CN116730942A - 1,3, 4-oxadiazole-2 (3H) -thioketone compound and preparation method and application thereof - Google Patents
1,3, 4-oxadiazole-2 (3H) -thioketone compound and preparation method and application thereof Download PDFInfo
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- CN116730942A CN116730942A CN202310708369.7A CN202310708369A CN116730942A CN 116730942 A CN116730942 A CN 116730942A CN 202310708369 A CN202310708369 A CN 202310708369A CN 116730942 A CN116730942 A CN 116730942A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 239000000047 product Substances 0.000 claims abstract description 44
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims abstract description 33
- -1 alkyne compound Chemical class 0.000 claims abstract description 29
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 claims abstract description 21
- 238000006243 chemical reaction Methods 0.000 claims abstract description 20
- 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
- 238000006683 Mannich reaction Methods 0.000 claims abstract description 3
- 238000003477 Sonogashira cross-coupling reaction Methods 0.000 claims abstract description 3
- 239000012467 final product Substances 0.000 claims abstract description 3
- 239000002994 raw material Substances 0.000 claims abstract description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 30
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- ZVFGHUJYTXEOSI-UHFFFAOYSA-N 4-iodobenzohydrazide Chemical compound NNC(=O)C1=CC=C(I)C=C1 ZVFGHUJYTXEOSI-UHFFFAOYSA-N 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 10
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 8
- 239000003242 anti bacterial agent Substances 0.000 claims description 8
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 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
- 238000000034 method Methods 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 230000000941 anti-staphylcoccal effect Effects 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 238000003786 synthesis reaction Methods 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 2
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 claims description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 20
- 241000191967 Staphylococcus aureus Species 0.000 abstract description 15
- 150000001875 compounds Chemical class 0.000 abstract description 4
- 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
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 abstract 2
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 22
- 229940100555 2-methyl-4-isothiazolin-3-one Drugs 0.000 description 19
- BEGLCMHJXHIJLR-UHFFFAOYSA-N methylisothiazolinone Chemical compound CN1SC=CC1=O BEGLCMHJXHIJLR-UHFFFAOYSA-N 0.000 description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 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
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 239000003814 drug Substances 0.000 description 7
- 239000003899 bactericide agent Substances 0.000 description 5
- FSRNSODMVRQPPI-UHFFFAOYSA-N 5-(4-iodophenyl)-3h-1,3,4-oxadiazole-2-thione Chemical compound C1=CC(I)=CC=C1C1=NNC(=S)O1 FSRNSODMVRQPPI-UHFFFAOYSA-N 0.000 description 4
- 101150003085 Pdcl gene Proteins 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
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- QGJOPFRUJISHPQ-NJFSPNSNSA-N carbon disulfide-14c Chemical compound S=[14C]=S QGJOPFRUJISHPQ-NJFSPNSNSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 3
- 230000001580 bacterial effect Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 208000035143 Bacterial infection Diseases 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 230000006978 adaptation Effects 0.000 description 2
- 208000022362 bacterial infectious disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000005516 engineering process Methods 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
- RUBRCWOFANAOTP-UHFFFAOYSA-N 3h-1,3,4-oxadiazole-2-thione Chemical compound S=C1NN=CO1 RUBRCWOFANAOTP-UHFFFAOYSA-N 0.000 description 1
- 241000191070 Escherichia coli ATCC 8739 Species 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 229940124350 antibacterial drug Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003115 biocidal 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
- 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
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- UARFKZSJGDQRLF-UHFFFAOYSA-N prop-2-ynylcyclohexane Chemical compound C#CCC1CCCCC1 UARFKZSJGDQRLF-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
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- 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
- C07D271/113—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
-
- 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
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- 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
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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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- General Health & Medical Sciences (AREA)
- Pest Control & Pesticides (AREA)
- General Chemical & Material Sciences (AREA)
- Environmental Sciences (AREA)
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- 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)
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- Animal Behavior & Ethology (AREA)
- Dentistry (AREA)
- Oncology (AREA)
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- 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 1,3, 4-oxadiazole-2 (3H) -thioketone compound and a preparation method and application thereof. The structural formula of the 1,3, 4-oxadiazole-2 (3H) -thioketone compound is shown as a formula (IV). According to the invention, a series of 1,3, 4-oxadiazole-2 (3H) -thioketone compounds with brand new structures are designed and synthesized by introducing a lipophilic phenyl side chain into the C5 position and hydrophilic aminoguanidine into the N3 position of 1,3, 4-oxadiazole-2 (3H) -thioketone, and the preparation method comprises the following steps: with 4-iodobenzoylAnd (3) synthesizing the hydrazine and the carbon disulfide serving as raw materials to obtain a first-step product (I), carrying out Sonogashira coupling reaction on the first-step product (I) and the alkyne compound (II) to obtain a second-step product (III), and carrying out Mannich reaction on the second-step product (III), formaldehyde and aminoguanidine hydrochloride to obtain a final product (IV). The 1,3, 4-oxadiazole-2 (3H) -thioketone 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 antibacterial drug or an industrial bactericide, and in particular relates to a 1,3, 4-oxadiazole-2 (3H) -thioketone compound with a novel structure, and a preparation method and application thereof.
