CN114478474B - Amide compound and preparation method thereof - Google Patents
Amide compound and preparation method thereof Download PDFInfo
- Publication number
- CN114478474B CN114478474B CN202210056304.4A CN202210056304A CN114478474B CN 114478474 B CN114478474 B CN 114478474B CN 202210056304 A CN202210056304 A CN 202210056304A CN 114478474 B CN114478474 B CN 114478474B
- Authority
- CN
- China
- Prior art keywords
- dmso
- nmr
- preparation
- reaction
- amide compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- -1 Amide compound Chemical class 0.000 title claims abstract description 43
- 238000002360 preparation method Methods 0.000 title claims abstract description 41
- 229940084723 FabH inhibitor Drugs 0.000 claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims description 25
- 238000000034 method Methods 0.000 claims description 23
- 150000001875 compounds Chemical class 0.000 claims description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 16
- 150000003141 primary amines Chemical class 0.000 claims description 10
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 9
- BNBQRQQYDMDJAH-UHFFFAOYSA-N benzodioxan Chemical compound C1=CC=C2OCCOC2=C1 BNBQRQQYDMDJAH-UHFFFAOYSA-N 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims description 7
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 7
- 239000012286 potassium permanganate Substances 0.000 claims description 7
- OVJPXFCIFGZPEE-UHFFFAOYSA-N benzaldehyde;1,4-dioxane Chemical compound C1COCCO1.O=CC1=CC=CC=C1 OVJPXFCIFGZPEE-UHFFFAOYSA-N 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- JYTHNNWTAZPKPW-UHFFFAOYSA-N 7-methyl-1h-indazol-3-amine Chemical compound CC1=CC=CC2=C1NN=C2N JYTHNNWTAZPKPW-UHFFFAOYSA-N 0.000 claims description 3
- PRDBLLIPPDOICK-UHFFFAOYSA-N [4-(trifluoromethyl)phenyl]methanamine Chemical compound NCC1=CC=C(C(F)(F)F)C=C1 PRDBLLIPPDOICK-UHFFFAOYSA-N 0.000 claims description 3
- IOQPZZOEVPZRBK-UHFFFAOYSA-N octan-1-amine Chemical compound CCCCCCCCN IOQPZZOEVPZRBK-UHFFFAOYSA-N 0.000 claims description 3
- CCAZAGUSBMVSAR-UHFFFAOYSA-N (4-phenoxyphenyl)methanamine Chemical compound C1=CC(CN)=CC=C1OC1=CC=CC=C1 CCAZAGUSBMVSAR-UHFFFAOYSA-N 0.000 claims description 2
- FJLUATLTXUNBOT-UHFFFAOYSA-N 1-Hexadecylamine Chemical compound CCCCCCCCCCCCCCCCN FJLUATLTXUNBOT-UHFFFAOYSA-N 0.000 claims description 2
- WKBALTUBRZPIPZ-UHFFFAOYSA-N 2,6-di(propan-2-yl)aniline Chemical compound CC(C)C1=CC=CC(C(C)C)=C1N WKBALTUBRZPIPZ-UHFFFAOYSA-N 0.000 claims description 2
- YBAGMTVKDRIMTB-UHFFFAOYSA-N 2-bromo-4-methoxyaniline Chemical compound COC1=CC=C(N)C(Br)=C1 YBAGMTVKDRIMTB-UHFFFAOYSA-N 0.000 claims description 2
- XAACOEWSHBIFGJ-UHFFFAOYSA-N 4-fluoro-3-methoxyaniline Chemical compound COC1=CC(N)=CC=C1F XAACOEWSHBIFGJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- 235000010233 benzoic acid Nutrition 0.000 claims description 2
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims description 2
- WIVYTYZCVWHWSH-UHFFFAOYSA-N tert-butyl n-(4-aminophenyl)carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=C(N)C=C1 WIVYTYZCVWHWSH-UHFFFAOYSA-N 0.000 claims description 2
- JRBPAEWTRLWTQC-UHFFFAOYSA-N dodecylamine Chemical compound CCCCCCCCCCCCN JRBPAEWTRLWTQC-UHFFFAOYSA-N 0.000 claims 1
- SLFVYFOEHHLHDW-UHFFFAOYSA-N n-(trifluoromethyl)aniline Chemical compound FC(F)(F)NC1=CC=CC=C1 SLFVYFOEHHLHDW-UHFFFAOYSA-N 0.000 claims 1
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 15
- 230000002401 inhibitory effect Effects 0.000 abstract description 8
- 241000894006 Bacteria Species 0.000 abstract description 7
- 125000000623 heterocyclic group Chemical group 0.000 abstract description 6
- 125000000217 alkyl group Chemical group 0.000 abstract description 5
- 239000003242 anti bacterial agent Substances 0.000 abstract description 5
- TVEXGJYMHHTVKP-UHFFFAOYSA-N 6-oxabicyclo[3.2.1]oct-3-en-7-one Chemical compound C1C2C(=O)OC1C=CC2 TVEXGJYMHHTVKP-UHFFFAOYSA-N 0.000 abstract description 3
- 206010018910 Haemolysis Diseases 0.000 abstract description 3
- 230000008588 hemolysis Effects 0.000 abstract description 3
- 231100000053 low toxicity Toxicity 0.000 abstract description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 61
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 33
- 239000007787 solid Substances 0.000 description 30
- 238000002474 experimental method Methods 0.000 description 19
- 108090000623 proteins and genes Proteins 0.000 description 19
- 235000018102 proteins Nutrition 0.000 description 18
- 102000004169 proteins and genes Human genes 0.000 description 18
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical class NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 12
- 241000588724 Escherichia coli Species 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- 125000001183 hydrocarbyl group Chemical group 0.000 description 10
- 239000003112 inhibitor Substances 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 9
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 150000001408 amides Chemical class 0.000 description 8
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 238000003032 molecular docking Methods 0.000 description 7
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- 229910052736 halogen Inorganic materials 0.000 description 6
- 150000002367 halogens Chemical group 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
- 125000001033 ether group Chemical group 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 239000007983 Tris buffer Substances 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 230000003115 biocidal effect Effects 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 4
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 4
- 125000000524 functional group Chemical group 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- RZXMPPFPUUCRFN-UHFFFAOYSA-N p-toluidine Chemical compound CC1=CC=C(N)C=C1 RZXMPPFPUUCRFN-UHFFFAOYSA-N 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 4
- 206010059866 Drug resistance Diseases 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 125000003368 amide group Chemical group 0.000 description 3
- 150000001448 anilines Chemical class 0.000 description 3
- 229940124350 antibacterial drug Drugs 0.000 description 3
- 229940088710 antibiotic agent Drugs 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000004136 fatty acid synthesis Effects 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 230000002209 hydrophobic effect Effects 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- IDPURXSQCKYKIJ-UHFFFAOYSA-N 1-(4-methoxyphenyl)methanamine Chemical compound COC1=CC=C(CN)C=C1 IDPURXSQCKYKIJ-UHFFFAOYSA-N 0.000 description 2
- RUFPHBVGCFYCNW-UHFFFAOYSA-N 1-naphthylamine Chemical compound C1=CC=C2C(N)=CC=CC2=C1 RUFPHBVGCFYCNW-UHFFFAOYSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 2
- KDSNLYIMUZNERS-UHFFFAOYSA-N 2-methylpropanamine Chemical compound CC(C)CN KDSNLYIMUZNERS-UHFFFAOYSA-N 0.000 description 2
- DOLQYFPDPKPQSS-UHFFFAOYSA-N 3,4-dimethylaniline Chemical compound CC1=CC=C(N)C=C1C DOLQYFPDPKPQSS-UHFFFAOYSA-N 0.000 description 2
- QZVQQUVWFIZUBQ-UHFFFAOYSA-N 3-fluoroaniline Chemical compound NC1=CC=CC(F)=C1 QZVQQUVWFIZUBQ-UHFFFAOYSA-N 0.000 description 2
- MAXBVGJEFDMHNV-UHFFFAOYSA-N 5-chloropyridin-2-amine Chemical compound NC1=CC=C(Cl)C=N1 MAXBVGJEFDMHNV-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- AFBPFSWMIHJQDM-UHFFFAOYSA-N N-methyl-N-phenylamine Natural products CNC1=CC=CC=C1 AFBPFSWMIHJQDM-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- ZSLZBFCDCINBPY-ZSJPKINUSA-N acetyl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 ZSLZBFCDCINBPY-ZSJPKINUSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 150000001413 amino acids Chemical group 0.000 description 2
- 230000000845 anti-microbial effect Effects 0.000 description 2
- 230000002155 anti-virotic effect Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 150000001491 aromatic compounds Chemical class 0.000 description 2
- 208000022362 bacterial infectious disease Diseases 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- SQNZJJAZBFDUTD-UHFFFAOYSA-N durene Chemical compound CC1=CC(C)=C(C)C=C1C SQNZJJAZBFDUTD-UHFFFAOYSA-N 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 230000002949 hemolytic effect Effects 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 239000006994 mh medium Substances 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000004088 simulation Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- BMVXCPBXGZKUPN-UHFFFAOYSA-N 1-hexanamine Chemical compound CCCCCCN BMVXCPBXGZKUPN-UHFFFAOYSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- FTZQXOJYPFINKJ-UHFFFAOYSA-N 2-fluoroaniline Chemical compound NC1=CC=CC=C1F FTZQXOJYPFINKJ-UHFFFAOYSA-N 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
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- JBIJLHTVPXGSAM-UHFFFAOYSA-N 2-naphthylamine Chemical compound C1=CC=CC2=CC(N)=CC=C21 JBIJLHTVPXGSAM-UHFFFAOYSA-N 0.000 description 1
- SBXDENYROQKXBE-UHFFFAOYSA-N 2-phenylbenzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1C1=CC=CC=C1 SBXDENYROQKXBE-UHFFFAOYSA-N 0.000 description 1
