CN110713459A - Design synthesis and application of quinolinone fumaramide derivatives - Google Patents

Design synthesis and application of quinolinone fumaramide derivatives Download PDF

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CN110713459A
CN110713459A CN201911223640.8A CN201911223640A CN110713459A CN 110713459 A CN110713459 A CN 110713459A CN 201911223640 A CN201911223640 A CN 201911223640A CN 110713459 A CN110713459 A CN 110713459A
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吉庆刚
李百慧
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    • C—CHEMISTRY; METALLURGY
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    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract

Herein is disclosed N1- (2-oxo-1, 2,3, 4-tetrahydroquinolin-3-yl) -N4Design synthesis and application of a phenyl fumaric amide compound, wherein the structure of the compound is shown as a general formula I:

Description

Design synthesis and application of quinolinone fumaramide derivatives
Technical Field
The invention belongs to the field of chemistry, relates to a novel 3-amino-3, 4-dihydroquinoline-2 (1H) -ketone compound, and particularly relates to an N1- (2-oxo-1, 2,3, 4-tetrahydroquinoline 䣳 -3-yl) -N4Designing, synthesizing and applying a phenyl fumaric amide compound.
Background
Fungal infections represent a significant threat to human health, and in particular deep fungal infections have a high incidence in immunocompromised persons, and the mortality rate caused by these has also increased dramatically in recent years. Currently, there are five major antifungal drugs in the clinic, including echinocandins (e.g., caspofungin), polyenes (e.g., amphotericin B), azoles (e.g., itraconazole), pyrimidines (e.g., flucytosine), and acrylamides (e.g., terbinafine). Because of the potential toxicity and side effects of these drugs, and the emergence of drug-resistant fungi, the treatment effect on deep fungal infections is unsatisfactory, and the clinical need for new antifungal drugs is urgent.
Chitin is a unique constituent of fungal cell walls and is not present in mammalian cells. Chitin synthase is a key enzyme for synthesizing chitin, and by using a chitin synthase inhibitor, the biosynthesis of chitin can be blocked, thereby inhibiting the growth of fungi. Therefore, the chitin synthase is a safe and highly selective antifungal drug target, and the design and development of a chitin synthase inhibitor with a novel structure is expected to develop a novel highly selective antifungal drug.
Quinolinone derivatives exhibit various biological activities, have attracted great attention in the field of pharmaceutical chemistry, and have been reported to be useful in anti-inflammatory, anti-cancer, anti-diabetic, and anti-psychotic applications. Many synthetic quinolinone antibacterial agents have been developed for treating various diseases, and more drugs containing the structure are synthesized, and the drugs can be used for resisting cancers, tumors, viruses, inflammations, bacteria and the like. The research article of the compound can see that: biomedicine & Pharmacotherapy, 2011: 204-; journal of Medicinal Chemistry, 2000: 177-; life Sciences, 1990: 1073-1081.
Fumaramides contain fragments of α, β -unsaturated ketones, which are common backbones of many natural compounds, especially in natural products of plant origin. These natural and synthetic derivatives containing α, β -unsaturated ketone moieties have been shown to be biologically active against a variety of diseases. The research article of the compound can see that: chemical Reviews, 2017.7762-7810. Medicinal chemistry, 2015.388-404. Current clinical pharmacology, 2010.1-29. Recent Patents on Anti-Cancer Drug Discovery, 2015.97-115.
In order to search for novel chitin synthetase inhibitors, the invention designs and synthesizes a class N1- (2-oxo-1, 2,3, 4-tetrahydroquinolin-3-yl) -N4The inhibition effect of the compound on chitin synthetase is determined by taking polyoxin B and fluconazole as reference, the activity of the compound on the aspects of antifungal and antibacterial is determined, and the application research of quinoline compounds is expandedAnd (6) obtaining the finished product.
The novel compounds related to the invention have not been reported so far in the aspect of inhibiting the activity of chitin synthase, so that the novel compounds are developed into novel antifungal preparations as chitin synthase inhibitors, and make greater contribution to the health of human beings.
