西林金黄色葡萄球菌(MRSA,北京朝阳医院分离株),金黄色葡萄球菌(SA ATCC6538),耐万古霉素肠球菌(VRE- 309),枯草杆菌(BS ATCC6633),所有菌株均以冻存甘油管方式保存于-80冰箱。LB琼脂平板(使用电子天平称取10gTryptone、5g Yeast extract、5g NaCl,溶解于1000mL蒸馏水,调节pH至7.0,加入20g琼脂粉,使用高压蒸汽灭菌锅在121℃下灭菌20min,分装至无菌培养皿(30mL/培养皿) 待冷却凝固后备用)。
菌液准备
测定时取出菌株的甘油冻存管,在室温下解冻,划线法接种于LB琼脂平板上进行活化,于 37℃培养箱培养20h;用无菌接种环挑取3个单菌落于3mL MHB培养基中,使用涡旋振荡器充分混匀成为菌液母液,使用血球计数板检测菌浓;使用MHB培养基将菌液母液稀释至2×104细胞/mL,成为待用菌液。
药液准备
用电子分析天平称取待测化合物,以无菌DMSO为溶剂配制为1mg/mL的化合物溶液;阳性对照药物使用无菌DMSO配制为320μg/mL的溶液,并用DMSO依次稀释为160μg/mL、80μg/mL、 40μg/mL、20μg/mL、10μg/mL、5μg/mL、2.5μg/mL等8个浓度梯度。
测定药物对不同菌的最小抑菌浓度(MIC)
取无菌96孔细胞培养板,使用8道微量移液器移取40μL MHB培养基至96孔细胞培养板各孔,使用微量移液器吸取2μL步骤3中所述的8个浓度梯度的阳性对照药,加入96孔细胞培养板第一列的8个孔中,为阳性对照组,使用微量移液器吸取2μL无菌DMSO,加入96孔细胞培养板第十二列的8个孔中,为阴性对照组,使用微量移液器吸取2μL待检测化合物溶液,依次加入96孔细胞培养板第二列至第十一列各孔中,使用8道微量移液器移取40μL步骤2中所述的待用菌液,加入96 孔细胞培养板各孔中,将上述96孔细胞培养板置于37℃培养箱,培养16小时后,观察96孔板各孔中的不同菌的生长状况,呈混浊状态的孔中所加的化合物无抗菌活性,呈澄清状态的孔中所加的化合物初步判断具有抗菌活性。将所检测到的各个具有抗菌活性的化合物从1mg/mL的初始浓度依次进行 2倍梯度稀释为1mg/ml,500μg/mL,250μg/mL,125μg/mL,62.5μg/mL,31.25μg/mL,15.625μg/mL, 7.8125μg/mL8个不同浓度的化合物溶液;用同样的方法测定,使用酶标仪读取各孔的吸光值OD600。对于每个化合物,不同菌生长被完全抑制的孔所对应的化合物终浓度(化合物溶液浓度/40)即为该化合物对不同菌株的MIC。
目标化合物的抗菌生物活性数据见表3和表4.
表3.化合物的抗菌活性(MIC,μg/mL)
从表3.可以看出化合物28、106、184、262、340和418对耐甲氧西林金黄色葡萄球菌(MRSA),金黄色葡萄球菌(SA ATCC6538),耐万古霉素肠球菌(VRE-309),枯草杆菌(BSATCC6633)都具有较好的抑制活性。尤其是化合物28和106对耐甲氧西林金黄色葡萄球菌(MRSA,北京朝阳医院分离株),金黄色葡萄球菌(SA ATCC6538),枯草杆菌(BS ATCC6633)的抑制活性与万古霉素相当,对耐万古霉素肠球菌(VRE-309)的抑制活性是万古霉素的10倍以上。28和106对耐甲氧西林金黄色葡萄球菌(MRSA,北京朝阳医院分离株)的抑制活性是甲氧西林的256倍以上,对金黄色葡萄球菌(SA ATCC6538)的抑制活性是甲氧西林的4倍.
