CN116730941B - 5-Phenyl-1, 3, 4-oxadiazole compound and preparation method and application thereof - Google Patents
5-Phenyl-1, 3, 4-oxadiazole compound and preparation method and application thereof Download PDFInfo
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- -1 5-Phenyl-1, 3, 4-oxadiazole compound Chemical class 0.000 title claims abstract description 43
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 239000000047 product Substances 0.000 claims abstract description 46
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims abstract description 22
- 241000589517 Pseudomonas aeruginosa Species 0.000 claims abstract description 18
- 241000588724 Escherichia coli Species 0.000 claims abstract description 17
- UBDZFAGVPPMTIT-UHFFFAOYSA-N 2-aminoguanidine;hydron;chloride Chemical compound [Cl-].NC(N)=N[NH3+] UBDZFAGVPPMTIT-UHFFFAOYSA-N 0.000 claims abstract description 11
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 claims abstract description 11
- ZEOMRHKTIYBETG-UHFFFAOYSA-N 2-phenyl-1,3,4-oxadiazole Chemical class O1C=NN=C1C1=CC=CC=C1 ZEOMRHKTIYBETG-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000012467 final product Substances 0.000 claims abstract description 3
- 239000002994 raw material Substances 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 42
- 238000006243 chemical reaction Methods 0.000 claims description 24
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 24
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 16
- 238000003756 stirring Methods 0.000 claims description 16
- 239000003242 anti bacterial agent Substances 0.000 claims description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 5
- 230000000941 anti-staphylcoccal effect Effects 0.000 claims description 3
- 238000003786 synthesis reaction Methods 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 19
- 241000191967 Staphylococcus aureus Species 0.000 abstract description 15
- 150000001875 compounds Chemical class 0.000 abstract description 4
- FKASFBLJDCHBNZ-UHFFFAOYSA-N 1,3,4-oxadiazole Chemical group C1=NN=CO1 FKASFBLJDCHBNZ-UHFFFAOYSA-N 0.000 abstract description 2
- HAMNKKUPIHEESI-UHFFFAOYSA-N aminoguanidine Chemical compound NNC(N)=N HAMNKKUPIHEESI-UHFFFAOYSA-N 0.000 abstract description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 24
- 238000005406 washing Methods 0.000 description 16
- 229940100555 2-methyl-4-isothiazolin-3-one Drugs 0.000 description 14
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 14
- BEGLCMHJXHIJLR-UHFFFAOYSA-N methylisothiazolinone Chemical compound CN1SC=CC1=O BEGLCMHJXHIJLR-UHFFFAOYSA-N 0.000 description 14
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 12
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 12
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 239000003814 drug Substances 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- 238000001914 filtration Methods 0.000 description 6
- JJJXBYDIBSYUGE-UHFFFAOYSA-N 3-phenyl-2h-1,3,4-oxadiazole Chemical compound C1OC=NN1C1=CC=CC=C1 JJJXBYDIBSYUGE-UHFFFAOYSA-N 0.000 description 5
- 239000003899 bactericide agent Substances 0.000 description 5
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- ZSSUKQHPALINBY-UHFFFAOYSA-N Secamine Natural products CCC1=CCCN(CCc2c3C(CCC(C(=O)OC)(c4[nH]c5ccccc5c4CCN6CCC=C(CC)C6)n3c7ccccc27)C(=O)OC)C1 ZSSUKQHPALINBY-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000007605 air drying Methods 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 238000006386 neutralization reaction Methods 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 3
- QEUAQXSDDNDOTG-UHFFFAOYSA-N 4-phenylbenzohydrazide Chemical compound C1=CC(C(=O)NN)=CC=C1C1=CC=CC=C1 QEUAQXSDDNDOTG-UHFFFAOYSA-N 0.000 description 2
- LZMCSSDFZRJZIS-UHFFFAOYSA-N 4-phenylmethoxybenzohydrazide Chemical compound C1=CC(C(=O)NN)=CC=C1OCC1=CC=CC=C1 LZMCSSDFZRJZIS-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 208000035143 Bacterial infection Diseases 0.000 description 2
- 230000006978 adaptation Effects 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 208000022362 bacterial infectious disease Diseases 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000013076 target substance Substances 0.000 description 2
- GEHIXSKXGCIKJJ-UHFFFAOYSA-N 2-(chloromethyl)-5-(4-methoxyphenyl)-1,3,4-oxadiazole Chemical compound C1=CC(OC)=CC=C1C1=NN=C(CCl)O1 GEHIXSKXGCIKJJ-UHFFFAOYSA-N 0.000 description 1