The background technology is as follows:
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. The 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 ketone groups on the ring, and 1,3, 4-oxadiazole-2 (3H) -thioketone compounds with brand new structures are constructed through bioisostere treatment and derivative, so that the bactericide with brand new structures can be possibly generated.
Disclosure of Invention
The first object of the invention is to provide a 1,3, 4-oxadiazole-2 (3H) -thioketone 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 1,3, 4-oxadiazole-2 (3H) -thioketone compound is shown as formula (IV):
wherein R is selected from
Preferably, R is selected from
The second purpose of the invention is to provide a preparation method of the 1,3, 4-oxadiazole-2 (3H) -thioketone compound shown in the structural formula (IV), wherein 4-iodobenzoyl hydrazine and carbon disulfide are used as raw materials in the preparation method, a first-step product (I) is synthesized, the first-step product (I) and an alkyne compound (II) are subjected to Sonogashira coupling reaction to prepare a second-step product (III), the second-step product (III) and formaldehyde and aminoguanidine hydrochloride are subjected to Mannich reaction to prepare a final product (IV), and the synthesis reaction formula of the 1,3, 4-oxadiazole-2 (3H) -thioketone compound is as follows:
；
wherein R is selected from
Preferably, R is selected from
Further preferably, the method comprises the following steps: the first step: adding 4-iodobenzoyl hydrazine, carbon disulfide and potassium hydroxide into a reactor, heating and stirring to react to obtain a first-step product (I); and a second step of: adding the first-step product (I), an alkyne compound (II), bis (triphenylphosphine) palladium dichloride, cuprous iodide, triethylamine and N, N-dimethylformamide into a reactor, and heating and stirring for reaction to obtain a second-step product (III); and a third step of: adding the second step product (III), formaldehyde and aminoguanidine hydrochloride into a reactor, and stirring for reaction to obtain the 1,3, 4-oxadiazole-2 (3H) -thioketone compound with the structural formula shown in the formula (IV).
The total yield of the preparation method can be 31-43%.
Preferably, the ratio of the amounts of the substances of 4-iodobenzoyl hydrazine, carbon disulfide and potassium hydroxide in the first step is 1:1.5:1; the ratio of the amounts of the product (I), the alkyne compound (II), the ditriphenylphosphine palladium dichloride and the cuprous iodide in the first step is 20:40:1:2; the ratio of the amounts of the substances of the second step product (III), aminoguanidine hydrochloride and formaldehyde in the third step is 1:1:3; the heating and stirring reaction in the first step and the second step is carried out at 70 ℃.
Preferably, the alkyne compound is selected from 4-propyne-1-morpholine or 3-benzene-1-propyne.
