CN113336675A - Antibacterial guanidine oligomer with anti-drug resistance and preparation method and application thereof - Google Patents
Antibacterial guanidine oligomer with anti-drug resistance and preparation method and application thereof Download PDFInfo
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- CN113336675A CN113336675A CN202110400321.0A CN202110400321A CN113336675A CN 113336675 A CN113336675 A CN 113336675A CN 202110400321 A CN202110400321 A CN 202110400321A CN 113336675 A CN113336675 A CN 113336675A
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- formula
- mixture
- antibacterial
- oligomer
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- 230000000844 anti-bacterial effect Effects 0.000 title claims abstract description 70
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 title claims abstract description 62
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 title claims abstract description 31
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- 206010059866 Drug resistance Diseases 0.000 title abstract description 18
- 239000000463 material Substances 0.000 claims abstract description 78
- 239000000203 mixture Substances 0.000 claims description 67
- -1 dimethylsulfydryl Chemical group 0.000 claims description 41
- 239000000178 monomer Substances 0.000 claims description 40
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 20
- 239000003814 drug Substances 0.000 claims description 18
- 229940079593 drug Drugs 0.000 claims description 18
- 238000003756 stirring Methods 0.000 claims description 18
- 238000002156 mixing Methods 0.000 claims description 17
- 238000005303 weighing Methods 0.000 claims description 17
- 239000007787 solid Substances 0.000 claims description 16
- 241000191967 Staphylococcus aureus Species 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 13
- 241000588724 Escherichia coli Species 0.000 claims description 12
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 claims description 11
- WOOWBQQQJXZGIE-UHFFFAOYSA-N n-ethyl-n-propan-2-ylpropan-2-amine Chemical compound CCN(C(C)C)C(C)C.CCN(C(C)C)C(C)C WOOWBQQQJXZGIE-UHFFFAOYSA-N 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 9
- 241000588626 Acinetobacter baumannii Species 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- 239000007864 aqueous solution Substances 0.000 claims description 8
- CPEKAXYCDKETEN-UHFFFAOYSA-N benzoyl isothiocyanate Chemical compound S=C=NC(=O)C1=CC=CC=C1 CPEKAXYCDKETEN-UHFFFAOYSA-N 0.000 claims description 8
- 238000004108 freeze drying Methods 0.000 claims description 8
- 239000011261 inert gas Substances 0.000 claims description 8
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 8
- 241000588697 Enterobacter cloacae Species 0.000 claims description 7
- 230000000845 anti-microbial effect Effects 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 7
- 230000002194 synthesizing effect Effects 0.000 claims description 7
- 241000589517 Pseudomonas aeruginosa Species 0.000 claims description 6
- PBAYPBWWGUUNNB-UHFFFAOYSA-N diiodoamine Chemical class INI PBAYPBWWGUUNNB-UHFFFAOYSA-N 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- 244000063299 Bacillus subtilis Species 0.000 claims description 5
- 235000014469 Bacillus subtilis Nutrition 0.000 claims description 5
- 241000194032 Enterococcus faecalis Species 0.000 claims description 5
- 241000588747 Klebsiella pneumoniae Species 0.000 claims description 5
- 229940032049 enterococcus faecalis Drugs 0.000 claims description 5
- 230000004048 modification Effects 0.000 claims description 5
- 238000012986 modification Methods 0.000 claims description 5
- 229910021642 ultra pure water Inorganic materials 0.000 claims description 3
- 239000012498 ultrapure water Substances 0.000 claims description 3
- 239000004599 antimicrobial Substances 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
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- 230000010355 oscillation Effects 0.000 claims description 2
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- 244000052616 bacterial pathogen Species 0.000 abstract description 14
- 210000000170 cell membrane Anatomy 0.000 abstract description 12
- 230000007246 mechanism Effects 0.000 abstract description 10
- 230000001954 sterilising effect Effects 0.000 abstract description 7
- 238000004659 sterilization and disinfection Methods 0.000 abstract description 7
- 210000000601 blood cell Anatomy 0.000 abstract description 6
- 210000004369 blood Anatomy 0.000 abstract description 5
- 239000008280 blood Substances 0.000 abstract description 5
- 230000009977 dual effect Effects 0.000 abstract description 5
- 238000001228 spectrum Methods 0.000 abstract description 5
- 231100000053 low toxicity Toxicity 0.000 abstract description 2
- 239000013611 chromosomal DNA Substances 0.000 abstract 1
- 229920001610 polycaprolactone Polymers 0.000 description 36
- 241000894006 Bacteria Species 0.000 description 16
- 230000002949 hemolytic effect Effects 0.000 description 15
- 108020004414 DNA Proteins 0.000 description 13
- 150000001875 compounds Chemical class 0.000 description 12
- 230000001988 toxicity Effects 0.000 description 10
- 231100000419 toxicity Toxicity 0.000 description 10
- 239000004632 polycaprolactone Substances 0.000 description 9
- 125000001841 imino group Chemical group [H]N=* 0.000 description 8
- 239000012528 membrane Substances 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 7
- 229920000642 polymer Polymers 0.000 description 7
- XJMOSONTPMZWPB-UHFFFAOYSA-M propidium iodide Chemical compound [I-].[I-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CCC[N+](C)(CC)CC)=C1C1=CC=CC=C1 XJMOSONTPMZWPB-UHFFFAOYSA-M 0.000 description 7
- 239000003242 anti bacterial agent Substances 0.000 description 6
- 238000010586 diagram Methods 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 230000003115 biocidal effect Effects 0.000 description 5
- 238000000502 dialysis Methods 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 108020000946 Bacterial DNA Proteins 0.000 description 4
- 230000001580 bacterial effect Effects 0.000 description 4
- 230000035772 mutation Effects 0.000 description 4
- KIDHWZJUCRJVML-UHFFFAOYSA-N putrescine Chemical compound NCCCCN KIDHWZJUCRJVML-UHFFFAOYSA-N 0.000 description 4
- 238000010186 staining Methods 0.000 description 4
- 238000011161 development Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 3
- 229930027917 kanamycin Natural products 0.000 description 3
- 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 3
- 229960000318 kanamycin Drugs 0.000 description 3
