RU2764522C1 - 3,3'[(hexano-1,6-diylbis (azanediyl)]bis-(7-hydroxy-6-methoxycarbonyl-2-oxo-2h-chromene) with antibacterial activity - Google Patents
3,3'[(hexano-1,6-diylbis (azanediyl)]bis-(7-hydroxy-6-methoxycarbonyl-2-oxo-2h-chromene) with antibacterial activity Download PDFInfo
- Publication number
- RU2764522C1 RU2764522C1 RU2021114978A RU2021114978A RU2764522C1 RU 2764522 C1 RU2764522 C1 RU 2764522C1 RU 2021114978 A RU2021114978 A RU 2021114978A RU 2021114978 A RU2021114978 A RU 2021114978A RU 2764522 C1 RU2764522 C1 RU 2764522C1
- Authority
- RU
- Russia
- Prior art keywords
- antibacterial activity
- oxo
- chromene
- methoxycarbonyl
- hydroxy
- Prior art date
Links
- 230000000844 anti-bacterial effect Effects 0.000 title claims abstract description 30
- 125000001821 azanediyl group Chemical group [H]N(*)* 0.000 title claims abstract description 9
- 230000001580 bacterial effect Effects 0.000 claims abstract description 15
- 230000015572 biosynthetic process Effects 0.000 claims description 19
- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N benzo-alpha-pyrone Natural products C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 abstract description 26
- 241000191967 Staphylococcus aureus Species 0.000 abstract description 20
- 235000001671 coumarin Nutrition 0.000 abstract description 14
- 241000894006 Bacteria Species 0.000 abstract description 11
- 239000003814 drug Substances 0.000 abstract description 11
- 230000000694 effects Effects 0.000 abstract description 10
- 241000193755 Bacillus cereus Species 0.000 abstract description 9
- 241000588724 Escherichia coli Species 0.000 abstract description 8
- -1 coumarin compound Chemical class 0.000 abstract description 8
- 239000000126 substance Substances 0.000 abstract description 8
- 229960000956 coumarin Drugs 0.000 abstract description 7
- 230000032770 biofilm formation Effects 0.000 abstract description 5
- 238000004113 cell culture Methods 0.000 abstract description 2
- 239000003112 inhibitor Substances 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 32
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- LEIVLXXHPABGQA-UHFFFAOYSA-N peuruthenicin Natural products C1=CC(=O)OC2=C1C=C(C(=O)OC)C(O)=C2 LEIVLXXHPABGQA-UHFFFAOYSA-N 0.000 description 11
- 150000004775 coumarins Chemical class 0.000 description 10
- VAAUVRVFOQPIGI-SPQHTLEESA-N ceftriaxone Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NC(=O)C(=O)NN1C VAAUVRVFOQPIGI-SPQHTLEESA-N 0.000 description 9
- 229960004755 ceftriaxone Drugs 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- 229940079593 drug Drugs 0.000 description 8
- 239000003242 anti bacterial agent Substances 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- NAQMVNRVTILPCV-UHFFFAOYSA-N hexane-1,6-diamine Chemical compound NCCCCCCN NAQMVNRVTILPCV-UHFFFAOYSA-N 0.000 description 6
- 235000015097 nutrients Nutrition 0.000 description 6
- 238000011161 development Methods 0.000 description 5
- 230000018109 developmental process Effects 0.000 description 5
- 239000012634 fragment Substances 0.000 description 5
- 229930186147 Cephalosporin Natural products 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 229940124350 antibacterial drug Drugs 0.000 description 4
- 230000003115 biocidal effect Effects 0.000 description 4
- 229940124587 cephalosporin Drugs 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- YQBNJPACAUPNLV-UHFFFAOYSA-N peucedanin Chemical compound O1C(=O)C=CC2=C1C=C1OC(C(C)C)=C(OC)C1=C2 YQBNJPACAUPNLV-UHFFFAOYSA-N 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 125000001359 1,2,3-triazol-4-yl group Chemical group [H]N1N=NC([*])=C1[H] 0.000 description 3
- CXNIUSPIQKWYAI-UHFFFAOYSA-N 4,5-bis(diphenylphosphino)-9,9-dimethyl-xanthene Substances C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 3
- 229920001817 Agar Polymers 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 241001360526 Escherichia coli ATCC 25922 Species 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 241000191940 Staphylococcus Species 0.000 description 3
- 241000191963 Staphylococcus epidermidis Species 0.000 description 3
- 239000008272 agar Substances 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 230000000845 anti-microbial effect Effects 0.000 description 3
- 229940088710 antibiotic agent Drugs 0.000 description 3
- 239000004599 antimicrobial Substances 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 150000001780 cephalosporins Chemical class 0.000 description 3
- 238000013461 design Methods 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 238000011081 inoculation Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 244000005700 microbiome Species 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 238000005556 structure-activity relationship Methods 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- GHCRWJLFNDIAHM-UHFFFAOYSA-N 3-(2-oxochromen-3-yl)chromen-2-one Chemical compound C1=CC=C2OC(=O)C(C3=CC=4C=CC=CC=4OC3=O)=CC2=C1 GHCRWJLFNDIAHM-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 208000035143 Bacterial infection Diseases 0.000 description 2
- 208000035473 Communicable disease Diseases 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 206010059866 Drug resistance Diseases 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- 241000194032 Enterococcus faecalis Species 0.000 description 2
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- 241000588915 Klebsiella aerogenes Species 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 2
- 241000293871 Salmonella enterica subsp. enterica serovar Typhi Species 0.000 description 2
- FJAQNRBDVKIIKK-LFLQOBSNSA-N [(3r,4s,5r,6s)-6-[8-chloro-4-hydroxy-3-[[4-hydroxy-3-(3-methylbut-2-enyl)benzoyl]amino]-2-oxochromen-7-yl]oxy-5-hydroxy-3-methoxy-2,2-dimethyloxan-4-yl] 5-methyl-1h-pyrrole-2-carboxylate Chemical compound O([C@@H]1[C@H](C(O[C@@H](OC=2C(=C3OC(=O)C(NC(=O)C=4C=C(CC=C(C)C)C(O)=CC=4)=C(O)C3=CC=2)Cl)[C@@H]1O)(C)C)OC)C(=O)C1=CC=C(C)N1 FJAQNRBDVKIIKK-LFLQOBSNSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000007059 acute toxicity Effects 0.000 description 2
- 231100000403 acute toxicity Toxicity 0.000 description 2
- 230000003214 anti-biofilm Effects 0.000 description 2
- 238000009635 antibiotic susceptibility testing Methods 0.000 description 2
- 208000022362 bacterial infectious disease Diseases 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 229940032049 enterococcus faecalis Drugs 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 229960003085 meticillin Drugs 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 2
- ZCCUUQDIBDJBTK-UHFFFAOYSA-N psoralen Chemical compound C1=C2OC(=O)C=CC2=CC2=C1OC=C2 ZCCUUQDIBDJBTK-UHFFFAOYSA-N 0.000 description 2
- 150000007660 quinolones Chemical class 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000013207 serial dilution Methods 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 150000003557 thiazoles Chemical class 0.000 description 2
- 150000003918 triazines Chemical class 0.000 description 2
- 238000002211 ultraviolet spectrum Methods 0.000 description 2
- QMNUDYFKZYBWQX-UHFFFAOYSA-N 1H-quinazolin-4-one Chemical class C1=CC=C2C(=O)N=CNC2=C1 QMNUDYFKZYBWQX-UHFFFAOYSA-N 0.000 description 1
- UJDQGRLTPBVSFN-TVNHLQOTSA-N 2-[(z)-[2-[[(6r,7r)-3-[[3-amino-4-(2-aminoethylcarbamoylamino)-2-methylpyrazol-1-ium-1-yl]methyl]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-7-yl]amino]-1-(5-amino-1,2,4-thiadiazol-3-yl)-2-oxoethylidene]amino]oxy-2-methylpropanoate;sulfuric acid Chemical compound OS(O)(=O)=O.CN1C(N)=C(NC(=O)NCCN)C=[N+]1CC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)C(=N/OC(C)(C)C([O-])=O)\C=3N=C(N)SN=3)[C@H]2SC1 UJDQGRLTPBVSFN-TVNHLQOTSA-N 0.000 description 1
- ZJHZBDRZEZEDGB-UHFFFAOYSA-N 4-[5-(4-carbamimidoylphenyl)furan-2-yl]benzenecarboximidamide Chemical compound C1=CC(C(=N)N)=CC=C1C1=CC=C(C=2C=CC(=CC=2)C(N)=N)O1 ZJHZBDRZEZEDGB-UHFFFAOYSA-N 0.000 description 1
- SAZHWFFOFMSQPA-UHFFFAOYSA-N 4-phenylcoumarin Chemical class C12=CC=CC=C2OC(=O)C=C1C1=CC=CC=C1 SAZHWFFOFMSQPA-UHFFFAOYSA-N 0.000 description 1
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 1
- 108091006112 ATPases Proteins 0.000 description 1
- 102000057290 Adenosine Triphosphatases Human genes 0.000 description 1
- 108020000946 Bacterial DNA Proteins 0.000 description 1
- 108020004256 Beta-lactamase Proteins 0.000 description 1
- 244000056139 Brassica cretica Species 0.000 description 1
- 235000003351 Brassica cretica Nutrition 0.000 description 1
- 235000003343 Brassica rupestris Nutrition 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 101100180402 Caenorhabditis elegans jun-1 gene Proteins 0.000 description 1
- 208000008964 Chemical and Drug Induced Liver Injury Diseases 0.000 description 1