The third object of the present invention is to provide an application of the 1,3, 4-oxadiazole-2 (3H) -thione compound shown in the structural formula (IV) or a salt thereof in 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 1,3, 4-oxadiazole-2 (3H) -thione 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, a series of 1,3, 4-oxadiazole-2 (3H) -thioketone 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 N3 position of 1,3, 4-oxadiazole-2 (3H) -thioketone, and antibacterial activity research is carried out. The research results show that: the 1,3, 4-oxadiazole-2 (3H) -thioketone 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 3-guanidinoaminomethyl-5- (4- (3-cyclopentylprop-1-yn-1-yl) phenyl) -1,3, 4-oxadiazole-2 (3H) -thione (IVa):
10mmol of 4-iodobenzoyl hydrazine, 15mmol of carbon disulfide, 10mmol of potassium hydroxide, 10mL of water and 10mL of ethanol are added into a 100mL flask, stirred and reacted for 10 hours at 70 ℃, after the reaction is finished, the mixture is neutralized by hydrochloric acid, filtered, washed by water, and filter residues are collected and recrystallized by ethanol to obtain a first-step product I, namely 5- (4-iodophenyl) -1,3, 4-oxadiazole-2 (3H) -thione, and the yield is 90 percent.
5mmol of the first-stage product I, 10mmol of 3-cyclopentyl-1-propynylIIa, 0.25mmol of PdCl 2 (PPh 3 ) 2 0.5mmol of cuprous iodide, 9mL of N, N-dimethylformamide and 3mL of triethylamine are added into a 25mL sealed tube, stirred and reacted for 2 hours at 70 ℃, after the reaction is finished, the mixture is filtered by kieselguhr, washed by chloroform, and the organic phase is collected and dried under reduced pressure, and the silica gel column chromatography (300-400 meshes, eluent is ethyl acetate: N-hexane volume ratio is 1:9) is performed, so that a second step of product IIIa is obtained, namely 5- (4- (3-cyclopentylprop-1-yn-1-yl) phenyl) -1,3, 4-oxadiazole-2 (3H) -thione is obtained, and the yield is 70%.
2mmol of the second-step product IIIa, 2mmol of aminoguanidine hydrochloride, 6mmol of formaldehyde and 10mL of N, N-dimethylformamide are added into a 100mL flask, the reaction is stirred for 24 hours at 30 ℃, the reaction is completed, the filtration and the spin-drying of the filtrate are carried out under reduced pressure, the ethanol recrystallization and purification are carried out, and finally the target product (IVa) is obtained, the yield is 50%, and the total yield is 31%. 1 H NMR(400MHz,DMSO-d 6 ,δ):8.19(s,1H,guanidine),7.84(s,1H,guanidine),7.78(d,J＝7.5Hz,2H,1-benzene),7.45(d,J＝7.5Hz,2H,1-benzene),6.63(s,2H,guanidine),4.49(s,2H,methylene),4.20(s,1H,sec amine),1.95(m,4H,methylene and cyclopentane),1.73(m,2H,cyclopentane),1.65(m,4H,cyclopentane),1.50(m,1H,cyclopentane)。HRMS(ESI)m/z:[M+H] + calcd for C 18 H 23 N 6 OS,371.1654；found 371.1671。
Example 2
Preparation of 3-guanidinoaminomethyl-5- (4- (3-cyclohexylprop-1-yn-1-yl) phenyl) -1,3, 4-oxadiazole-2 (3H) -thione (IVb):
10mmol of 4-iodobenzoyl hydrazine, 15mmol of carbon disulfide, 10mmol of potassium hydroxide, 10mL of water and 10mL of ethanol are added into a 100mL flask, stirred and reacted for 10 hours at 70 ℃, after the reaction is finished, the mixture is neutralized by hydrochloric acid, filtered, washed by water, and filter residues are collected and recrystallized by ethanol to obtain a first-step product I, namely 5- (4-iodophenyl) -1,3, 4-oxadiazole-2 (3H) -thione, and the yield is 90 percent.
5mmol of the first-stage product I, 10mmol of 3-cyclohexyl-1-propyne IIb, 0.25mmol of PdCl 2 (PPh 3 ) 2 0.5mmol of cuprous iodide, 9mL of N, N-dimethylformamide and 3mL of triethylamine are added into a 25mL sealed tube, stirred and reacted for 2 hours at 70 ℃, after the reaction is finished, the mixture is filtered by kieselguhr, washed by chloroform, and the organic phase is collected and dried under reduced pressure by spin, and the silica gel column chromatography (300-400 meshes, eluent is ethyl acetate: N-hexane volume ratio is 1:9) is performed to obtain a second step of product IIIb, namely 5- (4- (3-cyclohexylprop-1-yn-1-yl) phenyl) -1,3, 4-oxadiazol-2 (3H) -thione, and the yield is 80 percent.