- XEFRNCLPPFDWAC-UHFFFAOYSA-N 3,4,5-trimethoxyaniline Chemical compound COC1=CC(N)=CC(OC)=C1OC XEFRNCLPPFDWAC-UHFFFAOYSA-N 0.000 description 1
- 125000005809 3,4,5-trimethoxyphenyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 description 1
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 1
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- ODGIMMLDVSWADK-UHFFFAOYSA-N 4-trifluoromethylaniline Chemical compound NC1=CC=C(C(F)(F)F)C=C1 ODGIMMLDVSWADK-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 101710146995 Acyl carrier protein Proteins 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- MVVPIAAVGAWJNQ-DOFZRALJSA-N Arachidonoyl dopamine Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(=O)NCCC1=CC=C(O)C(O)=C1 MVVPIAAVGAWJNQ-DOFZRALJSA-N 0.000 description 1
- 244000063299 Bacillus subtilis Species 0.000 description 1
- 235000014469 Bacillus subtilis Nutrition 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 102000011802 Beta-ketoacyl synthases Human genes 0.000 description 1
- 108050002233 Beta-ketoacyl synthases Proteins 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 239000004593 Epoxy Substances 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
- 208000019331 Foodborne disease Diseases 0.000 description 1
- 206010018612 Gonorrhoea Diseases 0.000 description 1
- 102000003960 Ligases Human genes 0.000 description 1
- 108090000364 Ligases Proteins 0.000 description 1
- 231100000002 MTT assay Toxicity 0.000 description 1
- 238000000134 MTT assay Methods 0.000 description 1
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 1
- ACFIXJIJDZMPPO-NNYOXOHSSA-N NADPH Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@@H](OP(O)(O)=O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 ACFIXJIJDZMPPO-NNYOXOHSSA-N 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 241000589540 Pseudomonas fluorescens Species 0.000 description 1
- 239000012614 Q-Sepharose Substances 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 235000015278 beef Nutrition 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- XMQFTWRPUQYINF-UHFFFAOYSA-N bensulfuron-methyl Chemical compound COC(=O)C1=CC=CC=C1CS(=O)(=O)NC(=O)NC1=NC(OC)=CC(OC)=N1 XMQFTWRPUQYINF-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 150000003939 benzylamines Chemical class 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 108010079058 casein hydrolysate Proteins 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 238000011210 chromatographic step Methods 0.000 description 1
- 238000011281 clinical therapy Methods 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 229940126086 compound 21 Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 238000007824 enzymatic assay Methods 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- DDRPCXLAQZKBJP-UHFFFAOYSA-N furfurylamine Chemical compound NCC1=CC=CO1 DDRPCXLAQZKBJP-UHFFFAOYSA-N 0.000 description 1
- 208000001786 gonorrhea Diseases 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 229910052588 hydroxylapatite Inorganic materials 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- XMSZANIMCDLNKA-UHFFFAOYSA-N methyl hypofluorite Chemical compound COF XMSZANIMCDLNKA-UHFFFAOYSA-N 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- BHAAPTBBJKJZER-UHFFFAOYSA-N p-anisidine Chemical compound COC1=CC=C(N)C=C1 BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 208000013223 septicemia Diseases 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 238000009333 weeding Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D321/00—Heterocyclic compounds containing rings having two oxygen atoms as the only ring hetero atoms, not provided for by groups C07D317/00 - C07D319/00
- C07D321/02—Seven-membered rings
- C07D321/10—Seven-membered rings condensed with carbocyclic rings or ring systems
-
- 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
-
- 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
- C07D405/12—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 linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
An amide compound and a preparation method thereof, wherein the amide compound has a structural formula shown in a formula I:
a formula I; wherein R represents C 1 ～C 16 Alkyl, C 6 ～C 15 Aromatic radicals, C 4 ～C 7 One of the heterocycles. The anti-bacterial agent has a large binding energy with FabH, can be used as an FabH inhibitor for inhibiting the growth of bacteria, and has the advantages of good antibacterial activity, low toxicity, low hemolysis and the like.
Description
Technical Field
The application relates to an amide compound and a preparation method thereof, and belongs to the field of chemical synthesis.
Background
Antibacterial drugs (antibiotics and synthetic antibacterial drugs) are powerful weapons for humans to fight against various serious bacterial infectious diseases, but microorganisms gradually develop resistance to antibiotics used for a long time, and become one of the major threats of global sanitation, food safety and development. The latest release of the "global antimicrobial resistance monitoring system" (GLASS) by WHO shows that antibiotic resistance is widespread among 50 ten thousand suspected bacterial infections in 22 countries. The increasing worldwide antibiotic resistance makes more and more infections (such as pneumonia, tuberculosis, septicemia, gonorrhea and food-borne diseases) difficult to treat, even without drugs. Thus, there is an urgent need for clinical therapies to develop drugs with novel antibacterial mechanisms to combat existing drug resistance patterns.
Fatty acid synthesis (Fatty Acid Biosynthesis, FAS) is an important component of cellular biofilms and the like, is a vital stone of all life, and is essential in organisms. The antibacterial effect is realized by regulating the activities of some key enzymes and proteins in the fatty acid synthesis pathway, and the method is an effective way for developing novel antibacterial drugs. The beta-ketoacyl-ACP synthetase (beta-ketoacyl synthase, KAS) is the initial step of the reaction, plays a key regulation role in fatty acid synthesis, and has specificity of a substrate, and the general substrate is acyl-coa. FabH shows high conservation in the gene sequences and three-dimensional structures of gram-positive and gram-negative bacteria, whereas no homologous proteins can be found in humans. So that the small molecular inhibitor for inhibiting the activity of the FabH enzyme is expected to be a broad-spectrum antibacterial agent which has selectivity to bacteria and is nontoxic to human bodies.
Acyl groups are based on compounds linked by nitrogen atoms, known as amides, which are a class of carboxylic acid derivatives containing nitrogen. The amide compound has important value in life and production, has wide application, and has wide application in medicine, pesticide, industry, organic synthesis, perfume, dye, plastic, light spinning and other industries. Among agricultural chemicals, the amide derivative has wide biological activities such as antibiosis, disinsection, weeding, antivirus and the like, and in the medical field, the amide derivative has biological activities such as bacteriostasis, sterilization, anti-tumor and antivirus, has good antibacterial activity and broad antibacterial spectrum, is not easy to generate drug resistance, and has good application value.
Disclosure of Invention
The invention provides an amide compound and a preparation method thereof, which aim to solve the problem that microorganisms gradually generate drug resistance to antibiotics used for a long time. The compound is designed by using a computer-aided drug design method, has larger binding energy with FabH detected by a molecular docking method, can be used as a FabH inhibitor, and has the advantages of better antibacterial activity, low toxicity, low hemolysis and the like.
According to one aspect of the present application, an amide compound is provided.
An amide compound having the structural formula of formula i:
wherein R represents C 1 ～C 16 Alkyl, C 6 ～C 15 Aromatic radicals, C 4 ～C 7 One of the heterocycles.
Alternatively, wherein R represents C 6 ～C 16 An alkyl group.
Optionally, the C 6 ～C 15 The aromatic group being selected from at least one H in the aromatic ring being R 1 Substitution of the groups formed;
wherein R is 1 Selected from hydrogen, hydrocarbyl, substituted hydrocarbyl, non-hydrocarbyl;
preferably, the hydrocarbyl group is selected from C 1 ～C 8 Is a hydrocarbon group of (2);
preferably, the substituted hydrocarbyl group is a halogen substituted C 1 ～C 3 Alkyl of (a);
preferably, the non-hydrocarbon group is selected from one or more of halogen, phenoxy, phenyl, diaza.
Alternatively, the non-hydrocarbon group is selected from an ether group or a functional group containing an ether group;
wherein the ether group is selected from C 1 ～C 4 An ether group of (a);
wherein the functional group containing an ether group has a carbon number of C 1 ～C 6 。
Alternatively, the non-hydrocarbon group is selected from an amide group or a functional group containing an amide group;
wherein the functional group containing an amide group is C 1 ～C 6 Alkoxy groups of (a).