表4.部分化合物对不同临床分离的MRSA菌株的生物活性(MIC,μg/mL)
化合物编号 | 309-4 | 6281 | 309-8 | 6-42 | 8-21 | 309-3 | 309-1 | 309-7 | 8-24 | 309-6 | 309-4 |
28 | 0.78 | 1.56 | 1.56 | 0.78 | 0.78 | 1.56 | 0.78 | 0.78 | 1.56 | 1.56 | 0.78 |
106 | 0.78 | 1.56 | 0.78 | 0.78 | 0.78 | 0.78 | 0.78 | 0.78 | 0.78 | 1.56 | 0.78 |
340 | 6.25 | 6.25 | 6.25 | 6.25 | 6.25 | 6.25 | 6.25 | 6.25 | 12.5 | 12.5 | 6.25 |
418 | 12.5 | 12.5 | 12.5 | 12.5 | 12.5 | 12.5 | 12.5 | 12.5 | 12.5 | 12.5 | 12.5 |
万古霉素 | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 |
甲氧西林 | >200 | >200 | >200 | >200 | >200 | >200 | >200 | >200 | >200 | >200 | >200 |
从表4.可以看出化合物28、106、340和418对不同临床分离的耐甲氧西林金黄色葡萄球菌 (MRSA)都具有较好的抑制活性,特别是化合物28和106与万古霉素相当。28、106、340和418对不同临床分离的耐甲氧西林金黄色葡萄球菌(MRSA)抑制活性都远大于甲氧西林(至少16倍),例如,28和106对309-4株的抑制活性是甲氧西林的256倍以上。
Claims (6)
1.一类如下通式I表示的磺酰脲类衍生物:
式中:
R1选自H、卤素、酯基、硝基、氰基、三氟甲基、二氟甲基、一氟甲基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C1-C6烷硫基、卤代C1-C6烷硫基、C1-C6烷氧基羰基、卤代C3-C6环烷基或N,N-(C1-C6烷基)氨基甲酰基;
R2选自H、C1-C6烷氧基羰基、N,N-(C1-C6烷基)氨基甲酰基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C1-C6烷硫基、卤代C1-C6烷硫基、氨基、C1-C6烷基氨基、C1-C6酰胺基、C1-C6磺酰胺基、C1-C6亚胺基、C2-C6烯基、卤代C2-C6烯基、C2-C6炔基、卤代C3-C6环烷基或卤代C2-C6炔基、C2-C6羰基、C2-C6酯基、C2-C6肟基;
R3和R4选自H、F、Cl、CH3、OCH3、OC2H5、OCH2CH2CH3、CF3、OCF3、OCHF2、OCH2CF3、NHCH3、N(CH3)2、SCH3、CH=CHCH3、4-卤素取代苯环、杂环。
2.根据权利要求1所述磺酰脲类衍生物,其特征在于:所述衍生物中的卤素为氟、氯、溴或碘;C1-C6烷基为直链或支链烷基;卤代C1-C6烷基为直链或支链烷基,卤代C1-C6烷基上的氢原子可以部分或全部被卤原子取代;“卤代C2-C6烯基”、“卤代C2-C6炔基”和“卤代C3-C6环烷基”的定义与术语“卤代C1-C6烷基”相同;C2-C6亚胺基为有2-6个碳原子的直链或支链并可在任何位置上存在碳氮双键且为E构型;C2-C6烯基为有2-6个碳原子的直链或支链并可在任何位置上存在碳碳双键且为E构型;C2-C6炔基为有2-6个碳原子的直链或支链并可在任何位置上存在碳碳三键;C2-C6羰基为有2-6个碳原子的直链或支链并可在任何位置上存在有碳氧双键;C2-C6酯基为有2-6个碳原子的直链或支链并可在任何位置上存在有碳氧双键;C2-C6肟基为有2-6个碳原子的直链或支链并可在任何位置上存在碳氮双键且为E构型。
4.一类根据权利要求1-2所述的磺酰脲类衍生物,其特征在于可作为耐甲氧西林金黄色葡萄球菌(MRSA),金黄色葡萄球菌,耐万古霉素肠球菌,枯草杆菌抑制剂的用途,可用作一类抗菌药物。
5.一类抗菌药物,其特征在于它含有权利要求1和2所述的化合物以及一种或多种药学上可接受的载体;所述载体包括药学领域常规的稀释剂、赋形剂、填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、吸附载体、润滑剂或增效剂等。
6.根据权利要求5所述的抗菌药物,其特征在于它是含所述抗菌药物的注射剂、片剂、丸剂、胶囊、悬浮或乳剂等。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110299808.4A CN115108997A (zh) | 2021-03-22 | 2021-03-22 | 一类具抑菌活性的磺酰脲类化合物的合成与应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110299808.4A CN115108997A (zh) | 2021-03-22 | 2021-03-22 | 一类具抑菌活性的磺酰脲类化合物的合成与应用 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN115108997A true CN115108997A (zh) | 2022-09-27 |