- 229930182823 kanamycin A Natural products 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 230000008685 targeting Effects 0.000 description 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- GKXVJHDEWHKBFH-UHFFFAOYSA-N [2-(aminomethyl)phenyl]methanamine Chemical compound NCC1=CC=CC=C1CN GKXVJHDEWHKBFH-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000031018 biological processes and functions Effects 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000011109 contamination Methods 0.000 description 2
- 238000002296 dynamic light scattering Methods 0.000 description 2
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 230000002147 killing effect Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000000813 microbial effect Effects 0.000 description 2
- 244000052769 pathogen Species 0.000 description 2
- 230000002572 peristaltic effect Effects 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- XFNJVJPLKCPIBV-UHFFFAOYSA-N trimethylenediamine Chemical compound NCCCN XFNJVJPLKCPIBV-UHFFFAOYSA-N 0.000 description 2
- 238000010200 validation analysis Methods 0.000 description 2
- PWGJDPKCLMLPJW-UHFFFAOYSA-N 1,8-diaminooctane Chemical compound NCCCCCCCCN PWGJDPKCLMLPJW-UHFFFAOYSA-N 0.000 description 1
- GXVUZYLYWKWJIM-UHFFFAOYSA-N 2-(2-aminoethoxy)ethanamine Chemical compound NCCOCCN GXVUZYLYWKWJIM-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- FWBHETKCLVMNFS-UHFFFAOYSA-N 4',6-Diamino-2-phenylindol Chemical compound C1=CC(C(=N)N)=CC=C1C1=CC2=CC=C(C(N)=N)C=C2N1 FWBHETKCLVMNFS-UHFFFAOYSA-N 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- FDLQZKYLHJJBHD-UHFFFAOYSA-N [3-(aminomethyl)phenyl]methanamine Chemical compound NCC1=CC=CC(CN)=C1 FDLQZKYLHJJBHD-UHFFFAOYSA-N 0.000 description 1
- ISKQADXMHQSTHK-UHFFFAOYSA-N [4-(aminomethyl)phenyl]methanamine Chemical compound NCC1=CC=C(CN)C=C1 ISKQADXMHQSTHK-UHFFFAOYSA-N 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 229920002118 antimicrobial polymer Polymers 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- PBAYDYUZOSNJGU-UHFFFAOYSA-N chelidonic acid Natural products OC(=O)C1=CC(=O)C=C(C(O)=O)O1 PBAYDYUZOSNJGU-UHFFFAOYSA-N 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- NAQMVNRVTILPCV-UHFFFAOYSA-N hexane-1,6-diamine Chemical compound NCCCCCCN NAQMVNRVTILPCV-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000012567 medical material Substances 0.000 description 1
- 230000036457 multidrug resistance Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
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- 238000001878 scanning electron micrograph Methods 0.000 description 1
- 238000004626 scanning electron microscopy Methods 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
- A01N47/40—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having a double or triple bond to nitrogen, e.g. cyanates, cyanamides
- A01N47/42—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having a double or triple bond to nitrogen, e.g. cyanates, cyanamides containing —N=CX2 groups, e.g. isothiourea
- A01N47/44—Guanidine; Derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C277/08—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups of substituted guanidines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
- C07C279/08—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by singly-bound oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
- C07C279/12—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by nitrogen atoms not being part of nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/16—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to carbon atoms of rings other than six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C335/04—Derivatives of thiourea
- C07C335/06—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to acyclic carbon atoms
- C07C335/08—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to acyclic carbon atoms of a saturated carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C335/04—Derivatives of thiourea
- C07C335/06—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to acyclic carbon atoms
- C07C335/10—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
- C07C335/12—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton the carbon skeleton containing six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C335/04—Derivatives of thiourea
- C07C335/14—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to carbon atoms of rings other than six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C335/04—Derivatives of thiourea
- C07C335/24—Derivatives of thiourea containing any of the groups, X being a hetero atom, Y being any atom
- C07C335/26—Y being a hydrogen or a carbon atom, e.g. benzoylthioureas
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C335/30—Isothioureas
- C07C335/32—Isothioureas having sulfur atoms of isothiourea groups bound to acyclic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J7/00—Chemical treatment or coating of shaped articles made of macromolecular substances
- C08J7/12—Chemical modification
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2367/00—Characterised by the use of polyesters obtained by reactions forming a carboxylic ester link in the main chain; Derivatives of such polymers
- C08J2367/04—Polyesters derived from hydroxy carboxylic acids, e.g. lactones
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- 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
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- Chemical & Material Sciences (AREA)
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- Life Sciences & Earth Sciences (AREA)
- Health & Medical Sciences (AREA)
- Wood Science & Technology (AREA)
- Pest Control & Pesticides (AREA)
- Dentistry (AREA)
- General Health & Medical Sciences (AREA)
- Plant Pathology (AREA)
- Zoology (AREA)
- Environmental Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
- Agronomy & Crop Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses an antibacterial guanidine oligomer with drug resistance, a preparation method and application thereof in the field of materials. The structure disclosed by the invention has a dual antibacterial mechanism of destroying cell membranes and combining with chromosomal DNA, has the characteristics of quick sterilization and drug resistance, and shows broad antibacterial spectrum. In addition, the structure has low toxicity to blood cells and high safety in blood. Meanwhile, the structure can be applied to materials, the guanidine oligomer is modified on the surface of the materials, the modified materials have an antibacterial function, the modified materials are further manufactured into devices in a certain shape, and the devices also have the antibacterial function and can quickly and efficiently kill various pathogenic bacteria.
Description
Technical Field
The invention relates to the field of pharmaceutical and chemical materials, in particular to an antibacterial guanidine oligomer with drug resistance and a preparation method and application thereof.