- 241000588881 Chromobacterium Species 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 108010054814 DNA Gyrase Proteins 0.000 description 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical class C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 241001646719 Escherichia coli O157:H7 Species 0.000 description 1
- 206010017533 Fungal infection Diseases 0.000 description 1
- 229930182566 Gentamicin Natural products 0.000 description 1
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 1
- 108010015899 Glycopeptides Proteins 0.000 description 1
- 102000002068 Glycopeptides Human genes 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- YJQPYGGHQPGBLI-UHFFFAOYSA-N Novobiocin Natural products O1C(C)(C)C(OC)C(OC(N)=O)C(O)C1OC1=CC=C(C(O)=C(NC(=O)C=2C=C(CC=C(C)C)C(O)=CC=2)C(=O)O2)C2=C1C YJQPYGGHQPGBLI-UHFFFAOYSA-N 0.000 description 1
- 108010013639 Peptidoglycan Proteins 0.000 description 1
- 241000510545 Peucedanum morisonii Species 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- 241001147693 Staphylococcus sp. Species 0.000 description 1
- 208000037140 Steinert myotonic dystrophy Diseases 0.000 description 1
- 206010045240 Type I hypersensitivity Diseases 0.000 description 1
- 108010059993 Vancomycin Proteins 0.000 description 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 241001148470 aerobic bacillus Species 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229960000723 ampicillin Drugs 0.000 description 1
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 230000000244 anti-pseudomonal effect Effects 0.000 description 1
- 230000002365 anti-tubercular Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 102000006635 beta-lactamase Human genes 0.000 description 1
- 208000027119 bilirubin metabolic disease Diseases 0.000 description 1
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- QKSKPIVNLNLAAV-UHFFFAOYSA-N bis(2-chloroethyl) sulfide Chemical compound ClCCSCCCl QKSKPIVNLNLAAV-UHFFFAOYSA-N 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 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
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 229940036735 ceftaroline Drugs 0.000 description 1
- ZCCUWMICIWSJIX-NQJJCJBVSA-N ceftaroline fosamil Chemical compound S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OCC)C=2N=C(NP(O)(O)=O)SN=2)CC=1SC(SC=1)=NC=1C1=CC=[N+](C)C=C1 ZCCUWMICIWSJIX-NQJJCJBVSA-N 0.000 description 1
- 229960002405 ceftolozane Drugs 0.000 description 1
- 229960000479 ceftriaxone sodium Drugs 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- FJAQNRBDVKIIKK-UHFFFAOYSA-N chlorobiocin Natural products OC1C(OC=2C(=C3OC(=O)C(NC(=O)C=4C=C(CC=C(C)C)C(O)=CC=4)=C(O)C3=CC=2)Cl)OC(C)(C)C(OC)C1OC(=O)C1=CC=C(C)N1 FJAQNRBDVKIIKK-UHFFFAOYSA-N 0.000 description 1
- 201000001883 cholelithiasis Diseases 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000011284 combination treatment Methods 0.000 description 1
- WTIJXIZOODAMJT-DHFGXMAYSA-N coumermycin A1 Chemical compound O([C@@H]1[C@H](C(O[C@@H](OC=2C(=C3OC(=O)C(NC(=O)C=4C(=C(C(=O)NC=5C(OC6=C(C)C(O[C@H]7[C@@H]([C@H](OC(=O)C=8NC(C)=CC=8)[C@@H](OC)C(C)(C)O7)O)=CC=C6C=5O)=O)NC=4)C)=C(O)C3=CC=2)C)[C@@H]1O)(C)C)OC)C(=O)C1=CC=C(C)N1 WTIJXIZOODAMJT-DHFGXMAYSA-N 0.000 description 1
- 238000006880 cross-coupling reaction Methods 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940092559 enterobacter aerogenes Drugs 0.000 description 1
- 229960003276 erythromycin Drugs 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 229940124307 fluoroquinolone Drugs 0.000 description 1
- 235000021393 food security Nutrition 0.000 description 1
- 229960002518 gentamicin Drugs 0.000 description 1
- 244000000059 gram-positive pathogen Species 0.000 description 1
- 239000000383 hazardous chemical Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000011132 hemopoiesis Effects 0.000 description 1
- 208000036796 hyperbilirubinemia Diseases 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229960000318 kanamycin Drugs 0.000 description 1
- 229930027917 kanamycin Natural products 0.000 description 1
- SBUJHOSQTJFQJX-NOAMYHISSA-N kanamycin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N SBUJHOSQTJFQJX-NOAMYHISSA-N 0.000 description 1
- 229930182823 kanamycin A Natural products 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 230000005976 liver dysfunction Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 229940041033 macrolides Drugs 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 235000010460 mustard Nutrition 0.000 description 1
- 201000009340 myotonic dystrophy type 1 Diseases 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 229960002950 novobiocin Drugs 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- VHFGEBVPHAGQPI-MYYQHNLBSA-N oritavancin Chemical compound O([C@@H]1C2=CC=C(C(=C2)Cl)OC=2C=C3C=C(C=2O[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O[C@@H]2O[C@@H](C)[C@H](O)[C@@](C)(NCC=4C=CC(=CC=4)C=4C=CC(Cl)=CC=4)C2)OC2=CC=C(C=C2Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]2C(=O)N[C@@H]1C(N[C@H](C1=CC(O)=CC(O)=C1C=1C(O)=CC=C2C=1)C(O)=O)=O)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@@H](O)[C@H](C)O1 VHFGEBVPHAGQPI-MYYQHNLBSA-N 0.000 description 1
- 229960001607 oritavancin Drugs 0.000 description 1
- 108010006945 oritavancin Proteins 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 238000001050 pharmacotherapy Methods 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 238000011240 pooled analysis Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 1
- 230000018612 quorum sensing Effects 0.000 description 1
- 238000007430 reference method Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 229940041007 third-generation cephalosporins Drugs 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 229960003165 vancomycin Drugs 0.000 description 1
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 1
- 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 description 1
- 230000001018 virulence Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 230000003313 weakening effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- 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
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Изобретение относится к органической химии и микробиологии, конкретно к новому химическому соединению ряда бикумаринов, а именно к 3,3'-[(гексано-1,6-диилбис(азанедиил)]бис-(7-гидрокси-6-метоксикарбонил-2-оксо-2H-хромену) формулы (I),The invention relates to organic chemistry and microbiology, specifically to a new chemical compound of a number of bicoumarins, namely 3,3'-[(hexano-1,6-diylbis(azanediyl)]bis-(7-hydroxy-6-methoxycarbonyl-2- oxo-2H-chromene) of formula (I),
обладающему антибактериальной активностью.having antibacterial activity.
Указанные свойства позволяют предполагать возможность использования соединения в медицине.These properties suggest the possibility of using the compound in medicine.
Борьба с бактериальными и грибковыми инфекциями стала одной из основных проблем здравоохранения, продовольственной безопасности и развития. Устойчивость к антибактериальным препаратам угрожает эффективной профилактике и лечению все большего числа заболеваний и стала проблемой высокого риска в хирургии, трансплантации органов, лечении диабета и др. [Prestinaci, F.; Pezzotti, P.; Pantosti, A. Antimicrobial resistance: A global multifaceted phenomenon // Pathog. Glob. Health. - 2015. - V. 109. - P. 309-318; Chokshi, A.; Sifri, Z.; Cennimo, D.; Horng, H. Global contributors to antibiotic resistance // J. Global Infect. Dis. - 2019. - V. 11. - P. 36-42]. Несмотря на наличие большой группы веществ различных структурных типов, обладающих антибактериальной активностью - цефалоспорины [Toda, A.; Ohki, Н.; Yamanaka, Т.; Murano, K.; Okuda, S.; Kawabata, K.; Hatano, K.; Matsuda, K.; Misumi, K.; Itoh, K.; Satoh, K.; Inoue, S. Synthesis and SAR of novel parenteral anti-pseudomonal cephalosporins: Discovery of FR264205 // Bioorg. Med. Chem. Lett. - 2008. - V. 18. - P. 4849-4852], макролиды [Jenquin, J.R.; Yang, H.; Huigens, R.W.; Nakamori, M.; Berglund, J.A. Combination treatment of erythromycin and furamidine provides additive and synergistic rescue of mis-splicing in myotonic dystrophy type 1 models // ACS Pharmacol. Transl. Sci. - 2019. - V. 2. - P. 247-263] и гликопептиды [Corey, G.R.; Arhin, F.F.; Wikler, M.A.; Sahm, D.F.; Kreiswirth, B.N.; Mediavilla, J.R.; Good, S.; Fiset C.; Jiang, H.; Moeck, G.; Kabler, H.; Green, S.; O'Riordan, W. Pooled analysis of single-dose oritavancin in the treatment of acute bacterial skin and skin-structure infections caused by Gram-positive pathogens, including a large patient subset with methicillin-resistant Staphylococcus aureus // Int. J. Antimicrob. Agents - 2016. - V. 48. - P. 528-534], хинолоны и фторхинолоны [Pham, Т.D.; Ziora, Z.M., Blaskovich, M.A. Quinolone antibiotics // MedChemComm. - 2019. - V. 10. - P. 1719-1739; Naeem, A.; Badshah, S.L.; Muska, M.; Ahmad, N.; Khan, K. The current case of quinolones: synthetic approaches and antibacterial activity. Molecules - 2016. - V. 21. - Art. N 268; Gatadi, S.; Lakshmi, Т.V.; Nanduri, S. 4-(3H)-Quinazolinone derivatives: promising antibacterial drug leads // Eur. J. Med. Chem. - 2019. - V. 170. - P. 157-172], тиазолы [Cascioferro, S.; Parrino, В.; Carbone, D.; Schillaci, D.; Giovannetti, E.; Cirrincione, G.; Diana P. Thiazoles, their benzofused systems, and thiazolidinone derivatives: Versatile and promising tools to combat antibiotic resistance // J. Med Chem. - 2020. - V. 63. - P. 7923-7956] и триазины [Liu H., Long S., Rakesh K.P., Zha G.F. Structure-activity relationships (SAR) of triazine derivatives: Promising antimicrobial agents // Eur. J. Med. Chem. - 2020. - V. 185. - Art. N 111804] изыскание новых соединений с антибактериальным действием не ослабевает.