Optionally, the C 4 ～C 7 The heterocyclic ring being selected from C 4 ～C 7 Nitrogen heterocycle, C 4 ～C 7 Oxygen heterocycle, C 4 ～C 7 One of the sulfur heterocycles;
wherein the C 4 ～C 7 The heterocyclic ring being selected from at least one H in the ring being R 2 Substitution of the groups formed;
wherein R is 2 Selected from halogen, C 1 ～C 6 One or more of the alkyl groups.
Alternatively, the structural formula of the compound represented by formula I is selected from the following compounds:
the amide compound according to claim 1, wherein the structural formula of the compound represented by formula I is selected from the group consisting of:
according to a second aspect of the present application, there is provided a method for producing an amide-based compound.
The process for preparing an amide compound according to any one of the preceding claims, comprising the steps of:
(S1) reacting a mixture containing benzaldehyde and dioxane, potassium permanganate and water to obtain the benzoic acid and dioxane;
(S2) adding primary amine into a mixture containing benzodioxan, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, 1-hydroxybenzotriazole and methylene dichloride after a reaction II, and obtaining an amide compound after a reaction III;
the primary amine has the structural formula of R-NH 2 。
Alternatively, the molar ratio of potassium permanganate to benzaldehyde dioxane is 1.2:1-2:1.
Preferably, the molar ratio of potassium permanganate to benzaldehyde dioxane is 1.3:1-1.5:1.
Alternatively, the process may be carried out in a single-stage,
in reaction I:
reaction temperature: 50-80 ℃;
reaction time: 8-24 h.
Optionally, the primary amine is selected from one of fatty amine, substituted aniline, benzyl amine and nitrogen heterocyclic primary amine.
Optionally, the fatty amine is at least one selected from n-butylamine, n-octylamine and cyclohexylamine.
Optionally, the substituted aniline is at least one selected from aniline, p-toluidine and 3-fluoroaniline.
Optionally, the benzylamine is selected from at least one of benzylamine, 4-methoxybenzylamine, 4- (trifluoromethyl) benzylamine.
Optionally, the primary azacyclic amine is selected from at least one of 2-amino-5-chloropyridine, 3-amino-7-methyl-1H-indazole.
Alternatively, the molar ratio of benzodioxan, primary amine, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 1-hydroxybenzotriazole is 1:1-2:1-2.
Preferably, the molar ratio of the benzodioxan, the primary amine, the 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and the 1-hydroxybenzotriazole is 1:1.2-1.5:1.2-1.5.
Alternatively, the process may be carried out in a single-stage,
in reaction II:
reaction temperature: 60-80 ℃;
reaction time: and 5-10 h.
Alternatively, the process may be carried out in a single-stage,
in reaction III:
reaction temperature: 25-50 ℃;
reaction time: and 6-24 hours.
As a specific embodiment, the preparation method of the amide compound comprises the following steps:
in a 25ml dry round bottom flask was added benzodioxan (194 mg,1.0 mmol), HOBT (1.1 eq), EDC.HCl (1.1 eq) dissolved in 4ml dichloromethane and stirred at room temperature for 15 minutes then n-butylamine (80.3 mg,1.1 mmol) was added and stirring continued for 8 hours. After the reaction was stopped, the mixture was filtered through celite, and extracted three times with water and dichloromethane. The organic layer is Na 2 SO 4 Drying, extracting solvent from the dried organic layer, and purifying by column chromatography to obtain phaseThe product should be obtained.
According to a third aspect of the present application there is provided the use of an amide compound.
The application of the compound and/or the amide compound prepared by the preparation method in the preparation of the FaBH inhibitor.
In the present application edc.hcl means 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride; hoBt refers to 1-hydroxybenzotriazole.
In the present application, C 1 ～C 6 、C 4 ～C 7 And the like refer to the number of carbon atoms contained in the group.
In the present application, the term "hydrocarbyl" refers to a group formed by the loss of any one hydrogen atom from a hydrocarbon compound molecule; the hydrocarbon compounds include alkane compounds, alkene compounds, alkyne compounds, and aromatic compounds, such as p-tolyl groups formed by toluene losing a hydrogen atom at the para-position of the methyl group on the benzene ring, benzyl groups formed by toluene losing any one of the hydrogen atoms on the methyl group, and the like.
In the present application, the term "alkyl" refers to a group formed by the loss of any one hydrogen atom from an alkane compound molecule.
In the present application, the term "aromatic group" refers to a group formed by the removal of one hydrogen atom on an aromatic ring from an aromatic compound molecule; for example, toluene loses p-tolyl group formed by the hydrogen atom at the para-position of the methyl group on the benzene ring.
In the present application, the term "halogen" refers to at least one of fluorine, chlorine, bromine, iodine.
In the present application, the term "non-hydrocarbon substituent" means a group formed by losing any one hydrogen atom of a compound containing other elements than H and C (for example, halogen, S, O, P, N, etc.), for example, alkoxy, halogen, ether, amide, phenoxy, phenyl, diaza, etc.
In the present application, the term "heterocycle" refers to a group formed by losing any one of hydrogen atoms from an organic compound having a heterocyclic structure in a molecule, and atoms constituting the ring contain at least one hetero atom including nitrogen atom, sulfur atom and oxygen atom in addition to carbon atom.
The beneficial effects that this application can produce include:
the amide compound provided by the application has larger binding energy with FabH, can be used as a FabH inhibitor for inhibiting the growth of bacteria, and has the advantages of better antibacterial activity, low toxicity, low hemolysis and the like.
Drawings
FIG. 1 is a molecular docking simulation of E.coli FabH enzyme from example 19, wherein a and b are graphs of 3D and 2D modes of action of inhibitor in protein crystals (biphenyl sulfonamide) and FabH protein (PDB: 5 bnm), respectively, and FIGS. c and D are graphs of 3D and 2D modes of docking of compound 19 and FabH, respectively, and e is a comparison of 2 inhibitors in protein pockets.
Detailed Description
The present application is described in detail below with reference to examples, but the present application is not limited to these examples.
Unless otherwise indicated, both the starting materials and the catalysts in the examples of the present application were purchased commercially. Wherein:
benzaldehyde dioxane was from Shanghai Ala Biochemical technologies Co.
Edc.hcl was obtained from the biochemical sciences company of aladine, shanghai.
HoBt is available from Shanghai Ala Biochemical technologies Co.
All types of primary amines are available from Shanghai Ala Biochemical technologies Inc.
The instrument for nuclear magnetic testing was Bruker DPX 400, and the test conditions were room temperature.
The instrument for mass spectrometry was a Mariner System 5304 mass spectrometer.
Example 1
The preparation of N-butyl-3, 4-dihydro-2H-benzo [1,4] dioxepane-7-carboxamide is as follows:
benzaldehyde dioxane (1.085 g,6.1 mmol) was dissolved in 25ml of water, an aqueous solution of potassium permanganate (1.384g,8.4mmol in 30mL) was slowly added dropwise thereto at room temperature, the reaction was warmed to 70 ℃ after completion of the dropwise addition, stirring was continued for 5 hours, cooling to room temperature, then an aqueous solution of 10% koh was added to quench the reaction, and a solid was precipitated, filtered and repeatedly washed with water. The collected solid was acidified with 12M HCl, and the solid was filtered and dried to give pure benzodioxan.
In a 25ml dry round bottom flask was added benzodioxan (194 mg,1.0 mmol), HOBT (1.1 eq), EDC.HCl (1.1 eq) dissolved in 4ml dichloromethane and stirred at room temperature for 15 minutes then n-butylamine (80.3 mg,1.1 mmol) was added and stirring continued for 8 hours. After the reaction was stopped, the mixture was filtered through celite, and extracted three times with water and dichloromethane. The organic layer is Na 2 SO 4 Drying, extracting solvent from the dried organic layer, and purifying by column chromatography to obtain the corresponding product.
Example 2
The preparation of N-hexyl-3, 4-dihydro-2H-benzo [1,4] dioxepane-7-carboxamide is as follows: n-butylamine was replaced by n-hexylamine, and the other experimental procedures were the same as in example 1.
Example 3
The preparation of N-unfortunately-3, 4-dihydro-2H-benzo [1,4] dioxepane-7-carboxamide is as follows:
n-butylamine was replaced by n-octylamine and the other experimental procedures were as in example 1.
Example 4
The preparation of N-dodecyl-3, 4-dihydro-2H-benzo [1,4] dioxepane-7-carboxamide is as follows:
the procedure of example 1 was followed except that n-butylamine was changed to dodecylprimary amine.
Example 5
The preparation of N-hexadecyl-3, 4-dihydro-2H-benzo [1,4] dioxepane-7-carboxamide is as follows:
n-butylamine was replaced by hexadecylamine and the other experimental procedure was as in example 1.
Example 6
The preparation of N-isobutyl-3, 4-dihydro-2H-benzo [1,4] dioxepane-7-carboxamide is as follows:
the procedure of example 1 was followed except that n-butylamine was changed to isobutylamine.
Example 7
The preparation of N- (tert-butyl) -3, 4-dihydro-2H-benzo [1,4] dioxepane-7-carboxamide is as follows:
the procedure of example 1 was followed except that n-butylamine was changed to t-butylamine.
