CN107827880B - Carbonitrile compound containing imidazole and 1,3, 4-oxadiazole structure and preparation method and application thereof - Google Patents
Carbonitrile compound containing imidazole and 1,3, 4-oxadiazole structure and preparation method and application thereof Download PDFInfo
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- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 title claims abstract description 90
- -1 Carbonitrile compound Chemical class 0.000 title claims abstract description 34
- LELOWRISYMNNSU-UHFFFAOYSA-N Hydrocyanic acid Natural products N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 title claims abstract description 31
- FKASFBLJDCHBNZ-UHFFFAOYSA-N 1,3,4-oxadiazole Chemical group C1=NN=CO1 FKASFBLJDCHBNZ-UHFFFAOYSA-N 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 64
- 238000006243 chemical reaction Methods 0.000 claims abstract description 50
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims abstract description 28
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims abstract description 24
- 238000010992 reflux Methods 0.000 claims abstract description 15
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000005711 Benzoic acid Substances 0.000 claims abstract description 8
- 235000010233 benzoic acid Nutrition 0.000 claims abstract description 8
- 150000001558 benzoic acid derivatives Chemical class 0.000 claims abstract description 7
- 239000012295 chemical reaction liquid Substances 0.000 claims abstract description 7
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 3
- 239000007787 solid Substances 0.000 claims description 48
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 28
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- 239000005457 ice water Substances 0.000 claims description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 25
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 16
- 125000001424 substituent group Chemical group 0.000 claims description 16
- 239000003208 petroleum Substances 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 11
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 239000011737 fluorine Substances 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 3
- OXTQACXWHCLJDC-UHFFFAOYSA-N imidazole-1-carbohydrazide Chemical compound NNC(=O)N1C=CN=C1 OXTQACXWHCLJDC-UHFFFAOYSA-N 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- 239000002246 antineoplastic agent Substances 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 206010009944 Colon cancer Diseases 0.000 abstract description 11
- 206010058467 Lung neoplasm malignant Diseases 0.000 abstract description 11
- 208000029742 colonic neoplasm Diseases 0.000 abstract description 11
- 201000005202 lung cancer Diseases 0.000 abstract description 11
- 208000020816 lung neoplasm Diseases 0.000 abstract description 11
- 101000600434 Homo sapiens Putative uncharacterized protein encoded by MIR7-3HG Proteins 0.000 abstract description 9
- 102100037401 Putative uncharacterized protein encoded by MIR7-3HG Human genes 0.000 abstract description 9
- 230000002401 inhibitory effect Effects 0.000 abstract description 9
- 201000007270 liver cancer Diseases 0.000 abstract description 7
- 208000014018 liver neoplasm Diseases 0.000 abstract description 7
- 230000001093 anti-cancer Effects 0.000 abstract description 6
- 230000005764 inhibitory process Effects 0.000 abstract description 6
- 230000000694 effects Effects 0.000 abstract description 5
- 206010073071 hepatocellular carcinoma Diseases 0.000 abstract description 4
- 238000004166 bioassay Methods 0.000 abstract description 3
- 238000004737 colorimetric analysis Methods 0.000 abstract description 3
- 150000003536 tetrazoles Chemical class 0.000 abstract description 2
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 38
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 30
- 239000000203 mixture Substances 0.000 description 26
- 238000005160 1H NMR spectroscopy Methods 0.000 description 23
- 230000015572 biosynthetic process Effects 0.000 description 23
- 238000002390 rotary evaporation Methods 0.000 description 23
- 238000003786 synthesis reaction Methods 0.000 description 23
- 239000000126 substance Substances 0.000 description 20
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 11
- 229910019213 POCl3 Inorganic materials 0.000 description 8
- 239000000460 chlorine Substances 0.000 description 8
- 239000003814 drug Substances 0.000 description 6
- 230000004071 biological effect Effects 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 125000004093 cyano group Chemical group *C#N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 description 2
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 description 2
- 150000005072 1,3,4-oxadiazoles Chemical class 0.000 description 2
- 229910020323 ClF3 Inorganic materials 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 229940125890 compound Ia Drugs 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical group 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- LPNBBFKOUUSUDB-UHFFFAOYSA-N p-toluic acid Chemical compound CC1=CC=C(C(O)=O)C=C1 LPNBBFKOUUSUDB-UHFFFAOYSA-N 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 description 1
- SFKRXQKJTIYUAG-UHFFFAOYSA-N 2,3,4,5-tetrafluorobenzoic acid Chemical compound OC(=O)C1=CC(F)=C(F)C(F)=C1F SFKRXQKJTIYUAG-UHFFFAOYSA-N 0.000 description 1
- KVLBXIOFJUWSJQ-UHFFFAOYSA-N 2,3,5,6-tetrafluorobenzoic acid Chemical compound OC(=O)C1=C(F)C(F)=CC(F)=C1F KVLBXIOFJUWSJQ-UHFFFAOYSA-N 0.000 description 1
- QAOJBHRZQQDFHA-UHFFFAOYSA-N 2,3-dichlorobenzoic acid Chemical compound OC(=O)C1=CC=CC(Cl)=C1Cl QAOJBHRZQQDFHA-UHFFFAOYSA-N 0.000 description 1
- BKYWPNROPGQIFZ-UHFFFAOYSA-N 2,4-dimethylbenzoic acid Chemical compound CC1=CC=C(C(O)=O)C(C)=C1 BKYWPNROPGQIFZ-UHFFFAOYSA-N 0.000 description 1
- MRUDNSFOFOQZDA-UHFFFAOYSA-N 2,6-dichlorobenzoic acid Chemical compound OC(=O)C1=C(Cl)C=CC=C1Cl MRUDNSFOFOQZDA-UHFFFAOYSA-N 0.000 description 1
- FBRJYBGLCHWYOE-UHFFFAOYSA-N 2-(trifluoromethyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1C(F)(F)F FBRJYBGLCHWYOE-UHFFFAOYSA-N 0.000 description 1