Background
The microbial contamination of the surfaces of medical materials, food materials and other materials in the field of materials has become a common and serious problem, the development of the high-efficiency antibacterial agent for endowing the surfaces of the materials with antibacterial capability has become an urgent need of the industry, and recently, the concept of the anti-drug-resistance antibacterial agent is established, and the aim of solving the microbial contamination problem of the materials is to introduce the antibacterial agent into the materials.
The anti-drug resistant antimicrobial incorporated into the material should have the following characteristics: 1) has good killing effect on pathogens with multi-drug resistance, has good killing effect on various pathogenic bacteria, and has better antibacterial broad spectrum. 2) Can effectively kill drug-resistant bacteria in the using process, and the rate of drug resistance of the bacteria to the drug-resistant bacteria is low. 3) The material has good compatibility, and the antibacterial agent can be connected to the material or doped into the material through chemical reaction. It is well known that the root cause of antibiotic resistance is mutation of its target, rendering drugs of various mechanisms of action ineffective. Thus, if a drug can be targeted to multiple targets, or its target involves a complex biological process, the probability of developing drug resistance will be greatly reduced. Compounds of this type of antimicrobial polymers meet the concept of resistance to drugs. The main action mechanism of the antibacterial polymer is to destroy cell membranes, and the biosynthesis of the cell membranes relates to a complex biological process, so that the antibacterial polymer has the characteristics of low drug resistance generation rate and resistance to multi-drug resistant bacteria, and meets the requirements of a drug resistant antibacterial agent. The antibacterial agent with high-efficiency sterilization effect and low drug resistance generation rate is inoculated into the material, so that the problems of multiple bacteria resistance and drug resistance of the material can be solved.
Disclosure of Invention
In order to solve the problems, the invention discloses an antibacterial guanidine oligomer with drug resistance, a preparation method and application thereof.
An antimicrobial guanidine oligomer having resistance to drugs, the guanidine oligomer having the formula:
wherein n is more than or equal to 5 and less than or equal to 8;
wherein the molecular formula of R comprises any one of formula (I), formula (II), formula (III), formula (IV) and formula (V); r1 has a formula including any one of formula (I), formula (II), formula (III), formula (IV), formula (V) (VI), formula (VII), formula (VIII), (IX), (X) and (XI);
further wherein R is of formula (II) and R1 is of formula (IX), R is of formula (III) and R1 is any one of formulae (VII), (IX), (X), (XI), R is of formula (IV) and R1 is any one of formulae (I), (III), (IV), (VII), (VIII), (IX), (X), (XI), R is of formula (I) and R1 is any one of formulae (I), (III), (VI), (VII), (VIII), (IX), (X), (XI), R is of formula (V) and R1 is any one of formulae (III), (IV), (V), (VII), (IX), (X), (XI).
A preparation method for synthesizing an anti-drug resistant antibacterial guanidine oligomer comprises the following steps:
s1: preparing a dimercaptoiodoiminosalt monomer having the formula;
s2: reacting the dimethylsulfydryl iodinated imido salt monomer with H2N-R1-NH2Reacting anhydrous N, N-dimethylformamide DMF and N, N-diisopropylethylamine DIPEA to obtain the guanidine oligomer;
wherein the molecular formula of R in the dimercaptoiodoiminosalt monomer comprises any one of a formula (I), a formula (II), a formula (III), a formula (IV) and a formula (V); r1The formula (VI) includes any one of formula (I), formula (II), formula (III), formula (IV), formula (V) (VI), formula (VII), formula (VIII), (IX), (X) and (XI);
optionally, the step S1 includes the following steps: s11: weighing H2N-R-NH2And benzoyl isothiocyanate are added, dichloromethane is added to be uniformly mixed, a mixture is obtained through stirring, and the mixture is filtered and washed to obtain a dibenzoyl formamide dithiourea compound for the next reaction; s12: weighing the dibenzoamide dithiourea compound obtained in S11, adding methanol, uniformly mixing, then adding a sodium hydroxide aqueous solution, stirring to obtain a mixture, and filtering and washing the mixture to obtain a dithiourea compound for the next reaction; s13: weighing the dithiourea compound obtained in the step S12 and methyl iodide, adding absolute ethyl alcohol, uniformly mixing, stirring to obtain a mixture, and filtering and washing the mixture to obtain the white solid of the dimercapto imino iodide salt monomer.
Optionally, the step S2 includes the following steps: s21: weighing dimercapto imino iodide monomer and H2N-R1-NH2Uniformly mixing the mixture and anhydrous N, N-dimethylformamide DMF, adding N, N-diisopropylethylamine DIPEA, and stirring to obtain a mixture; s22: and (3) adjusting the pH value of the mixture in the S21 to 1-2, then intercepting to obtain a substance with the molecular weight of more than 1.5KDa, and freeze-drying to obtain a white solid, namely the guanidine oligomer.
The invention also discloses an antibacterial material modified by the oligomer, wherein the guanidine oligomer is used for the internal and surface modification of the material, the material and the surface of the material modified by the guanidine oligomer have antibacterial performance, and the antibacterial types comprise bacillus subtilis, escherichia coli, enterococcus faecalis, staphylococcus aureus, klebsiella pneumoniae, acinetobacter baumannii, pseudomonas aeruginosa and enterobacter cloacae.
Furthermore, the invention also discloses the application of the oligomer, the guanidine oligomer is used for antibiosis, and the antibacterial types of the guanidine oligomer comprise bacillus subtilis, escherichia coli, enterococcus faecalis, staphylococcus aureus, klebsiella pneumoniae, acinetobacter baumannii, pseudomonas aeruginosa and enterobacter cloacae.
The structure disclosed by the invention has a dual antibacterial mechanism of destroying cell membranes and combining with chromosome DNA, has the characteristics of quick sterilization and drug resistance, and shows broad antibacterial spectrum. Meanwhile, the structure has low toxicity to blood cells and higher therapeutic index. In addition, the structure can be added into the interior and the surface of the material in a chemical combination reaction fixing or doping mode, so that the material has an antibacterial function.