Adding 2mmol of the second-step product IIIb, 2mmol of aminoguanidine hydrochloride, 6mmol of formaldehyde and 10mL of N, N-dimethylformamide into a 100mL flask, stirring and reacting for 24 hours at 30 ℃, filtering, decompressing, spin-drying filtrate, recrystallizing with ethanol and purifying to obtain the target productProduct (IVb), yield 50% and total yield 36%. 1 H NMR(400MHz,DMSO-d 6 ,δ):8.19(s,1H,guanidine),7.84(s,1H,guanidine),7.78(d,J＝7.5Hz,2H,1-benzene),7.45(d,J＝7.5Hz,2H,1-benzene),6.63(s,2H,guanidine),4.49(s,2H,methylene),4.20(s,1H,sec amine),1.95(d,J＝7.0Hz,2H,methylene),1.62(m,4H,cyclohexane),1.53(m,2H,cyclohexane),1.46(m,5H,cyclohexane)。HRMS(ESI)m/z:[M+H] + calcd for C 19 H 25 N 6 OS,385.1810；found 385.1823。
Example 3
Preparation of 3-guanidinoaminomethyl-5- (4- (3-morpholinoprop-1-yn-1-yl) phenyl) -1,3, 4-oxadiazole-2 (3H) -thione (IVc):
10mmol of 4-iodobenzoyl hydrazine, 15mmol of carbon disulfide, 10mmol of potassium hydroxide, 10mL of water and 10mL of ethanol are added into a 100mL flask, stirred and reacted for 10 hours at 70 ℃, after the reaction is finished, the mixture is neutralized by hydrochloric acid, filtered, washed by water, and filter residues are collected and recrystallized by ethanol to obtain a first-step product I, namely 5- (4-iodophenyl) -1,3, 4-oxadiazole-2 (3H) -thione, and the yield is 90 percent.
5mmol of the first-stage product I, 10mmol of 4-propyne-1-morpholinium IIc, 0.25mmol of PdCl 2 (PPh 3 ) 2 0.5mmol of cuprous iodide, 9mL of N, N-dimethylformamide and 3mL of triethylamine are added into a 25mL sealed tube, stirred and reacted for 2 hours at 70 ℃, after the reaction is finished, the mixture is filtered by kieselguhr, washed by chloroform, and the organic phase is collected and dried under reduced pressure by spin, and the silica gel column chromatography (300-400 meshes, eluent is ethyl acetate: N-hexane volume ratio is 1:9) is performed to obtain a second step of product IIIc, namely 5- (4- (3-morpholinopropan-1-yn-1-yl) phenyl) -1,3, 4-oxadiazol-2 (3H) -thione, and the yield is 80 percent.
Adding 2mmol of the second-step product IIIc, 2mmol of aminoguanidine hydrochloride, 6mmol of formaldehyde and 10mL of N, N-dimethylformamide into a 100mL flask, stirring and reacting for 24 hours at 30 ℃, filtering, drying the filtrate under reduced pressure, and weighing the ethanolAnd (3) crystallizing and purifying to finally obtain the target product (IVc), wherein the yield is 60% and the total yield is 43%. 1 H NMR(400MHz,DMSO-d 6 ,δ):8.19(s,1H,guanidine),7.84(s,1H,guanidine),7.78(d,J＝7.5Hz,2H,1-benzene),7.45(d,J＝7.5Hz,2H,1-benzene),6.63(s,2H,guanidine),4.49(s,2H,methylene),4.29(s,2H,methylene),4.20(s,1H,sec amine),3.57(t,J＝7.0Hz,4H,tetrahydro-1,4-oxazine),2.48(t,J＝7.0Hz,4H,tetrahydro-1,4-oxazine)。HRMS(ESI)m/z:[M+H] + calcd for C 17 H 22 N 7 O 2 S,388.1555；found 388.1576。
Example 4
Preparation of 3-guanidinoaminomethyl-5- (4- (3-phenylprop-1-yn-1-yl) phenyl) -1,3, 4-oxadiazole-2 (3H) -thione (IVd):
10mmol of 4-iodobenzoyl hydrazine, 15mmol of carbon disulfide, 10mmol of potassium hydroxide, 10mL of water and 10mL of ethanol are added into a 100mL flask, stirred and reacted for 10 hours at 70 ℃, after the reaction is finished, the mixture is neutralized by hydrochloric acid, filtered, washed by water, and filter residues are collected and recrystallized by ethanol to obtain a first-step product I, namely 5- (4-iodophenyl) -1,3, 4-oxadiazole-2 (3H) -thione, and the yield is 90 percent.