- XRXMNWGCKISMOH-UHFFFAOYSA-N 2-bromobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1Br XRXMNWGCKISMOH-UHFFFAOYSA-N 0.000 description 1
- IKCLCGXPQILATA-UHFFFAOYSA-N 2-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1Cl IKCLCGXPQILATA-UHFFFAOYSA-N 0.000 description 1
- NSTREUWFTAOOKS-UHFFFAOYSA-N 2-fluorobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1F NSTREUWFTAOOKS-UHFFFAOYSA-N 0.000 description 1
- CJNZAXGUTKBIHP-UHFFFAOYSA-N 2-iodobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1I CJNZAXGUTKBIHP-UHFFFAOYSA-N 0.000 description 1
- CQQSQBRPAJSTFB-UHFFFAOYSA-N 4-(bromomethyl)benzoic acid Chemical compound OC(=O)C1=CC=C(CBr)C=C1 CQQSQBRPAJSTFB-UHFFFAOYSA-N 0.000 description 1
- TUXYZHVUPGXXQG-UHFFFAOYSA-N 4-bromobenzoic acid Chemical compound OC(=O)C1=CC=C(Br)C=C1 TUXYZHVUPGXXQG-UHFFFAOYSA-N 0.000 description 1
- XRHGYUZYPHTUJZ-UHFFFAOYSA-N 4-chlorobenzoic acid Chemical compound OC(=O)C1=CC=C(Cl)C=C1 XRHGYUZYPHTUJZ-UHFFFAOYSA-N 0.000 description 1
- ADCUEPOHPCPMCE-UHFFFAOYSA-N 4-cyanobenzoic acid Chemical compound OC(=O)C1=CC=C(C#N)C=C1 ADCUEPOHPCPMCE-UHFFFAOYSA-N 0.000 description 1
- BBYDXOIZLAWGSL-UHFFFAOYSA-N 4-fluorobenzoic acid Chemical compound OC(=O)C1=CC=C(F)C=C1 BBYDXOIZLAWGSL-UHFFFAOYSA-N 0.000 description 1
- GHICCUXQJBDNRN-UHFFFAOYSA-N 4-iodobenzoic acid Chemical compound OC(=O)C1=CC=C(I)C=C1 GHICCUXQJBDNRN-UHFFFAOYSA-N 0.000 description 1
- ZEYHEAKUIGZSGI-UHFFFAOYSA-N 4-methoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1 ZEYHEAKUIGZSGI-UHFFFAOYSA-N 0.000 description 1
- SWKPKONEIZGROQ-UHFFFAOYSA-N 4-trifluoromethylbenzoic acid Chemical compound OC(=O)C1=CC=C(C(F)(F)F)C=C1 SWKPKONEIZGROQ-UHFFFAOYSA-N 0.000 description 1
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- ILUJQPXNXACGAN-UHFFFAOYSA-N O-methylsalicylic acid Chemical compound COC1=CC=CC=C1C(O)=O ILUJQPXNXACGAN-UHFFFAOYSA-N 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000078 anti-malarial effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 1
- 229940127093 camptothecin Drugs 0.000 description 1
- XEVRDFDBXJMZFG-UHFFFAOYSA-N carbonyl dihydrazine Chemical compound NNC(=O)NN XEVRDFDBXJMZFG-UHFFFAOYSA-N 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000417 fungicide Substances 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 230000002363 herbicidal effect Effects 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000000749 insecticidal effect Effects 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- GPSDUZXPYCFOSQ-UHFFFAOYSA-N m-toluic acid Chemical compound CC1=CC=CC(C(O)=O)=C1 GPSDUZXPYCFOSQ-UHFFFAOYSA-N 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a carbonitrile compound containing imidazole and 1,3, 4-oxadiazole structures, and a preparation method and application thereof. The carbonitrile compound containing imidazole and 1,3, 4-oxadiazole structures consists of 4-chloro-2-cyano-5- (p-methylphenyl) -1HThe-imidazole-1-carbohydrazide and the substituted benzoic acid carry out cyclization reaction in phosphorus oxychloride under a reflux state, and after the reaction is finished, the reaction liquid is separated and purified to obtain the-imidazole-1-carbohydrazide-substituted benzoic acid. The preparation method is simple, the post-treatment is convenient, the obtained compounds show better anticancer activity, and the anticancer activity of the prepared compounds is determined by using a rapid tetrazole colorimetric method for human hepatoma cells, human lung cancer cells A549 and human colon cancer cells HCT 116. The bioassay result shows that the compound has certain inhibitory activity on all tested targets; the inhibition activity of most compounds on human colon cancer cell strain HCT116 and human liver cancer cell strain Huh7 is better than that of human lung cancer cell strain A549.
Description
Technical Field
The invention relates to a carbonitrile compound containing imidazole and 1,3, 4-oxadiazole structures, a preparation method and application thereof, in particular to 4-chloro-5- (p-methylphenyl) -1- (5- (substituted phenyl) -1,3, 4-oxadiazole-2-yl) -1H-imidazole-2-carbonitrile compounds, and a preparation method and application thereof.
Background
Imidazole structure compounds have wide biological activity, such as activity in the medical field, such as anti-tumor (Journal of medical Chemistry, 2002, 45(8): 1697-; in the field of agricultural chemicals, they are frequently used as fungicides (European Journal of Organic chemistry, 2017, (3): 695-. In addition, 1,3, 4-oxadiazole compounds have wide application in the pesticide and medicine fields, such as bactericidal (Journal of Agricultural and food chemistry, 2002, 50(13): 3757-3760), insecticidal (WO 9505368.1995-02-23), herbicidal (organic chemistry, 2010, 30(1): 92-97), anti-tumor (European Journal of medical chemistry, 2012, 48(26): 192-199), antifungal (Bioorganic and medical chemistry, 2008, 16(7):3632-3640), anti-inflammatory (Arzneimittel for chemistry, 2002, 57(2): 101-107), antimalarial (chemistry, 1999, 30(43 572-576) and antihypertensive (European of chemistry, 545, 535), etc. In view of good biological activity of imidazole and 1,3, 4-oxadiazole compounds, the novel carbonitrile compound containing both imidazole and 1,3, 4-oxadiazole structures is designed and synthesized by using an active substructure splicing method, and is expected to have good biological activity.
The invention designs and synthesizes a series of 4-chloro-5- (p-methylphenyl) -1- (5- (substituted phenyl) -1,3, 4-oxadiazole-2-yl) -1HThe study on the structure and the biological activity of the (E) -imidazole-2-carbonitrile compounds is not reported in the literature.
Disclosure of Invention
The invention aims to provide a carbonitrile compound containing imidazole and 1,3, 4-oxadiazole structures, a preparation method and application thereof, and specifically relates to 4-chloro-5- (p-methylphenyl) -1- (5- (substituted phenyl) -1,3, 4-oxadiazole-2-yl) -1H-imidazole-2-carbonitrile compounds, and a preparation method and application thereof.