Drawings
FIG. 1 is a schematic diagram of the reaction of the present invention;
FIG. 2 is a diagram of a flow test that C3 has a strong membrane rupture capability;
fig. 3 is an SEM image: the cell membrane surfaces of C3-treated acinetobacter baumannii and staphylococcus aureus are all shrunk to different degrees;
FIG. 4 is a diagram of C3 having the ability to bind bacterial genomic DNA;
FIG. 5 is a distribution diagram of FITC-labeled C3 in E.coli;
FIG. 6 is a graph comparing the rates of resistance development after treatment of E.coli 1464 generations with the sub-minimum inhibitory concentrations of kanamycin and C3, respectively;
FIG. 7 is a reaction scheme of C3 grafting to epsilon-Polycaprolactone (PCL) material surface;
FIG. 8a is a broad spectrum antibacterial effect diagram of C3 modified epsilon-Polycaprolactone (PCL) material;
FIG. 8b is a diagram showing the sterilization and recycling effects of the C3 modified epsilon-Polycaprolactone (PCL) material;
FIG. 8C is a chart of the hemolytic toxicity of C3 modified epsilon-Polycaprolactone (PCL) material;
FIG. 9 is a drawing of an antibacterial tube device made of modified epsilon-Polycaprolactone (PCL) material C3;
FIG. 10a is a graph showing the bactericidal effect of C3 modified epsilon-Polycaprolactone (PCL) material on buffers containing Staphylococcus aureus (clinical strains), Acinetobacter baumannii (clinical strains), Pseudomonas aeruginosa (clinical strains) and Enterobacter cloacae (clinical strains), respectively, when made into an antibacterial tube device;
FIG. 10b is a graph showing the bactericidal effect of the C3 modified epsilon-Polycaprolactone (PCL) material on blood containing Staphylococcus aureus (clinical strains) or Staphylococcus aureus when made into an antibacterial tube device;
FIGS. 11-1 through 11-55 are hydrogen spectra of 55 compounds of the present invention.
Detailed Description
The technical solution of the present invention is described in detail below by means of specific embodiments and with reference to the attached drawings, and the components or devices in the following embodiments are all general standard components or components known to those skilled in the art, and the structure and principle thereof can be known to those skilled in the art through technical manuals or through routine experiments.
Example one
Through tests, 55 antibacterial guanidine oligomers with broad-spectrum antibacterial property are developed by the invention, and the chemical formula of the oligomers is shown as follows:
wherein n is more than or equal to 5 and less than or equal to 8;
wherein the molecular formula of R comprises any one of formula (I), formula (II), formula (III), formula (IV) and formula (V); the formula of R1 includes any one of formula (I), formula (II), formula (III), formula (IV), formula (V) (VI), formula (VII), formula (VIII), (IX), (X) and (XI).
For convenience of recording, the molecular formulas of R are respectively D, A, B, C and E which are numbered in sequence as formula (I), formula (II), formula (III), formula (IV) and formula (V); the molecular formula of R1 is formula (I), formula (II), formula (III), formula (IV), formula (V) (VI), formula (VII), formula (VIII), (IX), (X) and (XI) which are numbered as 9, 1, 2, 3, 5, 6, 4, 10, 8, 7 and 11 respectively. Numbering example: when R is formula (III) and R1 is formula (IV), compound number is B3. The antibacterial properties of the 55 compounds are shown in tables 1 and 2; hemolytic toxicity as shown in table 3, table 3 shows that A8, B4, B7, B8, B11, C2, C3, C4, C7, C8, C9, C10, C11, D2, D4, D6, D7, D8, D9, D10, D11, E2, E3, E4, E5, E6, E7, E8, and E11 all have hemolytic concentrations greater than 2048 μ g/mL, and show lower hemolytic toxicity; the hydrogen spectra of the 55 compounds are shown in FIGS. 11-1 to 11-55.
Antibacterial Properties of Table 155 Compounds
Antibacterial property II of 255 compounds in table
Hemolytic toxicity of the 355 Compounds
Example two
As shown in fig. 1, the invention also discloses a preparation method of the synthetic anti-drug resistant antibacterial guanidine oligomer, which comprises the following steps:
s1: preparing a dimercaptoiodoiminosalt monomer having the formula;
s2: reacting the dimethylsulfydryl iodinated imido salt monomer with H2N-R1-NH2Reacting anhydrous N, N-dimethylformamide DMF and N, N-diisopropylethylamine DIPEA to obtain the guanidine oligomer;
wherein the molecular formula of R in the dimercaptoimino iodide monomer comprises any one of a formula (I), a formula (II), a formula (III), a formula (IV) and a formula (V); the formula of R1 includes any one of formula (I), formula (II), formula (III), formula (IV), formula (V) (VI), formula (VII), formula (VIII), (IX), (X) and (XI).
The step S1 includes the following steps:
s11: weighing H2N-R-NH2And benzoyl isothiocyanate, then adding dichloromethane, uniformly mixing, stirring at room temperature for 24-48h to obtain a mixture, and filtering and washing the mixture to obtain the dibenzoyl formamide dithiourea compound for the next reaction.
S12: weighing the dibenzoyl formamide dithiourea compound obtained in S11, adding methanol, uniformly mixing, then adding an aqueous solution of sodium hydroxide, stirring at room temperature for 24-48h to obtain a mixture, and filtering and washing the mixture to obtain the dithiourea compound for the next reaction.
S13: weighing the dithiourea compound obtained in the step S12 and methyl iodide, adding absolute ethyl alcohol, uniformly mixing, stirring at room temperature for 24-48h to obtain a mixture, and filtering and washing the mixture to obtain the white dimercapto imino iodide monomer solid.
The step S2 includes the following steps:
s21: weighing dimercapto imino iodide monomer and H obtained in S12N-R1-NH2And anhydrous N, N-dimethylformamide DMF, adding N, N-diisopropylethylamine DIPEA, and stirring at 65 ℃ for 96-144h under the protection of inert gas to obtain a mixture.
S22: and (3) adjusting the pH value of the mixture in the S21 to 1-2, then intercepting to obtain a substance with the molecular weight of more than 1.5KDa, and freeze-drying to obtain a white solid, namely the guanidine oligomer.