- HITIGLAGJBMISF-UHFFFAOYSA-N 4-(dimethylamino)benzohydrazide Chemical compound CN(C)C1=CC=C(C(=O)NN)C=C1 HITIGLAGJBMISF-UHFFFAOYSA-N 0.000 description 1
- REKQLYUAUXYJSZ-UHFFFAOYSA-N 4-methoxybenzohydrazide Chemical compound COC1=CC=C(C(=O)NN)C=C1 REKQLYUAUXYJSZ-UHFFFAOYSA-N 0.000 description 1
- 241000191070 Escherichia coli ATCC 8739 Species 0.000 description 1
- MKYBYDHXWVHEJW-UHFFFAOYSA-N N-[1-oxo-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propan-2-yl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(C(C)NC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 MKYBYDHXWVHEJW-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- ZZBKWQOQKPTOCN-UHFFFAOYSA-N n'-(2-chloroacetyl)-4-methoxybenzohydrazide Chemical compound COC1=CC=C(C(=O)NNC(=O)CCl)C=C1 ZZBKWQOQKPTOCN-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
-
- 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
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
- A01P1/00—Disinfectants; Antimicrobial compounds or mixtures thereof
-
- 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
-
- 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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- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pest Control & Pesticides (AREA)
- General Chemical & Material Sciences (AREA)
- Environmental Sciences (AREA)
- Zoology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Wood Science & Technology (AREA)
- Engineering & Computer Science (AREA)
- Plant Pathology (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Agronomy & Crop Science (AREA)
- Public Health (AREA)
- Communicable Diseases (AREA)
- Animal Behavior & Ethology (AREA)
- Dentistry (AREA)
- Oncology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicinal Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention discloses a 5-phenyl-1, 3, 4-oxadiazole compound, and a preparation method and application thereof. The structural formula of the 5-phenyl-1, 3, 4-oxadiazole compound is shown as a formula (IV). According to the invention, a series of 5-phenyl-1, 3, 4-oxadiazole compounds with brand new structures are designed and synthesized by introducing a lipophilic phenyl side chain at the C5 position and hydrophilic aminoguanidine at the C2 position of 1,3, 4-oxadiazole, and the preparation method comprises the following steps: the benzoyl hydrazine compound (I) and chloracetyl chloride are used as raw materials, a first-step product (II) is synthesized, the first-step product (II) reacts with phosphorus oxychloride to obtain a second-step product (III), and the second-step product (III) reacts with aminoguanidine hydrochloride to obtain a final product (IV). The 5-phenyl-1, 3, 4-oxadiazole compound has antibacterial activity, particularly has good antibacterial activity on staphylococcus aureus, escherichia coli and pseudomonas aeruginosa, and can be used as an antibacterial candidate compound.
Description
Technical Field
The invention belongs to the technical field of antibiosis, relates to an antibiosis medicine or an industrial bactericide, and in particular relates to a 5-phenyl-1, 3, 4-oxadiazole compound with a novel structure, and a preparation method and application thereof.
Background
Bacterial infection is a common disease and is also a common source of deterioration of materials or products in industry. Severely threatens human health and industrial production. Although several classes of bactericides or agents are currently available both pharmaceutically and industrially, the self-survival ability of microorganisms has prompted some resistance to these agents with a long history of their use. The discovery of new targets and bactericides of new structures has become an important topic of research in this area. 2-methyl-4-isothiazolin-3-ketone (MIT) is a broad-spectrum and high-efficiency bactericide widely used in industry, and is structurally characterized in that five-membered contains nitrogen and sulfur heteroatoms and has ketone groups on the ring, and a 5-phenyl-1, 3, 4-oxadiazole compound with a brand new structure is constructed through bioisostere treatment and derivative, so that the bactericide with a brand new structure is possibly generated.
Disclosure of Invention
The first object of the invention is to provide a 5-phenyl-1, 3, 4-oxadiazole compound or a salt thereof which has novel structure and obvious antibacterial activity on staphylococcus aureus, escherichia coli and pseudomonas aeruginosa.