Disclosure of Invention
It is an object of the present invention to provide a class N1- (2-oxo-1, 2,3, 4-tetrahydroquinolin-3-yl) -N4-phenyl fumaramides; it is another object of the present invention to provide a class N1- (2-oxo-1, 2,3, 4-tetrahydroquinolin-3-yl) -N4A preparation method of the phenyl fumaric amide compound; it is a further object of the present invention to provide such a class N1- (2-oxo-1, 2,3, 4-tetrahydroquinolin-3-yl) -N4Application of phenyl fumaramide compounds in preparing antibacterial/antifungal medicines.
In order to achieve the purpose, the invention provides the following technical scheme:
1. n in the invention1- (2-oxo-1, 2,3, 4-tetrahydroquinolin-3-yl) -N4The structure of the-phenyl fumaramide compound is shown as the general formula 1:
wherein R is H, -CH3、-F、-Cl、-OCH3And the like.
In particular N of the formula I1- (2-oxo-1, 2,3, 4-tetrahydroquinolin-3-yl) -N4The-phenyl fumaramide compound is any one of the following compounds.
Figure 416711DEST_PATH_IMAGE002
Figure 916962DEST_PATH_IMAGE003
Figure 150629DEST_PATH_IMAGE004
Figure 685515DEST_PATH_IMAGE005
Figure 609084DEST_PATH_IMAGE006
N is above1- (2-oxo-1, 2,3, 4-tetrahydroquinolin-3-yl) -N4A synthetic method of the-phenyl fumaramide compound, which is shown in Scheme 1.
Figure 534315DEST_PATH_IMAGE007
Specifically, the above Scheme1 reaction conditions were as follows:
a) adding aniline compound and maleic anhydride into a reactor by taking dimethylbenzene, ethyl acetate, dichloromethane and the like as solvents, preferably dichloromethane, stirring at room temperature for 2 ~ 5 hours, preferably 2 hours according to a feeding ratio of 1:2, preferably 1:1.2, and filtering to obtain white solid after the reaction is finished;
b) the compound 3a-s and 3-amino-3, 4-dihydroquinoline-2 (1H) -ketone are put into a reaction bottle by taking xylene, ethyl acetate, dichloromethane and the like as solvents, preferably dichloromethane, according to the molar ratio of 1:2, preferably 1:1.2, and are reacted at 10 ~ 50 ℃, preferably 25 ℃, triethyl phosphite, trimethyl phosphite or triphenylphosphine and iodine are taken as catalysts, and the reaction time is 2-5H, preferably 3H.
N is above1- (2-oxo-1, 2,3, 4-tetrahydroquinolin-3-yl) -N4Application of the-phenyl fumaramide compound in preparing anti-pathogenic microorganism medicines. The microorganism is pathogenic bacteria or pathogenic fungi, such as Escherichia coli, Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, Bacillus subtilis, Bacillus proteus, and copper green pseudomonas; candida albicans, Cryptococcus neoformans, Aspergillus flavus, Aspergillus fumigatus, etc.
Detailed Description
In order to enhance the understanding of the present invention, the present invention will be further described in conjunction with the following examples, which are provided for illustration only and are not to be construed as limiting the scope of the present invention, and the non-essential modifications and adaptations thereof by those skilled in the art according to the present invention are included in the scope of the present invention.
All reagents used were either analytically or chemically pure, purchased commercially, and were not specifically treated if not indicated. The progress of the reaction was monitored by TLC and developed at 254 nm with an ultraviolet lamp, and a portion was developed with iodine and concentrated sulfuric acid. Melting points were determined using an X-4 micro melting point apparatus. Hydrogen and carbon nuclear magnetic resonance spectroscopy were carried out using a Fourier transform NMR spectrometer model Bruker Av-600, using a deuterated reagent such as CDCl3，DMSO-d6And MeOD, containing the internal standard substance TMS. Chemical shift delta is expressed in ppm, coupling constant J is expressed in Hz, and s, d, t, q and m respectively represent singlet, doublet, triplet, quartet and multiplet. HRMS (ESI) was determined using Bruker impact II.