Example 8
The preparation of N-cyclohexyl-3, 4-dihydro-2H-benzo [1,4] dioxepane-7-carboxamide is as follows:
the procedure of example 1 was followed except that n-butylamine was changed to cyclohexylamine.
Example 9
The preparation of N-phenyl-3, 4-dihydro-2H-benzo [1,4] dioxepane-7-carboxamide is as follows:
the procedure of example 1 was followed except that n-butylamine was changed to aniline.
Example 10
The preparation of N- (p-tolyl) -3, 4-dihydro-2H-benzo [1,4] dioxepane-7-carboxamide is as follows:
n-butylamine was changed to p-toluidine and the other experimental procedure was as in example 1.
Example 11
The preparation of N- (3, 4-dimethylphenyl) -3, 4-dihydro-2H-benzo [1,4] dioxepane-7-carboxamide is as follows:
the procedure of example 1 was followed except that n-butylamine was changed to 3, 4-dimethylaniline.
Example 12
The preparation of N-methylene-3, 4-dihydro-2H-benzo [1,4] dioxepane-7-carboxamide is as follows:
n-butylamine was changed to durene and the other experimental procedure was as in example 1.
Example 13
The preparation of N- (2, 6-diisopropylphenyl) -3, 4-dihydro-2H-benzo [1,4] dioxepane-7-carboxamide is as follows:
the procedure of example 1 was followed except that n-butylamine was changed to 2, 6-diisopropylaniline.
Example 14
The preparation of N- (3-fluorophenyl) -3, 4-dihydro-2H-benzo [1,4] dioxepane-7-carboxamide is as follows:
the procedure of example 1 was followed except that n-butylamine was changed to 3-fluoroaniline.
Example 15
The preparation of N- (2-fluorophenyl) -3, 4-dihydro-2H-benzo [1,4] dioxepane-7-carboxamide is as follows:
the procedure of example 1 was followed except that n-butylamine was changed to 2-fluoroaniline.
Example 16
The preparation of N- (4- (trifluoromethyl) phenyl) -3, 4-dihydro-2H-benzo [1,4] dioxepane-7-carboxamide is as follows:
n-butylamine was changed to p-trifluoromethylaniline and the other experimental procedure was as in example 1.
Example 17
The preparation of N- (4-methoxyphenyl) -3, 4-dihydro-2H-benzo [1,4] dioxepane-7-carboxamide is as follows:
n-butylamine was changed to p-aminoanisole, and the other experimental procedures were the same as in example 1.
Example 18
The preparation of N- (2-fluoro-4-methoxyphenyl) -3, 4-dihydro-2H-benzo [1,4] dioxepane-7-carboxamide is as follows:
n-butylamine was changed to 4-methoxy-2-fluoroaniline and the other experimental procedure was as in example 1.
Example 19
The preparation of N- (2-bromo-4-methoxyphenyl) -3, 4-dihydro-2H-benzo [1,4] dioxepane-7-carboxamide is as follows:
n-butylamine was changed to 2-bromo-4-methoxyaniline and the other experimental procedures were the same as in example 1.
Example 20
The preparation of N- (3, 4, 5-trimethoxyphenyl) -3, 4-dihydro-2H-benzo [1,4] dioxepane-7-carboxamide is as follows:
n-butylamine was changed to 3,4, 5-trimethoxyaniline and the other experimental procedures were the same as in example 1.
Example 21
The preparation of tert-butyl (4- (3, 4 dihydro-2H-benzo [1,4] dioxepane-7-carboxamido) phenyl) carbamate is as follows:
n-butylamine was changed to tert-butyl-4-aminophenylcarbamate and the other experimental procedure was as in example 1.
Example 22
The preparation of N- (5-chloropyridin-2-yl) -3, 4-dihydro-2H-benzo [1,4] dioxepane-7-carboxamide is as follows:
n-butylamine was changed to 2-amino-5-chloropyridine and the other experimental procedure was as in example 1.
Example 23
N- (7-methyl-1H-indazol-3-yl) -3, 4-dihydro-2H-benzo [1,4] dioxepane-7-carboxamide is prepared as follows:
n-butylamine was changed to 3-amino-7-methyl-1H-indazole and the other experimental procedure was as in example 1.
Example 24
The preparation of N- (naphthalen-2-yl) -3, 4-dihydro-2H-benzo [1,4] dioxepane-7-carboxamide is as follows:
n-butylamine was changed to 2-naphthylamine and the other experimental procedures were the same as in example 1.
Example 25
The preparation of N- (naphthalen-1-yl) -3, 4-dihydro-2H-benzo [1,4] dioxepane-7-carboxamide is as follows:
n-butylamine was changed to 1-naphthylamine and the other experimental procedures were the same as in example 1.
Example 26
The preparation of N-benzyl-3, 4-dihydro-2H-benzo [1,4] dioxepane-7-carboxamide is as follows:
the procedure of example 1 was followed except that n-butylamine was changed to benzylamine.
Example 27
The preparation of N- (4-methoxybenzyl) -3, 4-dihydro-2H-benzo [1,4] dioxepane-7-carboxamide is as follows:
n-butylamine was replaced by 4-methoxybenzylamine and the other experimental procedures were as in example 1.
Example 28
The preparation of N- (1-phenethyl) -3, 4-dihydro-2H-benzo [1,4] dioxepane-7-carboxamide is as follows:
the procedure of example 1 was repeated except that n-butylamine was changed to (+ -) -A-methylbenzylamine.
Example 29
The preparation of N- (4- (trifluoromethyl) benzyl) -3, 4-dihydro-2H-benzo [1,4] dioxepane-7-carboxamide is as follows:
n-butylamine was changed to 4- (trifluoromethyl) benzylamine and the other experimental procedure was as in example 1.
Example 30
The preparation of N- (furan-2-ylmethyl) -3, 4-dihydro-2H-benzo [1,4] dioxepan-7-carboxamide is as follows:
n-butylamine was changed to 2-furanmethylamine and the other experimental procedure was as in example 1.
Example 31
The preparation of N- (4-phenoxybenzyl) -3, 4-dihydro-2H-benzo [1,4] dioxepane-7-carboxamide is as follows:
the procedure of example 1 was followed except that n-butylamine was changed to 4-phenoxybenzylamine.
Analytical example 1 structural characterization of Compounds
Example 1: white solid. Yield: 89%. 1 H NMR(400MHz,DMSO-d 6 )δ8.29(t,J＝5.7Hz,1H),7.55–7.38(m,2H),6.99(d,J＝8.2Hz,1H),4.16(dt,J＝7.9,5.5Hz,4H),3.21(td,J＝7.0,5.5Hz,2H),2.12(p,J＝5.6Hz,2H),1.47(ddd,J＝12.5,8.4,6.6Hz,2H),1.39–1.21(m,2H),0.88(t,J＝7.3Hz,3H). 13 C NMR(151MHz,DMSO-d 6 )δ165.44,153.69,150.76,130.24,123.01,121.57,121.09,70.89,70.84,39.28,31.70,31.62,20.10,14.18.MS(ESI):m/z 250.2[M+H] + 。