The structural formula of the 5-phenyl-1, 3, 4-oxadiazole compound is shown as a formula (IV):
(IV)
Wherein R is selected from、、Or (b)。
Preferably, R is selected fromOr (b)。
The second purpose of the invention is to provide a preparation method of the 5-phenyl-1, 3, 4-oxadiazole compound shown in the structural formula (IV), wherein the preparation method takes benzoyl hydrazine compound (I) and chloroacetyl chloride as raw materials, the first-step product (II) is synthesized to obtain a first-step product (II), the first-step product (II) reacts with phosphorus oxychloride to obtain a second-step product (III), the second-step product (III) reacts with aminoguanidine hydrochloride to obtain a final product (IV), and the synthesis reaction formula of the 5-phenyl-1, 3, 4-oxadiazole compound is as follows:
；
wherein R is selected from 、、Or (b)。
Preferably, R is selected fromOr (b)。
Further preferably, the method comprises the following steps: the first step: adding a benzoyl hydrazine compound (I), chloroacetyl chloride and ethyl acetate into a reactor, heating and stirring for reaction to obtain a first-step product (II); and a second step of: adding the first-step product (II), phosphorus oxychloride and acetonitrile into a reactor, heating and stirring for reaction to obtain a second-step product (III); and a third step of: adding the second-step product (III), aminoguanidine hydrochloride, potassium carbonate, potassium iodide and N, N-dimethylformamide into a reactor, and stirring for reaction to obtain the 5-phenyl-1, 3, 4-oxadiazole compound.
The total yield of the preparation method disclosed by the invention can be 28% -43%.
Preferably, the ratio of the amounts of the benzoyl hydrazine compound (I) and the chloroacetyl chloride in the first step is 1:1.5; the ratio of the amounts of the product (II) of the first step and the phosphorus oxychloride in the second step is 1:2; the amount ratio of the substances of the second step product (III), aminoguanidine hydrochloride, potassium carbonate and potassium iodide in the third step is 1:1:3.6:0.5; the heating and stirring reaction in the first step and the second step is carried out at 70 ℃.
Preferably, the benzoyl hydrazine compound is selected from 4- (phenyl) benzoyl hydrazine or 4- (benzyloxy) benzoyl hydrazine.
The third object of the present invention is to provide an application of the above 5-phenyl-1, 3, 4-oxadiazole compound having a structural formula shown in formula (IV) or a salt thereof in the preparation of antibacterial agents.
Preferably, the antibacterial agent is an anti-staphylococcus aureus, escherichia coli and/or pseudomonas aeruginosa agent.
A fourth object of the present invention is to provide an antibacterial agent comprising the above 5-phenyl-1, 3, 4-oxadiazole compound having the structural formula (IV) or a salt thereof as an active ingredient.
Compared with the prior art, the invention has the following beneficial effects:
According to modern medicine design theory and organic synthesis experimental technology, 2-methyl-4-isothiazolin-3-ketone (MIT) is modified, and a series of 5-phenyl-1, 3, 4-oxadiazole compounds with brand new structures are designed and synthesized by introducing lipophilic phenyl side chains at the C5 position and hydrophilic aminoguanidine at the C2 position of 1,3, 4-oxadiazole, and antibacterial activity research is carried out. The research results show that: the 5-phenyl-1, 3, 4-oxadiazole compound with novel structure has remarkable antibacterial activity on staphylococcus aureus, escherichia coli and pseudomonas aeruginosa, and has great application value in treating bacterial infection diseases or industrial microorganism harm. Some target substances have remarkable antibacterial effect on staphylococcus aureus, escherichia coli and pseudomonas aeruginosa, are superior to a control medicament 2-methyl-4-isothiazolin-3-one (MIT), and can be used as antibacterial candidate compounds for research.
Detailed Description
The following examples are further illustrative of the invention and are not intended to be limiting thereof.
Example 1
Preparation of 2-guanidinoaminomethyl-5- (4- (dimethylamino) phenyl) -1,3, 4-oxadiazole (IVa):
10mmol of 4- (dimethylamino) benzoyl hydrazine, 15 of mmol of chloroacetyl chloride and 50 of mL of ethyl acetate are added into a 100 mL flask to be stirred and reacted for 1 hour at 70 ℃, after the reaction is finished, filtering is carried out, and filter residues are collected to obtain a first-step product IIa, namely N' - (2-chloroacetyl) -4- (dimethylamino) benzoyl hydrazine, and the yield is 90%.