Example 1 preparation of Aniline chalcone 3 a:
maleic anhydride (2.37g,24.16mmol) was dissolved in 60ml of anhydrous dichloromethane, aniline (2 ml, 21.96 mmol) was added, the mixture was stirred at room temperature for 2 hours, a white precipitate formed, and pure solid, white powder was obtained by filtration and washing with dichloromethane; the synthesis of compounds 3b-s was performed as in example 1.
Example 2N1- (2-oxo-1, 2,3, 4-tetrahydroquinolin-3-yl) -N4Synthesis of (o-tolyl) fumaramide) (1 a)
To a 50mL round bottom flask was added CH2Cl2(30 mL), triethyl phosphite (0.44mL,2.5 mmol), I was added under ice-water bath2(0.636g, 2.5 mmol), adding acid (0.510 g, 2.5 mmol) and triethylamine (1.74 ml, 12.5 mmol) after iodine simple substance is completely dissolved, stirring for 20 min, dropwise adding compound amine (0.487g, 3.0mmol), removing ice water bath, reacting at room temperature for 3h, detecting reaction by TLC point plate, removing solvent by rotary evaporation after reaction is finished, adding 50ml ethyl acetate, washing with 1MHCl (30 ml)X 3), then washed with saturated sodium bicarbonate solution (30 ml x 3), dewatered with anhydrous sodium sulfate, rotary evaporated to remove solvent to give white solid, recrystallized from methanol/ethyl acetate to give pure title compound in 80% yield. Physical constants and spectral data for 1a are as follows:1H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H CONH), 10.41(s, 1H CONH), 9.23 (d, J = 7.7 Hz, 1H CONH), 7.62 (d, J = 7.8 Hz, 1H Ar-H),7.24 -7.14 (m, 4H Ar-H), 7.08 (t,J= 7.2 Hz, 1H Ar-H), 6.95 (t,J= 7.4 Hz,1H Ar-H), 6.89 (d,J= 7.8 Hz, 1H Ar-H), 6.41 (s, 2H CH=CH), 4.62-4.51 (m,6.9 Hz, 1H quinoline-CH), 3.16-3.07 (m,1H ), 2.99-2.87 (m, 1H), 2.25 (s, 3HAr-CH3).13C NMR (101 MHz, DMSO-d6) δ 168.58, 165.13, 163.72, 137.90, 136.49,134.80, 131.39, 130.79, 130.40, 128.62, 128.09, 126.41, 125.51,124.62,122.79, 122.67, 115.64, 48.66, 31.61, 18.40. HRMS (ESI): calcd for C20H20N3O3[M+H]+，350.1499，found，350.1499. C20H19N3NaO3[M+Na]+, 372.1319, found, 372.1317 。
example 3N1- (2-oxo-1, 2,3, 4-tetrahydroquinolin-3-yl) -N4Synthesis of (m-tolyl) fumaramide (1 b)
The synthesis of compound 1b was as above, and the physical constants and spectral data of 1b are as follows:
1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H CONH ), 10.41 (s, 1H CONH ),9.12 (s, 1H CONH ), 7.47-7.38 (m, 2H Ar-H ), 7.25-7.14 (m, 3H Ar-H), 6.95 (t,J=7.4 Hz, 1H Ar-H ), 6.89 (d,J= 7.7 Hz, 2H Ar-H ), 6.37 (s, 2H CH=CH), 4.62- 4.50 (m, 1H quinoline-CH ), 3.18-3.08 (m, 1H), 2.97-2.86 (m, 1H), 2.28 (s,3H Ar-CH3).13C NMR (101 MHz, DMSO-d6) δ 168.64, 165.06, 163.79, 139.16,138.42, 137.90, 134.30,130.42, 129.07, 128.63, 128.07, 124.76,122.79, 122.70,120.34, 117.09, 115.63, 48.63, 31.66, 21.64. HRMS (ESI): calcd for C20H19N3NaO3[M+Na]+, 372.1319, found, 372.1318。
example 4N1- (2-oxo-1, 2,3, 4-tetrahydroquinolin-3-yl) -N4Synthesis of- (p-tolyl) fumaramide (1 c)
The synthesis of compound 1c was as above, and the physical constants and spectral data for 1c are as follows:
1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H CONH ), 10.40 (s, 1H CONH), 9.16(s, 1H CONH), 7.51 (d,J= 8.1 Hz, 2H Ar-H ), 7.24 - 7.17 (m, 2H Ar-H), 7.12(d,J= 8.1 Hz, 2H Ar-H ), 6.95 (t,J= 7.4 Hz, 1H Ar-H), 6.89 (d,J= 7.8Hz, 1H Ar-H), 6.37 (s, 2H CH=CH), 4.59-4.50 (m, 1H quinoline-CH), 3.17-3.08(m, 1H), 2.97-2.87 (m, 1H ), 2.26 (s, 3H Ar-CH3).13C NMR(101MHz,DMSO-d6) δ168.65, 165.08, 163.59, 137.90, 136.70, 134.11, 133.04, 130.62, 129.61,128.62 ,128.06, 122.78, 122.71, 119.88, 115.63, 48.66, 31.65, 20.95. HRMS(ESI): calcd for C20H19N3NaO3[M+Na]+, 372.1319, found, 372.1317。
example 5N1- (2-methoxyphenyl) -N4Synthesis of- (2-oxo-1, 2,3, 4-tetrahydroquinolin-3-yl) fumaramide (1 d)
The synthesis of compound 1d is as above, and the physical constants and spectral data of 1d are as follows:
1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H CONH), 10.42 (s, 1H CONH), 9.21(d, J = 6.8 Hz, 1H CONH ), 8.10 (d,J= 7.5 Hz, 1H Ar-H ), 7.24-7.16 (m, 2HAr-H), 7.13 - 7.06 (m, 1H Ar-H ), 7.04 (d,J= 7.7 Hz, 1H Ar-H ), 6.99-6.86(m, 3H Ar-H), 6.40 (s, 2H CH=CH ), 4.63 - 4.52 (m, 1H quinoline-CH ), 3.81(s, 3H Ar-OCH3), 3.17-3.09 (m, 1H ), 2.99-2.88 (m, 1H).13C NMR(101MHz,DMSO-d6)δ 168.59, 165.2, 163.30, 150.11, 137.92, 134.59, 130.93, 128.60, 128.08,127.63, 125.13, 122.79, 122.69, 122.08, 120.73, 115.64, 111.72, 56.24, 48.62,31.59. HRMS (ESI): calcd for C20H20N3O4[M+H]+，366.1448，found，366.1449.C20H19N3NaO4[M+Na]+, 388.1268, found, 388.1267。
example 6N1- (4-methoxyphenyl) -N4- (2-oxo-1, 2,3, 4-tetrahydroquinolin-3-yl) fumaramide (1 e)
The synthesis of compound 1e is as above, and the physical constants and spectral data of 1e are as follows:
1H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H CONH), 10.40 (s, 1HCONH ), 9.21(d,J= 7.3 Hz, 1H CONH ), 7.54 (d,J= 8.5 Hz, 2H Ar-H), 7.25-7.15 (m, 2HAr-H ), 6.99 - 6.85 (m, 4H Ar-H), 6.42 - 6.31 (m, 2H CH=CH ), 4.59-4.50 (m,1Hquinoline-CH), 3.72 (s, 3H Ar-OCH3), 3.16-3.09 (m, 1H), 2.97-2.86 (m, 1H ).13CNMR (101 MHz, DMSO-d6) δ 168.66, 165.09, 163.34, 155.98, 137.91, 133.98,132.31, 130.72, 128.62, 128.06, 122.78, 122.72, 121.43, 115.63, 114.39,55.65, 48.66, 31.65. HRMS (ESI): calcd for C20H19N3NaO4[M+Na]+, 388.1268,found, 388.1269。
example 7N1- (2-nitrophenyl) -N4Synthesis of- (2-oxo-1, 2,3, 4-tetrahydroquinolin-3-yl) fumaramide (1 f)
The synthesis of compound 1f is as above, and the physical constants and spectral data of 1f are as follows:
1H NMR (400 MHz, DMSO-d6) δ 11.20 (s, 1H CONH), 10.42 (s, 1H CONH), 8.98(d, J = 7.7 Hz, 1H CONH ), 7.98 (dd,J= 6.6, 5.6 Hz, 1H Ar-H), 7.78 (d,J=8.0 Hz, 1H Ar-H), 7.75-7.70 (m, 1H Ar-H), 7.42-7.36 (m, 1H Ar-H ), 7.25-7.15(m, 2H Ar-H ), 6.95 (t,J= 7.4 Hz, 1H Ar-H ), 6.89 (d, JJ=7.8 Hz, 1H Ar-H), 6.50- 6.41 (m, 2H CH=CH ), 4.59-4.48 (m, 1H quinoline-CH ), 3.15-3.05 (m,1H), 2.97-2.86 (m, 1H ).13C NMR (101 MHz, DMSO-d6) δ 168.59, 164.74, 164.52,142.50, 137.88, 134.56, 133.39, 131.50, 130.92, 128.59, 128.07, 125.85,125.80, 125.40, 122.80, 122.67, 115.64, 48.62, 31.60。
example 8N1- (3-nitrophenyl) -N4Synthesis of- (2-oxo-1, 2,3, 4-tetrahydroquinolin-3-yl) fumaramide (1 g)
The synthesis of 1g of compound is as above, and the physical constants and spectral data for 1g are as follows:
1H NMR (400 MHz, DMSO-d6)δ 11.19 (s, 1H CONH), 10.42 (s, 1H CONH), 8.98(d,J= 7.6 Hz, 1H CONH ), 7.98 (d,J= 8.0 Hz, 1H Ar-H), 7.80-7.69 (m, 2HAr-H), 7.39 (t,J= 7.5 Hz, 1H Ar-H ), 7.24-7.13 (m, 2H Ar-H), 6.95 (t,J=7.4 Hz, 1H Ar-H), 6.88 (d,J= 7.8 Hz, 1H Ar-H ), 6.51- 6.41 (m, 2H CH=CH),4.58-4.48 (m, 1H quinoline-CH ), 3.15-3.07 (m,1H ), 2.96-2.85 (m, 1H).13C NMR(101MHz,DMSO-d6) δ168.59, 164.73, 164.52, 142.51, 137.87, 134.56, 133.39,131.50, 130.91, 128.59, 128.08, 125.86, 125.81, 125.40, 122.80, 122.67,115.64, 48.62, 31.60. HRMS (ESI): calcd for C20H19N3NaO3[M+Na]+, 403.1013,found, 403.1014。
example 9N1- (4-nitrophenyl) -N4Synthesis of- (2-oxo-1, 2,3, 4-tetrahydroquinolin-3-yl) fumaramide (1 h)
The synthesis of compound 1h is as above, and the physical constants and spectral data for 1h are as follows:
1H NMR (400 MHz, DMSO) δ 11.38 (s, 1H), 10.41 (s, 1H), 8.93 (d,J= 4.9Hz, 1H), 8.23 (d,J= 8.7 Hz, 2H), 7.87 (d,J= 8.8 Hz, 2H), 7.24-7.14 (m,2H), 6.95 (t,J= 7.4 Hz, 1H), 6.89 (d,J= 7.7 Hz, 1H), 6.52-6.41 (m, 2H),4.58 - 4.49 (m, 1H), 3.15-3.07 (m, 1H), 2.97-2.87 (m, 1H).13C NMR (101 MHz,DMSO) δ 168.65, 167.02, 165.43, 164.66, 145.61, 142.72, 137.87, 133.83,132.73, 130.13, 128.62, 128.07, 125.49, 125.46, 122.79, 122.67, 119.47,119.42, 48.58, 31.68。