Анализ литературных данных показывает, что в ряду антибактериальных препаратов, используемых в клинике, преобладают соединения известных классов, но они не могут в достаточной мере решить проблему бактериальных инфекций, поскольку часто обладают краткосрочным действием, связанным с развитием бактериальной устойчивости к лекарственным средствам [Theuretzbacher, U.; Gottwalt, S.; Beyer, P.; Butler, M.; Czaplewski, L.; Lienhardt, C.; Moja, L.; Paul, M.; Paulin, S.; Rex, J.H.; Silver, L.L.; Spigelman, M.; Thwaites, G.F.; Paccaud, J.P.; Harbarth, S. Analysis of the clinical antibacterial and antituberculosis pipeline // Lancet Infect. Dis. - 2019. - V. 19. - e40.].The fight against bacterial and fungal infections has become a major health, food security and development problem. Antibacterial drug resistance threatens effective prevention and treatment of an increasing number of diseases and has become a high-risk problem in surgery, organ transplantation, diabetes management, and others [Prestinaci, F.; Pezzotti, P.; Pantosti, A. Antimicrobial resistance: A global multifaceted phenomenon // Pathog. Glob. health. - 2015. - V. 109. - P. 309-318; Chokshi, A.; Sifri, Z.; Cennimo, D.; Horng, H. Global contributors to antibiotic resistance // J. Global Infect. Dis. - 2019. - V. 11. - P. 36-42]. Despite the presence of a large group of substances of various structural types with antibacterial activity - cephalosporins [Toda, A.; Ohki, N.; Yamanaka, T.; Murano, K.; Okuda, S.; Kawabata, K.; Hatano, K.; Matsuda, K.; Misumi, K.; Itoh, K.; Satoh, K.; Inoue, S. Synthesis and SAR of novel parenteral anti-pseudomonal cephalosporins: Discovery of FR264205 // Bioorg. Med. Chem. Lett. - 2008. - V. 18. - P. 4849-4852], macrolides [Jenquin, J.R.; Yang, H.; Huigens, R. W.; Nakamori, M.; Berglund, J.A. Combination treatment of erythromycin and furamidine provides additive and synergistic rescue of mis-splicing in myotonic dystrophy type 1 models // ACS Pharmacol. Transl. sci. - 2019. - V. 2. - P. 247-263] and glycopeptides [Corey, G.R.; Arhin, F. F.; Wikler, M.A.; Sahm, D. F.; Kreiswirth, B. N.; Mediavilla, J.R.; Good, S.; Fiset C.; Jiang, H.; Moeck, G.; Kabler, H.; Green, S.; O'Riordan, W. Pooled analysis of single-dose oritavancin in the treatment of acute bacterial skin and skin-structure infections caused by Gram-positive pathogens, including a large patient subset with methicillin-resistant Staphylococcus aureus // Int. J. Antimicrob. Agents - 2016. - V. 48. - P. 528-534], quinolones and fluoroquinolones [Pham, T.D.; Ziora, Z.M., Blaskovich, M.A. Quinolone antibiotics // MedChemComm. - 2019. - V. 10. - P. 1719-1739; Naem, A.; Badshah, S. L.; Muska, M.; Ahmad, N.; Khan, K. The current case of quinolones: synthetic approaches and antibacterial activity. Molecules - 2016. - V. 21. - Art. No. 268; Gatadi, S.; Lakshmi, T.V.; Nanduri, S. 4-(3H)-Quinazolinone derivatives: promising antibacterial drug leads // Eur. J. Med. Chem. - 2019. - V. 170. - P. 157-172], thiazoles [Cascioferro, S.; Parrino, V.; Carbone, D.; Schillaci, D.; Giovannetti, E.; Cirrincione, G.; Diana P. Thiazoles, their benzofused systems, and thiazolidinone derivatives: Versatile and promising tools to combat antibiotic resistance // J. Med Chem. - 2020. - V. 63. - P. 7923-7956] and triazines [Liu H., Long S., Rakesh K.P., Zha G.F. Structure-activity relationships (SAR) of triazine derivatives: Promising antimicrobial agents // Eur. J. Med. Chem. - 2020. - V. 185. - Art. N 111804] the search for new compounds with antibacterial action is not weakening. An analysis of the literature data shows that among the antibacterial drugs used in the clinic, compounds of known classes predominate, but they cannot adequately solve the problem of bacterial infections, since they often have a short-term effect, associated with the development of bacterial drug resistance [Theuretzbacher, U.; Gottwalt, S.; Beyer, P.; Butler, M.; Czaplewski, L.; Lienhardt, C.; Moja, L.; Paul, M.; Paulin, S.; Rex, J. H.; Silver, L. L.; Spigelman, M.; Thwaites, G. F.; Paccaud, J.P.; Harbarth, S. Analysis of the clinical antibacterial and antituberculosis pipeline // Lancet Infect. Dis. - 2019. - V. 19. - e40.].
В связи с этим, синтез и изучение новых химических соединений, обладающих широким спектром активности против грамотрицательных и грамположительных антибактериальных инфекций, представляет важную и актуальную задачу.In this regard, the synthesis and study of new chemical compounds with a wide spectrum of activity against gram-negative and gram-positive antibacterial infections is an important and urgent task.
Известны природные и синтетические кумарины, обладающие антибактериальной активностью [Al-Najedy, Y.K.; Kadhum, А.А. Н.; Al-Amiery, A.A.; Mohamad А.В. Coumarins: The Antimicrobial agents // Sys. Rev. Pharm. - 2017. - V. 8. - P. 62-70]. Известно, что антибактериальная активность клинически используемых природных кумаринов -новобиоцина (II), хлоробиоцина (III) и кумермицина A1 (IV) обусловлена их способностью к связыванию с субъединицей ДНК-гиразы бактерий и ингибированию суперспирализации ДНК путем блокирования активности АТФ-азы [Vanden Broeck, А.; McEwen, A.G.; Chebaro, Y.; Potier, N.; Lamour, V. Structural Basis for DNA Gyrase Interaction with Coumermycin A1 // J. Med. Chem. - 2019. - V. 62. - P. 4225-4231].Known natural and synthetic coumarins with antibacterial activity [Al-Najedy, Y.K.; Kadhum, A.A. N.; Al-Amiery, A.A.; Mohamad A.V. Coumarins: The Antimicrobial agents // Sys. Rev. Pharm. - 2017. - V. 8. - P. 62-70]. It is known that the antibacterial activity of clinically used natural coumarins - novobiocin (II), chlorobiocin (III) and cumermycin A1 (IV) is due to their ability to bind to the bacterial DNA gyrase subunit and inhibit DNA supercoiling by blocking the activity of ATPase [Vanden Broeck, A.; McEwen, A. G.; Chebaro, Y.; Potier, N.; Lamour, V. Structural Basis for DNA Gyrase Interaction with Coumermycin A1 // J. Med. Chem. - 2019. - V. 62. - P. 4225-4231].
Изучение кумаринов в качестве антибактериальных агентов выявило способность этих соединений к ингибированию образования биопленок бактериальными культурами [Lee, J.-H.; Kim, Y.-G.; Cho, H.S.; Ryu, S.Y.; Cho, M.H.; Lee, J. Coumarins reduce biofilm formation and the virulence of Escherichia coli O157:H7 // Phytomedicine - 2014. - V. 21. - P. 1037-1042; D'Almeida, R.E.; Molina, R.D.I.; Viola, С.M.; Luciardi, M.C.; Nieto Penalver, C.; Bardon, A.; Arena, M.E. Comparison of seven structurally related coumarins on the inhibition of Quorum sensing of Pseudomonas aeruginosa and Chromobacterium violaceutn II Bioorgan. Chem. - 2017. - V. 73. - P. 37-42; da Cunha, M.G.; Sardi, J.С.O.; Freires, I.A.; Franchin, M.; Rosalen, P.L. Antimicrobial, anti-adherence and antibiofilm activity against Staphylococcus aureus of a 4-phenyl coumarin derivative isolated from Brazilian geopropolis // Microbial Pathogenesis - 2020. - V. 139. - Art. N 103855].The study of coumarins as antibacterial agents revealed the ability of these compounds to inhibit the formation of biofilms by bacterial cultures [Lee, J.-H.; Kim, Y.-G.; Cho, H.S.; Ryu, S.Y.; Cho, M. H.; Lee, J. Coumarins reduce biofilm formation and the virulence of Escherichia coli O157:H7 // Phytomedicine - 2014. - V. 21. - P. 1037-1042; D'Almeida, R.E.; Molina, R.D.I.; Viola, C. M.; Luciardi, M.C.; Nieto Penalver, C.; Bardon, A.; Arena, M.E. Comparison of seven structurally related coumarins on the inhibition of Quorum sensing of Pseudomonas aeruginosa and Chromobacterium violaceutn II Bioorgan. Chem. - 2017. - V. 73. - P. 37-42; da Cunha, M. G.; Sardi, J.C.O.; Freires, I. A.; Franchin, M.; Rosalen, P.L. Antimicrobial, anti-adherence and antibiofilm activity against Staphylococcus aureus of a 4-phenyl coumarin derivative isolated from Brazilian geopropolis // Microbial Pathogenesis - 2020. - V. 139. - Art. No. 103855].