Adding 5 mmol of the first-step product IIa, 10 mmol of phosphorus oxychloride and 30 of acetonitrile of mL into a 100 mL flask, stirring and reacting for 12 hours at 70 ℃, removing the solvent after the reaction is finished, adding 30 mL of ethyl acetate for dissolution, washing with water, washing with saturated sodium bicarbonate solution, washing with saturated sodium chloride solution, collecting an organic phase, drying the organic phase under reduced pressure, purifying by silica gel column chromatography (300-400 meshes, eluent is ethyl acetate: n-hexane with a volume ratio of 1:1), and obtaining a second-step product IIIa, namely 2-chloromethyl-5- (4- (dimethylamino) phenyl) -1,3, 4-oxadiazole, wherein the yield is 80%.
Adding 2mmol of the second step product IIIa, 2mmol of aminoguanidine hydrochloride, 7.2 of mmol of potassium carbonate, 1 of mmol of potassium iodide and 20 of mL of N, N-dimethylformamide into a 100 mL flask, stirring at 30 ℃ for reaction for 12 hours, adding 40 of mL of water after the reaction is finished, adding hydrochloric acid for neutralization, filtering, washing, and air-drying to obtain a target product (IVa), wherein the yield is 60 percent 43%.1H NMR (400 MHz, DMSO-d6, δ): 8.19 (s, 1H, guanidine), 7.84 (s, 1H, guanidine), 7.59 (d, J = 7.5 Hz, 2H, 1-benzene), 6.92 (d, J = 7.5 Hz, 2H, 1-benzene), 6.63 (s, 2H, guanidine), 5.00 (s, 1H, sec amine), 3.91 (s, 2H, methylene), 3.02 (s, 6H, methyl).HRMS (ESI): m/z calcd for C12H18N7O+: 276.1572 [M+H]+; found: 276.1594.
Example 2
Preparation of 2-guanidinoaminomethyl-5- (4- (methoxy) phenyl) -1,3, 4-oxadiazole (IVb):
10 mmol of 4- (methoxy) benzoyl hydrazine, 15 mmol of chloroacetyl chloride and 50 of ethyl acetate of mL are added into a 100 mL flask to be stirred and reacted for 1 hour at 70 ℃, after the reaction is finished, the filter residue is filtered and collected, and the product IIb of the first step is obtained, namely N' - (2-chloroacetyl) -4- (methoxy) benzoyl hydrazine, and the yield is 90 percent.
Adding 5 mmol of the first-step product IIb, 10 of phosphorus oxychloride of mmol and 30 of acetonitrile of mL into a 100mL flask, stirring and reacting for 12 hours at 70 ℃, removing the solvent after the reaction is finished, adding 30 of mL of ethyl acetate for dissolution, washing with water, washing with saturated sodium bicarbonate solution, washing with saturated sodium chloride solution, collecting an organic phase, drying under reduced pressure, purifying by silica gel column chromatography (300-400 meshes, eluent is ethyl acetate: n-hexane with a volume ratio of 1:1), and obtaining a second-step product IIIb, namely 2-chloromethyl-5- (4- (methoxy) phenyl) -1,3, 4-oxadiazole, wherein the yield is 80%.
Adding 2mmol of the second step product IIIb, 2mmol of aminoguanidine hydrochloride, 7.2 of mmol of potassium carbonate, 1 of mmol of potassium iodide and 20 of mL of N, N-dimethylformamide into a 100 mL flask, stirring at 30 ℃ for reaction for 12 hours, adding 40 of mL of water after the reaction is finished, adding hydrochloric acid for neutralization, filtering, washing, and air-drying to obtain a target product (IVb), wherein the yield is 60 percent 43%.1H NMR (400 MHz, DMSO-d6, δ): 8.19 (s, 1H, guanidine), 8.02 (d, J = 7.5 Hz, 2H, 1-benzene), 7.84 (s, 1H, guanidine), 7.03 (d, J = 7.5 Hz, 2H, 1-benzene), 6.63 (s, 2H, guanidine), 5.00 (s, 1H, sec amine), 3.91 (s, 2H, methylene), 3.81 (s, 3H, methyl).HRMS (ESI): m/z calcd for C11H15N6O2 +: 263.1256 [M+H]+; found: 263.1267.