Experimental example 1
This experimental example will be described in detail with reference to the compound C3.
Materials and methods: all reagents were supplied by Acros, TCI (USA), Sigma-Aldrich, Michelin, Adamax et al organic reagents and Bilyunnan Biotech, all used without further purification (among others). Ultrapure water for the experiments was obtained from a Milli-Q purification instrument. The inert gas is nitrogen or argon.
The synthetic synthesis procedure for C3 is shown in fig. 1. Firstly, synthesizing dimercapto iodide imide salt monomer. 1, 4-butanediamine (0.84g,9.5mmol) and benzoyl isothiocyanate (3.25g,20.0mmol) were weighed out, then 100mL of dichloromethane was added and mixed uniformly, stirred at room temperature for 24-48h to obtain a mixture, and the mixture was filtered and washed to obtain a dibenzoyl formamide dithiourea compound for the next reaction. The dibenzoamide dithiourea compound (3.1g,7.5mmol) obtained in the previous step was weighed, 100mL of methanol was added and mixed uniformly, then aqueous sodium hydroxide (5.0M,7.5mL,37.5mmol) was added and stirred at room temperature for 24-48h to obtain a mixture, and the mixture was filtered and washed to obtain the dithiourea compound for the next reaction. The dithiourea compound (1.3g,6.5mmol) obtained in the previous step and methyl iodide (2.33g,16.4mmol) were weighed, 100mL of anhydrous ethanol was added and mixed uniformly, and stirred at room temperature for 24-48 hours to obtain a mixture, and the mixture was filtered and washed to obtain 3.1g of dimercaptoiodoimide salt monomer (butyldimercaptoiodoimide salt monomer) as a white solid.
Weighing dimercaptoiodized imino salt monomer (butyl dimercaptoiodized imino salt monomer) (0.30g,0.6mmol) and 1, 4-butanediamine (0.05g,0.6mmol), adding 1.0mL of anhydrous N, N-dimethylformamide DMF, uniformly mixing, adding N, N-diisopropylethylamine DIPEA (0.31g,2.4mmol), stirring at 65 ℃ under the protection of inert gas to obtain a mixture, adjusting the pH of the mixture to 1-2, dialyzing in a dialysis bag with the molecular weight cutoff of 1.5kDa for 10 hours, changing water every two hours, and freeze-drying to obtain 0.06g of white solid.
C3 has broad-spectrum antibacterial activity compound C3 was tested for its antibacterial activity against a variety of bacteria (table one and table two). C3 showed good antibacterial activity, and the minimum inhibitory concentration was in the lower range (μ g/mL) for all tests. Besides, the activity of C3 on 5 high-drug-resistant clinical pathogens is tested, and the minimum inhibitory concentration is found to be in a lower range (mu g/mL). The antibacterial activity data show that C3 not only can widely kill various pathogenic bacteria and has good antibacterial broad spectrum, but also can effectively kill various drug-resistant pathogenic bacteria and has anti-drug resistance.
C3 has lower hemolytic toxicity most of the polymers half hemolytic concentration is more than 2048 μ g/mL (Table III), wherein the half hemolytic concentration of C3 is more than 2048 μ g/mL, showing lower hemolytic toxicity. The C3 can effectively kill various pathogenic bacteria and drug-resistant pathogenic bacteria, simultaneously keeps lower hemolytic toxicity, has little damage to blood cells, and indicates that the biocompatibility of the C3 is higher.
Validation of membrane targeting mechanism we assessed the membrane rupture ability of C3 using flow-through experiments. In flow experiments, Propidium Iodide (PI) is used as a fluorescent dye to assess the integrity of bacterial cell membranes. After centrifugation of E.coli cultured to stationary phase, the medium was discarded, washed three times with PBS, and then resuspended to OD with 100. mu.M PI-containing PBS600nmThe cells were incubated at 37 ℃ for 4h with the addition of C3 at the indicated concentration, 0.1. The samples were analyzed using a BD Accuri C6 Plus flow cytometer. Since Propidium Iodide (PI) can only enter cells with damaged cell membranes, PI can be a good indicator of the integrity of bacterial cell membranes in flow experiments. As shown in FIG. 2, the results indicate that the E.coli treated with C3 has more PI accumulation and thus emits stronger fluorescence. Untreated E.coli showed very low fluorescence.
We further used scanning electron microscopy to demonstrate the membrane rupture ability of C3. As shown in FIG. 3, the C3 treated bacteria showed significant membrane breakage and shrinkage relative to the untreated A.baumannii and S.aureus controls.
Validation of binding to DNA antibacterial mechanism the oligomer was designed based primarily on a dual antibacterial mechanism of membrane targeting and DNA targeting. In addition to the demonstration of the membrane-breaking ability of C3, we also demonstrated that the oligomer has the ability to bind bacterial DNA. Dynamic Light Scattering (DLS) studies showed that C3 all promoted aggregation of E.coli genomic DNA. As shown in FIG. 4, the particle size of the oligomer-DNA complex formed by binding C3 to DNA is much larger than that of C3 and that of DNA, demonstrating that the strong affinity between C3 and DNA can bind to bacterial DNA.
After confirming that C3 has the ability to bind DNA in vitro, we observed its binding to bacterial DNA with fluorescein FITC labeled C3. As shown in FIG. 5, which shows the staining of Escherichia coli bacteria by fluorescein FITC-labeled C3, the staining channel of C3 ("C3"), the staining channel of cell membrane ("FM 4-64") and the staining channel of DNA ("DAPI") can be well combined together, indicating that C3 can bind to the DNA of bacteria in bacteria, further demonstrating the mechanism by which C3 can bind to DNA.