Известно, что образование бактериальной биопленки способствует развитию устойчивости к антибиотикам и лекарственным агентам. В оптимизации эффективности лечения инфекционных заболеваний помимо снижения дозы антибиотиков, значительную роль играет разрушение биопленок. В этой связи, значителен интерес к поиску новых антибактериальных агентов в ряду производных кумаринов [Hu, С.F.; Zhang, P.L.; Sui, Y.F.; Lv, J.S.; Ansari, M.F.; Battini, N.; Li, S.; Zhou, С.H.; Geng, R.X. Ethylenic conjugated coumarin thiazolidinediones as new efficient antimicrobial modulators against clinical methicillin-resistant Staphylococcus aureus // Bioorg. Chem. - 2020. - V. 94. - e103434.]. При этом внимание привлекают гибридные молекулы, содержащие кумарин-1,2,4-триазольные фрагменты [Ge, X.; Xu, Z. 1,2,4-Triazole hybrids with potential antibacterial activity against methicillin-resitant Staphylococcus aureus // Arch Pharm. - 2021. - V. 354. - e2000223] и кумарин-1,2,3-триазольные фрагменты [Lipeeva, А.V.; Zakharov, D.О.; Burova, L.G.; Frolova, T.S.; Baev, D.S.; Shirokikh, I.V.; Evstropov, A.N.; Sinitsyna, О.I.; Tolstikova, T.G.; Shults, E.E. Design, Synthesis and Antibacterial Activity of Coumarin-1,2,3-triazole Hybrids Obtained from Natural Furocoumarin Peucedanin // Molecules - 2019. - V. 24. - е2126]. Так, ранее, на основе природного кумарина пеурутеницина (V) [Шульц, Э.Э.; Петрова, Т.Н.; Шакиров, М.М.; Черняк, Е.И.; Покровский, Л.М.; Нехорошев, С.А.; Толстиков, Г.А. Кумарины корней горичника Морисона {Peucedanum morisonii Bess // Химия в интересах устойчивого развития. - 2003. - Т. 11. - С. 683-688] нами были получены гибридные соединения с антибактериальной активностью, содержащие в структуре фрагменты кумарина (V) и фурокумарина, соединенные 1H-1,2,3-триазол-4-ил)пент-1-инильным (VIa), 1H-1,2,3-триазол-4-ил)гекс-1-инильным (VIб) и 1H-1,2,3-триазол-4-ил)окт-1-инильным (VIв) фрагментом. Было показано, что антибактериальная активность значительно зависит от длины линкерной цепи. Минимальная ингибирующая концентрация (МИК) в отношении Staphylococcus aureus 209р (S. aureus) составила 250 (VIa), 425 (VIб), 51.25 (VIв) мкг/мл [Lipeeva, А.V.; Zakharov, D.О.; Burova, L.G.; Frolova, T.S.; Baev, D.S.; Shirokikh, I.V.; Evstropov, A.N.; Sinitsyna, О.I.; Tolstikova, T.G.; Shults, E.E. Design, Synthesis and Antibacterial Activity of Coumarin-1,2,3-triazole Hybrids Obtained from Natural Furocoumarin Peucedanin // Molecules - 2019. - V. 24. - e2126].It is known that the formation of bacterial biofilm contributes to the development of resistance to antibiotics and drug agents. In order to optimize the effectiveness of the treatment of infectious diseases, in addition to reducing the dose of antibiotics, the destruction of biofilms plays a significant role. In this regard, there is significant interest in the search for new antibacterial agents in the series of coumarin derivatives [Hu, C.F.; Zhang, P. L.; Sui, Y. F.; Lv, J.S.; Ansari, M. F.; Battini, N.; Li, S.; Zhou, C.H.; Geng, R.X. Ethylenic conjugated coumarin thiazolidinediones as new efficient antimicrobial modulators against clinical methicillin-resistant Staphylococcus aureus // Bioorg. Chem. - 2020. - V. 94. - e103434.]. At the same time, hybrid molecules containing coumarin-1,2,4-triazole fragments [Ge, X.; Xu, Z. 1,2,4-Triazole hybrids with potential antibacterial activity against methicillin-resitant Staphylococcus aureus // Arch Pharm. - 2021. - V. 354. - e2000223] and coumarin-1,2,3-triazole fragments [Lipeeva, A.V.; Zakharov, D.O.; Burova, L.G.; Frolova, T.S.; Baev, D.S.; Shirokikh, I.V.; Evstropov, A.N.; Sinitsyna, O.I.; Tolstikova, T. G.; Shults, E.E. Design, Synthesis and Antibacterial Activity of Coumarin-1,2,3-triazole Hybrids Obtained from Natural Furocumarin Peucedanin // Molecules - 2019. - V. 24. - e2126]. So, earlier, on the basis of natural coumarin peurutenicin (V) [Schultz, E.E.; Petrova, T.N.; Shakirov, M.M.; Chernyak, E.I.; Pokrovsky, L.M.; Nekhoroshev, S.A.; Tolstikov, G.A. Coumarins of Morison's mustard roots {Peucedanum morisonii Bess // Chemistry for Sustainable Development. - 2003. - T. 11. - S. 683-688] we have obtained hybrid compounds with antibacterial activity containing fragments of coumarin (V) and furocoumarin in the structure, connected 1H-1,2,3-triazol-4-yl) pent-1-ynyl (VIa), 1H-1,2,3-triazol-4-yl)hex-1-ynyl (VIb) and 1H-1,2,3-triazol-4-yl)oct-1- inyl (VIc) fragment. It has been shown that antibacterial activity is significantly dependent on the length of the linker chain. The minimum inhibitory concentration (MIC) against Staphylococcus aureus 209p (S. aureus) was 250 (VIa), 425 (VIb), 51.25 (VIc) μg/ml [Lipeeva, A.V.; Zakharov, D.O.; Burova, L.G.; Frolova, T.S.; Baev, D.S.; Shirokikh, I.V.; Evstropov, A.N.; Sinitsyna, O.I.; Tolstikova, T. G.; Shults, E.E. Design, Synthesis and Antibacterial Activity of Coumarin-1,2,3-triazole Hybrids Obtained from Natural Furocumarin Peucedanin // Molecules - 2019. - V. 24. - e2126].
Задачей предлагаемого изобретения является разработка нового антибактериального агента на основе доступных соединений: растительного кумарина пеурутеницина (V) и гексаметилендиамина.The objective of the present invention is the development of a new antibacterial agent based on the available compounds: the plant coumarin peurutenicin (V) and hexamethylenediamine.
Поставленная задача решается новым химическим соединением - 3,3'-[(гексано-1,6-диилбис(азанедиил)]бис-(7-гидрокси-6-метоксикарбонил-2-оксо-2H-хроменом) формулы (I), проявляющим выраженную антибактериальную активность.The problem is solved by a new chemical compound - 3,3'-[(hexano-1,6-diylbis(azanediyl)]bis-(7-hydroxy-6-methoxycarbonyl-2-oxo-2H-chromene) of formula (I), showing pronounced antibacterial activity.
Аналогом по структуре заявляемого соединения является кумариновый димер (VII) [Li, J.; Xue, X.Y.; Li, X.; Hou, Z.; Yang, X.H.; Qu, D.; Zhou, Y.; Zhang, Z.D.; Luo, X.X.; Li, J.Т.; Li, M.K. Synthesis of biscoumarin and dihydropyran derivatives as two novel classes of potential anti-bacterial derivatives // Arch. Pharm. Res. - 2016. - V. 39. - P. 1349-1355.] Это соединение проявило умеренную антабактериальную активность (МИК: 31.2-125 мкг/мл) в отношении двух грамм-положительных (Staphylococcus pneumoniae and S. aureus) и трех грамм-отрицательных штаммов бактерий (Escherichia coli (Е. coli), Enterobacter aerogenes (Е. aerogenes), Salmonella typhi (S. typhi)) и не уступало антибактериальным агентам: стрептомицину (МИК: 31.2-62.5 мкг/мл), канамицину (MIC: 62.5-125 мг/мл) и ванкомицину МИК: 31.2-250 мкг/мл). Способность к подавлению образования биопленки бактериями для этого соединения не известна.An analogue in the structure of the claimed compound is the coumarin dimer (VII) [Li, J.; Xue, X.Y.; Li, X.; Hou, Z.; Yang, X.H.; Qu, D.; Zhou, Y.; Zhang, Z.D.; Luo, X.X.; Li, J.T.; Li, M.K. Synthesis of biscoumarin and dihydropyran derivatives as two novel classes of potential anti-bacterial derivatives // Arch. Pharm. Res. - 2016. - V. 39. - P. 1349-1355.] This compound showed moderate antibacterial activity (MIC: 31.2-125 μg / ml) against two gram-positive (Staphylococcus pneumoniae and S. aureus) and three gram-positive (Staphylococcus pneumoniae and S. aureus) negative strains of bacteria (Escherichia coli (E. coli), Enterobacter aerogenes (E. aerogenes), Salmonella typhi (S. typhi)) and was not inferior to antibacterial agents: streptomycin (MIC: 31.2-62.5 µg/ml), kanamycin (MIC: 62.5-125 mg/ml) and vancomycin MIC: 31.2-250 µg/ml). The ability to inhibit biofilm formation by bacteria is not known for this compound.
Аналогом по свойствам заявляемого соединения является антибиотик цефалоспоринового ряда широкого спектра действия Цефтриаксон - {(6R,7R)-7[(Z)-2-(2-аминотиазол-4-ил)-2-(метоксиимино)ацетиламино]-3-[(2-метил-5,6-диоксо-1,2,5,6-тетрагидро-1,2,4-триазин-3-илтио)метил]-8-оксо-5-тиа-1-азабицикло[4.2.0]окт-2-ен-2-карбоновая кислота (в виде динатриевой соли)} (VIII).An analogue of the properties of the claimed compound is a broad-spectrum cephalosporin antibiotic Ceftriaxone - {(6R,7R)-7[(Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetylamino]-3-[ (2-methyl-5,6-dioxo-1,2,5,6-tetrahydro-1,2,4-triazin-3-ylthio)methyl]-8-oxo-5-thia-1-azabicyclo[4.2. 0]oct-2-en-2-carboxylic acid (as disodium salt)} (VIII).