The carbonitrile compound containing an imidazole and 1,3, 4-oxadiazole structure is characterized in that the structure is shown as the formula (I):
in the formula (I), H on a benzene ring is mono-substituted, poly-substituted or not substituted by a substituent R, n is the number of the substituent R on the benzene ring, n is an integer of 0-5, n =0 represents that H on the benzene ring is not substituted, namely that no substituent is arranged on the benzene ring, n =1 represents that H on the benzene ring is mono-substituted by the substituent R, n = 2-5 represents that H on the benzene ring is poly-substituted by the substituent Rn, the substituents R on different substitution positions are the same or different, and the substituent R is C1-C8 alkyl or halogenated alkyl, C1-C3 alkoxy, halogen, nitro or cyano.
The carbonitrile compound containing imidazole and 1,3, 4-oxadiazole structure is characterized in that the number of substituent groups R is 1-2, namely n = 1-2 is preferred
The carbonitrile compound containing an imidazole and 1,3, 4-oxadiazole structure is characterized in that R is C1-C5 alkyl or substituted alkyl, methoxy, F, Cl, Br, I, nitro or cyano, preferably methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl, methoxy, F, Cl, Br, nitro or cyano; most preferred is m-methyl, p-methyl, o-methoxy, p-methoxy, 2, 4-dimethyl, o-trifluoromethyl, p-trifluoromethyl, 4-CH2Br, o-fluorine, m-fluorine, p-fluorine, o-chlorine, p-chlorine, o-bromine, p-bromine, o-iodine, p-cyano, 2, 3-dichloro, 2, 6-dichloro, 2,3,5, 6-tetrafluoro or 2,3,4, 5-tetrafluoro.
The preparation method of the carbonitrile compound containing imidazole and 1,3, 4-oxadiazole structures is characterized in that the carbonitrile compound is 4-chloro-2-cyano-5- (p-methylphenyl) -1 shown in a formula (II)HCarrying out cyclization reaction on imidazole-1-carbohydrazide and substituted benzoic acid shown as a formula (III) in phosphorus oxychloride under a reflux state, and after the reaction is finished, separating and purifying reaction liquid to obtain a carbonitrile compound containing imidazole and 1,3, 4-oxadiazole structures shown as a formula (I);
r in the formula (III) is the same as R in the formula (I), H on a benzene ring is mono-substituted, poly-substituted or not substituted by substituent R, n is the number of substituent R on the benzene ring, n is an integer of 0-5, n =0 represents that H on the benzene ring is not substituted, n =1 represents that H on the benzene ring is mono-substituted by substituent R, n = 2-5 represents that H on the benzene ring is poly-substituted by substituent Rn, the substituent R on different substitution positions are the same or different, and the substituent R is C1-C8 alkyl or haloalkyl, C1-C3 alkoxy, halogen, nitro or cyano.
The preparation method of the carbonitrile compound containing imidazole and 1,3, 4-oxadiazole structures is characterized in that the carbonitrile compound is 4-chloro-2-cyano-5- (p-methylphenyl) -1 shown in a formula (II)HThe ratio of the amounts of the imidazole-1-carbohydrazide, the substituted benzoic acid shown in the formula (III) and the phosphorus oxychloride is 1: 1.0-1.3: 10.0-300.0; preferably 1: 1.0-1.2: 100.0-200.0.
The preparation method of the carbonitrile compound containing the imidazole and 1,3, 4-oxadiazole structures is characterized in that the completion condition of the reaction is monitored by adopting a TLC method, the reaction time is 3-12 hours, and the specific reaction time is related to reactants.
The preparation method of the carbonitrile compound containing imidazole and 1,3, 4-oxadiazole structures is characterized in that the separation and purification method of the reaction liquid comprises the following steps: after the reaction is finished, concentrating the reaction liquid to remove phosphorus oxychloride, adding ice water, stirring to separate out a solid, filtering, washing with water, and recrystallizing to obtain the carbonitrile compound containing imidazole and 1,3, 4-oxadiazole structures shown in the formula (I).
The preparation method of the carbonitrile compound containing an imidazole and 1,3, 4-oxadiazole structure is characterized in that a solvent for recrystallization is one or more of ethanol, ethyl acetate, n-hexane and petroleum ether.
The carbonitrile compound containing imidazole and 1,3, 4-oxadiazole structures is applied as an anticancer drug.
In the embodiment of the invention, the anti-cancer activity of human liver cancer cells Huh7(human hepatoma cell line), human lung cancer cells A549(human lung cancer cells) and human colon cancer cells HCT116(human colon cancer cells line) is determined on the prepared compound by adopting a tetrazole rapid colorimetry (MTT method). The bioassay result shows that the compound (I) has certain inhibitory activity on all tested targets; the inhibition activity of most compounds on human colon cancer cell strain HCT116 and human liver cancer cell strain Huh7 is better than that of human lung cancer cell strain A549.
By adopting the technology, compared with the prior art, the invention has the beneficial effects that:
the invention provides a novel carbonitrile compound containing imidazole and 1,3, 4-oxadiazole structures, the compound has simple preparation method and convenient post-treatment, the obtained compounds all show better anticancer activity, such as the compounds Ib, Ih, Ik, Ir, Is and It have relatively better inhibitory activity on human colon cancer cell strains HCT116, and IC thereof5010.41 +/-1.1, 20.60 +/-0.8, 8.03 +/-0.5, 20.61 +/-0.9, 11.28 +/-0.8 and 17.00 +/-2.2 mu M respectively. The compounds Id, Ih, Ik and Ip have relatively good inhibitory activity on human lung cancer cell strain A549, and the IC thereof50The values are 16.42 + -0.6, 21.05 + -4.1, 35.52 + -1.2 and 23.25 + -6.3 μ M, respectively. IC of Compounds Is and Iw50The values are respectively 10.06 +/-0.8 and 17.14 +/-1.7 mu M, and the inhibition activity to a human liver cancer cell strain Huh7 is better.
Detailed Description
The present invention is further illustrated by the following examples, but the scope of the invention is not limited thereto.