Example 3
Preparation of 2-guanidinoaminomethyl-5- (4- (phenyl) -1,3, 4-oxadiazole (IVc):
10 mmol of 4- (phenyl) benzoyl hydrazine, 15 mmol of chloroacetyl chloride and 50 of ethyl acetate of mL are added into a 100 mL flask to be stirred and reacted for 1 hour at 70 ℃, after the reaction is finished, the filter residue is filtered and collected to obtain a first-step product IIc, namely N' - (2-chloroacetyl) -4- (phenyl) benzoyl hydrazine, and the yield is 80 percent.
Adding 5mmol of the first-step product IIc, 10 of phosphorus oxychloride of mmol and 30 of acetonitrile of mL into a 100 mL flask, stirring and reacting for 12 hours at 70 ℃, removing the solvent after the reaction is finished, adding 30 of mL of ethyl acetate for dissolution, washing with water, washing with saturated sodium bicarbonate solution, washing with saturated sodium chloride solution, collecting an organic phase, drying the organic phase under reduced pressure, purifying by silica gel column chromatography (300-400 meshes, eluent is ethyl acetate: n-hexane with a volume ratio of 1:1), and obtaining a second-step product IIIc, namely 2-chloromethyl-5- (4- (phenyl) -1,3, 4-oxadiazole, wherein the yield is 70%.
Adding 2mmol of the second step product IIIc, 2mmol of aminoguanidine hydrochloride, 7.2 of mmol of potassium carbonate, 1 of mmol of potassium iodide and 20 of mL of N, N-dimethylformamide into a 100 mL flask, stirring at 30 ℃ for reaction for 12 hours, adding 40 of mL of water after the reaction is finished, adding hydrochloric acid for neutralization, filtering, washing, and air-drying to obtain a target product (IVc), wherein the yield is 60 percent 33%.1H NMR (400 MHz, DMSO-d6, δ): 8.19 (s, 1H, guanidine), 7.96 (d, J = 7.5 Hz, 2H, 1-benzene), 7.84 (s, 1H, guanidine), 7.75 (d, J = 7.5 Hz, 2H, 1-benzene), 7.49 (t, J = 7.5 Hz, 2H, 1-benzene), 7.41 (t, J = 7.5 Hz, 1H, 1-benzene), 7.25 (d, J = 7.5 Hz, 2H, 1-benzene), 6.63 (s, 2H, guanidine), 5.00 (s, 1H, sec amine), 3.91 (s, 2H, methylene).HRMS (ESI): m/z calcd for C16H17N6O+: 309.1463 [M+H]+; found: 309.1477.
Example 4
Preparation of 2-guanidinoaminomethyl-5- (4- (benzyloxy) phenyl) -1,3, 4-oxadiazole (IVd):
10 mmol of 4- (benzyloxy) benzoyl hydrazine, 15 mmol of chloroacetyl chloride and 50 mL of ethyl acetate are added into a 100 mL flask to be stirred and reacted for 1 hour at 70 ℃, after the reaction is finished, filtering is carried out, and filter residues are collected to obtain a first-step product IId, namely N' - (2-chloroacetyl) -4- (benzyloxy) benzoyl hydrazine, and the yield is 80%.
Adding 5 mmol of the first-step product IId, 10 of phosphorus oxychloride of mmol and 30 of acetonitrile of mL into a 100mL flask, stirring and reacting for 12 hours at 70 ℃, removing the solvent after the reaction is finished, adding 30 of mL of ethyl acetate for dissolution, washing with water, washing with saturated sodium bicarbonate solution, washing with saturated sodium chloride solution, collecting an organic phase, drying the organic phase under reduced pressure, purifying by silica gel column chromatography (300-400 meshes, eluent is ethyl acetate: n-hexane with a volume ratio of 1:1), and obtaining a second-step product IIId, namely 2-chloromethyl-5- (4- (benzyloxy) phenyl) -1,3, 4-oxadiazole, wherein the yield is 70%.