Бактерицидная активность этого антибиотика 3-его поколения обусловлена подавлением синтеза клеточной стенки бактерий (нарушает синтез муреина). Препарат отличается устойчивостью к действию большинства β-лактамаз грамотрицательных и грамположительных микроорганизмов. Основными недостатками указанного препарата являются: аллергические реакции, изменения кроветворения, в том числе, тяжелая анемия, нарушения функций печени [Peker, Е.; Cagan, Е.; Dogan, М. Ceftriaxone induced toxic hepatitis // World J. Gastroenterology - 2009. - V. 15. - P. 2669-2671] и почек и влияние на ЦНС [Dickson, S.D.; Salazar, K.С. Diagnosis and management of immediate hypersensitivity reactions to cephalosporins // Clin Rev Allergy Immunol. - 2013. - V. 45. - P. 131-142; Bickford, C.L.; Spencer, A.P. Biliary sludge and hyperbilirubinemia associated with ceftriaxone in an adult: case report and review of the literature // Pharmacotherapy - 2005. - V. 25. - P. 1389-1395; Klein, N.C; Cunha, B.A. Third-generation cephalosporins. Med Clin North Am. - 1995. - V. 79. - N 4. - P. 705-719]. Известно, что цефтриаксон подавляет формирование биопленки штаммами Enterococcus faecalis [Thieme L, Klinger-Strobel M, Hartung A, Stein C, Makarewicz O, Pletz MW. In vitro synergism and anti-biofilm activity of ampicillin, gentamicin, ceftaroline and ceftriaxone against Enterococcus faecalis. J Antimicrob Chemother. 2018 Jun 1;73(6):1553-1561. doi: 10.1093/jac/dky051].The bactericidal activity of this 3rd generation antibiotic is due to the suppression of the synthesis of the bacterial cell wall (it disrupts the synthesis of murein). The drug is resistant to the action of most β-lactamases of gram-negative and gram-positive microorganisms. The main disadvantages of this drug are: allergic reactions, changes in hematopoiesis, including severe anemia, liver dysfunction [Peker, E.; Cagan, E.; Dogan, M. Ceftriaxone induced toxic hepatitis // World J. Gastroenterology - 2009. - V. 15. - P. 2669-2671] and kidneys and effects on the central nervous system [Dickson, S.D.; Salazar, K.S. Diagnosis and management of immediate hypersensitivity reactions to cephalosporins // Clin Rev Allergy Immunol. - 2013. - V. 45. - P. 131-142; Bickford, C. L.; Spencer, A.P. Biliary sludge and hyperbilirubinemia associated with ceftriaxone in an adult: case report and review of the literature // Pharmacotherapy - 2005. - V. 25. - P. 1389-1395; Klein, N.C.; Cunha, B.A. Third generation cephalosporins. Med Clin North Am. - 1995. - V. 79. - N 4. - P. 705-719]. Ceftriaxone is known to inhibit biofilm formation by strains of Enterococcus faecalis [Thieme L, Klinger-Strobel M, Hartung A, Stein C, Makarewicz O, Pletz MW. In vitro synergism and anti-biofilm activity of ampicillin, gentamicin, ceftaroline and ceftriaxone against Enterococcus faecalis. J Antimicrob Chemother. 2018 Jun 1;73(6):1553-1561. doi:10.1093/jac/dky051].
Способ получения соединения (I) ил пеуретеницина (V) реализуется по приведенной схеме на Фиг. 1. Окислительное бромирование пеурутеницина (V) бромом в присутствии оксона в хлористом метилене по ранее предложенной методике [Lipeeva, А.V.; Zakharov, D.О.; Gatilov, Y.V.; Pokrovskii, М.A.; Pokrovskii, A.G.; Shults, Е.Е. Design and synthesis of 3-(N-substituted)aminocoumarins as anticancer agents fron 3-bromopeuruthenicin // ChemistrySelect - 2019. - V. 4. - No 34. - P. 10197-10201] приводит к образованию 3-бромпупеурутеницина (IX) с выходом 86%. Реакцию кросс-сочетания бромида пеурутеницина (IX) с гексаметилендиамином проводили в ультразвуковой бане в присутствии каталитической системы Pd(OAc)2 - BINAP и триэтиламина (3 экв.) при нагревании до 80°С в течение 16 ч. После колоночной хроматографии на силикагеле выделили два продукта - 3-(6-аминогексиламино)пеурутеницин (X) (выход 56%) и бикумарин (I) (выход 22%) в виде желтых порошкообразных соединений. Последующее каталитическое аминирование 3-бромпеурутеницина (IX) действием аминопроизводного (X) в ДМФА в присутствии каталитической системы Pd(OAc)2 - Xantphos и основания триэтиламина (5 экв) привело к образованию бикумарина (I) (выход 53%).The method for obtaining compound (I) or peurethenicin (V) is carried out according to the scheme shown in FIG. 1. Oxidative bromination of peurutenicin (V) with bromine in the presence of oxon in methylene chloride according to the previously proposed method [Lipeeva, A.V.; Zakharov, D.O.; Gatilov, YV; Pokrovskii, M.A.; Pokrovskii, AG; Shults, E.E. Design and synthesis of 3-(N-substituted)aminocoumarins as anticancer agents fron 3-bromopeuruthenicin // ChemistrySelect - 2019. - V. 4. - No 34. - P. 10197-10201] leads to the formation of 3-bromopeurutenicin (IX) with a yield of 86%. The reaction of cross-coupling of peurutenicin bromide (IX) with hexamethylenediamine was carried out in an ultrasonic bath in the presence of the catalytic system Pd(OAc) 2 - BINAP and triethylamine (3 equiv.) by heating to 80°C for 16 h. After column chromatography on silica gel, two products - 3-(6-aminohexylamino)peurutenicin (X) (yield 56%) and bicoumarin (I) (yield 22%) in the form of yellow powdery compounds. Subsequent catalytic amination of 3-bromopeurutenicin (IX) by the action of the amino derivative (X) in DMF in the presence of the Pd(OAc) 2 - Xantphos catalytic system and triethylamine base (5 equiv) led to the formation of bicoumarin (I) (yield 53%).
Достоинством изобретения является способ получения нового соединения (I) путем химической модификации растительного кумарина пеурутеницина (V) и его антибактериальная активность. Физико-химические данные новых, впервые полученных соединений (I,Х) приведены в примере 1.The advantage of the invention is a method for obtaining a new compound (I) by chemical modification of the plant coumarin peurutenicin (V) and its antibacterial activity. Physico-chemical data of new, first obtained compounds (I, X) are given in example 1.
Биологическая активность соединения (I) изучалась путем определения острой токсичности и антибактериальной активности по отношению к штаммам грамположительных бактерий Staphylococcus aureus АТСС 6538 FDA 209Р, Staphylococcus aureus 12, Staphylococcus aureus 209 K-20, Staphylococcus aureus «Виотко», Staphylococcus aureus 209 P-20, Staphylococcus epidermidis K-20, Bacillus cereus ATCC 10702 и к грамотрицательному штамму Escherichia coli ATCC 25922 методом серийных разведений в питательной среде [Руководство по проведению доклинических исследований лекарственных средств. Часть первая / под ред. А.Н. Миронова. - М.: Гриф и К, 2012. - 944 с.; Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically, 11th Edition, 2018, 112 p. https://clsi.org/standarts/products/microbiology/documents/m07/]. Определяли МИК тест культур. МИК считалась наименьшая доза вещества, полностью подавлявшая рост бактерий. Ингибирование образования биопленки изучалось по модифицированному методу [Fletcher, М. The effects of culture concentration and age, time, and temperature on bacterial attachment to polystyrene // Can. J. Microbiol. - 1977. V. 23. - P. 1-6] по способности штаммов микроорганизмов прикрепляться на ПВХ-фрагменты интубационной трубки.The biological activity of compound (I) was studied by determining the acute toxicity and antibacterial activity against strains of gram-positive bacteria Staphylococcus aureus ATCC 6538 FDA 209P, Staphylococcus aureus 12, Staphylococcus aureus 209 K-20, Staphylococcus aureus "Viotko", Staphylococcus aureus 209 P-20 , Staphylococcus epidermidis K-20, Bacillus cereus ATCC 10702 and to the gram-negative strain of Escherichia coli ATCC 25922 by the method of serial dilutions in a nutrient medium [Guidelines for conducting preclinical studies of drugs. Part one / ed. A.N. Mironov. - M.: Grif and K, 2012. - 944 p.; Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically, 11th Edition, 2018, 112 p. https://clsi.org/standards/products/microbiology/documents/m07/]. The MIC test cultures were determined. The MIC was considered to be the lowest dose of a substance that completely inhibited bacterial growth. Inhibition of biofilm formation was studied by a modified method [Fletcher, M. The effects of culture concentration and age, time, and temperature on bacterial attachment to polystyrene // Can. J. Microbiol. - 1977. V. 23. - P. 1-6] according to the ability of strains of microorganisms to attach to PVC fragments of the endotracheal tube.
По результатам трех повторных экспериментов рассчитывали средние значения МИК и стандартную погрешность (M±SEM). Статистическую обработку данных проводили с помощью пакета программ "Statistika 8.0".Based on the results of three repeated experiments, the mean MIC values and standard error (M±SEM) were calculated. Statistical data processing was carried out using the Statistika 8.0 software package.
В качестве контроля антибактериальной активности был взят антибактериальный препарат «Цефтриаксон» производства ОАО «Синтез» - порошок для приготовления раствора для внутривенного или внутримышечного введения, содержащий действующее вещество - цефтриаксон натрия.As a control of antibacterial activity, the antibacterial drug "Ceftriaxone" manufactured by JSC "Sintez" was taken - a powder for preparing a solution for intravenous or intramuscular administration, containing the active substance - ceftriaxone sodium.
Острую токсичность определяли на аутбредных мышах массой 23-28 г при однократном внутрижелудочном способе введения. Параметры токсичности рассчитывали по методу Кербера. Введение соединения (I) в дозах 500, 1000 и 1200 мг/кг не приводило к гибели животных. Таким образом, LD50 соединения (I) - > 1200 мг/кг. Изучаемое вещество (I) относится к 3-ему классу умеренно опасных веществ.Acute toxicity was determined on outbred mice weighing 23-28 g with a single intragastric route of administration. Toxicity parameters were calculated using the Kerber method. The introduction of compound (I) at doses of 500, 1000 and 1200 mg/kg did not lead to the death of animals. Thus, LD 50 of compound (I) -> 1200 mg/kg. The studied substance (I) belongs to the 3rd class of moderately hazardous substances.