Determination of the rate of resistance development by C3 introduces a dual antibacterial mechanism that reduces the rate at which bacteria develop resistance to compounds. The target of the membrane-targeted antibacterial polymer is the cell membrane, and due to the complex biosynthesis of the cell membrane, drug resistance is generated only when multiple random mutations occur simultaneously and cause changes in the membrane structure. Thus, membrane-targeted polymers are considered a class of antimicrobial compounds with low drug resistance. As a membrane-targeting polymer, C3 also has low drug resistance. In addition, C3 uses bacterial DNA as a secondary target, and therefore bacteria require both membrane and DNA structural mutations to develop resistance to C3. We experimentally determined the rate of C3 resistance, as shown in fig. 6, when escherichia coli is treated repeatedly with kanamycin, the standard antibiotic with the second minimum inhibitory concentration, the strain has resistance mutation, which is shown as the minimum inhibitory concentration to kanamycin is increased continuously, and the minimum inhibitory concentration is increased by 48 times after the bacterium is replicated 1464 generations. In contrast, C3 was almost free of drug resistance under the same conditions. The above results indicate that bacterial resistance is difficult to develop relative to the traditional antibiotic C3.
Experimental example 2
Synthesis of A8: firstly, synthesizing dimercapto iodide imide salt monomer. 1, 8-octanediamine (1.38g,9.5mmol) and benzoyl isothiocyanate (3.25g,20.0mmol) are weighed, then 100mL of dichloromethane is added for uniform mixing, the mixture is stirred at room temperature for 24-48h to obtain a mixture, and the mixture is filtered and washed to obtain a dibenzoyl diamide dithiourea compound for the next reaction. The dibenzoamide dithiourea compound (3.5g,7.5mmol) obtained in the previous step was weighed, 100mL of methanol was added and mixed uniformly, then aqueous sodium hydroxide (5.0M,7.5mL,37.5mmol) was added and stirred at room temperature for 24-48h to obtain a mixture, and the mixture was filtered and washed to obtain the dithiourea compound for the next reaction. The dithiourea compound (1.7g,6.5mmol) obtained in the previous step and methyl iodide (2.33g,16.4mmol) were weighed, 100mL of anhydrous ethanol was added and mixed uniformly, and stirred at room temperature for 24-48 hours to obtain a mixture, and the mixture was filtered and washed to obtain 3.4g of dimercaptoiodoimide salt monomer (octyldimercaptoiodoimide salt monomer) as a white solid.
Weighing dimercaptoiodized imino salt monomer (butyldimercaptoiodized imino salt monomer) (0.32g,0.6mmol) and N' N-bis (3-aminopropyl) methylamine (0.09g,0.6mmol), adding 1.0mL of anhydrous N, N-dimethylformamide DMF, mixing uniformly, adding N, N-diisopropylethylamine DIPEA (0.31g,2.4mmol), stirring at 65 ℃ under the protection of inert gas to obtain a mixture, adjusting the pH of the mixture to 1-2, dialyzing in a dialysis bag with the molecular weight cutoff of 1.5kDa for 10h, changing water every two hours, and freeze-drying to obtain 0.07g of white solid.
Experimental example 3
Synthesis of B4: firstly, synthesizing dimercapto iodide imide salt monomer. 1, 6-hexanediamine (1.1g,9.5mmol) and benzoyl isothiocyanate (3.25g,20.0mmol) were weighed out and then 100mL of dichloromethane was added and mixed well, and stirred at room temperature for 24-48h to obtain a mixture, which was filtered and washed to obtain a dibenzoyl formamide dithiourea compound for the next reaction. The dibenzoamide dithiourea compound (3.3g,7.5mmol) obtained in the previous step was weighed, 100mL of methanol was added and mixed uniformly, then aqueous sodium hydroxide (5.0M,7.5mL,37.5mmol) was added and stirred at room temperature for 24-48h to obtain a mixture, and the mixture was filtered and washed to obtain the dithiourea compound for the next reaction. The dithiourea compound (1.5g,6.5mmol) obtained in the above step and methyl iodide (2.33g,16.4mmol) were weighed, 100mL of anhydrous ethanol was added and mixed uniformly, and stirred at room temperature for 24-48 hours to obtain a mixture, and the mixture was filtered and washed to obtain 3.0g of dimercaptoiodoimide salt monomer (hexyldimercaptoiodoimide salt monomer) as a white solid.
Weighing dimercaptoiodized imino salt monomer (hexyl dimercaptoiodized imino salt monomer) (0.31g,0.6mmol) and 1, 3-propanediamine (0.04g,0.6mmol), adding 1.0mL of anhydrous N, N-dimethylformamide DMF, uniformly mixing, adding N, N-diisopropylethylamine DIPEA (0.31g,2.4mmol), stirring at 65 ℃ under the protection of inert gas to obtain a mixture, adjusting the pH of the mixture to 1-2, dialyzing in a dialysis bag with the molecular weight cutoff of 1.5kDa for 10 hours, changing water every two hours, and freeze-drying to obtain 0.07g of white solid.
Experimental example 4
Synthesis of D6: firstly, synthesizing dimercapto iodide imide salt monomer. 1, 4-cyclohexyl diamine (1.1g,9.5mmol) and benzoyl isothiocyanate (3.25g,20.0mmol) were weighed out and then 100mL of dichloromethane was added and mixed well, and stirred at room temperature for 24-48h to obtain a mixture, which was filtered and washed to obtain a dibenzoyl formamide dithiourea compound for the next reaction. The dibenzoamide dithiourea compound (3.3g,7.5mmol) obtained in the previous step was weighed, 100mL of methanol was added and mixed uniformly, then aqueous sodium hydroxide (5.0M,7.5mL,37.5mmol) was added and stirred at room temperature for 24-48h to obtain a mixture, and the mixture was filtered and washed to obtain the dithiourea compound for the next reaction. The dithiourea compound (1.5g,6.5mmol) obtained in the above step and methyl iodide (2.33g,16.4mmol) were weighed, 100mL of anhydrous ethanol was added and mixed uniformly, and stirred at room temperature for 24-48 hours to obtain a mixture, and the mixture was filtered and washed to obtain 3.0g of dimercaptoiodoimide salt monomer (cyclohexyldimercaptoiodoimide salt monomer) as a white solid.