Family
ID=83323767
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202110299808.4A Pending CN115108997A (zh) | 2021-03-22 | 2021-03-22 | 一类具抑菌活性的磺酰脲类化合物的合成与应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN115108997A (zh) |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080176846A1 (en) * | 2006-10-20 | 2008-07-24 | Irm Llc | Compositions and methods for modulating c-kit and pdgfr receptors |
WO2010123591A2 (en) * | 2009-01-09 | 2010-10-28 | The Uab Research Foundation | Small molecule inhibitors of nads, namnat, and nmnat |
WO2012074490A1 (en) * | 2010-11-29 | 2012-06-07 | Agency For Science, Technology And Research | Control of bacterial growth |
CN105439970A (zh) * | 2015-10-16 | 2016-03-30 | 南开大学 | 一类可控土壤降解速度的磺酰脲类新结构的发现与应用 |
CN107089953A (zh) * | 2017-05-10 | 2017-08-25 | 南开大学 | 一类土壤降解速度可控的新型绿色磺酰脲类除草剂制备方法与土壤降解的研究和应用 |
CN107698525A (zh) * | 2017-09-27 | 2018-02-16 | 南开大学 | 一类取代苯氧磺酰脲类化合物及其制备方法和用途 |
CN112239429A (zh) * | 2020-09-30 | 2021-01-19 | 南开大学 | 一类土壤降解速度可控的磺酰脲除草剂新结构与新功能的发现与应用 |
-
2021
- 2021-03-22 CN CN202110299808.4A patent/CN115108997A/zh active Pending
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080176846A1 (en) * | 2006-10-20 | 2008-07-24 | Irm Llc | Compositions and methods for modulating c-kit and pdgfr receptors |
WO2010123591A2 (en) * | 2009-01-09 | 2010-10-28 | The Uab Research Foundation | Small molecule inhibitors of nads, namnat, and nmnat |
WO2012074490A1 (en) * | 2010-11-29 | 2012-06-07 | Agency For Science, Technology And Research | Control of bacterial growth |
CN105439970A (zh) * | 2015-10-16 | 2016-03-30 | 南开大学 | 一类可控土壤降解速度的磺酰脲类新结构的发现与应用 |
CN107089953A (zh) * | 2017-05-10 | 2017-08-25 | 南开大学 | 一类土壤降解速度可控的新型绿色磺酰脲类除草剂制备方法与土壤降解的研究和应用 |
CN107698525A (zh) * | 2017-09-27 | 2018-02-16 | 南开大学 | 一类取代苯氧磺酰脲类化合物及其制备方法和用途 |
CN112239429A (zh) * | 2020-09-30 | 2021-01-19 | 南开大学 | 一类土壤降解速度可控的磺酰脲除草剂新结构与新功能的发现与应用 |
Non-Patent Citations (4)
Title |
---|
WEI WEI: ""Design, synthesis and SAR study of novel sulfonylureas containing an alkenyl moiety"", 《ORGANIC & BIOMOLECULAR CHEMISTRY》, no. 14, pages 8356 * |