Результаты изучения антибактериальной активности соединения приведены в таблице 1.The results of studying the antibacterial activity of the compound are shown in Table 1.
Из данных таблицы видно, что соединение (I) обладает значительной антибактериальной активностью по отношению к шести штаммам стафилококка с минимальной ингибирующей концентрацией в пределах 1.71-8.33 мкг/мл. Его активность, в основном, находится на уровне используемого в медицине препарата. Соединение (I) в дозе 2 мкг/мл подавляет рост Bacillus cereus (строка 3), а в дозе 8 мкг/мл подавляет рост Escherichia coli (строка 4). Соединение (I) активно подавляет пленкообразование бактерий Staphylococcus epidermidis K-20, Staphylococcus aureus ATCC 6538 FDA 209P, Bacillus cereus ATCC 10702 и Escherichia coli ATCC 25922 в дозах 1.42-6.67 мкг/мл.It can be seen from the table data that compound (I) has significant antibacterial activity against six strains of staphylococcus with a minimum inhibitory concentration in the range of 1.71-8.33 μg/ml. Its activity is mainly at the level of the drug used in medicine. Compound (I) at a dose of 2 μg/ml inhibits the growth of Bacillus cereus (line 3), and at a dose of 8 μg/ml inhibits the growth of Escherichia coli (line 4). Compound (I) actively inhibits the film formation of bacteria Staphylococcus epidermidis K-20, Staphylococcus aureus ATCC 6538 FDA 209P, Bacillus cereus ATCC 10702 and Escherichia coli ATCC 25922 at doses of 1.42-6.67 μg/ml.
Дополнительно, определялась антибактериальная активность в отношении Staphylococcus aureus ATCC 6538 FDA 209P для исходных соединений пеурутеницина (V), 3-бромпеурутеницина (IX), а также для 3-(6-аминогексиламино)-7-гидрокси-6-метоксикарбонил-2-оксо-2H-хромена (X). При этом найдено, что кумарин (IX) ингибировал стафилококковую культуру в значительно более высокой концентрации, чем соединение (I): значение МИК для (IX) составляет 92.5±4.79 мкг/мл. Соединения (V) и (X) не подавляли рост культуры S. aureus по результатам первичного скрининга в дозах 500 и 250 мкг/мл.Additionally, the antibacterial activity against Staphylococcus aureus ATCC 6538 FDA 209P was determined for the parent compounds of peurutenicin (V), 3-brompeurenicin (IX), as well as for 3-(6-aminohexylamino)-7-hydroxy-6-methoxycarbonyl-2-oxo -2H-chromene (X). It was found that coumarin (IX) inhibited staphylococcal culture at a significantly higher concentration than compound (I): the MIC value for (IX) is 92.5±4.79 μg/ml. Compounds (V) and (X) did not inhibit the growth of S. aureus culture according to the results of primary screening at doses of 500 and 250 μg/ml.
Таким образом, новое соединение - 3,3'-[(гексано-1,6-диилбис(азанедиил)]бис-(7-гидрокси-6-метоксикарбонил-2-оксо-2H-хромен) (I), также как и Цефтриаксон, подавляет рост бактериальных штаммов Staphylococcus sp., Bacillus cereus и Escherichia coli, а также подавляет пленкообразование бактериями на уровне препарата сравнения Цефтриаксона.Thus, the new compound is 3,3'-[(hexano-1,6-diylbis(azanediyl)]bis-(7-hydroxy-6-methoxycarbonyl-2-oxo-2H-chromene) (I), as well as Ceftriaxone inhibits the growth of bacterial strains of Staphylococcus sp., Bacillus cereus and Escherichia coli, and also inhibits film formation by bacteria at the level of the reference drug Ceftriaxone.
Изобретение иллюстрируется следующими примерами.The invention is illustrated by the following examples.
Спектральные исследования выполнены в Химическом Сервисном Центре коллективного пользования СО РАН.Spectral studies were carried out at the Chemical Service Center for Collective Use of the Siberian Branch of the Russian Academy of Sciences.
Пример 1. Синтез 3,3'-[(гексано-1,6-диилбис(азанедиил)]бис-(7-гидрокси-6-метоксикарбонил-2-оксо-2H-хромена) (I). Стадия 1. Смесь 200 мг (0.67 ммоль) 3-бромпеурутеницина (IX), 110 мг (0.95 ммоль) гексаметилендиамина, 6 мг (0.0268 ммоль, 4 mol. %) Pd(OAc)2, 0.033 г BINAP (0.0536 ммоль, 8 мол %) и 0.27 мл (2.01 ммоль, 3 экв.) триэтиламина нагревали при 80°С в ультразвуковой бане в течение 16 часов. По окончании реакции реакционную массу обработали водой (5 мл) и хлороформом (10 мл), органический слой отделили, высушили над сульфатом магния и упарили. Остаток хроматографировали на колонке с силикагелем (элюент - хлороформ: этанол 10:0 → 10:3). Последовательно выделили две фракции. Растиранием фракций в эфире выделили продукты реакции в виде желтых порошков. Из 1-ой фракции - бикумарин (I) (81.5 мг, выход 22%); из второй фракции - 3-(6-аминогексиламино)пеурутеницин (X) (125.5 мг, выход 56%).Example 1 Synthesis of 3,3'-[(hexano-1,6-diylbis(azanediyl)]bis-(7-hydroxy-6-methoxycarbonyl-2-oxo-2H-chromene) (I) Step 1 Mixture 200 mg (0.67 mmol) 3-bromopeurutenicin (IX), 110 mg (0.95 mmol) hexamethylenediamine, 6 mg (0.0268 mmol, 4 mol %) Pd(OAc) 2 , 0.033 g BINAP (0.0536 mmol, 8 mol %) and 0.27 ml (2.01 mmol, 3 equiv.) triethylamine was heated at 80°C in an ultrasonic bath for 16 hours.After the reaction, the reaction mixture was treated with water (5 ml) and chloroform (10 ml), the organic layer was separated, dried over magnesium sulfate and The residue was chromatographed on a column of silica gel (eluent - chloroform: ethanol 10:0 → 10:3). Two fractions were successively isolated. Trituration of the fractions in ether gave the reaction products in the form of yellow powders. From the 1st fraction - bicoumarin (I) (81.5 mg, 22% yield), and from the second fraction, 3-(6-aminohexylamino)peurutenicin (X) (125.5 mg, 56% yield).
Стадия 2. К перемешиваемому раствору 200 мг (0.67 ммоль) 3-бромпеурутеницина (IX) и 260 мг (0.66 ммоль) 3-(6-аминогексиламино)пеурутеницина (X) в 5 мл ДМФА в токе аргона последовательно добавили 1.5 мг (2 мол %) Pd(OAc)2, 3.7 мг (2 мол %) Xantphos и 0.46 мл (.35 ммоль, 5 экв) триэтиламина. Реакционную смесь перемешивали при 120°С в течение 16 часов, затем перенесли на чашку Петри для свободного испарения растворителя. Остаток растворили в хлороформе и хроматографировали на колонке с силикагелем (элюент - хлороформ: этанол 10:1 → 10:3) последовательно выделили (I) 196 мг (53%) 3,3'-[(гексано-1,6-диилбис(азанедиил)]бис-(7-гидрокси-6-метоксикарбонил-2-оксо-2H-хромена) (I) и 35 мг (16%) 3-бромпеурутеницина (IX).
3,3'-[(Гексано-1,6-диилбис(азанедиил)]бис-(7-гидрокси-6-метоксикарбонил-2-оксо-2H-хромен) (I). Т. пл. 164-166°С (из эфира). ИК-спектр (ν, см-1): 3405, 3396, 2927, 2854, 2289, 2125, 1749, 1733, 1675, 1606, 1550, 1436, 1145, 1112, 1079, 995, 746, 723, 698, 667, 613. УФ-спектр (λmax, нм) (lgε): 230 (3.87), 275 (3.35), 301 (3.14), 333 (2.78), 349 (2.79). Спектр 1Н ЯМР (400 МГц, CDCl3, δ, м.д.): 1.55 (м, 4Н, СН2 3',4'), 1.70 (м, 2Н, NH), 1.80 (м, 4Н, СН2 3',4'), 3.39, 3.64 (оба м, по 2Н, СН2 1',6'), 4.21 (с, 6Н, 2×ОСН3), 6.99 (с, 2Н, 2×Н8), 8.19 (с, 2Н, 2×Н5), 8.41 (с, 2Н, 2×Н4). 11.32 (s, 2Н, 2×OH). Спектр 13С ЯМР (125 МГц, CDCl3) δC: 26.08 (С-2'), 26.35 (С-4'), 29.43 (С-3'), 29.67 (С-5'), 37.93 (С-6'), 39.23 (С-1'), 52.74 (2×ОСН3), 96.29 (2×С-8), 110.57 (2×С-4а), 110.95 (2×С-6), 111.48 (2×С-3), 120.70 (2×С-4), 143.20 (2×С-5), 158.68 (2×С-8а), 159.19 (2×С-2), 161.50 (2×С=O), 169.52 (2×С-7). Найдено, %: С 61.18; Н 5.16; N 4.86. C28H28N2O10. Вычислено, %: С 60.87; Н 5.11; N 5.07.3,3'-[(Hexano-1,6-diylbis(azanediyl)]bis-(7-hydroxy-6-methoxycarbonyl-2-oxo-2H-chromene) (I), mp 164-166°С (from ether) IR (v, cm -1 ): 3405, 3396, 2927, 2854, 2289, 2125, 1749, 1733, 1675, 1606, 1550, 1436, 1145, 1112, 1079, 995, 746, 723, 698, 667, 613. UV spectrum ( λmax , nm) (logε): 230 (3.87), 275 (3.35), 301 (3.14), 333 (2.78), 349 (2.79) 1 H NMR spectrum (400 MHz, CDCl 3 , δ, ppm): 1.55 (m, 4H, CH 2 3',4' ), 1.70 (m, 2H, NH), 1.80 (m, 4H, CH 2 3', 4' ), 3.39, 3.64 (both m, over 2H, CH 2 1',6' ), 4.21 (s, 6H, 2×OCH 3 ), 6.99 (s, 2H, 2×H 8 ), 8.19 (s , 2Н, 2×Н 5 ), 8.41 (s, 2Н, 2×Н 4 ) 11.32 (s, 2Н, 2×OH) 13 С NMR spectrum (125 MHz, CDCl 3 ) δ C : 26.08 (С- 2'), 26.35 (С-4'), 29.43 (С-3'), 29.67 (С-5'), 37.93 (С-6'), 39.23 (С-1'), 52.74 (2×OCH 3 ), 96.29 (2xC-8), 110.57 (2xC-4a), 110.95 (2xC-6), 111.48 (2xC-3), 120.70 (2xC-4), 143.20 (2 ×С-5), 158.68 (2×С-8a), 159.19 (2×С-2), 161.50 (2×С=O), 169.52 (2×С-7) Found, %: С 61.18; 5.16, N 4.86 C 28 H 28 N 2 O 10 Calculated, %: From 60.87; H 5.11; N 5.07.