Example 1 Synthesis of Compound Ia (R = H)
0.287 g (2.0 mmol) of 4-chloro-2-cyano-5- (p-methylphenyl) -1H-imidazole-1 carbohydrazide 15mL of POCl3Adding benzoic acid (2.2 mmol) for reflux reaction, and vacuum rotary evaporation to remove part of POCl320mL of ice water was added to the reaction flask, and the mixture was stirred at room temperature for 3.5 hours, whereupon a solid substance was precipitated, filtered, washed with water several times, and recrystallized from ethanol to obtain 0.527g of the compound Ia as a yellow solid with a yield of 73.2%. m.p. 104-106 ℃;1H NMR (500 MHz, CDCl3)δ: 8.14(d,J= 7.0 Hz, 2H), 7.70 (d,J= 8.0 Hz, 2H), 7.62～7.50 (m, 4H), 7.29 (s,1H), 2.40 (s, 3H);HRMS (ESI), m/z calcd for C19H13ClN5O [M+H]+362.0809; found,362.0805.
example 2 Synthesis of Compound Ib (R = m-methyl)
0.287 g (2.0 mmol) of 4-chloro-2-cyano-5- (p-methylphenyl) -1H10mL of POCl was added to imidazole-1 carbohydrazide3Then, 2.4 mmol of m-methylbenzoic acid was added, and the reaction was refluxed. Finally, removing part of POCl by vacuum rotary evaporation3Then, 20mL of ice water was added to the reaction flask, and the mixture was stirred at room temperature for 4.0 hours, whereby a solid substance was precipitated, filtered, washed with water several times, and recrystallized from n-hexane to obtain 0.481g of a yellow solid compound Ib with a yield of 64.3%. m.p. 120-124 ℃;1H NMR (500 MHz, CDCl3)δ: 8.02 (s, 1H), 7.99 (d,J= 7.5 Hz, 1H), 7.72 (d,J= 8.0 Hz, 2H), 7.44～7.40 (m, 2H), 7.32 (d,J= 8.0 Hz, 2H), 2.46 (s, 3H), 2.43 (s, 3H) ; HRMS(ESI), m/z calcd for C20H15ClN5O [M+H]+376.0965; found, 376.0959.
example 3 Synthesis of Compound Ic (R = p-methyl)
0.287 g (2.0 mmol) of 4-chloro-2-cyano-5- (p-methylphenyl) -1H13mL of POCl was added to imidazole-1 carbohydrazide3Then, 2.3 mmol of p-toluic acid was added thereto, and the reaction was refluxed. Finally, removing part of POCl by vacuum rotary evaporation3Then, 20mL of ice water was added to the reaction flask, and the mixture was stirred at room temperature for 3.0 hours, whereupon a solid substance was precipitated, filtered, washed with water several times, and recrystallized from ethyl acetate and petroleum ether to give 0.480 g of a yellow solid compound Ic in a yield of 63.9%. m.p. 103-105 ℃;1H NMR (500MHz, CDCl3)δ: 8.05 (d,J= 8.5 Hz, 2H), 7.70 (d,J= 8.0 Hz, 2H), 7.35 (d,J= 8.0 Hz, 2H), 7.30 (d,J= 8.0 Hz, 2H), 2.46 (s, 3H), 2.41 (s, 3H) ; HRMS(ESI), m/z calcd for C20H15ClN5O [M+H]+376.0965; found, 376.0957.
example 4 Synthesis of Compound Id (R = ortho-methoxy)
0.287 g (2.0 mmol) of 4-chloro-2-cyano-5- (p-tolyl) chloride was addedPhenyl) -1H16mL of POCl was added to imidazole-1 carbohydrazide3Then 2.1 mmol of o-methoxybenzoic acid is added for reflux reaction. Finally, removing part of POCl by vacuum rotary evaporation3Then, 20mL of ice water was added to the reaction flask, and the mixture was stirred at room temperature for 4.0 hours, whereupon a solid substance was precipitated, filtered, washed with water several times, and recrystallized from n-hexane to obtain 0.457 g of a yellow solid compound Id in a yield of 58.4%. m.p. 115-119 ℃;1H NMR (500 MHz,CDCl3)δ: 8.10 (d,J= 8.0 Hz, 1H), 7.69 (d,J= 8.0 Hz, 2H), 7.58 (d,J=8.0 Hz, 1H), 7.49 (td,J= 7.5, 1.5 Hz, 1H), 7.41 (t,J= 7.5 Hz, 1H), 7.28(d,J= 8.5 Hz, 2H), 3.89 (s, 3H), 2.41 (s, 3H) ; HRMS (ESI), m/z calcd forC20H15ClN5O2[M+H]+392.0914; found, 392.0932.
example 5 Synthesis of Compound Ie (R = p-methoxy)
0.287 g (2.0 mmol) of 4-chloro-2-cyano-5- (p-methylphenyl) -1H-imidazole-1 carbohydrazide 15mL of POCl3Then 2.3 mmol of p-methoxybenzoic acid is added for reflux reaction. Finally, removing part of POCl by vacuum rotary evaporation320mL of ice water was added to the reaction flask, and the mixture was stirred at room temperature for 3.5 hours, after which a solid substance was precipitated, filtered, washed with water several times, and recrystallized from ethanol to purify the resulting product, 0.464 g of yellow solid compound Ie, in a yield of 59.2%. m.p. 102-104 ℃;1H NMR (500 MHz,CDCl3)δ: 8.09 (d,J= 8.5 Hz, 2H), 7.72 (d,J= 8.0 Hz, 2H), 7.30 (d,J=8.0 Hz, 2H), 7.02 (d,J= 8.0 Hz, 2H), 3.89 (s, 3H), 2.41 (s, 3H) ; HRMS(ESI), m/z calcd for C20H15ClN5O2[M+H]+392.0914; found, 392.0925.
example 6 Synthesis of Compound If (R =2, 4-dimethyl)
0.287 g (2.0 mmol) of 4-chloro-2-cyano-5- (p-methylphenyl) -1H13mL of POCl was added to imidazole-1 carbohydrazide3Then, 2.2 mmol of 2, 4-dimethylbenzoic acid was added, and the reaction was refluxed. Finally, removing part of POCl by vacuum rotary evaporation3Adding 20mL of ice water into the reaction bottle, stirring at room temperature for 5.0 h, and adding solid substancesPrecipitated, filtered, washed several times with water and purified with n-hexane to obtain 0.546 g of a yellow solid compound If, with a yield of 70.2%. m.p. 122-124 ℃;1H NMR (500 MHz,CDCl3)δ: 7.71～7.69. (m, 2H), 7.55 (s, 1H), 7.20 (d,J= 8.0 Hz, 2H), 7.16(d,J= 8.5 Hz, 2H), 2.37 (s, 6H), 2.23 (s, 3H) ; HRMS (ESI), m/z calcd forC21H17ClN5O [M+H]+390.1122; found, 390.1128.