5mmol of the first-stage product I, 10mmol of 3-benzene-1-propyne IId, 0.25mmol of PdCl 2 (PPh 3 ) 2 0.5mmol of cuprous iodide, 9mL of N, N-dimethylformamide and 3mL of triethylamine are added into a 25mL sealed tube, stirred and reacted for 2 hours at 70 ℃, after the reaction is finished, the mixture is filtered by kieselguhr, washed by chloroform, and the organic phase is collected, dried under reduced pressure, and purified by silica gel column chromatography (300-400 meshes, eluent is ethyl acetate: N-hexane volume ratio is 1:9), thus obtaining a second step of product IIId, namely 5- (4- (3-phenylprop-1-yn-1-yl) phenyl) -1,3, 4-oxadiazole-2 (3H) -thione, and the yield is 80 percent.
2mmol of the second-step product IIId, 2mmol of aminoguanidine hydrochloride, 6mmol of formaldehyde and 10mL of N, N-dimethylformamide are added into a 100mL flask, and the mixture is stirred at 30 ℃ for reaction for 24 hoursAfter the completion of filtration, the filtrate was dried by spin-drying under reduced pressure, and the ethanol was recrystallized and purified to obtain the target product (IVd), the yield was 60%, and the total yield was 43%. 1 H NMR(400MHz,DMSO-d 6 ,δ):8.19(s,1H,guanidine),7.84(s,1H,guanidine),7.78(d,J＝7.5Hz,2H,1-benzene),7.45(d,J＝7.5Hz,2H,1-benzene),7.25(m,3H,1-benzene),7.16(d,J＝7.5Hz,2H,1-benzene),6.63(s,2H,guanidine),4.49(s,2H,methylene),4.20(s,1H,sec amine),3.29(s,2H,methylene)。HRMS(ESI)m/z:[M+H] + calcd for C 19 H 19 N 6 OS,379.1341；found 379.1352。
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 (1, 3, 4-oxadiazole-2 (3H) -thione compound 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 1,3, 4-oxadiazol-2 (3H) -thione prepared in examples 1-4) were 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 for mixing, 100. Mu.L of the broth was added to column 3 for mixing, and so forth, and finally 100. Mu.L of the broth was removed from column 10 for mixing, and 100. Mu.L of the broth was removed for discarding. 100 mu L of the mixture is taken to have the concentration of 10 6 Adding cfu/mL bacterial liquid into each well of columns 1-11, taking 100 mu L of bacterial liquid with concentration of 10 6 cfu/mL of bacterial liquid is added into four holes before the 12 th row, 100 mu LMH broth is added into four holes after the 12 th row, the final volume of each hole is 200 mu L, the concentrations of samples to be detected in the 1 st to 11 th rows 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 row are no-dosing (positive growth control), and the four holes after the 12 th row are no-dosing (sterile control). Three replicates were made for each sample tested. The 96-well plate is put at 37 DEG CAfter incubation in the oven for 24 hours, OD was measured with a microplate reader 600 Value, OD 600 The concentration of wells with 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 3-guanidylaminomethyl-5- (4- (3-cyclopentylprop-1-yn-1-yl) phenyl) -1,3, 4-oxadiazole-2 (3H) -thione (IVa) on staphylococcus aureus, escherichia coli and pseudomonas aeruginosa is respectively 2 mug/mL, 4 mug/mL and 4 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-one (MIT).