3-(6-Аминогексиламино)-7-гидрокси-6-метоксикарбонил-2-оксо-2H-хромен {3-(6-аминогексиламино)пеурутеницин} (X). Т. пл. 118-119°С (из эфира). ИК-спектр (ν, см-1): 3428, 3286, 3054, 2929, 2856, 1722, 1668, 1646, 1600, 1550, 1504, 1436, 1371, 1309, 1259, 1197, 1145, 1116, 1076, 923, 873, 750, 725, 698. УФ-спектр (λmax, нм) (lgε): 332(3.55), 320(3.57), 285(3.81), 274(3.8), 231(4.48). Спектр 1Н ЯМР (400 МГц, CDCl3, δ, м.д.): 1.22 (м, 2Н, СН2 4'), 1.30 (уш. с, 2Н, NH2), 1.40 (м, 2Н, СН2 3'), 1.53 (м, 2Н, CH2 5'), 3.06-3.18 (м, 4Н, СН2 2',6'), 3.37 (м, 3Н, СН2 1' и NH). 3.96 (с, 3Н, ОСН3), 7.00 (с, 1Н, Н8), 7.94 (с, 1Н, Н5), 8.17 (с, 1Н, Н4), 11.06 (с, 1Н, ОН). Спектр 13С ЯМР (125 МГц, CDCl3) δС: 25.93 (С-2'), 26.10 (С-4'), 29.17 (С-3'). 29.41 (С-5'), 37.67 (С-6'), 38.98 (С-1'), 52.49 (ОСН3), 99.41 (С-8), 110.31 (С-4а), 113.39 (С-6), 114.63 (С-3), 133.95 (С-4), 149.49 (С-5), 158.43 (С-8а), 158.90 (С-2), 161.36 (С=O), 170.46 (С-7). Найдено, %: С 60.54; Н 6.16; N 8.26. C17H22N2O5. Вычислено, %: С 61.07; Н 6.63; N 8.38.3-(6-Aminohexylamino)-7-hydroxy-6-methoxycarbonyl-2-oxo-2H-chromene {3-(6-aminohexylamino)peurutenicin} (X). T. pl. 118-119°C (from ether). IR spectrum (ν, cm -1 ): 3428, 3286, 3054, 2929, 2856, 1722, 1668, 1646, 1600, 1550, 1504, 1436, 1371, 1309, 1259, 1197, 1145, 1116, 23 , 873, 750, 725, 698. UV spectrum ( λmax , nm) (logε): 332(3.55), 320(3.57), 285(3.81), 274(3.8), 231(4.48). 1 H NMR spectrum (400 MHz, CDCl 3 , δ, ppm): 1.22 (m, 2H, CH 2 4' ), 1.30 (br. s, 2H, NH 2 ), 1.40 (m, 2H, CH 2 3' ), 1.53 (m, 2H, CH 2 5' ), 3.06-3.18 (m, 4H, CH 2 2',6' ), 3.37 (m, 3H, CH 2 1' and NH). 3.96 (s, 3H, OCH 3), 7.00 (s, 1H, 8 H), 7.94 (s, 1H, H 5), 8.17 (s, 1H, H 4), 11.06 (s, 1H, OH). 13 C NMR spectrum (125 MHz, CDCl 3 ) δ C : 25.93 (C-2'), 26.10 (C-4'), 29.17 (C-3'). 29.41 (C-5'), 37.67 (C-6'), 38.98 (C-1'), 52.49 (OCH 3 ), 99.41 (C-8), 110.31 (C-4a), 113.39 (C-6) , 114.63 (C-3), 133.95 (C-4), 149.49 (C-5), 158.43 (C-8a), 158.90 (C-2), 161.36 (C=O), 170.46 (C-7). Found, %: С 60.54; H 6.16; N 8.26. C 17 H 22 N 2 O 5 . Calculated, %: С 61.07; H 6.63; N 8.38.
Пример 2. Исследование антибактериальной активности соединения (I). В качестве тест-культур использованы штаммы: Staphylococcus aureus ATCC 6538 FDA 209P, Bacillus cereus ATCC 10702, Escherichia coli ATCC 25922 из коллекции Федерального бюджетного учреждения науки Государственного научного центра прикладной микробиологии и биотехнологии (ФБУН ГНЦ ПМБ) г. Оболенск, а также штаммы из коллекции кафедры микробиологии, вирусологии, иммунологии Федерального государственного бюджетного образовательного учреждения высшего образования Новосибирского государственного медицинского университета (ФГБОУ ВО НГМУ) Минздрава России: клинически изолированный штамм - Staphylococcus aureus 12, Staphylococcus aureus 209 K-20, Staphylococcus aureus «Виотко», Staphylococcus aureus 209 P-20, Staphylococcus epidermidis K-20.Example 2 Study of the antibacterial activity of the compound (I). The following strains were used as test cultures: Staphylococcus aureus ATCC 6538 FDA 209P, Bacillus cereus ATCC 10702, Escherichia coli ATCC 25922 collections of the Department of Microbiology, Virology, Immunology of the Federal State Budgetary Educational Institution of Higher Education of the Novosibirsk State Medical University (FGBOU VO NSMU) of the Ministry of Health of Russia: clinically isolated strain - Staphylococcus aureus 12, Staphylococcus aureus 209 K-20, Staphylococcus aureus "Viotko", Staphylococcus aureus 209 P-20, Staphylococcus epidermidis K-20.
Культивирование бактерий проводили на агаровой и бульонной средах Мюллер-Хинтон в аэробных условиях при температуре 37°С. Время культивирования составляло 1-2 дня. Анализ антибактериальной активности проводили методом последовательных разведений в жидкой среде в общем объеме 1 мл. Все соединения предварительно растворяли в 0.05 мл диметилсульфоксида и доводили до нужной концентрации 0.9% раствором хлорида натрия и питательным бульоном. Вносимую дозу суточных культур бактерий определяли по Мс Farland и контролировали высевом на плотную питательную среду. Минимальной ингибирующей концентрацией (МИК) считалась наименьшая доза вещества, полностью подавлявшая рост бактерий. Отсутствие признаков роста в жидкой среде контролировали путем высева на поверхность агаровой среды с последующей инкубацией в стандартных условиях. В качестве отрицательного контроля тест-культуру вводили в 1 мл бульона и культивировали в тех же условиях с последующим посевом на агаровую питательную среду и учетом роста бактерий. По результатам повторных экспериментов рассчитаны средние значения МИК и стандартная погрешность (M±SEM) [ГОСТ Р ИСО 20776-1-2010. Часть 1. Референтный метод лабораторного исследования активности антимикробных агентов против быстрорастущих аэробных бактерий, вызывающих инфекционные болезни; Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically, 11th Edition, 2018, 112 p. https://clsi.org/standarts/products/microbiology/documents/m07/; Руководство по проведению доклинических исследований лекарственных средств. Часть первая / под ред. А.Н. Миронова. - М.: Гриф и К, 2012. - 944 с.].Bacteria were cultivated on Muller-Hinton agar and broth media under aerobic conditions at a temperature of 37°C. The cultivation time was 1-2 days. The analysis of antibacterial activity was carried out by the method of serial dilutions in a liquid medium in a total volume of 1 ml. All compounds were preliminarily dissolved in 0.05 ml of dimethyl sulfoxide and brought to the desired concentration with 0.9% sodium chloride solution and nutrient broth. The applied dose of daily cultures of bacteria was determined by MS Farland and controlled by inoculation on a dense nutrient medium. The minimum inhibitory concentration (MIC) was considered to be the lowest dose of a substance that completely inhibited bacterial growth. The absence of signs of growth in the liquid medium was controlled by inoculation on the surface of the agar medium, followed by incubation under standard conditions. As a negative control, the test culture was introduced into 1 ml of broth and cultivated under the same conditions, followed by inoculation on an agar nutrient medium and taking into account the growth of bacteria. Based on the results of repeated experiments, the average MIC values and standard error (M±SEM) were calculated [GOST R ISO 20776-1-2010. Part 1. Reference method for laboratory testing of the activity of antimicrobial agents against rapidly growing aerobic bacteria that cause infectious diseases; Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically, 11th Edition, 2018, 112 p. https://clsi.org/standards/products/microbiology/documents/m07/; Guidelines for conducting preclinical studies of drugs. Part one / ed. A.N. Mironov. - M.: Grif and K, 2012. - 944 p.].