example 7 Synthesis of Compound Ig (R = ortho-trifluoromethyl)
0.287 g (2.0 mmol) of 4-chloro-2-cyano-5- (p-methylphenyl) -1H-imidazole-1 carbohydrazide 15mL of POCl3Then, 2.4 mmol of o-trifluoromethylbenzoic acid was added, and the reaction was refluxed. Finally, removing part of POCl by vacuum rotary evaporation320mL of ice water was added to the reaction flask, and the mixture was stirred at room temperature for 3.0 hours, after which solid matter was precipitated, filtered, washed with water several times, and recrystallized from ethyl acetate and petroleum ether to obtain 0.615 g of yellow solid compound Ig, with a yield of 71.6%. m.p. 127-131 ℃;1H NMR(500 MHz, DMSO-d 6 )δ: 7.99～7.91 (m, 2H), 7.86～7.81 (m, 2H), 7.73 (d,J=8.0 Hz, 2H), 7.30 (d,J= 8.0 Hz, 2H), 2.35 (s, 3H) ; HRMS (ESI), m/z calcdfor C20H12ClF3N5O [M+H]+430.0682; found, 430.0687.
example 8 Synthesis of Compound Ih (R = p-trifluoromethyl)
0.287 g (2.0 mmol) of 4-chloro-2-cyano-5- (p-methylphenyl) -1H10mL of POCl was added to imidazole-1 carbohydrazide3Then, 2.3 mmol of p-trifluoromethylbenzoic acid was added, and the reaction was refluxed. Finally, removing part of POCl by vacuum rotary evaporation3Then, 20mL of ice water was added to the reaction flask, and the mixture was stirred at room temperature for 4.0 hours, whereupon a solid substance was precipitated, filtered, washed with water several times, and recrystallized from ethanol to obtain 0.638 g of a yellow solid compound Ih in a yield of 74.2%. m.p. 123-126 ℃;1H NMR (500 MHz,CDCl3)δ: 8.31 (d,J= 8.0 Hz, 2H), 7.83 (d,J= 8.0 Hz, 2H), 7.70 (d,J=8.0 Hz, 2H), 7.31 (d,J= 8.0 Hz, 2H), 2.43 (s, 3H) ; HRMS (ESI), m/z calcdfor C20H12ClF3N5O [M+H]+430.0682; found, 430.0678.
example 9 Compound Ii (R = 4-CH)2Br) synthesis
0.287 g (2.0 mmol) of 4-chloro-2-cyano-5- (p-methylphenyl) -1HAddition of 20mL of POCl to imidazole-1 carbohydrazide3Then, 2.2 mmol of 4- (bromomethyl) benzoic acid was added thereto, and the mixture was refluxed. Finally, removing part of POCl by vacuum rotary evaporation3Then, 20mL of ice water was added to the reaction flask, and the mixture was stirred at room temperature for 3.5 hours, whereupon a solid substance was precipitated, filtered, washed with water several times, and recrystallized from petroleum ether to obtain 0.566 g of a yellow solid compound Ii with a yield of 62.4%. m.p. 114-118 ℃;1H NMR (500 MHz,DMSO-d 6 )δ: 7.91 (d,J= 8.0 Hz, 2H), 7.75 (d,J= 8.0 Hz, 2H), 7.43 (d,J=8.0 Hz, 2H), 7.35 (d,J= 8.0 Hz, 2H), 4.57 (s, 2H), 2.37 (s, 3H) ; HRMS(ESI), m/z calcd for C20H14BrClN5O [M+H]+454.0070; found, 454.0079.
example 10 Synthesis of Compound Ij (R = o-fluoro)
0.287 g (2.0 mmol) of 4-chloro-2-cyano-5- (p-methylphenyl) -1H10mL of POCl was added to imidazole-1 carbohydrazide3Then 2.0 mmol of o-fluorobenzoic acid is added for reflux reaction. Finally, removing part of POCl by vacuum rotary evaporation3Then, 20mL of ice water was added to the reaction flask, and the mixture was stirred at room temperature for 5.0 hours, whereupon a solid substance was precipitated, filtered, washed with water several times, and recrystallized from petroleum ether to obtain 0.529 g of a yellow solid compound Ij with a yield of 69.7%. m.p. 129-132 ℃;1H NMR (500 MHz, CDCl3)δ:8.22～8.18 (m, 1H), 7.93 (d,J= 8.0 Hz, 2H), 7.61～7.58 (m, 1H), 7.37～7.33(m, 2H), 7.32～7.25 (m, 2H), 2.42 (s, 3H) ; HRMS (ESI), m/z calcd forC19H12ClFN5O [M+H]+380.0714; found, 380.0735.
example 11 Synthesis of Compound Ik (R = m-fluoro)
0.287 g (2.0 mmol) of 4-chloro-2-cyano-5- (p-methylphenyl) -1H-imidazole-1 carbohydrazide 15mL of POCl3Adding m-fluorobenzeneAcid 2.1 mmol, reflux reaction. Finally, removing part of POCl by vacuum rotary evaporation320mL of ice water was added to the reaction flask, and the mixture was stirred at room temperature for 3.0 hours, after which a solid substance was precipitated, filtered, washed with water several times, and recrystallized from ethyl acetate and petroleum ether to obtain 0.545 g of a yellow solid compound Ik with a yield of 71.8%. m.p. 111-114 ℃;1H NMR (500MHz, DMSO-d 6 )δ: 7.95 (s, 1H), 7.90～7.83 (m, 1H), 7.74 (d,J= 8.0 Hz, 2H),7.72～7.61 (m, 1H), 7.59～7.52(m, 1H), 7.34 (d,J= 8.0 Hz, 2H), 2.36 ( s,3H). HRMS (ESI), m/z calcd for C19H12ClFN5O [M+H]+380.0714; found, 380.0743.
example 12 Synthesis of Compound Il (R = p-fluoro)
0.287 g (2.0 mmol) of 4-chloro-2-cyano-5- (p-methylphenyl) -1H10mL of POCl was added to imidazole-1 carbohydrazide3Then, 2.0 mmol of p-fluorobenzoic acid is added for reflux reaction. Finally, removing part of POCl by vacuum rotary evaporation320mL of ice water was added to the reaction flask, and the mixture was stirred at room temperature for 5.0 hours, after which a solid substance was precipitated, filtered, washed with water several times, and recrystallized from ethanol to obtain 0.541 g of a yellow solid compound Il with a yield of 71.3%. m.p. 128-130 ℃;1H NMR (500 MHz, CDCl3)δ:8.06 (d,J= 8.0 Hz, 2H), 7.74 (d,J= 8.5 Hz, 2H), 7.69 (d,J= 8.5 Hz, 2H),7.29 (d,J= 8.5 Hz, 2H), 2.43 (s, 3H). HRMS (ESI), m/z calcd for C19H12ClFN5O[M+H]+380.0714; found, 380.0736.