Adding 2 mmol of the second step product IIId, 2 mmol of aminoguanidine hydrochloride, 7.2 of mmol of potassium carbonate, 1 of mmol of potassium iodide and 20 of mL of N, N-dimethylformamide into a 100mL flask, stirring at 30 ℃ for reaction for 12 hours, adding 40 of mL of water after the reaction is finished, adding hydrochloric acid for neutralization, filtering, washing, and air-drying to obtain a target product (IVd), wherein the yield is 50 percent 28%.1H NMR (400 MHz, DMSO-d6, δ): 8.19 (s, 1H, guanidine), 8.02 (d, J = 7.5 Hz, 2H, 1-benzene), 7.84 (s, 1H, guanidine), 7.48 (d, J = 7.5 Hz, 2H, 1-benzene), 7.40 (t, J = 7.5 Hz, 2H, 1-benzene), 7.32 (t, J = 7.5 Hz, 1H, 1-benzene), 7.03 (d, J = 7.5 Hz, 2H, 1-benzene), 6.63 (s, 2H, guanidine), 5.16 (s, 2H, methylene), 5.00 (s, 1H, sec amine), 3.91 (s, 2H, methylene).HRMS (ESI): m/z calcd for C17H19N6O2 +: 339.1569 [M+H]+; found: 339.1580.
Example 5
Antibacterial Activity test of the target Compound:
The MIC of the target substance was measured by a microdilution method using 2-methyl-4-isothiazolin-3-one (MIT) as a control agent, and the antibacterial activity of the target compound (5-phenyl-1, 3, 4-oxadiazoles prepared in examples 1 to 4) against Staphylococcus aureus (Staphylococcus aureus ATCC 6538P), escherichia coli (ESCHERICHIA COLI ATCC 8739) and Pseudomonas aeruginosa (Pseudomonas aeruginosa ATCC 9027) was measured.
The experimental procedure of the microdilution method is as follows:
200. Mu.L of the sample to be tested (2-methyl-4-isothiazolin-3-one and 5-phenyl-1, 3, 4-oxadiazole compound prepared in example 1-4) was added to column 1 of the 96-well plate, 100. Mu.L of MH broth was added to columns 2-12, 100. Mu.L of the broth was added to column 2 of the broth from column 1, 100. Mu.L of the broth was added to column 3 of the broth from column 2, and the broth was analogized, and 100. Mu.L of the broth from column 10 was added to column 11 of the broth, and 100. Mu.L of the excess liquid was removed and discarded. 100 mu L of bacterial liquid with the concentration of 10 6 cfu/mL is added into each of the 1 st to 11 th columns, 100 mu L of bacterial liquid with the concentration of 10 6 cfu/mL is added into the four holes before the 12 th column, 100 mu L of MH broth is added into the four holes after the 12 th column, the final volume of each hole is 200 mu L, the concentrations of samples to be detected in the 1 st to 11 th columns are 128, 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25 and 0.12 mu g/mL in sequence, the four holes before the 12 th column are no-dosing (positive growth control), and the four holes after the 12 th column are no-dosing (sterile control). Three replicates were made for each sample tested. After incubation of the 96-well plates in an oven at 37 ℃ for 24 hours, the OD 600 values were measured with a microplate reader and the concentration of wells with OD 600 values close to the sterile control was the minimum inhibitory concentration MIC.
The results show that:
(1) MIC of 2-methyl-4-isothiazolin-3-one (MIT) on staphylococcus aureus, escherichia coli and pseudomonas aeruginosa was 16 mug/mL, 16 mug/mL and 16 mug/mL respectively.
(2) The MIC of the 2-guanidylaminomethyl-5- (4- (dimethylamino) phenyl) -1,3, 4-oxadiazole (IVa) on staphylococcus aureus, escherichia coli and pseudomonas aeruginosa is 4 mug/mL, 4 mug/mL and 4 mug/mL respectively, and the antibacterial effect on staphylococcus aureus, escherichia coli and pseudomonas aeruginosa is better than that of the control medicament 2-methyl-4-isothiazolin-3-ketone (MIT).
(3) The MIC of the 2-guanidylaminomethyl-5- (4- (methoxy) phenyl) -1,3, 4-oxadiazole (IVb) on staphylococcus aureus, escherichia coli and pseudomonas aeruginosa is respectively 4 mug/mL, 4 mug/mL and 8 mug/mL, and the antibacterial effect on staphylococcus aureus, escherichia coli and pseudomonas aeruginosa is better than that of the control medicament 2-methyl-4-isothiazolin-3-ketone (MIT).