(3) The MIC of 3-guanidylaminomethyl-5- (4- (3-cyclohexylprop-1-yn-1-yl) phenyl) -1,3, 4-oxadiazole-2 (3H) -thione (IVb) on staphylococcus aureus, escherichia coli and pseudomonas aeruginosa is 8 mug/mL, 8 mug/mL and 16 mug/mL respectively, the antibacterial effect on staphylococcus aureus and escherichia coli is superior to that of a control medicament 2-methyl-4-isothiazolin-3-one (MIT), and the antibacterial effect on pseudomonas aeruginosa is equivalent to that of the control medicament 2-methyl-4-isothiazolin-3-one (MIT).
(4) The MIC of 3-guanidylaminomethyl-5- (4- (3-morpholinopropan-1-yn-1-yl) phenyl) -1,3, 4-oxadiazole-2 (3H) -thione (IVc) on staphylococcus aureus, escherichia coli and pseudomonas aeruginosa is respectively 1 mug/mL, 2 mug/mL and 4 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-one (MIT).
(5) The MIC of 3-guanidylaminomethyl-5- (4- (3-phenylprop-1-yn-1-yl) phenyl) -1,3, 4-oxadiazole-2 (3H) -thione (IVd) on staphylococcus aureus, escherichia coli and pseudomonas aeruginosa is 1 mug/mL, 1 mug/mL and 2 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-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)
1.1,3,4-oxadiazole-2 (3H) -thioketone compounds or salts thereof, and the structural formula of the 1,3, 4-oxadiazole-2 (3H) -thioketone compounds is shown as formula (IV):
r is selected from
2. The 1,3, 4-oxadiazole-2 (3H) -thione compound of claim 1, wherein R is selected from the group consisting of
3. A process for preparing 1,3, 4-oxadiazole-2 (3H) -thioketone compound according to claim 1, characterized in that 4-iodobenzoyl hydrazine and carbon disulfide are used as raw materials, a first step product (I) is synthesized, the first step product (I) and alkyne compound (II) are subjected to Sonogashira coupling reaction to obtain a second step product (III), the second step product (III) and formaldehyde and aminoguanidine hydrochloride are subjected to Mannich reaction to obtain a final product 1,3, 4-oxadiazole-2 (3H) -thioketone compound (IV), and the synthesis reaction formula of the 1,3, 4-oxadiazole-2 (3H) -thioketone compound is as follows:
；
wherein R is selected from
4. The process of claim 3 wherein R is selected from the group consisting of
5. A method of preparation according to claim 3, comprising the steps of: the first step: adding 4-iodobenzoyl hydrazine, carbon disulfide and potassium hydroxide into a reactor, heating and stirring to react to obtain a first-step product (I); and a second step of: adding the first-step product (I), an alkyne compound (II), bis (triphenylphosphine) palladium dichloride, cuprous iodide, triethylamine and N, N-dimethylformamide into a reactor, and heating and stirring for reaction to obtain a second-step product (III); and a third step of: adding the second-step product (III), formaldehyde and aminoguanidine hydrochloride into a reactor, and stirring for reaction to obtain the 1,3, 4-oxadiazole-2 (3H) -thioketone compound.
6. The method according to claim 5, wherein the amount of the 4-iodobenzoyl hydrazine, carbon disulfide and potassium hydroxide in the first step is 1:1.5:1; the ratio of the amounts of the product (I), the alkyne compound (II), the ditriphenylphosphine palladium dichloride and the cuprous iodide in the first step is 20:40:1:2; the ratio of the amounts of the substances of the second step product (III), aminoguanidine hydrochloride and formaldehyde in the third step is 1:1:3; the heating and stirring reaction in the first step and the second step is carried out at 70 ℃.
7. Use of a 1,3, 4-oxadiazole-2 (3H) -thione compound or a salt thereof according to claim 1 in the manufacture 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 1,3, 4-oxadiazole-2 (3H) -thione compound or a salt thereof 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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| CN113336720A (en) * | 2021-06-21 | 2021-09-03 | 广东省科学院微生物研究所(广东省微生物分析检测中心) | Guanidyl thiazole compound and preparation method and application thereof |
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