Example 2: colorless oil. The yield was 80%. 1 H NMR(400MHz,DMSO-d 6 )δ8.29(t,J＝5.7Hz,1H),7.53–7.35(m,2H),6.99(d,J＝8.3Hz,1H),4.16(dt,J＝7.8,5.5Hz,4H),3.20(td,J＝7.1,5.7Hz,2H),2.12(p,J＝5.6Hz,2H),1.48(t,J＝7.1Hz,2H),1.27(tt,J＝8.6,5.4Hz,7H),0.92–0.76(m,3H). 13 C NMR(151MHz,DMSO-d 6 )δ165.41,153.68,150.76,130.24,123.00,121.57,121.08,70.89,70.84,31.62,31.49,29.54,26.62,22.53,14.39.MS(ESI):m/z 278.3[M+H] + 。
Example 3: pale yellow solid. Yield 90%. 1 H NMR(400MHz,DMSO-d 6 )δ8.29(s,1H),7.53–7.33(m,2H),6.99(d,J＝8.2Hz,1H),4.16(dt,J＝7.9,5.5Hz,4H),3.19(q,J＝6.6Hz,2H),2.19–2.03(m,2H),1.48(t,J＝7.0Hz,2H),1.35–1.13(m,10H),0.94–0.77(m,3H). 13 C NMR(151MHz,DMSO-d 6 )δ165.41,153.69,150.76,130.24,123.00,121.58,121.08,70.90,70.85,31.72,31.62,29.55,29.21,29.13,26.94,22.56,14.43.MS(ESI):m/z306.1[M+H] + 。
Example 4: white solid. The yield thereof was found to be 78%. 1 H NMR(400MHz,DMSO-d 6 )δ8.30(t,J＝5.6Hz,1H),7.50–7.37(m,2H),6.99(d,J＝8.2Hz,1H),4.17(dt,J＝8.2,5.5Hz,4H),3.20(q,J＝6.6Hz,2H),2.13(t,J＝5.6Hz,2H),1.48(t,J＝6.9Hz,2H),1.24(d,J＝6.0Hz,18H),0.91–0.73(m,3H). 13 C NMR(101MHz,DMSO-d 6 )δ165.41,153.68,150.76,130.24,123.00,121.57,121.08,70.89,70.84,31.77,31.62,29.54,29.52,29.49,29.47,29.23,29.18,26.92,22.57,14.43.MS(ESI):m/z 362.4[M+H] + 。
Example 5: white solid. The yield thereof was found to be 83%. 1 H NMR(400MHz,DMSO-d 6 )δ8.30(t,J＝5.6Hz,1H),7.52–7.37(m,2H),6.99(d,J＝8.2Hz,1H),4.16(dt,J＝8.1,5.5Hz,4H),3.19(q,J＝6.6Hz,2H),2.13(t,J＝5.5Hz,2H),1.48(t,J＝7.0Hz,2H),1.23(s,24H),0.85(t,J＝6.6Hz,3H). 13 C NMR(101MHz,DMSO-d 6 )δ165.40,153.68,150.76,130.24,122.99,121.57,121.08,70.89,70.84,31.76,31.62,29.54,29.50,29.48,29.45,29.23,29.17,26.92,22.57,14.43.MS(ESI):m/z 418.6[M+H] + 。
Example 6: white solid. The yield thereof was found to be 91%. 1 H NMR(400MHz,DMSO-d 6 )δ8.32(t,J＝5.8Hz,1H),7.52–7.38(m,2H),6.99(d,J＝8.3Hz,1H),4.17(dt,J＝7.5,5.4Hz,4H),3.03(dd,J＝7.0,5.8Hz,2H),2.21–2.03(m,2H),1.81(dt,J＝13.5,6.8Hz,1H),0.86(d,J＝6.7Hz,6H). 13 C NMR(151MHz,DMSO-d 6 )δ165.60,153.70,150.77,130.28,123.06,121.58,121.12,70.90,70.85,47.15,31.62,28.54,20.67.MS(ESI):m/z 250.3[M+H] + 。
Example 7: yellow solid. The yield was 89%. 1 H NMR(400MHz,DMSO-d 6 )δ7.61(s,1H),7.45(d,J＝2.2Hz,1H),7.41(dd,J＝8.3,2.3Hz,1H),6.96(d,J＝8.3Hz,1H),4.15(dt,J＝7.2,5.5Hz,4H),2.18–2.05(m,2H),1.35(s,9H). 13 C NMR(151MHz,DMSO-d 6 )δ165.56,153.55,150.62,131.34,123.25,121.36,121.34,70.91,70.89,51.16,31.68,29.07.MS(ESI):m/z 250.2[M+H] + 。
Example 8: white solid. The yield was 85%. 1 H NMR(400MHz,DMSO-d 6 )δ8.07(d,J＝8.0Hz,1H),7.51–7.41(m,2H),6.99(d,J＝8.3Hz,1H),4.16(dt,J＝7.7,5.5Hz,4H),3.72(tq,J＝11.0,6.7,5.3Hz,1H),2.12(p,J＝5.6Hz,2H),1.75(ddq,J＝26.0,8.8,4.6Hz,4H),1.66–1.52(m,1H),1.38–1.20(m,4H),1.20–1.03(m,1H). 13 C NMR(101MHz,DMSO-d 6 )δ164.64,153.68,150.72,130.37,123.21,121.50,121.22,70.92,70.88,48.74,32.89,31.66,25.74,25.44.MS(ESI):m/z 276.4[M+H] + 。
Example 9: brown solid. The yield was 93%. 1 H NMR(400MHz,DMSO-d 6 )δ10.09(s,1H),7.82–7.70(m,2H),7.68–7.53(m,2H),7.38–7.27(m,2H),7.08(t,J＝7.3Hz,2H),4.21(dt,J＝7.6,5.5Hz,4H),2.15(p,J＝5.6Hz,2H). 13 C NMR(151MHz,DMSO-d 6 )δ164.77,154.19,150.78,139.65,130.22,129.01,123.99,123.67,121.77,121.60,120.79,70.95,70.89,31.52.MS(ESI):m/z 270.3[M+H] + 。
Example 10: pale yellow solid. The yield thereof was found to be 75%. 1 H NMR(400MHz,DMSO-d 6 )δ10.01(s,1H),7.68–7.59(m,3H),7.57(dd,J＝8.3,2.2Hz,1H),7.13(d,J＝8.2Hz,2H),7.10–7.01(m,1H),4.21(dt,J＝8.2,5.4Hz,4H),2.27(s,3H),2.15(p,J＝5.5Hz,2H). 13 C NMR(101MHz,DMSO-d 6 )δ164.55,154.09,150.76,137.11,132.91,130.29,129.38,123.58,121.72,121.53,120.80,70.93,70.87,31.52,20.94.MS(ESI):m/z 284.1[M+H] + 。
Example 11: light purple solid. The yield thereof was found to be 71%. 1 H NMR(400MHz,DMSO-d 6 )δ9.94(s,1H),7.61(d,J＝2.2Hz,1H),7.57(dd,J＝8.4,2.3Hz,1H),7.45(d,J＝2.4Hz,1H),7.32(dd,J＝8.7,2.4Hz,1H),7.06(d,J＝8.4Hz,1H),6.91(d,J＝8.8Hz,1H),4.21(dt,J＝7.5,5.5Hz,4H),3.74(d,J＝5.3Hz,6H),2.15(p,J＝5.6Hz,2H). 13 C NMR(151MHz,DMSO-d 6 )δ164.31,154.07,150.78,148.86,145.51,133.21,130.30,123.52,121.75,121.43,112.67,112.33,105.90,70.96,70.89,56.19,55.84,31.54.MS(ESI):m/z 278.5[M+H] + 。
Example 12: 1 H NMR(400MHz,DMSO-d 6 )δ9.53(s,1H),7.62(d,J＝2.2Hz,1H),7.59(dd,J＝8.3,2.3Hz,1H),7.06(d,J＝8.3Hz,1H),6.91(s,2H),4.21(dt,J＝7.7,5.5Hz,4H),2.25(s,3H),2.16(q,J＝5.5Hz,2H),2.11(s,6H). 13 C NMR(101MHz,DMSO-d 6 )δ164.38,154.07,150.86,135.98,135.75,133.20,129.82,128.72,123.40,121.76,121.45,70.90,70.86,31.54,21.00,18.44. 13 C NMR(101MHz,DMSO-d 6 )δ166.96,155.27,151.61,150.78,140.07,129.34,126.18,125.29,123.13,121.91,121.20,70.85,70.80,31.31.MS(ESI):m/z 312.4[M+H] + 。
example 13: 1 H NMR(400MHz,DMSO-d6)δ9.59(s,1H),7.68–7.50(m,2H),7.38–7.24(m,1H),7.18(d,J＝7.6Hz,2H),7.07(d,J＝8.2Hz,1H),4.22(q,J＝5.9Hz,4H),3.04(p,J＝6.9Hz,2H),2.17(q,J＝5.6Hz,2H),1.12(dd,J＝25.2,6.9Hz,12H).13C NMR(101MHz,DMSO-d6)δ164.34,152.96,149.72,145.46,132.12,128.55,126.87,122.24,122.17,120.66,120.24,69.73,69.69,30.35,27.44,22.86,22.56.MS(ESI):m/z354.5[M+H] + 。
example 14: pale yellow solid. The yield thereof was found to be 68%. 1 H NMR(400MHz,DMSO-d 6 )δ10.26(s,1H),7.74(dt,J＝11.9,2.3Hz,1H),7.67–7.49(m,3H),7.37(td,J＝8.2,6.8Hz,1H),7.08(d,J＝8.3Hz,1H),6.91(td,J＝8.4,2.6Hz,1H),4.22(dt,J＝8.4,5.5Hz,4H),2.16(p,J＝5.6Hz,2H). 13 C NMR(151MHz,DMSO-d 6 )δ165.03,163.29,161.69,154.39,150.78,141.45,130.63,129.80,123.76,121.74,116.38,116.36,110.41,107.35,70.96,70.89,31.46.MS(ESI):m/z 288.3[M+H] + 。
Example 15: white solid. The yield thereof was found to be 74%. 1 H NMR(400MHz,DMSO-d 6 )δ9.98(s,1H),7.65–7.51(m,3H),7.31–7.17(m,3H),7.07(d,J＝8.3Hz,1H),4.21(dt,J＝11.1,5.5Hz,4H),2.15(p,J＝5.6Hz,2H).13C NMR(101MHz,DMSO-d6)δ164.70,157.53,155.08,154.39,150.81,129.23,127.69,127.31,126.21,124.67,123.73,121.79,116.23,70.94,70.88,31.46.MS(ESI):m/z 288.3[M+H] + 。
Example 16: pale yellow solid. Yield rate:81％。 1 H NMR(400MHz,DMSO-d 6 )δ10.42(s,1H),8.00(d,J＝8.5Hz,2H),7.70(d,J＝8.5Hz,2H),7.65(d,J＝2.3Hz,1H),7.60(dd,J＝8.4,2.3Hz,1H),7.09(d,J＝8.3Hz,1H),4.22(dt,J＝9.0,5.6Hz,4H),2.16(p,J＝5.6Hz,2H). 13 C NMR(151MHz,DMSO-d 6 )δ165.24,154.50,150.78,143.33,129.65,126.34,126.30,126.27,123.88,121.85,121.76,120.50,70.96,70.88,31.44.MS(ESI):m/z 338.5[M+H] + 。