刘卓;潘里;于淑晶;李正名;: "N-(4\'-芳环取代嘧啶基-2\'-基)-2-乙氧羰基苯磺酰脲衍生物的合成及抑菌活性", 高等学校化学学报, no. 08 * |
席真;牛聪伟;班树荣;李庆霞;欧阳砥;黄明智;: "除草剂靶酶―AHAS酶及基因突变体与除草剂设计(Ⅱ).AHAS及W464突变酶与除草活性分子的相互作用", 农药学学报, no. 04 * |
班树荣;牛聪伟;陈文彬;李青山;席真;: "N-(5’-溴-4’-取代嘧啶-2\'-基)苯磺酰脲化合物的合成和生物活性", 有机化学, no. 04 * |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Liaras et al. | Novel (E)-1-(4-methyl-2-(alkylamino) thiazol-5-yl)-3-arylprop-2-en-1-ones as potent antimicrobial agents | |
JP2005509594A (ja) | Nadシンテターゼ阻害剤およびその使用 | |
Khan et al. | Schiff bases of thiazole as antibacterial and antifungal agents | |
WO2010136804A1 (en) | Pyrimidine derivatives for use as antibiotics | |
CN115108997A (zh) | 一类具抑菌活性的磺酰脲类化合物的合成与应用 | |
KR101764349B1 (ko) | 펩티드 디포밀라제 저해 및 항균 활성을 갖는 신규한 프라비마이신 화합물 | |
CN115385917B (zh) | 一类色胺酮7位或9位取代芳香硫醚衍生物、其制备方法及应用 | |
RU2480471C1 (ru) | Антибактериальные соединения на основе сульфаниловой кислоты и пиридоксина | |
CN101914096A (zh) | 2-取代芳杂环基-1,3-噻唑啉衍生物及其制备方法和应用 | |
CN114099680B (zh) | 一种akt抑制剂iv的应用、革兰氏阳性菌抑制剂及革兰氏阳性菌的体外抑制方法 | |
US8680087B2 (en) | Macrocyclic amides, pharmaceutical compositions, preparation methods and uses thereof | |
CN109111405B (zh) | 一种芳香硫醚类化合物及其农药和医药用途 | |
CN113730414A (zh) | 鸭嘴花碱衍生物在制备抗菌药物中的应用 | |
CN107698525B (zh) | 一类取代苯氧磺酰脲类化合物及其制备方法和用途 | |
CN107880035B (zh) | 一种1,3,4-噻(噁)二唑-吩嗪-1-甲酰胺类化合物的制备方法和应用 | |
CN107056687B (zh) | 含吡啶基团的1,4-戊二烯-3-酮肟酯类化合物、制备方法及用途 | |
Svizhak et al. | Antimicrobial properties of new derivatives of imidazole | |
CN116023338A (zh) | 一类具抑菌剂活性的磺酰脲类化合物的合成及应用 | |
US11932640B1 (en) | Pyrrolo[3,4-b]quinoline compounds as antibacterial agents | |
US11807607B1 (en) | Aminocarbazole compounds as antibacterial agents | |
US11780809B1 (en) | Carbazole compounds as antibacterial agents | |
US11773084B1 (en) | 4-arylamino-2-(6-indolylamino)pyrimidine compounds as antibacterial agents | |
CN110878061B (zh) | 一种2-芳基取代的苯并噁唑啉类化合物及其合成方法与应用 | |
CN114380802B (zh) | 一类含咔唑基咪唑盐类化合物及其制备方法和应用 | |
US11891362B1 (en) | N2,N4-disubstituted pyrimidine-2,4-diamine compounds as antibacterial agents |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
WD01 | Invention patent application deemed withdrawn after publication | ||
WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20220927 |