Weighing dimercaptoiodimide salt monomer (cyclohexyl dimercaptoiodimide salt monomer) (0.31g,0.6mmol) and 1, 3-xylylenediamine (0.08g,0.6mmol), adding 1.0mL of anhydrous N, N-dimethylformamide DMF, mixing uniformly, adding N, N-diisopropylethylamine DIPEA (0.31g,2.4mmol), stirring at 65 ℃ under the protection of inert gas to obtain a mixture, adjusting the pH of the mixture to 1-2, dialyzing in a dialysis bag with the molecular weight cutoff of 1.5kDa for 10h, changing water every two hours, and freeze-drying to obtain 0.05g of white solid.
Experimental example 5
Synthesis of E7: firstly, synthesizing dimercapto iodide imide salt monomer. 1, 4-xylylenediamine (1.30g,9.5mmol) and benzoyl isothiocyanate (3.25g,20.0mmol) were weighed, then 100mL of dichloromethane was added and mixed uniformly, stirred at room temperature for 24-48h to obtain a mixture, and the mixture was filtered and washed to obtain a dibenzoyl formamide dithiourea compound for the next reaction. The dibenzoamide dithiourea compound (3.5g,7.5mmol) obtained in the previous step was weighed, 100mL of methanol was added and mixed uniformly, then aqueous sodium hydroxide (5.0M,7.5mL,37.5mmol) was added and stirred at room temperature for 24-48h to obtain a mixture, and the mixture was filtered and washed to obtain the dithiourea compound for the next reaction. The dithiourea compound (1.6g,6.5mmol) obtained in the previous step and methyl iodide (2.33g,16.4mmol) were weighed, 100mL of anhydrous ethanol was added and mixed uniformly, and stirred at room temperature for 24-48 hours to obtain a mixture, and the mixture was filtered and washed to obtain 3.2g of dimethylmercaptyliodiimide monomer (xylylenediamine dimethylmercaptyliodiimide monomer) as a white solid.
Weighing dimercaptoiodized imino salt monomer (xylylenediamine dimercaptoiodized imino salt monomer) (0.32g,0.6mmol) and 2,2' -oxybis (ethylamine) (0.06g,0.6mmol), adding 1.0mL of anhydrous N, N-dimethylformamide DMF, mixing uniformly, adding N, N-diisopropylethylamine DIPEA (0.31g,2.4mmol), stirring at 65 ℃ under the protection of inert gas for 120h to obtain a mixture, adjusting the pH of the mixture to 1-2, dialyzing in a dialysis bag with the molecular weight cutoff of 1.5kDa for 10h, changing water every two hours, and freeze-drying to obtain 0.07g of white solid.
EXAMPLE III
In order to expand the application of the antibacterial guanidine oligomer in material antibiosis, the invention also provides an antibacterial material modified by the oligomer.
Taking oligomer C3 as an example, C3 is modified on the surface of an epsilon-Polycaprolactone (PCL) material and the antibacterial ability of the epsilon-polycaprolactone material is measured. The specific method is as follows.
As shown in FIG. 7, the surface of the PCL material is hydrolyzed by aqueous solution of sodium hydroxide, ester bonds on the surface of the PCL material are hydrolyzed to expose carboxyl, then a condensing agent (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride) is added into the aqueous solution of C3, the PCL material after the hydrolysis treatment of the sodium hydroxide is soaked in the mixture after uniform mixing, the PCL material is taken out after oscillation for 24h, and the PCL material with the surface modified by C3 is obtained by washing with ultrapure water.
Antibacterial property of modified material in order to prove that the material has an antibacterial function after the C3 is connected to the surface of the material, the antibacterial property of the PCL material modified by the C3 is tested. As shown in fig. 8a, the bacteria with a certain concentration is dropped on the surface of the PCL material modified with C3, and the PCL material surface is tested after 1h to completely kill the pathogenic bacteria. Wherein bacillus subtilis, colibacillus, enterococcus faecalis, staphylococcus aureus, klebsiella pneumoniae and enterobacter cloacae can be killed, and the broad-spectrum antibacterial property can be still maintained after C3 is grafted to the material. In addition, we also tested whether the PCL material modified with C3 can be repeatedly sterilized, as shown in fig. 8b, the PCL material subjected to the sterilization test was washed clean, and the above sterilization test was repeated, taking staphylococcus aureus as an example, the PCL material modified with C3 still has good antibacterial activity after 7 repeated tests, which indicates that the material can maintain the sterilization function for a long time after C3 is grafted to the material. In addition to antibacterial ability, we also tested the hemolytic toxicity of PCL material modified with C3 to blood cells, as shown in fig. 8C, the buffer solution containing blood cells was dropped on the surface of PCL material modified with C3, and compared with triton X-100 with one hundred percent hemolytic effect after 1h, only low level of hemolytic toxicity of PCL material was detected, which indicates that the PCL material still maintains low hemolytic toxicity and high safety after C3 is modified on the material.
The antibacterial property of the modified PCL material prepared into a device proves that the PCL material modified with C3 has good antibacterial property and high safety, so that the application of the PCL material modified with C3 is further expanded. As shown in FIG. 9, the PCL material modified with C3 is bent into a tube with a diameter of 2-4mm, the two tubes are connected to a peristaltic pump, the tube is filled with a buffer solution containing pathogenic bacteria with a certain concentration, the peristaltic pump is started to circulate the bacterial solution in the tube for a certain time, and the number of the residual bacteria is measured. The tubes were tested for their bactericidal effect against staphylococcus aureus (clinical strain), acinetobacter baumannii (clinical strain), pseudomonas aeruginosa (clinical strain) and enterobacter cloacae (clinical strain), respectively, as shown in fig. 10a, the tubes were able to completely kill pathogenic bacteria within a 5min circulation time. Since some pathogenic bacteria such as Staphylococcus aureus have a strong hemolytic effect on blood cells, we also tested the ability of the tube to sterilize Staphylococcus aureus in the blood. The liquid in the tube is replaced by the blood containing staphylococcus aureus (clinical strain) or staphylococcus aureus, and pathogenic bacteria are killed after the liquid circularly flows in the tube for 30min, which shows that the tube also has an antibacterial effect on the pathogenic bacteria in the blood.