Example 17: grey solid. The yield was 81%. 1 H NMR(400MHz,DMSO-d 6 )δ9.97(s,1H),7.68–7.62(m,2H),7.60(d,J＝2.2Hz,1H),7.56(dd,J＝8.3,2.3Hz,1H),7.06(d,J＝8.3Hz,1H),6.98–6.80(m,2H),4.20(dt,J＝7.5,5.5Hz,4H),3.73(s,3H). 13 C NMR(101MHz,DMSO-d 6 )δ164.33,155.92,154.03,150.76,132.70,130.31,123.51,122.37,121.71,121.46,114.14,70.94,70.87,55.63,31.53.MS(ESI):m/z 300.1[M+H] + 。
Example 18: yellow solid. The yield thereof was found to be 87%. 1 H NMR(400MHz,DMSO-d 6 )δ9.82(s,1H),7.64–7.51(m,2H),7.36(t,J＝8.9Hz,1H),7.06(d,J＝8.3Hz,1H),6.92(dd,J＝12.3,2.8Hz,1H),6.79(ddd,J＝8.8,2.8,1.0Hz,1H),4.21(dt,J＝10.8,5.5Hz,4H),3.33(s,3H),2.15(t,J＝5.6Hz,2H). 13 C NMR(101MHz,DMSO-d 6 )δ163.68,157.49,154.99,153.20,149.74,128.23,127.84,122.54,120.71,117.62,109.17,101.39,101.15,69.86,69.81,55.10,30.42.MS(ESI):m/z 318.3[M+H] + 。
Example 19: brown solid. The yield thereof was found to be 83%. 1 H NMR(400MHz,DMSO-d 6 )δ9.82(s,1H),7.65–7.55(m,2H),7.36(d,J＝8.8Hz,1H),7.27(d,J＝2.8Hz,1H),7.06(d,J＝8.3Hz,1H),6.99(dd,J＝8.8,2.8Hz,1H),4.21(dt,J＝9.3,5.5Hz,4H),3.79(s,3H),2.20–2.09(m,2H). 13 C NMR(101MHz,Chloroform-d)δ164.28,157.89,153.68,150.25,129.83,129.29,128.92,122.98,121.66,121.21,121.04,117.18,113.83,70.35,70.30,55.62,30.92.MS(ESI):m/z 379.6[M+H] + 。
Example 20: grey solid. The yield thereof was found to be 69%. 1 H NMR(400MHz,DMSO-d 6 )δ9.97(s,1H),7.62(d,J＝2.2Hz,1H),7.57(dd,J＝8.3,2.3Hz,1H),7.23(s,2H),7.07(d,J＝8.4Hz,1H),4.21(dt,J＝7.7,5.5Hz,4H),3.76(s,6H),3.63(s,3H),2.16(t,J＝5.6Hz,2H). 13 C NMR(151MHz,DMSO-d 6 )δ164.51,154.20,153.02,150.78,135.81,134.05,130.12,123.58,121.79,121.44,98.39,70.96,70.88,60.58,56.18,31.51.MS(ESI):m/z 360.4[M+H] + 。
Example 21: white solid. The yield was 86%. 1 H NMR(400MHz,DMSO-d 6 )δ10.00(s,1H),9.28(s,1H),7.69–7.51(m,4H),7.39(d,J＝8.6Hz,2H),7.06(d,J＝8.3Hz,1H),4.21(dt,J＝7.9,5.5Hz,4H),2.15(t,J＝5.6Hz,2H),1.47(s,9H). 13 C NMR(101MHz,DMSO-d 6 )δ164.37,154.08,153.27,150.77,135.74,134.05,130.27,123.55,121.73,121.50,121.33,79.33,70.95,70.88,31.54,28.63.MS(ESI):m/z 385.3[M+H] + 。
Example 22: brown solid. The yield was 89%. 1 H NMR(400MHz,DMSO-d 6 )δ10.84(s,1H),8.42(d,J＝2.6Hz,1H),8.19(d,J＝8.9Hz,1H),7.94(dd,J＝9.0,2.7Hz,1H),7.65(dq,J＝4.1,2.3Hz,2H),7.08–6.99(m,1H),4.21(dt,J＝13.8,5.6Hz,4H),2.15(p,J＝5.6Hz,2H). 13 C NMR(151MHz,DMSO-d 6 )δ165.39,154.64,151.39,150.74,146.71,138.22,129.08,125.89,124.03,122.21,121.67,116.28,70.88,70.83,31.40.MS(ESI):m/z305.6[M+H] + 。
Example 23: pale yellow solid. The yield was 81%. 1 H NMR(400MHz,DMSO-d 6 )δ12.83(s,1H),10.59(s,1H),7.78–7.61(m,2H),7.47(d,J＝8.1Hz,1H),7.09(dd,J＝17.5,7.5Hz,2H),6.96(dd,J＝8.2,6.9Hz,1H),4.22(dt,J＝11.3,5.6Hz,4H),2.49(s,3H),2.16(p,J＝5.5Hz,2H). 13 C NMR(101MHz,DMSO-d 6 )δ164.92,154.34,150.82,141.60,140.89,129.18,126.40,123.80,121.95,121.73,120.36,120.28,119.50,117.39,70.90,70.85,31.48,16.87.MS(ESI):m/z 324.4[M+H] + 。
Example 24: orange solid. The yield thereof was found to be 87%. 1 H NMR(400MHz,DMSO-d 6 )δ10.30(s,1H),8.44(d,J＝1.9Hz,1H),7.95–7.75(m,4H),7.73–7.59(m,2H),7.45(dddd,J＝25.8,8.0,6.8,1.3Hz,2H),7.10(d,J＝8.3Hz,1H),4.23(q,J＝6.0Hz,4H),2.17(t,J＝5.6Hz,2H). 13 C NMR(101MHz,DMSO-d 6 )δ164.99,154.26,150.80,137.28,133.78,130.38,130.13,128.54,127.88,127.83,126.81,125.18,123.71,121.81,121.65,121.40,116.91,70.96,70.89,31.49.MS(ESI):m/z 320.2[M+H] + 。
Example 25: purple solid. The yield thereof was found to be 72%. 1 H NMR(400MHz,DMSO-d 6 )δ10.30(s,1H),8.02–7.90(m,2H),7.86(dd,J＝7.1,2.3Hz,1H),7.80–7.66(m,2H),7.61–7.47(m,4H),7.11(d,J＝8.3Hz,1H),4.23(dt,J＝8.5,5.5Hz,4H),2.17(p,J＝5.6Hz,2H). 13 C NMR(151MHz,DMSO-d 6 )δ165.49,154.30,150.88,134.35,134.21,129.79,129.73,128.50,126.69,126.50,126.39,125.99,124.41,123.82,123.75,121.82,70.97,70.92,31.54.MS(ESI):m/z 320.2[M+H] + 。
Example 26: 1 H NMR(400MHz,DMSO-d 6 )δ8.92(t,J＝6.0Hz,1H),7.62–7.42(m,2H),7.38–7.26(m,4H),7.26–7.18(m,1H),7.02(d,J＝8.3Hz,1H),4.44(d,J＝6.0Hz,2H),4.18(dt,J＝9.3,5.6Hz,4H),2.13(p,J＝5.6Hz,2H). 13 C NMR(101MHz,DMSO-d 6 )δ165.58,153.91,150.82,140.21,129.82,128.70,127.62,127.14,123.14,121.68,121.24,70.90,70.85,43.03,31.57.MS(ESI):m/z 284.2[M+H] + 。
example 27: white solid. The yield thereof was found to be 76%. 1 H NMR(400MHz,DMSO-d 6 )δ8.85(t,J＝5.9Hz,1H),7.57–7.43(m,2H),7.26–7.17(m,2H),7.00(d,J＝8.3Hz,1H),6.93–6.83(m,2H),4.36(d,J＝5.9Hz,2H),4.17(dt,J＝9.3,5.5Hz,4H),3.72(s,3H),2.12(p,J＝5.5Hz,2H). 13 C NMR(151MHz,DMSO-d 6 )δ165.44,158.60,153.86,150.80,132.18,129.91,129.00,123.11,121.65,121.21,114.11,70.90,70.85,55.51,42.48,31.58.MS(ESI):m/z 314.4[M+H] + 。
Example 28: white solid. The yield was 92%. 1 H NMR(400MHz,DMSO-d 6 )δ8.67(d,J＝8.0Hz,1H),7.55(d,J＝2.3Hz,1H),7.50(dd,J＝8.3,2.2Hz,1H),7.40–7.34(m,2H),7.31(t,J＝7.6Hz,2H),7.26–7.17(m,1H),7.01(d,J＝8.4Hz,1H),5.21–5.04(m,1H),4.17(dt,J＝7.5,5.5Hz,4H),2.12(dq,J＝11.9,6.3,5.9Hz,2H),1.45(d,J＝7.1Hz,3H). 13 C NMR(151MHz,DMSO-d 6 )δ164.84,153.86,150.76,145.47,129.99,128.65,126.99,126.49,123.35,121.59,121.31,70.93,70.88,48.87,31.62,22.69.MS(ESI):m/z 298.1[M+H] + 。
Example 29: white solid. The yield thereof was found to be 72%. 1 H NMR(400MHz,DMSO-d 6 )δ9.02(t,J＝6.0Hz,1H),7.69(d,J＝8.1Hz,2H),7.57–7.45(m,4H),7.02(d,J＝8.3Hz,1H),4.52(d,J＝5.9Hz,2H),4.18(dt,J＝9.7,5.5Hz,4H),2.13(p,J＝5.6Hz,2H). 13 C NMR(151MHz,DMSO-d 6 )δ165.74,154.03,150.84,145.12,129.53,128.28,125.66,125.63,123.17,121.74,121.25,70.91,70.85,42.76,31.54.MS(ESI):m/z 352.3[M+H] + 。
Example 30: yellow solid. The yield was 88%. 1 H NMR(400MHz,DMSO-d 6 )δ8.84(t,J＝5.7Hz,1H),7.56(dd,J＝1.9,0.9Hz,1H),7.52–7.44(m,2H),7.00(d,J＝8.3Hz,1H),6.38(dd,J＝3.2,1.8Hz,1H),6.24(dd,J＝3.2,0.9Hz,1H),4.42(d,J＝5.7Hz,2H),4.17(dt,J＝9.9,5.5Hz,4H),2.12(dq,J＝10.9,5.4Hz,2H). 13 C NMR(151MHz,DMSO-d 6 )δ165.45,153.95,152.95,150.79,142.40,129.59,123.19,121.66,121.31,110.91,107.21,70.89,70.84,36.49,31.55.MS(ESI):m/z 274.2[M+H] + 。
Example 31: pale yellow solid. The yield was 85%. 1 H NMR(400MHz,DMSO-d 6 )δ8.92(t,J＝6.0Hz,1H),7.59–7.44(m,2H),7.40–7.34(m,2H),7.34–7.27(m,2H),7.11(t,J＝7.4Hz,1H),6.99(dd,J＝16.9,8.4Hz,5H),4.42(d,J＝5.9Hz,2H),4.17(dt,J＝9.2,5.5Hz,4H),2.13(p,J＝5.5Hz,2H). 13 C NMR(101MHz,DMSO-d 6 )δ165.55,157.41,155.71,153.90,150.80,135.43,130.44,129.78,129.41,123.66,123.13,121.66,121.23,119.17,118.71,70.89,70.84,42.49,31.55.MS(ESI):m/z 276.5[M+H] + 。
Analytical example 2 bacterial inhibition experiments