Пример 3. Моделирование пленкообразования проводили на ПВХ-фрагментах интубационной трубки, которые полностью погружались в жидкую питательную среду с соответствующим разведением субстанции, после чего вносилась посевная доза микроорганизмов. На вторые сутки фрагмент трубки извлекали, подвергали отмывке с использованием солевого раствора, а затем помещали в 0.02% раствор этилендиаминтетрауксусной кислоты на 10 минут для открепления бактериальных клеток от субстрата, далее производили высев на плотные питательные среды с последующей инкубацией в стандартных условиях. Определяли минимальную ингибирующую концентрацию.Example 3. Modeling of film formation was carried out on PVC fragments of an endotracheal tube, which were completely immersed in a liquid nutrient medium with an appropriate dilution of the substance, after which a seed dose of microorganisms was introduced. On the second day, the tube fragment was removed, washed with a saline solution, and then placed in a 0.02% solution of ethylenediaminetetraacetic acid for 10 minutes to detach bacterial cells from the substrate, then seeded on solid nutrient media, followed by incubation under standard conditions. The minimum inhibitory concentration was determined.
Таким образом, в результате исследования установлено, что соединение (I) обладает выраженным антибактериальным эффектом в отношении условно-патогенных культур бактерий штаммов Staphylococcus aureus, Bacillus cereus и Escherichia coli, а также подавляет пленкообразование бактериями на уровне препарата сравнения цефтриаксона.Thus, as a result of the study, it was found that compound (I) has a pronounced antibacterial effect against opportunistic bacterial cultures of strains of Staphylococcus aureus, Bacillus cereus and Escherichia coli, and also inhibits film formation by bacteria at the level of the reference drug ceftriaxone.
Таким образом, предлагаемое изобретение обладает следующими преимуществами, а именно:Thus, the present invention has the following advantages, namely:
- Антибактериальная активность в отношении культур клеток условно-патогенных бактерий штаммов Staphylococcus aureus, Bacillus cereus и Escherichia coli.- Antibacterial activity against cell cultures of opportunistic bacteria strains of Staphylococcus aureus, Bacillus cereus and Escherichia coli.
- Ингибирование пленкообразования бактериальными штаммами S. aureus, В. cereus и Е. coli.- Inhibition of film formation by bacterial strains of S. aureus, B. cereus and E. coli.
- Низкая токсичность на животных- Low toxicity on animals
- Использование для получения заявляемого соединения доступного кумарина пеурутеницина.- The use of the available coumarin peurutenicin to obtain the claimed compound.
Исследование выполнено при частичной финансовой поддержке Российского фонда фундаментальных исследований (грант №19-53-44003).The study was supported in part by the Russian Foundation for Basic Research (grant no. 19-53-44003).
Claims (3)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| RU2021114978A RU2764522C1 (en) | 2021-05-25 | 2021-05-25 | 3,3'[(hexano-1,6-diylbis (azanediyl)]bis-(7-hydroxy-6-methoxycarbonyl-2-oxo-2h-chromene) with antibacterial activity |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| RU2021114978A RU2764522C1 (en) | 2021-05-25 | 2021-05-25 | 3,3'[(hexano-1,6-diylbis (azanediyl)]bis-(7-hydroxy-6-methoxycarbonyl-2-oxo-2h-chromene) with antibacterial activity |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| RU2764522C1 true RU2764522C1 (en) | 2022-01-18 |
Family
ID=80040568
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| RU2021114978A RU2764522C1 (en) | 2021-05-25 | 2021-05-25 | 3,3'[(hexano-1,6-diylbis (azanediyl)]bis-(7-hydroxy-6-methoxycarbonyl-2-oxo-2h-chromene) with antibacterial activity |
Country Status (1)
| Country | Link |
|---|---|
| RU (1) | RU2764522C1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2835303C1 (en) * | 2024-07-23 | 2025-02-24 | Федеральное государственное бюджетное образовательное учреждение высшего образования "Саратовский национальный исследовательский государственный университет имени Н.Г. Чернышевского" | 5-amino-1-(2,4-dinitrophenyl)-3-(3-nitrophenyl)-1h-pyrazole-4-carboxamide, having antimicrobial properties |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2598028C2 (en) * | 2011-04-13 | 2016-09-20 | Астразенека Аб | Chromenone compounds as pi3-kinase inhibitors for treating cancer |
| RU2678969C1 (en) * | 2018-03-28 | 2019-02-05 | Общество С Ограниченной Ответственностью "Сир" | Antiarrhythmic drug based on hybrid molecules of amlodipine with (7-methoxicumarin-4-yl)acetic acid |
| WO2019178119A1 (en) * | 2018-03-12 | 2019-09-19 | President And Fellows Of Harvard College | Aminocoumarin compounds and methods of their use |
-
2021
- 2021-05-25 RU RU2021114978A patent/RU2764522C1/en active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2598028C2 (en) * | 2011-04-13 | 2016-09-20 | Астразенека Аб | Chromenone compounds as pi3-kinase inhibitors for treating cancer |
| WO2019178119A1 (en) * | 2018-03-12 | 2019-09-19 | President And Fellows Of Harvard College | Aminocoumarin compounds and methods of their use |
| RU2678969C1 (en) * | 2018-03-28 | 2019-02-05 | Общество С Ограниченной Ответственностью "Сир" | Antiarrhythmic drug based on hybrid molecules of amlodipine with (7-methoxicumarin-4-yl)acetic acid |
Non-Patent Citations (3)
| Title |
|---|
| LI J. et al. Arch. Pharm. Res., vol.39, 2016, P. 1349-1355. * |
| LI J. et al. Arch. Pharm. Res., vol.39, 2016, P. 1349-1355. LIPEEVA А.V. et al. Molecules, vol.24, 2019. - e2126. * |
| LIPEEVA А.V. et al. Molecules, vol.24, 2019. - e2126. * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2835303C1 (en) * | 2024-07-23 | 2025-02-24 | Федеральное государственное бюджетное образовательное учреждение высшего образования "Саратовский национальный исследовательский государственный университет имени Н.Г. Чернышевского" | 5-amino-1-(2,4-dinitrophenyl)-3-(3-nitrophenyl)-1h-pyrazole-4-carboxamide, having antimicrobial properties |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Hokai et al. | Auranofin and related heterometallic gold (I)–thiolates as potent inhibitors of methicillin-resistant Staphylococcus aureus bacterial strains | |
| Karataş et al. | Synthesis, characterization and antimicrobial activities of novel silver (I) complexes with coumarin substituted N-heterocyclic carbene ligands | |
| Hannoun et al. | Synthesis and antibacterial evaluation of a novel library of 2-(thiazol-5-yl)-1, 3, 4-oxadiazole derivatives against methicillin-resistant Staphylococcus aureus (MRSA) | |
| Huigens Iii et al. | Inhibition of Acinetobacter baumannii, Staphylococcus aureus and Pseudomonas aeruginosa biofilm formation with a class of TAGE-triazole conjugates | |
| Vik et al. | (+)-Agelasine D: improved synthesis and evaluation of antibacterial and cytotoxic activities | |
| JP6896628B2 (en) | Antimicrobial polymyxin for the treatment of bacterial infections | |
| MX2014015249A (en) | N-substituted second generation derivatives of antifungal antibiotic amphotericin b and methods of their preparation and application. | |
| Üstün et al. | Synthesis, characterization, antimicrobial and antibiofilm activity, and molecular docking analysis of NHC precursors and their Ag-NHC complexes | |
| Elshaarawy et al. | Antibacterial susceptibility of new copper (II) N-pyruvoyl anthranilate complexes against marine bacterial strains–In search of new antibiofouling candidate | |
| Danilchenko et al. | Antimicrobial activity of new 5-(furan-2-yl)-4-amino-1, 2, 4-triazole-3-thiol derivatives | |
| Ali et al. | Synthesis, characterization and antibacterial evaluation of oxoazetidin? benzene sulfonamide derivatives as a hybrid antimicrobial agents | |
| RU2764522C1 (en) | 3,3'[(hexano-1,6-diylbis (azanediyl)]bis-(7-hydroxy-6-methoxycarbonyl-2-oxo-2h-chromene) with antibacterial activity | |
| WO2019022637A1 (en) | Antiseptic medicinal agent | |
| US6395773B1 (en) | Anti-drug resistant strain agents and antichlamydia agents | |
| CN103880930B (en) | Vancomycin analog derivative and preparation method thereof and pharmaceutical usage | |
| Kaplancıklı | Synthesis of some novel Carbazole derivatives and evaluation of their antimicrobial activity | |
| US20060100291A1 (en) | Antibacterial compounds | |
| Varshney et al. | Synthesis and evaluation of in vitro antimicrobial activity of novel 2, 3-disubstituted-4-thiazolidinones from fatty acid hydrazides | |
| RU2757741C1 (en) | Ciprofloxacin derivative with antibacterial activity against antibiotic-resistant strains of microorganisms | |
| Venepally et al. | Synthesis and biological evaluation of 3, 6-dialkylsubstituted-[1, 2, 4] triazolo [3, 4-b][1, 3, 4] thiadiazoles | |
| CN110878051A (en) | 5- (2-hydroxybenzoyl) pyrazole compound and preparation method and application thereof | |
| US20170355671A1 (en) | Peripherally substituted monocyclic beta-lactams | |
| RU2781220C1 (en) | 6-(p-TOLYL)-2-PHENYL-5-(2,2,2-TRICHLORACETIL)-4H-1,3-DIOXIN-4-OH, SHOWING ANTIMICROBIAL ACTIVITY | |
| Saverina et al. | Synthesis and antibacterial activity of new bis-quaternary ammonium compounds based on 2, 5-diformylfuran and pentaerythritol | |
| RU2817115C1 (en) | 5-substituted 5-trichloroacetyl-2-phenyl-4h-1,3-dioxin-4-ones, having antimicrobial activity |