example 13 Synthesis of Compound Im (R = o-chloro)
0.287 g (2.0 mmol) of 4-chloro-2-cyano-5- (p-methylphenyl) -1HImidazole-1 carbohydrazide 14mL of POCl3Then 2.5 mmol of o-chlorobenzoic acid is added for reflux reaction. Finally, removing part of POCl by vacuum rotary evaporation3Then, 20mL of ice water was added to the reaction flask, and the mixture was stirred at room temperature for 3.5 hours, whereupon a solid substance was precipitated, filtered, washed with water several times, and recrystallized from n-hexane to obtain 0.544 g of a yellow solid compound Im with a yield of 68.8%. 117-120 ℃ in m.p.;1H NMR (500 MHz, CDCl3)δ:8.04 (d,J= 7.0 Hz, 1H), 7.68 (d,J= 8.0 Hz, 2H), 7.58 (d,J= 8.0 Hz, 1H),7.50 (td,J= 7.5, 1.5 Hz, 1H), 7.42 (t,J= 7.5 Hz, 1H), 7.24 (d,J= 8.5Hz, 2H), 2.41 (s, 3H). HRMS (ESI), m/z calcd for C19H12Cl2N5O [M+H]+396.0419;found, 396.0425.
example 14 Synthesis of Compound In (R = p-chloro)
0.287 g (2.0 mmol) of 4-chloro-2-cyano-5- (p-methylphenyl) -1H16mL of POCl was added to imidazole-1 carbohydrazide3Then, 2.3 mmol of p-chlorobenzoic acid was added, and the reaction was refluxed. Finally, removing part of POCl by vacuum rotary evaporation320mL of ice water was added to the reaction flask, and the mixture was stirred at room temperature for 4.3 hours, after which solid matter was precipitated, filtered, washed with water several times, and recrystallized from petroleum ether to obtain 0.537 g of In as a yellow solid In a yield of 67.9%. m.p. 125-128 ℃;1H NMR (500 MHz, CDCl3)δ:8.03 (d,J= 8.0 Hz, 2H), 7.69 (d,J= 8.5 Hz, 2H), 7.67 (d,J= 8.5 Hz, 2H),7.28 (d,J= 8.5 Hz, 2H), 2.39 (s, 3H). HRMS (ESI), m/z calcd for C19H12Cl2N5O[M+H]+396.0419; found, 396.0422.
example 15 Synthesis of Compound Io (R = ortho-bromo)
0.287 g (2.0 mmol) of 4-chloro-2-cyano-5- (p-methylphenyl) -1H16mL of POCl was added to imidazole-1 carbohydrazide3Then 2.5 mmol of o-bromobenzoic acid is added for reflux reaction. Finally, removing part of POCl by vacuum rotary evaporation320mL of ice water was added to the reaction flask, and the mixture was stirred at room temperature for 4.0 hours, after which a solid substance was precipitated, filtered, washed with water several times, and recrystallized from ethyl acetate and petroleum ether to obtain 0.593 g of a yellow solid compound Io with a yield of 67.4%. m.p. 106-109 ℃;1H NMR (500MHz, CDCl3)δ: 8.01 (dd,J= 6.0, 1.5 Hz, 1H), 7.80 (dd,J= 7.0, 1.0 Hz,1H), 7.71 (d,J= 7.5 Hz, 2H), 7.49 (td,J= 6.5, 1.0 Hz, 1H), 7.43 (td,J=6.0, 2.0 Hz, 1H), 7.30 (d,J= 8.0 Hz, 2H), 2.41 (s, 3H). HRMS (ESI), m/zcalcd for C19H12BrClN5O [M+H]+439.9914; found, 439.9931.
example 16 Synthesis of Compound Ip (R = p-bromo)
0.287 g (2.0 mmol) of 4-chloro-2-cyano-5- (p-methylphenyl) -1H11mL of POCl was added to imidazole-1 carbohydrazide3Then, 2.2 mmol of p-bromobenzoic acid was added and the reaction was refluxed. Finally, removing part of POCl by vacuum rotary evaporation320mL of ice water was added to the reaction flask, and the mixture was stirred at room temperature for 5.0 hours, after which a solid substance was precipitated, filtered, washed with water several times, and recrystallized from petroleum ether to obtain 0.587 g of yellow solid compound Ip in a yield of 66.8%. m.p. 108-111 ℃;1H NMR (500 MHz, CDCl3)δ:8.01 (d,J= 8.0 Hz, 2H), 7.68 (d,J= 8.5 Hz, 2H), 7.66 (d,J= 8.5 Hz, 2H),7.26 (d,J= 8.5 Hz, 2H), 2.39 (s, 3H). HRMS (ESI), m/z calcd for C19H12BrClN5O[M+H]+439.9914; found, 439.9923.
example 17 Synthesis of Compound Iq (R = ortho-iodine)
0.287 g (2.0 mmol) of 4-chloro-2-cyano-5- (p-methylphenyl) -1HAddition of 12mL of POCl to imidazole-1 carbohydrazide3Then 2.3 mmol of o-iodobenzoic acid is added for reflux reaction. Finally, removing part of POCl by vacuum rotary evaporation320mL of ice water was added to the reaction flask, and the mixture was stirred at room temperature for 5.2 hours, whereupon a solid substance was precipitated, filtered, washed with water several times, and recrystallized from ethanol to obtain 0.631 g of a yellow solid compound Iq with a yield of 64.7%. m.p. 106-108 ℃;1H NMR (500 MHz, DMSO-d 6 )δ: 8.17 (d,J= 8.0 Hz, 1H), 8.05 (d,J= 8.0 Hz, 1H), 7.74 (d,J= 8.0 Hz,2H), 7.67～7.65 (m, 1H), 7.40 (td,J= 6.0, 2.0 Hz, 1H), 7.30 (d,J= 8.0 Hz,2H), 2.35 (s, 3H). HRMS (ESI), m/z calcd for C19H12ClIN5O [M+H]+487.9775;found, 487.9779.
EXAMPLE 18 Synthesis of Compound Ir (R = p-iodo)
0.287 g (2.0 mmol) of 4-chloro-2-cyano-5- (p-methylphenyl) -1H10mL of POCl was added to imidazole-1 carbohydrazide3Then adding 2.0 mmol of p-iodobenzoic acid, and carrying out reflux reaction. Finally, removing part of POCl by vacuum rotary evaporation3Then, 20mL of ice water was added to the reaction flask, and the mixture was stirred at room temperature for 4.0 hours, whereupon a solid substance was precipitated, filtered, washed with water several times, and recrystallized from ethyl acetate, ethanol and petroleum ether to give 0.657 g of a yellow solid compound Ir in a yield of 67.4%. m.p. 130-133 ℃;1H NMR(500 MHz, CDCl3)δ: 8.17 (d,J= 8.0 Hz, 2H), 7.73 (d,J= 8.5 Hz, 2H), 7.66(d,J= 8.5 Hz, 2H), 7.31 (d,J= 8.5 Hz, 2H), 2.40 (s, 3H). HRMS (ESI), m/zcalcd for C19H12ClIN5O [M+H]+487.9775; found, 487.9783.
example 19 Synthesis of Compound Is (R = p-cyano)
0.287 g (2.0 mmol) of 4-chloro-2-cyano-5- (p-methylphenyl) -1H-imidazole-1 carbohydrazide 15mL of POCl3Then, 2.4 mmol of p-cyanobenzoic acid was added, and the reaction was refluxed. Finally, removing part of POCl by vacuum rotary evaporation3Then, 20mL of ice water was added to the reaction flask, and the mixture was stirred at room temperature for 6.0 hours, whereupon a solid substance was precipitated, filtered, washed with water several times, and recrystallized from n-hexane to obtain 0.527g of a yellow solid compound Is, with a yield of 68.2%. m.p. 136-139 ℃;1H NMR (500 MHz, CDCl3)δ: 8.09 (d,J= 8.0 Hz, 2H), 7.70 (d,J= 8.5 Hz, 2H), 7.68 (d,J= 8.5 Hz,2H), 7.31 (d,J= 8.5 Hz, 2H), 2.41 (s, 3H). HRMS (ESI), m/z calcd forC20H12ClN6O [M+H]+387.0761; found, 387.0759.
example 20 Synthesis of Compound It (R =2, 3-dichloro)
0.287 g (2.0 mmol) of 4-chloro-2-cyano-5- (p-methylphenyl) -1H16mL of POCl was added to imidazole-1 carbohydrazide3Then, 2.2 mmol of 2, 3-dichlorobenzoic acid was added thereto, and the mixture was refluxed. Finally, removing part of POCl by vacuum rotary evaporation3Adding 20mL of ice water into the reaction bottle, stirring at room temperature for 4.6 h to precipitate solid substances, filtering, washing with water for several times, and recrystallizing with n-hexane and petroleum ether to obtain 0.598 g of yellow solid compound It with the yield of 69.6%. m.p. 102-105 ℃;1H NMR (500MHz, DMSO-d 6 )δ: 7.85 (d,J= 6.0 Hz, 1H), 7.80～7.79 (m, 2.0 Hz, 1H), 7.74(d,J= 8.0 Hz, 2H), 7.51～7.44 (m, 1H), 7.31 (d,J= 8.0 Hz, 2H), 2.35 (s,3H). HRMS (ESI), m/z calcd for C19H11Cl3N5O [M+H]+430.0029; found, 430.0023.
EXAMPLE 21 Synthesis of Compound Iu (R =2, 6-dichloro)
0.287 g (2.0 mmol) of 4-chloro-2-cyano-5- (p-methylphenyl) -1H10mL of POCl was added to imidazole-1 carbohydrazide3Then, 2.4 mmol of 2, 6-dichlorobenzoic acid was added thereto, and the mixture was refluxed. Finally, removing part of POCl by vacuum rotary evaporation320mL of ice water was added to the reaction flask, and the mixture was stirred at room temperature for 5.5 hours, after which a solid substance was precipitated, filtered, washed with water several times, and recrystallized from ethanol and petroleum ether to obtain 0.562 g of a yellow solid compound Iu with a yield of 65.4%. m.p. 109-112 ℃;1H NMR (500MHz, DMSO-d 6 )δ: 7.86 (d,J= 6.0 Hz, 1H), 7.81～7.77 (m, 2.0 Hz, 1H), 7.74(d,J= 8.0 Hz, 2H), 7.51～7.43 (m, 1H), 7.33 (d,J= 8.0 Hz, 2H), 2.35 (s,3H). HRMS (ESI), m/z calcd for C19H11Cl3N5O [M+H]+430.0029; found, 430.0033.
example 22 Compound Iv (R =2,3,5, 6-F)4) Synthesis of (2)
0.287 g (2.0 mmol) of 4-chloro-2-cyano-5- (p-methylphenyl) -1HAddition of 12mL of POCl to imidazole-1 carbohydrazide3Then 2.1 mmol of 2,3,5, 6-tetrafluorobenzoic acid is added for reflux reaction. Finally, removing part of POCl by vacuum rotary evaporation3Then, 20mL of ice water was added to the reaction flask, and the mixture was stirred at room temperature for 5.0 hours, whereupon a solid substance was precipitated, filtered, washed with water several times, and recrystallized from ethyl acetate and ethanol to obtain 0.605 g of a yellow solid compound Iv with a yield of 69.7%. m.p. 144-148 ℃;1HNMR (500 MHz, DMSO-d 6 )δ: 7.94 (s, 1H), 7.74 (d,J= 8.0 Hz, 2H), 7.32 (d,J= 8.0 Hz, 2H), 2.36 (s, 3H). HRMS (ESI), m/z calcd for C19H9ClF4N5O [M+H]+434.0432; found, 434.0437.
example 23 formationCompound Iw (R =2,3,4, 5-F)4) Synthesis of (2)
0.287 g (2.0 mmol) of 4-chloro-2-cyano-5- (p-methylphenyl) -1H-imidazole-1 carbohydrazide 15mL of POCl3Then 2.4 mmol of 2,3,4, 5-tetrafluorobenzoic acid is added for reflux reaction. Finally, removing part of POCl by vacuum rotary evaporation3Then, 20mL of ice water was added to the reaction flask, and the mixture was stirred at room temperature for 3.0 hours, after which a solid substance was precipitated, filtered, washed with water several times, and recrystallized from ethyl acetate and petroleum ether to obtain 0.612 g of a yellow solid compound Iw with a yield of 70.5%. m.p. 126-129 ℃;1HNMR (500 MHz, DMSO-d 6 )δ: 7.96～7.90 (m, 1H), 7.75 (d,J= 8.0 Hz, 2H), 7.33(d,J= 8.5 Hz, 2H), 2.37 (s, 3H). HRMS (ESI), m/z calcd for C19H9ClF4N5O [M+H]+434.0432; found, 434.0441.