The culture medium required for the strain was Mueller-Hinton medium (MH medium: casein hydrolysate 17.5 g, soluble starch 1.5 g, 1000ml beef extract). The Minimum Inhibitory Concentration (MIC) values of the test compounds were determined by colorimetry of MTT (3- (4, 5-dimethylpyridin-2-yl) -2, 5-diphenylbromide). The compound was dissolved in Dimethylsulfoxide (DMSO) to prepare a storage solution at a concentration of 100 μg/ml, and the storage solution was added to a specified volume of sterile liquid MH medium in a gradient amount. A specific volume of the compound solution containing the medium is added to the microtiter plate. A suspension of bacteria at about 105cfu/ml was prepared and added dropwise to the microtiter plate, incubated with serial dilutions of the compounds, at 37℃for 24h. After each microtiter plate was observed by microscopy to determine its MIC value, phosphate buffer (PBS; 50ml,0.01M, pH 7.4,2.9g Na) with an MTT concentration of 2mg/ml was added to each well 2 HPO 4 ·12H 2 O，0.2g KH 2 PO 4 8.0g NaCl,0.2g KCl,1000ml distilled water). The reaction solution in each well was removed after standing at room temperature for 4-5 hours, and 100ml of isopropyl alcohol further containing 5% HCl (final concentration of 1M) was added to extract the dye. After incubation for 12 hours at room temperature, the Optical Density (OD) was measured by setting the microplate reader at 550 nm.
The test results are shown in the following table:
as can be seen from Table 1, most compounds have a certain antimicrobial capacity against both gram-positive and gram-negative bacteria. The antibacterial activity was evaluated by introducing different amine compounds. Based on caliamycin B as a reference, the antibacterial effect of the compound with longer carbon chain is better when the amino group of the amide is replaced by a fatty chain when various amide compounds are used for inhibiting two gram-negative bacteria (escherichia coli and pseudomonas fluorescens) and two gram-positive bacteria (staphylococcus aureus and bacillus subtilis). For amide derivatives containing a benzene ring, the substituents of the benzene ring have an important influence on the activity. The antibacterial activity of the derivative containing methoxy, fluorine and trifluoromethyl substituent is obviously better than that of the derivative of methyl and 2, 6-isopropyl substituted aniline. Even containing methoxy and fluorine substituted benzylamine derivatives, the antibacterial activity of the benzylamine and the kang amine derivatives is obviously better than that of benzylamine and kang amine derivatives. Compound 21 is a particular example, probably because it contains bromo groups, which is detrimental to activity. The activity of the substituted amide derivative containing nitrogen heterocycle is also obviously better than that of short-chain aliphatic. The naphthalene ring-containing derivatives are inferior to benzene rings in antibacterial activity due to their excessively large structures.
Analytical example 3 E.coli FabH inhibition assay
The native E.coli FabH protein was overexpressed on E.coli DH10B cells by pE30 vector and homogenized by 3 chromatographic steps (Q-Sepharose, monoQ, and hydroxyapatite) at 4 ℃. Seleno-substituted proteins are expressed in E.coli BL21 (DE 3) cells and purified in a similar manner. The resulting FabH-containing cells were added to 200mM Tris (Tris) containing 5mM imidazole and 0.5M NaCl, the cells were lysed by sonication, and centrifuged (20000 rpm,40min,4 ℃). The resulting supernatant was applied dropwise to a Ni-NTA agar column, washed, and subjected to gradient elution with 5-500mM imidazole solution exceeding 20 times the column volume. Eluted protein was concentrated through 20mM Tris (pH 7.6) containing 1mM Dithiothreitol (DTT) and 100mM NaCl, and the pure FabH protein was stored in 20mM Tris (pH 7.6) solution containing 100mM NaCl,1mM DTT and 20% glycerol and stored at-80℃for later enzymatic assay.
In a reaction with a final concentration of 20. Mu.L, a solution containing 0.5mM DTT,0.25mM MgCl was added 2 And 2.5. Mu.M holo-ACP (active acyl carrier protein) 20mM Na 2 HPO 4 Adding 1nMFabH into the solution, and finally adding H 2 O was fixed to a volume of 15. Mu.L. After 1 minute of incubation, 2. Mu.L of a mixed solution containing 25. Mu.M acetyl-CoA, 0.5mM NADA and 0.5mM NADPH was added to the FabH reaction solution, and reacted for 25 minutes. The reaction was stopped by adding 20. Mu.L ice-cold 50% TCA and after incubation on ice for 5 min, the precipitated proteins were centrifuged. The precipitate was washed with ice-cold 10% tca and resuspended in 0.5M NaOH (5 μl). The 3H signal incorporated into the final product can be read by liquid scintillation. When determining the IC50 values, the added inhibitors are from concentrated DMSO stock solution, but must be such as to ensure the final DMSOThe concentration is not more than 2%.
Further examination of the E.coli FabH inhibitory activity of these several compounds gave the results shown in Table 2:
all compounds tested showed inhibitory activity against E.coli FabH, with methyl and fluoro substituent derivatives having higher activity, with methoxy groups having the best activity, with methoxy groups substituted with amino acids at the binding pocket having conformational complementarity and significant non-bonding interactions, important for binding conformation stabilization. Thus, methoxy-bearing molecules have a higher affinity for FabH proteins. Of these, compound 19 was the most active, reaching an IC50 of 2.4. Mu.M for the FabH inhibitor. Not only the antibacterial activity, but also the biosafety is an important index of antibacterial lead. Thus, the compounds selected above were also tested for their hemolytic and cytotoxic activity against the mouse embryonic fibroblast cell line (NIH-3T 3) using the MTT assay. As shown in table 2:
these compounds exhibit low hemolytic activity. In addition, cytotoxicity data indicate that compounds with inhibitory activity are low toxic.