(4) The MIC of the 2-guanidylaminomethyl-5- (4- (phenyl) -1,3, 4-oxadiazole (IVc) on staphylococcus aureus, escherichia coli and pseudomonas aeruginosa is 1 mug/mL, 1 mug/mL respectively, and the antibacterial effect on staphylococcus aureus, escherichia coli and pseudomonas aeruginosa is better than that of the control medicament 2-methyl-4-isothiazolin-3-ketone (MIT).
(5) The MIC of the 2-guanidylaminomethyl-5- (4- (benzyloxy) phenyl) -1,3, 4-oxadiazole (IVd) on staphylococcus aureus, escherichia coli and pseudomonas aeruginosa is respectively 1 mug/mL, 0.5 mug/mL and 1 mug/mL, and the antibacterial effect on staphylococcus aureus, escherichia coli and pseudomonas aeruginosa is superior to that of the control medicament 2-methyl-4-isothiazolin-3-one (MIT).
The foregoing is merely a preferred embodiment of the present invention, and it should be noted that the above-mentioned preferred embodiment should not be construed as limiting the invention, and the scope of the invention should be defined by the appended claims. It will be apparent to those skilled in the art that various modifications and adaptations can be made without departing from the spirit and scope of the invention, and such modifications and adaptations are intended to be comprehended within the scope of the invention.
Claims (10)
- The structural formula of the 5-phenyl-1, 3, 4-oxadiazole compound or the salt thereof is shown as the formula (IV):(IV)R is selected from、、Or (b)。
- 2. The 5-phenyl-1, 3, 4-oxadiazole compound of claim 1, wherein R is selected from the group consisting ofOr (b)。
- 3. A process for preparing 5-phenyl-1, 3, 4-oxadiazole compound according to claim 1, characterized in that the first step of product (II) is synthesized by using benzoyl hydrazine compound (I) and chloroacetyl chloride as raw materials, the first step of product (II) reacts with phosphorus oxychloride to obtain the second step of product (III), the second step of product (III) reacts with aminoguanidine hydrochloride to obtain the final product 5-phenyl-1, 3, 4-oxadiazole compound (IV), and the synthesis reaction formula of the 5-phenyl-1, 3, 4-oxadiazole compound is as follows:；Wherein R is selected from 、、Or (b)。
- 4. The process for producing 5-phenyl-1, 3, 4-oxadiazole according to claim 3, wherein R is selected from the group consisting ofOr (b)。
- 5. A method of preparation according to claim 3, comprising the steps of: the first step: adding a benzoyl hydrazine compound (I), chloroacetyl chloride and ethyl acetate into a reactor, heating and stirring for reaction to obtain a first-step product (II); and a second step of: adding the first-step product (II), phosphorus oxychloride and acetonitrile into a reactor, heating and stirring for reaction to obtain a second-step product (III); and a third step of: adding the second-step product (III), aminoguanidine hydrochloride, potassium carbonate, potassium iodide and N, N-dimethylformamide into a reactor, and stirring for reaction to obtain the 5-phenyl-1, 3, 4-oxadiazole compound.
- 6. The preparation method according to claim 5, wherein the ratio of the amounts of the benzoyl hydrazine compound (I) and the chloroacetyl chloride in the first step is 1:1.5; the ratio of the amounts of the product (II) of the first step and the phosphorus oxychloride in the second step is 1:2; the amount ratio of the substances of the second step product (III), aminoguanidine hydrochloride, potassium carbonate and potassium iodide in the third step is 1:1:3.6:0.5; the heating and stirring reaction in the first step and the second step is carried out at 70 ℃.
- 7. Use of a 5-phenyl-1, 3, 4-oxadiazole compound or a salt thereof as claimed in claim 1 for the preparation of an antibacterial agent.
- 8. The use according to claim 7, wherein the antibacterial agent is an anti-staphylococcus aureus, escherichia coli and/or pseudomonas aeruginosa agent.
- 9. An antibacterial agent comprising the 5-phenyl-1, 3, 4-oxadiazole compound or its salt according to claim 1 as an active ingredient.
- 10. The antibacterial agent of claim 9, wherein the antibacterial agent is an anti-staphylococcus aureus, escherichia coli and/or pseudomonas aeruginosa agent.
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