In conclusion, the oligomer can simultaneously target cell membranes and nucleic acids of bacteria, retains all antibacterial advantages of the traditional antibacterial polymer due to the dual antibacterial mechanism, has wide antibacterial spectrum and faster bactericidal kinetics, and can kill drug-resistant pathogenic bacteria. The oligomer is grafted to the surface of the material to prepare the antibacterial material, so that most of pathogenic bacteria and drug-resistant bacteria can be killed by the material, and the material has stronger antibacterial capability. Furthermore, the oligomer-modified material is made into a device with a certain shape, the device also has antibacterial capability, various practical use environments are simulated, and the made device can also keep a better antibacterial effect.
In the previous description, numerous specific details were set forth in order to provide a thorough understanding of the present invention. The foregoing description is only a preferred embodiment of the invention, which can be embodied in many different forms than described herein, and therefore the invention is not limited to the specific embodiments disclosed above. And that those skilled in the art may, using the methods and techniques disclosed above, make numerous possible variations and modifications to the disclosed embodiments, or modify equivalents thereof, without departing from the scope of the claimed embodiments. Any simple modification, equivalent change and modification of the above embodiments according to the technical essence of the present invention are within the scope of the technical solution of the present invention.
Claims (10)
1. An antibacterial guanidine oligomer having resistance to drug, wherein the guanidine oligomer has the following formula:
wherein n is more than or equal to 5 and less than or equal to 8;
wherein the molecular formula of R comprises any one of formula (I), formula (II), formula (III), formula (IV) and formula (V); r1 has a formula including any one of formula (I), formula (II), formula (III), formula (IV), formula (V) (VI), formula (VII), formula (VIII), (IX), (X) and (XI);
2. the oligomer of claim 1 wherein R is of formula (II) and R1 is of formula (IX), R is of formula (III) and R1 is any one of formulae (VII), (IX), (X), (XI), R is of formula (IV) and R1 is any one of formulae (I), (III), (IV), (VII), (VIII), (IX), (X), (XI), R is of formula (I) and R1 is any one of formulae (I), (III), (VI), (VII), (VIII), (IX), (X), (XI), R is of formula (V) and R1 is any one of formulae (III), (IV), (V), (VI), (IX), (X), (XI).
3. A preparation method for synthesizing an anti-drug resistant antibacterial guanidine oligomer comprises the following steps:
s1: preparing a dimercaptoiodoiminosalt monomer having the formula;
s2: reacting the dimethylsulfydryl iodinated imido salt monomer with H2N-R1-NH2Reacting anhydrous N, N-dimethylformamide DMF and N, N-diisopropylethylamine DIPEA to obtain the guanidine oligomer;
wherein the molecular formula of R in the dimercaptoiodoiminosalt monomer comprises any one of a formula (I), a formula (II), a formula (III), a formula (IV) and a formula (V); r1The formula (VI) includes any one of formula (I), formula (II), formula (III), formula (IV), formula (V) (VI), formula (VII), formula (VIII), (IX), (X) and (XI);
4. the method of claim 3, wherein the step S1 includes the steps of:
s11: weighing H2N-R-NH2And benzoyl isothiocyanate are added, dichloromethane is added to be uniformly mixed, a mixture is obtained through stirring, and the mixture is filtered and washed to obtain a dibenzoyl formamide dithiourea compound for the next reaction;
s12: weighing the dibenzoamide dithiourea compound obtained in S11, adding methanol, uniformly mixing, then adding a sodium hydroxide aqueous solution, stirring to obtain a mixture, and filtering and washing the mixture to obtain a dithiourea compound for the next reaction;
s13: weighing the dithiourea compound obtained in the step S12 and methyl iodide, adding absolute ethyl alcohol, uniformly mixing, stirring to obtain a mixture, and filtering and washing the mixture to obtain the white solid of the dimercapto imino iodide salt monomer.
5. The method of claim 3, wherein the step S2 includes the steps of:
s21: weighing dimercapto imino iodide monomer and H2N-R1-NH2Uniformly mixing the mixture and anhydrous N, N-dimethylformamide DMF, adding N, N-diisopropylethylamine DIPEA, and stirring to obtain a mixture;
s22: and (3) adjusting the pH value of the mixture in the S21 to 1-2, then intercepting to obtain a substance with the molecular weight of more than 1.5KDa, and freeze-drying to obtain a white solid, namely the guanidine oligomer.
6. The manufacturing method of claim 5, wherein the mixture is obtained in step S21 by stirring for 96-144h under the protection of inert gas.
7. An antimicrobial material modified with the oligomer of claim 1.
8. The antibacterial material of claim 7, wherein the guanidine oligomer is used for internal and surface modification of materials, the guanidine oligomer-modified materials and surfaces of materials have antibacterial properties, and the antibacterial species include Bacillus subtilis, Escherichia coli, enterococcus faecalis, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter cloacae.
9. A method for preparing the antibacterial material of any one of claims 7 to 8, characterized in that the surface of the PCL material is hydrolyzed by sodium hydroxide aqueous solution, ester bonds on the surface of the PCL material are hydrolyzed to expose carboxyl groups, then a condensing agent is added into the guanidine oligomer aqueous solution, after uniform mixing, the PCL material subjected to sodium hydroxide hydrolysis treatment is soaked in the aqueous solution, after 24h of oscillation, the PCL material is taken out, and is washed by ultrapure water to obtain the PCL material with the guanidine oligomer modified on the surface.
10. Use of the oligomer of claim 1 for antimicrobial applications, wherein the guanidine oligomer is used in antimicrobial applications, and wherein the antimicrobial species of guanidine oligomer comprise bacillus subtilis, escherichia coli, enterococcus faecalis, staphylococcus aureus, klebsiella pneumoniae, acinetobacter baumannii, pseudomonas aeruginosa, enterobacter cloacae.
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