Analytical example 3 model analysis
To further define the binding mode of the interaction between the targeting protein and the small molecule, we selected the best active compound 19 to perform a molecular docking simulation with E.coli FabH enzyme according to the ligation model of E.coli FabH (PDB: 5 BNM). As shown in FIG. 1, b is a 2D mode of action diagram of biphenyl skeleton type inhibitors and FabH protein (PDB: 5 bnm) in protein crystals in a 5bnm protein database (true). HIS244 and ASN274 form 2 hydrogen bonds with the OH of the inhibitor, and additionally a large number of hydrophobic amino acids (green in color, such as PHE304, ILE250, GLY209, GLY305, PHE157, etc.) form hydrophobic pockets, enhancing the binding capacity of the inhibitor to the protein; panels c and D are modes of docking of compound 19 with FabH (3D and 2D panels). The calculation showed that the fraction of the docking of compound 19 and the FabH enzyme was-7.827 Kcal/mol, which is low enough to demonstrate its strong affinity for the protein. Meanwhile, the epoxy alkoxy of the compound 19 and the amino residue Asn274 of the FabH enzyme form a hydrogen bond, which is of great significance for improving the antibacterial activity of the lead compound 19. Panel e is a comparison of 2 inhibitors in protein pockets, compound 19 is green, and the original inhibitor molecule is cyan, as can be seen from the figure, the two molecules can be substantially congruent, demonstrating that the predicted conformation of the inhibitor docking is substantially reasonable. The left part (i.e. the hydrophobic part) of the two molecules can be substantially well folded and the regions of larger conformational difference are mainly located in the right part, so that modification of the right part has the potential to optimise the more active molecules. We finally concluded that Compound 19 is an E.coli FabH inhibitor and can be a potential antibiotic.
The foregoing description is only a few examples of the present application and is not intended to limit the present application in any way, and although the present application is disclosed in the preferred examples, it is not intended to limit the present application, and any person skilled in the art may make some changes or modifications to the disclosed technology without departing from the scope of the technical solution of the present application, and the technical solution is equivalent to the equivalent embodiments.
Claims (10)
1. An amide compound, characterized in that the amide compound is selected from the following compounds:
2. the method for producing an amide compound according to claim 1, comprising the steps of:
(S1) reacting a mixture containing benzaldehyde and dioxane, potassium permanganate and water to obtain the benzoic acid and dioxane;
(S2) adding primary amine into a mixture containing benzodioxan, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, 1-hydroxybenzotriazole and methylene dichloride after a reaction II, and obtaining an amide compound after a reaction III;
the primary amine is at least one selected from n-octylamine, dodecylamine, hexadecylamine, 2, 6-diisopropylaniline, trifluoromethylaniline, 4-methoxy-2-fluoroaniline, 2-bromo-4-methoxyaniline, tert-butyl-4-aminophenylcarbamate, 3-amino-7-methyl-1H-indazole, 4- (trifluoromethyl) benzylamine and 4-phenoxybenzylamine.
3. The preparation method according to claim 2, wherein the molar ratio of potassium permanganate to benzaldehyde dioxane is 1.2:1-2:1.
4. The preparation method according to claim 2, wherein the molar ratio of potassium permanganate to benzaldehyde dioxane is 1.3:1-1.5:1.
5. The method according to claim 2, wherein,
in reaction I:
reaction temperature: 50 o C ~80 o C；
Reaction time: 8-24 h.
6. The method according to claim 2, wherein the molar ratio of benzodioxan, primary amine, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, and 1-hydroxybenzotriazole is 1:1-2:1-2.
7. The method according to claim 2, wherein the molar ratio of the benzodioxan, the primary amine, the 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and the 1-hydroxybenzotriazole is 1:1.2 to 1.5:1.2 to 1.5.
8. The method according to claim 2, wherein,
in reaction II:
reaction temperature: 60 o C ~80 o C；
Reaction time: 5 h-10 h.
9. The process according to claim 2, wherein in reaction iii:
reaction temperature: 25 o C ~50 o C；
Reaction time: 6 h-24 h.
10. Use of an amide compound according to claim 1 and/or an amide compound according to any one of claims 2 to 9 in the preparation of a FaBH inhibitor.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210056304.4A CN114478474B (en) | 2022-01-18 | 2022-01-18 | Amide compound and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210056304.4A CN114478474B (en) | 2022-01-18 | 2022-01-18 | Amide compound and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114478474A CN114478474A (en) | 2022-05-13 |
| CN114478474B true CN114478474B (en) | 2023-06-30 |
Family
ID=81472722
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210056304.4A Active CN114478474B (en) | 2022-01-18 | 2022-01-18 | Amide compound and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114478474B (en) |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101445469B (en) * | 2003-09-24 | 2013-02-13 | 梅特希尔基因公司 | Inhibitors of histone deacetylase |
| US7842810B2 (en) * | 2005-03-31 | 2010-11-30 | Janssen Pharmaceutica, Nv | Bicyclic pyrazole compounds as antibacterial agents |
| WO2020072492A1 (en) * | 2018-10-02 | 2020-04-09 | Baruch S. Blumberg Institute | Benzamide derivatives as cgas-sting pathway agonists |
| CN109516961B (en) * | 2018-12-25 | 2021-01-01 | 浙江大学 | Aminoquinazolinone and aminoisoquinolinone derivatives and uses thereof |
-
2022
- 2022-01-18 CN CN202210056304.4A patent/CN114478474B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN114478474A (en) | 2022-05-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| McGeary et al. | Structure-activity relationship study and optimisation of 2-aminopyrrole-1-benzyl-4, 5-diphenyl-1H-pyrrole-3-carbonitrile as a broad spectrum metallo-β-lactamase inhibitor | |
| Xiao et al. | Tyrosyl-tRNA synthetase inhibitors as antibacterial agents: Synthesis, molecular docking and structure–activity relationship analysis of 3-aryl-4-arylaminofuran-2 (5H)-ones | |
| Li et al. | Design and synthesis of thiazole derivatives as potent FabH inhibitors with antibacterial activity | |
| Sosič et al. | Second-generation sulfonamide inhibitors of D-glutamic acid-adding enzyme: activity optimisation with conformationally rigid analogues of D-glutamic acid | |
| Amperayani et al. | Synthesis and in vitro and in silico antimicrobial studies of novel piperine–pyridine analogs | |
| Eletmany et al. | Novel arylazo nicotinate derivatives as effective antibacterial agents: Green synthesis, molecular modeling, and structure-activity relationship studies | |
| Wehrli et al. | Discovery and development of substituted thiadiazoles as inhibitors of Staphylococcus aureus Sortase A | |
| Tomašič et al. | Design, synthesis, and biological evaluation of 1‐ethyl‐3‐(thiazol‐2‐yl) urea derivatives as Escherichia coli DNA gyrase inhibitors | |
| Xiao et al. | Novel fluorescent cephalosporins: synthesis, antimicrobial activity and photodynamic inactivation of antibiotic resistant bacteria | |
| Rai et al. | Synthesis and antibacterial activity of benzamides and sulfonamide derived from 2-amino-5-bromo/nitropyridine against bacterial strains isolated from clinical patients | |
| Cheng et al. | Synthesis, molecular modeling and biological evaluation of PSB as targeted antibiotics | |
| CN114478474B (en) | Amide compound and preparation method thereof | |
| Li et al. | Discovery of vinylogous carbamates as a novel class of β-ketoacyl-acyl carrier protein synthase III (FabH) inhibitors | |
| Dhara et al. | New oxadiazole derivatives: Synthesis and appraisal of their potential as antimicrobial agents | |
| CN108117502A (en) | The preparation of a kind of 2- substitutions-(S)-(3- sulfydryl -2- methylpropionyls)-glycine derivative and purposes | |
| Zhou et al. | Study of Schiff-base-derived with dioxygenated rings and nitrogen heterocycle as potential β-ketoacyl-acyl carrier protein synthase III (FabH) inhibitors | |
| Zhang et al. | Synthesis and evaluation of novel urea and amide derivatives of 2-amino-4-phenylthiazole as potential antibacterial agents | |
| CN113214302A (en) | 3-substituted five-membered cyclic borate derivative for inhibiting metal beta-lactamase and/or serine beta-lactamase | |
| CN105541853A (en) | Polysubstituted type gamma-pyranopyrrolidone compound as well as preparation method and application thereof | |
| He et al. | Substituted‐Amidine Functionalized Monocyclic β‐Lactams: Synthesis and In Vitro Antibacterial Profile | |
| Al-Rawi et al. | Synthesis and characterization of new schiff bases heterocyclic compounds and their N-acyl, thiourea and imidazole derived from D-erythroascorbic acid | |
| Hlaváček et al. | Inhibitors of N α-acetyl-l-ornithine deacetylase: synthesis, characterization and analysis of their inhibitory potency | |
| Blindheim et al. | Synthetic Strategies towards Imidazopyridinones and 7‐Azaoxindoles and their Evaluation as Antibacterial Agents | |
| Tkachenko et al. | Synthesis and the antimicrobial activity of ethyl 5-methyl-2-(alkylthio)-4-oxo-3, 4-dihydrothieno [2, 3-d] pyrimidine-6-carboxylates | |
| CN116655515B (en) | N-alkoxy-1-acyl-1H-pyrrole-2-amide compound and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |