CN117343065A - Mangrove microbial source quinazolinone alkaloid derivative and anti-inflammatory application - Google Patents
Mangrove microbial source quinazolinone alkaloid derivative and anti-inflammatory application Download PDFInfo
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- CN117343065A CN117343065A CN202311137998.5A CN202311137998A CN117343065A CN 117343065 A CN117343065 A CN 117343065A CN 202311137998 A CN202311137998 A CN 202311137998A CN 117343065 A CN117343065 A CN 117343065A
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- acid
- salt
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- compound
- inflammatory
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- AVRPFRMDMNDIDH-UHFFFAOYSA-N 1h-quinazolin-2-one Chemical class C1=CC=CC2=NC(O)=NC=C21 AVRPFRMDMNDIDH-UHFFFAOYSA-N 0.000 title abstract description 6
- 230000000813 microbial effect Effects 0.000 title description 5
- -1 alkaloid compound Chemical class 0.000 claims abstract description 34
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- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 229930004668 tropane alkaloid Natural products 0.000 description 1
- 150000003813 tropane derivatives Chemical class 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
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Abstract
The invention discloses a mangrove microorganism source quinazolinone alkaloid derivative and anti-inflammatory application, and experiments prove that the alkaloid compound has good NO inhibition activity in macrophage RAW264.7, has an inhibition IC50 of 8-100 mu M, is safe to host cells, has NO toxic or side effect, and can be used for treating inflammation. Can provide a new choice and path for developing non-steroidal anti-inflammatory drugs, and has good application prospect.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to an alkaloid compound and application thereof in preparing anti-inflammatory medicines.
Background
Alkaloid compounds generally refer to a class of nitrogen-containing organic matters derived from the biological kingdom, most of the alkaloid compounds have complex cyclic structures, nitrogen atoms are in rings, and the biogenic synthesis route of the alkaloid compounds is formed by cyclization of amino acids (ornithine, lysine, phenylalanine, histidine, tryptophan and the like) and cleavage reaction of carbon-nitrogen bonds. Common types of alkaloids are pyridine alkaloids, tropane alkaloids, quinoline alkaloids, isoquinoline alkaloids and indole alkaloids. Alkaloid compounds have a wide range of biological activities such as: anti-tumor, antibacterial, antiviral, antituberculosis, hypoglycemic, etc., is one of the important effective components in Chinese herbal medicine. Various alkaloid drugs are currently marketed or in clinical stages.
Inflammation is the basic defense mechanism of immunity and can prevent injury caused by harmful stimuli such as pathogens and poisons. However, the inflammatory process itself may lead to tissue damage and to a variety of diseases. The current clinical anti-inflammatory agents are mainly non-steroidal anti-inflammatory agents. Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used worldwide, in the form of prescription and "over-the-counter" prescription drugs. These drugs are used to treat short-term pain disorders such as headache and menstrual pain, as well as long-term chronic inflammatory diseases such as rheumatoid arthritis. However, prolonged administration of non-steroidal anti-inflammatory drugs can cause gastrointestinal toxicity, including gastroesophageal reflux, hemorrhage, perforation, and obstruction, increasing the risk of vascular, gastrointestinal, and heart failure. Therefore, the search and development of effective and low-toxicity anti-inflammatory drugs has important significance.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a mangrove microorganism source quinazolinone alkaloid derivative with anti-inflammatory activity. The experiment of the invention proves that the alkaloid compound has good NO inhibition activity in macrophage RAW264.7, and inhibits IC 50 8-100 mu M, is safe to host cells, has no toxic or side effect, can be used for treating inflammation, and provides a new choice and path for researching and developing anti-inflammatory drugs.
The above object of the present invention is achieved by the following technical solutions:
a mangrove microbial source quinazolinone alkaloid derivative, which has a chemical structural formula shown as follows:
in addition, diketopiperazine ring side chain substituents can also be other arbitrary substituents including aliphatic substituents, aromatic ring substituents.
Preferably, the anti-inflammatory activity is strongest for the following compounds:
therefore, the application of the alkaloid compound, or pharmaceutically acceptable salt, stereoisomer or prodrug thereof in preparing anti-inflammatory drugs is also within the protection scope of the invention.
Preferably, the anti-inflammatory activity is NO inhibitory activity.
The pharmaceutically acceptable salt of the alkaloid compound is inorganic acid salt, inorganic alkali salt or double salt thereof.
The inorganic acid salt is hydrochloric acid, hydroiodic acid, hydrobromic acid, nitric acid, boric acid, carbonic acid, sulfuric acid, phosphoric acid or silicic acid.
The inorganic base is sodium hydroxide, potassium hydroxide, barium hydroxide, calcium hydroxide, ammonium hydroxide or lithium hydroxide.
The alkaloid compound prodrug refers to a substance which can be converted into the alkaloid compound or a salt thereof in vivo.
The invention also provides an anti-inflammatory drug which comprises the alkaloid compound, or pharmaceutically acceptable salt, stereoisomer or prodrug thereof.
Preferably, the medicament also comprises a medicinal carrier and/or excipient, and is prepared into different dosage forms.
The medicine is in the form of powder, tablet, granule, capsule, solution, syrup, suspension, injection, powder injection, water injection, aerosol, ointment, eye drop or suppository.
The medicine is administered via gastrointestinal tract, injection, respiratory tract, skin, mucosa or cavity.
Compared with the prior art, the invention has the beneficial effects that:
the invention provides mangrove microbial source quinazolineKetone alkaloid derivative, experiment shows that the alkaloid compound has excellent NO inhibiting activity in macrophage RAW264.7, and can inhibit IC 50 8-100 mu M, is safe to host cells, has no toxic or side effect, and can be used for treating inflammation. Can provide a new choice and path for developing non-steroidal anti-inflammatory drugs, and has good application prospect.
Drawings
FIG. 1 is a synthetic scheme for a mangrove microbial source quinazolinone alkaloid derivative.
Detailed Description
The invention will be further described with reference to the following specific embodiments, but the examples are not intended to limit the invention in any way. Raw materials reagents used in the examples of the present invention are conventionally purchased raw materials reagents unless otherwise specified.
The compounds referred to in the following examples are the following series of alkaloids:
EXAMPLE 1 Synthesis and identification of alkaloid Compounds
The synthetic route of alkaloid compounds is shown in figure 1.
1. Synthesis of Compounds
(1) 48mg (0.15 mmol) of brevenanamide M was taken in a round-bottomed flask, a mixture of 2mL of methanol and 1.9mg (0.015 mmol) of p-toluenesulfonic acid was slowly added dropwise under ice bath conditions and stirred at room temperature overnight. TLC showed complete reaction of starting material. The reaction solution was transferred to a separating funnel, dissolved in 5mL of methylene chloride, and adjusted to pH 9-10 with 10% potassium hydroxide solution. 5mL of saturated brine was added thereto for washing. The organic phase was separated and the aqueous phase was back extracted twice with 2 x 5ml dichloromethane. The organic phases were combined and dried over anhydrous magnesium sulfate. With polarity EA: and (3) separating and purifying by a silica gel chromatographic column with PE=1:2 to obtain the compound 1a.
(2) 40mg (0.1 mmol) of 1a are taken in a round-bottomed flask, 15mg of sodium methoxide (0.2 mmol) and 4mL of triethylamine are added and stirred at room temperature for 15min, the reaction is stirred at 75℃and monitored by TLC. The reaction solution was transferred to a separating funnel, dissolved in 5mL of dichloromethane, and adjusted to pH 2-3 with 10% dilute hydrochloric acid. 5mL of saturated brine was added thereto for washing. The organic phase was separated and the aqueous phase was back extracted twice with 2 x 5ml dichloromethane. The organic phases were combined and dried over anhydrous magnesium sulfate. With polarity EA: and (3) separating and purifying by a silica gel chromatographic column with PE=1:4 to obtain the compound 1b.
(3) 40mg (0.1 mmol) of 1a are taken in a round-bottomed flask, 20mg of sodium hydride (0.3 mmol) and 5mL of acetone are added, and after stirring at room temperature for 15min, 4mg (0.01 mmol) of tetrabutylammonium iodide and 33mg (0.12 mmol) of 2-iodoaniline are added, and the reaction is monitored by TLC. The reaction solution was transferred to a separating funnel, dissolved in 5mL of dichloromethane, and adjusted to pH 2-3 with 10% dilute hydrochloric acid. 5mL of saturated brine was added thereto for washing. The organic phase was separated and the aqueous phase was back extracted twice with 2 x 5ml dichloromethane. The organic phases were combined and dried over anhydrous magnesium sulfate. With polarity EA: and (3) separating and purifying by a silica gel chromatographic column with PE=1:4 to obtain compounds 1 c-18 c.
2. Identification of Compounds
(1) Authentication method
The structure of the alkaloid compounds was confirmed by NMR and HR-ESI-MS.
(2) Identification result
Compound 1a as white solid in 98% yield; melting point is 183.6-185.6 ℃. 1 H NMR(600MHz,CDCl 3 )δ H 8.28(d,J＝4.4Hz,1H),8.24(dd,J＝8.0,1.1Hz,1H),7.79(ddd,J＝8.4,7.1,1.5Hz,1H),7.74(dd,J＝8.1,0.6Hz,1H),5.53(ddd,J＝8.9,6.4,0.7Hz,1H),5.27(d,J＝4.8Hz,1H),3.52(s,3H),3.46-3.29(m,2H). 13 C NMR(150MHz,CDCl 3 )δ C 170.2,160.2,146.8,146.8,135.9,134.9,129.8,129.8,128.6,128.6,128.1,127.8,127.3,127.0,120.8,83.8,57.4,56.0,40.0.HRMS(ESI)for[M+H] + :calcd for C 19 H 18 N 3 O 3 336.1270.found:336.1342. The structural formula is:
compound 1b, white solid in 20% yield; melting point is 103.2-105.1 ℃. 1 H NMR(600MHz,CD 3 OD)δ H 8.34(dd,J＝8.0,1.1Hz,1H),7.92(ddd,J＝8.5,7.2,1.5Hz,1H),7.85-7.74(m,1H),7.70(ddd,J＝8.2,7.3,1.1Hz,1H),7.27-7.11(m,1H),7.06(dd,J＝10.6,4.8Hz,2H),6.80-6.62(m,2H),5.47(dd,J＝5.7,2.9Hz,1H),3.52(dd,J＝13.9,5.7Hz,1H),3.42(tt,J＝14.5,7.3Hz,1H),3.34(dd,J＝13.2,5.9Hz,1H),3.32-3.26(m,1H),1.08(t,J＝7.3Hz,3H). 13 C NMR(150MHz,CD 3 OD)δ C 178.9,161.3,159.4,147.1,139.3,136.5,135.5,130.8,130.8,130.2,129.6,129.6,129.4,128.6,127.7,122.5,58.1,38.7,37.7,14.2.HRMS(ESI)for[M+H] + :calcd for C 20 H 19 N 4 O 2 347.1430.Found:347.1342. Structural formula:
compound 1c as white solid, 73% yield; melting point 145.7-160.1 ℃. 1 H NMR(600MHz,CDCl 3 )δ H 8.23(dd,J＝8.0,1.0Hz,1H),7.77(ddd,J＝8.0,1.1Hz,1H),7.79(ddd,J＝8.5,7.2,1.5Hz,1H),7.72-7.65(m,1H),7.57-7.46(m,1H),7.38-7.17(m,10H),5.61(dd,J＝7.9,7.2Hz,1H),5.26-5.00(m,2H),4.39(d,J＝14.8Hz,1H),3.55-3.40(m,5H). 13 C NMR(150MHz,CDCl 3 )δ C 167.3,160.1,146.8,146.7,136.1,135.7,134.8,129.8,129.8,129.0,129.0,128.8,128.8,128.5,128.5,128.3,127.9,127.7,127.2,121.0,87.7,57.6,57.2,48.7,40.3.HRMS(ESI)for[M+H] + :calcd for C 26 H 24 N 3 O 3 426.1739.Found:426.1808. The structural formula is:
compound 2c as a pale yellow solid in 58% yield; melting point is 184.0-186.4 ℃. 1 H NMR(600MHz,CD 3 COCD 3 )δ H 8.19(ddd,J＝6.4,4.2,1.7Hz,3H),7.87(ddd,J＝8.4,7.2,1.5Hz,1H),7.77-7.69(m,1H),7.64-7.55(m,1H),7.36-7.13(m,1H),5.54(s,1H),5.48(dd,J＝9.0,6.0Hz,1H),5.12(d,J＝15.9Hz,1H),4.89(d,J＝15.9Hz,1H),3.59(s,3H),3.45(ddd,J＝19.4,13.5,7.5Hz,2H). 13 C NMR(150MHz,CD 3 COCD 3 )δ C 167.9,160.6,148.3,147.9,147.8,145.8,137.5,135.5,130.6,130.6,130.0,130.0,129.0,129.0,128.6,128.4,127.6,127.3,124.3,124.3,122.0,89.9,58.3,57.1,49.4,40.8.HRMS(ESI)for[M+H] + :calcd for C 26 H 23 N 4 O 5 471.1590.found:471.1661. The structural formula is:
compound 3c as white solid, 61% yield; melting point is 173.8-175.5 ℃. 1 H NMR(600MHz,CD 3 COCD 3 )δ H 8.17(dd,J＝7.9,1.1Hz,1H),7.90-7.79(m,1H),7.71(d,J＝8.1Hz,1H),7.58(t,J＝7.5Hz,1H),7.32-7.09(m,5H),6.57(d,J＝2.2Hz,2H),6.41(d,J＝2.2Hz,1H),5.46(dd,J＝9.1,5.8Hz,1H),5.37(s,1H),5.08(d,J＝15.0Hz,H),4.46(d,J＝15.1Hz,1H),3.72(s,6H),3.58(s,3H),3.43(ddd,J＝19.3,13.5,7.5Hz,2H). 13 C NMR(150MHz,CD 3 COCD 3 )δ C 167.7,162.2,160.6,148.1,148.0,139.9,137.7,135.4,130.6,130.6,129.0,129.0,128.5,128.5,127.7,127.5,127.3,122.0,107.1,107.1,100.1,89.0,58.4,57.3,55.6,55.6,49.1,40.8.HRMS(ESI)for[M+H] + :calcd for C 28 H 27 N 3 O 5 486.1951.Found:486.2022. Structural formula:
compound 4c as white solid in 75% yield; melting point is 157.5-162.8 ℃. 1 H NMR(600MHz,CD 3 COCD 3 )δ H 8.16(dd,J＝7.9,1.2Hz,1H),7.90-7.83(m,1H),7.74(d,J＝8.1Hz,1H),7.58(t,J＝7.5Hz,1H),7.23(t,J＝6.4Hz,4H),7.22-7.17(m,1H),5.45(s,1H),5.38(dd,J＝8.7,6.1Hz,1H),3.65(s,1H),3.36(ddd,J＝19.6,13.5,7.4Hz,H),3.18(s,3H). 13 C NMR(150MHz,CD 3 COCD 3 )δ C 167.8,160.5,148.2,148.0,137.7,135.4,130.5,130.5,129.0,128.5,128.5,128.3,127.5,127.3,121.9,91.0,58.1,57.3,40.9,33.5.HRMS(ESI)for[M+H] + :calcd for C 20 H 20 N 3 O 3 350.1426.found:350.1499. The structural formula is:
compound 5c as white solid in 66% yield; melting point is 144.4-145.9 ℃. 1 H NMR(600MHz,CD 3 COCD 3 )δ H 8.17(dd,J＝8.0,1.1Hz,1H),7.87(ddd,J＝8.5,7.2,1.5Hz,1H),7.76(dd,J＝8.1,0.5Hz,1H),7.59(ddd,J＝8.1,7.2,1.1Hz,1H),7.32-7.22(m,4H),7.22-7.14(m,1H),5.46(s,1H),5.37(dd,J＝9.0,5.9Hz,1H),3.74-3.66(m,1H),3.64(s,3H),3.52(ddd,J＝1337,8.5,6.6Hz,3H),3.43(dd,J＝13.5,9.0Hz,1H),3.36(dd,J＝13.5,5.9Hz,1H),1.71-1.62(m,2H),1.28(d,J＝7.9Hz,10H),0.86(d,J＝6.9Hz,3H). 13 C NMR(150MHz,CD 3 COCD 3 )δ C 167.4,160.6,148.2,148.0,137.8,135.4,130.6,130.6,129.0,129.0,128.6,128.3,127.5,127.3,121.9,89.9,58.4,56.8,46.9,40.9,32.5,30.0,29.5,29.2,27.5,23.3,14.3.HRMS(ESI)for[M+H] + :calcd for C 27 H 24 N 3 O 3 448.2522.found:448.2594. Structural formula:
compound 6c as white solid in 63% yield; melting point 173.5-175.1 ℃. 1 H NMR(600MHz,CD 3 COCD 3 )δ H 8.17(dd,J＝8.0,1.4Hz,1H),7.83(ddd,J＝8.4,7.2,1.5Hz,1H),7.64(d,J＝8.1,1H),7.61-7.54(m,1H),7.41(d,J＝7.4Hz,2H),7.37-7.27(m,7H),7.23(dt,J＝9.2,4.3Hz,1H),5.81(q,J＝7.2Hz,1H),5.44(dd,J＝9.3,5.8Hz,1H),5.03(s,1H),3.55-3.47(m,4H),3.42(dd,J＝13.5,5.8Hz,1H),1.76(d,J＝7.2Hz,3H). 13 C NMR(150MHz,CD 3 COCD 3 )δ C 167.3,160.6,147.9,147.8,140.7,137.8,135.4,130.6,130.6,129.6,129.6,129.0,129.0,128.7,128.6,128.4,128.4,128.3,127.5,127.3,122.0,86.4,58.5,56.0,52.4,40.8,18.2.HRMS(ESI)for[M+H] + :calcd for C 27 H 26 N 3 O 3 440.1896.found:440.1965. The structural formula is:
compound 7c as white solid in 59% yield; melting point 130.4-135.6 deg.c. 1 H NMR(600MHz,CD 3 COCD 3 )δ H 8.17(dd,J＝7.9,1.1Hz,1H),7.86(ddd,J＝8.5,7.2,1.5Hz,1H),7.81-7.70(m,1H),7.66-7.50(m,1H),7.31-7.23(m,4H),7.23-7.27(m,1H),5.47(s,1H),5.38(dd,J＝9.0,5.9Hz,1H),3.72(dt,J＝13.8,6.9Hz,1H),3.67-3.58(m,4H),3.52(t,J＝6.7Hz,2H),3.40(ddd,J＝19.4,13.5,7.5Hz,2H),1.95-7.80(m,4H). 13 CNMR(150MHz,CD 3 COCD 3 )δ C 167.6,160.6,148.1,148.0,137.7,135.4,130.5,130.5,129.0,129.0,128.5,128.3,127.5,127.3,121.9,89.8,58.3,56.8,45.8,40.8,34.4,30.7,27.9.HRMS(ESI)for[M+H] + :calcd for C 23 H 25 BrN 3 O 3 470.1001.found:470.1000, the structural formula is:
compound 8c as white solid in 65% yield; melting point is 133.2-135.1 ℃. 1 H NMR(600MHz,CD 3 COCD 3 )δ H 8.16(dd,J＝7.9,1.3Hz,1H),7.94-7.79(m,1H),7.75(d,J＝8.0Hz,1H),7.68-7.48(m,1H),7.33-7.22(m,4H),7.22-7.15(m,1H),5.48(s,1H),5.37(dd,J＝9.0,6.0Hz,1H),4.63-4.40(m,2H),3.82(dt,J＝13.9,6.9Hz,1H),3.71-3.60(m,2H),3.39(ddd,J＝19.5,13.5,7.5Hz,2H),2.11-2.04(m,2H). 13 C NMR(150MHz,CD 3 COCD 3 )δ C 167.6,160.6,148.0,148.0,137.7,135.4,130.5,130.5,129.0,129.0,128.5,128.3,127.5,127.3,121.9,90.2,83.0,58.3,56.9,43.8,33.8.HRMS(ESI)for[M+H] + :calcd for C 21 H 21 ClN 3 O 3 398.1193.found:398.1270. The structural formula is:
compound 9c as white solid in 51% yield; melting point 129.7-131.1 ℃. 1 H NMR(600MHz,CD 3 COCD 3 )δ H 8.17(dd,J＝7.9,1.1Hz,1H),7.86(ddd,J＝8.5,7.2,1.5Hz,1H),7.81-7.70(m,1H),7.66-7.50(m,1H),7.31-7.23(m,4H),7.23-7.27(m,1H),5.47(s,1H),5.38(dd,J＝9.0,5.9Hz,1H),3.72(dt,J＝13.8,6.9Hz,1H),3.67-3.58(m,4H),3.52(t,J＝6.7Hz,2H),3.40(ddd,J＝19.4,13.5,7.5Hz,2H),1.95-7.80(m,4H). 13 CNMR(150MHz,CD 3 COCD 3 )δ C 167.6,160.6,148.1,148.0,137.7,135.4,130.5,130.5,129.0,129.0,128.5,128.3,127.5,127.3,121.9,89.8,58.3,56.8,45.8,40.8,34.4,30.7,27.9.HRMS(ESI)for[M+H] + :calcd for C 23 H 25 BrN 3 O 3 470.1001.found:470.1072. The structural formula is:
compound 10c as white solid in 56% yield; melting point is 123.6-127.2 ℃. 1 H NMR(600MHz,CD 3 COCD 3 )δ H 8.17(dd,J＝7.9,1.3Hz,1H),7.86(ddd,J＝8.5,7.2,1.5Hz,1H),7.75(d,J＝7.8Hz,1H),7.66-7.50(m,1H),7.32-7.12(m,5H),5.48(s,1H),5.47(s,1H),5.38(dd,J＝9.0,5.9Hz,1H),4.50(t,J＝5.7Hz,1H),4.42(t,J＝5.9Hz,1H),3.75(dt,J＝13.9,7.0Hz,1H),3.64(s,3H),3.60(dt,J＝14.1,7.2Hz,1H),3.43(dd,J＝13.5,9.0Hz,1H),3.36(dd,J＝13.5,6.0Hz,1H),1.84-1.67(m,4H). 13 C NMR(150MHz,CD 3 COCD 3 )δ C 167.6,160.6,148.1,148.0,137.8,135.4,130.5,130.5,129.0,129.0,128.5,128.3,127.5,127.3,121.9,89.9,84.8,58.3,56.8,46.5,40.9,28.4,25.2.HRMS(ESI)for[M+H] + :calcd for C 23 H 25 FN 3 O 3 410.1802.Found:410.1872. The structural formula is:
compound 11c as white solid in 53% yield; melting point 166.8-169.2 ℃. 1 H NMR(600MHz,CD 3 COCD 3 )δ H 8.17(dd,J＝8.0,1.4Hz,1H),7.85(ddd,J＝8.4,7.2,1.5Hz,1H),7.70(d,J＝8.1Hz,1H),7.63-7.53(m,1H),7.51-7.44(m,2H),7.28-7.19(m,5H),7.13-7.07(m,2H),5.45(dd,J＝9.1,5.9Hz,1H),5.41(s,1H),5.02(d,J＝15.1Hz,1H),4.63(d,J＝15.1Hz,1H),3.55(s,3H),3.42(ddd,J＝19.4,13.5,7.5Hz,2H). 13 C NMR(150MHz,CD 3 COCD 3 )δ C 167.6,164.0,162.4,160.6,148.0,148.0,137.6,135.4,134.1,134.0,131.3,131.2,130.6,129.0,128.5,128.4,127.6,127.3,121.9,116.1,115.9,89.3,58.3,57.1,48.7,40.8.HRMS(ESI)for[M+H] + :calcd for C 26 H 23 FN 3 O 3 444.1645.found:444.1715. The structural formula is:
compound 12c as white solid in 59% yield; melting point 149.2-151.3 deg.c. 1 H NMR(600MHz,CD 3 OD)δ H 8.03(dd,J＝8.0,1.0Hz,1H),7.69(ddd,J＝8.4,7.2,1.5Hz,1H),7.66-7.54(m,1H),7.48-7.37(m,1H),7.12-7.01(m,5H),6.96(dt,J＝13.0,7.4Hz,4H),6.82-6.74(m,1H),5.19(dd,J＝8.2,7.0Hz,1H),5.08(s,1H),3.66(dd,J＝14.1,7.2Hz 1H),3.42(s,3H),3.18(ddd,J＝6.0,4.8,2.1Hz,3H),2.51(ddt,J＝56.6,14.4,7.4Hz,2H),1.97-1.73(m,2H). 13 C NMR(150MHz,CD 3 OD)δ C 167.3,159.8,146.2,146.1,140.7,135.5,134.6,129.1,129.1,127.9,127.9,127.8,127.8,127.6,127.7,127.6,127.0,126.5,126.1,125.4,120.3,88.1,57.2,56.3,45.8,39.6,32.6,28.7.HRMS(ESI)for[M+H] + :calcd for C 28 H 28 FN 3 O 3 454.2052.found:454.2122. The structural formula is:
compound 13c as white solid in 50% yield; melting point is 113.7-114.3 ℃. 1 H NMR(600MHz,CD 3 COCD 3 )δ H 8.19(dd,J＝7.9,1.3Hz,1H),7.88(ddd,J＝8.5,7.2,1.5Hz,1H),7.77(d,J＝7.8Hz,1H),7.65-7.55(m,1H),7.27(dd,J＝3.8Hz,1.7Hz,4H),7.23-7.13(m,4H),5.53(s,1H),5.40(dd,J＝8.9,6.0Hz,1H),3.79(dt,J＝13.8,6.9Hz,1H),3.73(t,J＝7.1Hz 1H),3.65(s,3H),3.42(qt,J＝13.5,7.5Hz,2H),2.38-2.27(m,2H),1.97-1.73(m,2H),1.97(tdd,J＝9.6,7.6,2.2Hz,2H). 13 C NMR(150MHz,CD 3 COCD 3 )δ C 167.8,160.6,148.0,137.7,135.4,130.5,130.5,130.4,129.7,129.0,129.0,128.6,128.3,127.5,127.3,122.0,89.9,58.3,56.8,45.9,40.8,31.7,22.1.HRMS(ESI)for[M+H] + :calcd for C 23 H 23 F 3 N 3 O 3 446.1613.found:446.1683. Its structural formula is:
compound 14c as white solid in 65% yield; melting point 113.9-118.1 deg.c. 1 H NMR(600MHz,CD 3 COCD 3 )δ H 8.17(d,J＝7.9Hz,1H),7.89-7.81(m,1H),7.75(d,J＝8.0Hz,1H),7.57(t,J＝7.5Hz,1H),7.30-7.13(m,5H),5.46(s,1H),5.36(dd,J＝9.0,5.9Hz,1H),3.73-3.65(m,1H),3.64(s,3H),3.57-3.47(m,1H),3.43(dd,J＝13.5,9.1Hz,1H),3.36(dd,J＝13.5,5.9Hz,1H),1.70-1.60(m,2H),1.35-1.26(m,7H),0.86(t,J＝7.1Hz,3H). 13 C NMR(150MHz,CD 3 COCD 3 )δ C 167.4,160.5,148.2,148.0,137.8,135.4,130.5,130.5,128.9,128.9,128.5,128.3,127.5,127.3,121.9,89.9,58.3,56.8,47.0,40.9,32.2,29.1,27.1,23.2,14.3.HRMS(ESI)for[M+H] + :calcd for C 25 H 30 N 3 O 3 420.2209.found:420.2279. The structural formula is:
compound 15c as white solid in 68% yield; melting point 113.6-116.8 deg.c. 1 H NMR(600MHz,CD 3 COCD 3 )δ H 8.16(d,J＝7.9Hz,1H),7.94-7.81(m,1H),7.74(d,J＝8.0Hz,1H),7.56(dd,J＝7.8,7.2Hz,1H),7.31-7.22(m,4H),7.22-7.15(m,1H),5.45(s,1H),5.37(dd,J＝9.0,6.0Hz,1H),3.74-3.66(m,1H),3.63(s,3H),3.56-3.47(m,1H),3.42(dd,J＝13.5,9.0Hz,1H),3.35(dd,J＝13.5,5.9Hz,1H),1.72-1.55(m,2H),1.36(dt,J＝15.0,7.5Hz,2H),0.91(t,J＝7.4Hz,3H). 13 C NMR(150MHz,CD 3 COCD 3 )δ C 167.4,160.5,148.2,147.9,137.8,135.3,130.5,130.5,128.9,128.9,128.5,128.3,127.4,127.3,121.9,89.8,58.3,56.8,46.6,40.8,31.3,20.6,14.1.HRMS(ESI)for[M+H] + :calcd for C 23 H 26 N 3 O 3 392.1896.found:392.1967. The structural formula is:
compound 16c as white solid in 62% yield; melting point is 123.9-131.5 ℃. 1 H NMR(600MHz,CD 3 COCD 3 )δ H 8.17(dd,J＝7.9,1.5Hz,1H),7.91-7.81(m,1H),7.74(d,J＝8.1Hz,1H),7.60-7.52(m,1H),7.29-7.22(m,4H),7.22-7.17(m,1H),5.47(s,1H),5.38(dd,J＝9.0,5.9Hz,1H),3.76-3.67(m,1H),3.66-3.59(m,6H),3.39(ddd,J＝19.4,13.5,7.5Hz,2H),1.87-1.79(m,4H). 13 C NMR(150MHz,CD 3 COCD 3 )δ C 167.6,160.5,148.0,147.9,137.7,135.3,130.5,130.5,129.0,129.0,128.5,128.3,127.5,127.3,121.9,89.8,58.3,56.8,46.0,45.4,40.8,30.5,26.6.HRMS(ESI)for[M+H] + :calcd for C 23 H 25 ClN 3 O 3 426.1506.Found:426.1577. The structural formula is:
compound 17c as white solid in 58% yield; melting point is 131.6-133.5 ℃. 1 H NMR(600MHz,CD 3 COCD 3 )δ H 8.16(dd,J＝7.9,1.3Hz,1H),7.94-7.79(m,1H),7.75(d,J＝8.0Hz,1H),7.68-7.48(m,1H),7.33-7.22(m,4H),7.22-7.15(m,1H),5.48(s,1H),5.37(dd,J＝9.0,6.0Hz,1H),4.63-4.40(m,2H),3.82(dt,J＝13.9,6.9Hz,1H),3.71-3.60(m,4H),3.39(ddd,J＝19.5,13.5,7.5Hz,2H),2.11-2.04(m,2H). 13 C NMR(150MHz,CD 3 COCD 3 )δ C 167.6,160.6,148.0,148.0,137.7,135.4,130.5,130.5,129.0,128.5,128.3,127.5,127.3,121.9,90.2,83.0,81.9,58.3,56.9,43.8,43.8,40.8.HRMS(ESI)for[M+H] + :calcd for C 22 H 23 FN 3 O 3 396.1645.found:396.1712. The structural formula is:
compound 18c as white solid in 63% yield; melting point is 163.4-164.1 ℃. 1 H NMR(600MHz,CD 3 COCD 3 )δ H 8.24-8.13(m,1H),7.92-7.83(m,1H),7.71(d,J＝8.1Hz,1H),7.58(t,J＝7.5Hz,1H),7.37(td,J＝7.9,6.1Hz,1H),7.28-7.17(m,7H),7.05(td,J＝8.6,2.5Hz,1H),5.50-5.41(m,2H),5.07(d,J＝15.4Hz,1H),4.66(d,J＝15.4Hz,1H),3.57(s,3H),3.43(ddd,J＝19.4,13.5,7.5Hz,2H). 13 C NMR(150MHz,CD 3 COCD 3 )δ C 167.8,160.6,148.0,140.9,137.6,135.4,131.2,131.2,130.6,129.0,128.6,128.4,127.6,127.3,125.0,125.0,122.0,115.9,115.7,115.2,115.0,89.5,58.3,57.2,49.0,40.8.HRMS(ESI)for[M+H] + :calcd for C 26 H 23 FN 3 O 3 444.1645.found:444.1775. The structural formula is:
EXAMPLE 2 detection of NO inhibitory Activity of alkaloid Compounds at cellular level and detection of antiproliferative Activity on cells
1. Detection of NO inhibitory Activity of alkaloid Compounds at cellular level
1. Cell line: RAW264.7 cells
2. The detection method comprises the following steps:
taking a 96-well plate according to 1×10 5 RAW264.7 cells in log phase per well were seeded in 96-well plates at 100 μl per well. Culturing in an incubator for 24h to adhere the cells and enter the logarithmic phase. After 24h, the new complete medium was replaced and LPS (final concentration 1. Mu.g/mL) and either the sample solution or indomethacin solution were added, and three replicates were performed for each concentration, i.e., 3 wells were set for each concentration. The positive control group only added LPS and no drug, the negative control group only added cells and complete medium, and the blank holes only added complete medium. After 24h incubation in incubator, 50 μl of cell culture supernatant was added to a new 96-well plate, and 50 μl of nitric oxide detection reagent I and 50 μl of nitric oxide detection reagent II were added, respectively. The absorbance (OD) at 540nm was measured with a microplate reader.
2. Antiproliferative activity of alkaloids on cells
1. Cell line: RAW264.7 cells
2. The detection method comprises the following steps:
a96-well plate was used, and RAW264.7 cells in the logarithmic growth phase of 1X 105 cells/well were inoculated into the 96-well plate at 100. Mu.L per well. Culturing in an incubator for 24h to adhere the cells and enter the logarithmic phase. After 24h, the new complete medium was replaced, LPS (final concentration 1. Mu.g/mL) and either the sample solution or indomethacin solution were added, and three replicates were performed for each concentration, i.e. 3 replicates were performed for each concentration. The positive control group only added LPS and no drug, the negative control group only added cells and complete medium, and the blank holes only added complete medium. After 24h incubation in an incubator, 50. Mu.L of MTT solution at a concentration of 1mg/mL was added to each well. Finally, the incubator continues to cultivate for 4 hours, the culture medium and MTT are sucked off, 150 mu of LDMSO is added into each hole, shaking and mixing are carried out, and an absorbance value (OD) at 490nm is measured by an enzyme-labeled instrument. Inhibition of cell growth by a drug is expressed in terms of survival, with higher survival indicating lower drug toxicity.
3. Detection result
The alkaloid compound has NO inhibition rate and cell proliferation inhibition survival rate in RAW264.7 cells at 50 mu M concentration. NO half Inhibitory Concentration (IC) of alkaloid compounds in RAW264.7 cells 50 ) The test results are shown in Table 1.
TABLE 1 NO inhibitory Activity and antiproliferative Activity of alkaloid compounds in RAW264.7 cells
As can be seen from the results in Table 1, most of the alkaloid compounds have good activity for inhibiting NO, and especially, compounds 1b and 14c have the strongest NO inhibiting activity. Meanwhile, the alkaloid compounds have better safety to host cells under effective anti-inflammatory doses except the compound 15c, can be prepared into anti-inflammatory drugs for application, and have important significance for treating inflammation. In addition, the method provides a scheme for the subsequent development of safer and more effective anti-inflammatory drugs.
It is to be understood that the above examples of the present invention are provided by way of illustration only and not by way of limitation of the embodiments of the present invention. Other variations or modifications of the above teachings will be apparent to those of ordinary skill in the art. It is not necessary here nor is it exhaustive of all embodiments. Any modification, equivalent replacement, improvement, etc. which come within the spirit and principles of the invention are desired to be protected by the following claims.
Claims (10)
1. A quinazolinone alkaloid compound is characterized by having a chemical structural formula as shown in the specification:
2. the quinazolinone alkaloid compound according to claim 1, characterized by the chemical structural formula as follows:
3. the use of an alkaloid compound as defined in claim 1, or a pharmaceutically acceptable salt, or a stereoisomer, or a prodrug thereof, for the preparation of an anti-inflammatory drug.
4. The use according to claim 3, wherein the anti-inflammatory activity is NO inhibitory activity.
5. The use according to claim 3, wherein the pharmaceutically acceptable salt is an inorganic acid salt, an inorganic base salt or a double salt.
6. The use according to claim 5, wherein the inorganic acid salt is hydrochloric acid, hydroiodic acid, hydrobromic acid, nitric acid, boric acid, carbonic acid, sulfuric acid, phosphoric acid or silicic acid.
7. The use according to claim 5, wherein the inorganic base is sodium hydroxide, potassium hydroxide, barium hydroxide, calcium hydroxide, ammonium hydroxide or lithium hydroxide.
8. The use according to claim 2, wherein the alkaloid compound prodrug is a substance that can be converted in vivo into the alkaloid compound or a salt thereof.
9. An anti-inflammatory agent comprising the alkaloid compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.
10. The medicament according to claim 9, further comprising pharmaceutically acceptable carriers and/or excipients, and being formulated into different dosage forms.
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