EXAMPLE 24 anticancer Activity assay
Test targets: human hepatoma cells Huh7(human hepatoma cell line), human lung cancer cells A549(human lung cancer cell line), and human colon cancer cells HCT116(human colon cancer cell line) were seeded in 96-well plates at 5000 cells per well, using DMEM medium (GIBCO, USA) for Huh7 and A549, and using 1640 medium (GIBCO, USA) for HCT116, in a volume of 100. mu.L. Culturing for 24 hours, and removing the culture medium for later use after the cells grow adherently.
The anti-cancer activity of the human liver cancer cell Huh7, the human lung cancer cell A549 and the human colon cancer cell HCT116 is determined on the synthesized compound by adopting a rapid tetrazolium colorimetric method (MTT method). After preparing the drugs with different concentrations by using the culture medium, placing the drugs in a medium containing 5% CO2Is cultured in the cell culture box for 48 hours or 96 hours. After the measurement time, 2.5 mg/mL MTT was added, the mixture was incubated for 4 hours, the supernatant was discarded, 100. mu.L of DMSO solution was added to each well, and the mixture was mixed well for 15 seconds, and then the absorbance (OD value) at 570nm was measured with a multifunctional microplate reader. The positive control is the group with MTT, the negative control is the group without MTT, and the administration group is the group with medicine and MTT. Two multiple holes are arranged in each hole. The absorbance is the average of three samples. Cell proliferation inhibition rate = (OD)Positive for-ODMedicine)/(ODPositive for-ODNegative of) 100%. Finally, the half inhibitory cell concentration IC is obtained by plotting the cell proliferation inhibition rate to the drug concentration50The values, test results are shown in table 1.
TABLE 1 cytotoxicity (IC) of the target Compounds on different cell lines50/μM)
Table 4.1 Cytotoxicity(IC50/μM) of target compounds on different celllines
Note thata: camptothecin, as a positive control group.
The results of the bioassay in table 1 show that the compound (I) of the present invention exhibits certain inhibitory activity against all targets tested; the inhibiting activity of most compounds on human colon cancer cell strain HCT116 and human liver cancer cell strain Huh7 Is better than that of human lung cancer cell strain A549, and the inhibiting activity of compounds Ib, Ih, Ik, Ir, Is and It on human colon cancer cell strain HCT116 Is relatively better, and IC Is5010.41 +/-1.1, 20.60 +/-0.8, 8.03 +/-0.5, 20.61 +/-0.9, 11.28 +/-0.8 and 17.00 +/-2.2 mu M respectively. The compounds Id, Ih, Ik and Ip have relatively good inhibitory activity on human lung cancer cell strain A549, and the IC thereof50The values are 16.42 + -0.6, 21.05 + -4.1, 35.52 + -1.2 and 23.25 + -6.3 μ M, respectively. IC of Compounds Is and Iw50The values are respectively 10.06 +/-0.8 and 17.14 +/-1.7 mu M, and the inhibition activity to a human liver cancer cell strain Huh7 is better.
Claims (8)
1. A carbonitrile compound containing an imidazole and 1,3, 4-oxadiazole structure is characterized in that the structure is shown as the formula (I):
in the formula (I), a substituent R is m-methyl, o-methoxy, p-trifluoromethyl, m-fluorine, p-bromine, p-iodine, p-cyano, 2, 3-dichloro or 2,3,4, 5-tetrafluoro.
2. The preparation method of the carbonitrile compound containing an imidazole and 1,3, 4-oxadiazole structure according to claim 1, which is characterized by comprising the following steps (I) and (II)HCarrying out cyclization reaction on imidazole-1-carbohydrazide and substituted benzoic acid shown as a formula (III) in phosphorus oxychloride under a reflux state, and after the reaction is finished, separating and purifying reaction liquid to obtain a carbonitrile compound containing imidazole and 1,3, 4-oxadiazole structures shown as a formula (I);
in the formula, a substituent R is m-methyl, o-methoxy, p-trifluoromethyl, m-fluorine, p-bromine, p-iodine, p-cyano, 2, 3-dichloro or 2,3,4, 5-tetrafluoro.
3. The method for preparing the carbonitrile compound having an imidazole and 1,3, 4-oxadiazole structure according to claim 2, wherein the compound is 4-chloro-2-cyano-5- (p-methylphenyl) -1 represented by the formula (II)HThe ratio of the amounts of the-imidazole-1-carbohydrazide, the substituted benzoic acid shown in the formula (III) and the phosphorus oxychloride is 1: 1.0-1.3: 10.0-300.0.
4. The method for preparing the carbonitrile compound having an imidazole and 1,3, 4-oxadiazole structure according to claim 2, wherein the compound is 4-chloro-2-cyano-5- (p-methylphenyl) -1 represented by the formula (II)HThe ratio of the amounts of the-imidazole-1-carbohydrazide, the substituted benzoic acid shown in the formula (III) and the phosphorus oxychloride is 1: 1.0-1.2: 100.0-200.0.
5. The method for preparing the carbonitrile compound containing an imidazole and 1,3, 4-oxadiazole structure according to claim 2, wherein the completion of the reaction is monitored by a TLC method, and the reaction time is 3-12 hours.
6. The method for preparing the carbonitrile compound containing an imidazole and 1,3, 4-oxadiazole structure according to claim 2, wherein the reaction liquid is separated and purified by: after the reaction is finished, concentrating the reaction liquid to remove phosphorus oxychloride, adding ice water, stirring to separate out a solid, filtering, washing with water, and recrystallizing to obtain the carbonitrile compound containing imidazole and 1,3, 4-oxadiazole structures shown in the formula (I).
7. The method for preparing the carbonitrile compound containing an imidazole and 1,3, 4-oxadiazole structure according to claim 6, wherein the solvent for recrystallization is one or more of ethanol, ethyl acetate, n-hexane, and petroleum ether.
8. The use of the carbonitrile compound containing an imidazole and 1,3, 4-oxadiazole structure according to claim 1 in the preparation of an anticancer agent.
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| Synthesis, characterization, and anticancer activity of 1,2,3-triazole-derived 1,3,4-oxadiazole containing N-heterocyclic moieties.;Sirassu Narsimha, et al.,;《Heterocyclic Letters》;20151231;第5卷(第4期);第2230-9632页. * |
| Tetra-substituted imidazoles as a new class of inhibitors of the p53–MDM2 interaction.;Andrea Vaupel, et al.,;《Bioorganic & Medicinal Chemistry Letters》;20140322;第24卷;第2110–2114页. * |
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