example 10N1- (2-chlorophenyl) -N4-（Synthesis of 2-oxo-1, 2,3, 4-tetrahydroquinolin-3-yl) fumaramide (1 i)
The synthesis of compound 1i was as above, and the physical constants and spectral data of 1i are as follows:1H NMR (400 MHz,DMSO-d6) δ 11.27 (s, 1H CONH), 10.44 (s, 1H CONH), 9.24 (d,J= 7.1 Hz, 1HCONH ), 7.92 (d,J= 7.7 Hz, 1H Ar-H ), 7.50 (d,J= 7.8 Hz, 1H Ar-H ), 7.38-7.32 (m, 1H Ar-H ), 7.23 - 7.14 (m, 3H Ar-H ), 6.98- 6.87 (m, 2H Ar-H ),6.54-6.38 (m, 2H CH=CH), 4.63-4.49 (m, 1H quinoline-CH ), 3.15-3.07 (m, 1H ),3.00-2.89 (m, 1H ).13C NMR (101 MHz, DMSO-d6) δ168.59, 164.73, 164.52,142.51, 137.87, 134.56, 133.39, 131.50, 130.91, 128.59, 128.08, 125.86,125.81, 125.40, 122.80, 122.67, 115.64, 48.62, 31.60. HRMS (ESI): calcd forC19H16ClN3NaO3[M+Na]+, 392.0772, found, 392.0772。
example 11N1- (4-chlorophenyl) -N4Synthesis of- (2-oxo-1, 2,3, 4-tetrahydroquinolin-3-yl) fumaramide (1 j)
The synthesis of compound 1j is as above, and the physical constants and spectral data of 1j are as follows:
1H NMR (400 MHz, DMSO-d6) δ 11.57 (s, 1H CONH), 10.43 (s, 1H CONH), 9.21(s, 1H CONH), 8.15-8.05 (m, 1H Ar-H), 7.27- 7.13 (m, 5H Ar-H ), 6.96 (t,J=7.4 Hz, 1H Ar-H ), 6.89 (d,J= 7.8 Hz, 1H Ar-H), 6.50-6.36 (m, 2H CH=CH ),4.62-4.53 (m, 1H quinoline-CH), 3.18-3.08 (m, 1H), 3.00-2.88 (m, 1H ).13C NMR(101 MHz, DMSO-d6) δ168.66, 164.90, 164.27, 138.26, 137.89, 135.23, 133.94,130.31, 129.38, 129.13, 128.87, 128.62, 128.07, 127.51, 122.79, 122.69,121.39, 115.63, 48.62, 31.67. HRMS (ESI): calcd for C19H17ClN3O3[M+H]+，370.0953，found，370.0950. C19H16ClN3NaO3[M+Na]+, 392.0772, found, 392.0770。
example 12N1- (2-bromophenyl) -N4Synthesis of- (2-oxo-1, 2,3, 4-tetrahydroquinolin-3-yl) fumaramide (1 k)
The synthesis of compound 1k was as above, with the physical constants and spectral data for 1k as follows:
1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H CONH ), 10.42 (s, 1H CONH ),9.19 (d,J= 6.0 Hz, 1H CONH ), 7.79 (d,J= 7.7 Hz, 1H Ar-H), 7.66 (d,J=7.9 Hz, 1H Ar-H ), 7.39 (t,J= 7.6 Hz, 1H Ar-H), 7.26-7.10 (m, 3H Ar-H),7.00- 6.84 (m, 2H Ar-H), 6.53-6.38 (m, 2H CH=CH ), 4.62 - 4.51 (m, 1Hquinoline-CH), 3.16-3.06 (m, 1H), 3.00-2.85 (t, J = 14.6 Hz).13C NMR(101MHz,DMSO-d6) δ168.54, 165.05, 164.02, 163.79, 137.89, 136.46, 134.06, 133.15,131.20, 128.61, 128.42, 128.08, 127.40, 126.93, 122.79, 122.65, 115.64,48.65, 31.58. HRMS (ESI): calcd for C19H16BrN3NaO3[M+Na]+, 436.0267, found,436.0263.
example 13N1- (3-bromophenyl) -N4Synthesis of- (2-oxo-1, 2,3, 4-tetrahydroquinolin-3-yl) fumaramide (1 l)
The synthesis of compound 1l was as above, with 1l having the following physical constants and spectral data:
1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H CONH ), 10.41 (s, 1H CONH ),8.96 (d,J= 7.6 Hz, 1H CONH ), 7.98 (s, 1H Ar-H ), 7.50 (d,J= 7.4 Hz, 1HAr-H ), 7.34-7.15 (m, 4H Ar-H ), 6.95 (t,J= 7.4 Hz, 1H Ar-H ), 6.89 (d,J=7.8 Hz, 1H Ar-H ), 6.47- 6.36 (m, 2H CH=CH ), 4.62-4.48(m, 1H quinoline-CH),3.16-3.07 (m, 1H), 2.96-2.86 (m, 1H).13C NMR (151 MHz, DMSO-d6) δ168.62,164.85, 164.52, 140.89, 137.91, 133.89, 131.20, 130.34, 128.61, 128.06,126.56, 122.79, 122.69, 122.21, 122.01, 118.68, 115.65, 48.66, 31.72. HRMS(ESI): calcd for C19H17BrN3O3[M+H]+,414.0448, found, 414.0451.C19H16BrN3NaO3[M+Na]+, 436.0267, found, 436.0265。
example 14N1- (4-bromophenyl) -N4Synthesis of- (2-oxo-1, 2,3, 4-tetrahydroquinolin-3-yl) fumaramide (1 m)
The synthesis of compound 1m is as above, and the physical constants and spectral data of 1m are as follows:
1H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H CONH), 10.41 (s, 1H CONH ), 9.01(d,J= 7.5 Hz, 1H CONH), 7.60 (d,J= 8.6 Hz, 2H Ar-H), 7.50 (d,J= 8.6 Hz,2H Ar-H), 7.25-7.13 (m, 2H Ar-H ), 6.95 (t,J= 7.4 Hz, 1H Ar-H), 6.89 (d,J= 7.8 Hz, 1H Ar-H ), 6.46- 6.35 (m, 2H CH=CH), 4.59-4.48 (m, 1H quinoline-CH ),3.16-3.06 (m, 1H), 2.96-2.85 (m, 1H ).13C NMR (151 MHz, DMSO-d6) δ168.60,164.95, 164.19, 138.65, 137.91, 133.89, 132.03, 130.51, 128.61, 128.05,122.78, 122.69, 121.83, 115.65, 115.59, 48.68, 31.69.
HRMS (ESI): calcd for C19H17BrN3O3[M+H]+,414.0448, found, 414.0443.C19H16BrN3NaO3[M+Na]+, 436.0267, found, 436.0265。
example 15 preparation of N1- (2-fluorophenyl) -N4Synthesis of- (2-oxo-1, 2,3, 4-tetrahydroquinolin-3-yl) fumaramide (1 n)
The synthesis of compound 1n is as above, and the physical constants and spectral data of 1n are as follows:
1H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H CONH ), 10.41 (s, 1H CONH ),9.02 (d, J = 7.6 Hz, 1H CONH ), 7.65 (d,J= 8.8 Hz, 2H Ar-H), 7.37 (d,J=8.8 Hz, 2H Ar-H), 7.24-7.15 (m, 2H Ar-H), 6.95 (t,J= 7.4 Hz, 1H Ar-H ),6.89 (d,J= 7.8 Hz, 1H Ar-H ), 6.45 -6.34 (m, 2H CH=CH ), 4.59-4.49 (m, 1Hquinoline-CH), 3.16-3.07 (m, 1H ), 2.96-2.87 (m, 1H ).13C NMR (101 MHz, DMSO-d6) δ168.49, 165.28, 163.67, 137.88, 134.53, 130.94, 128.63, 128.09, 124.86,124.83, 123.87, 122.80, 122.62, 115.94 ,115.75 ,115.64 ,48.67, 31.54. HRMS(ESI): calcd for C19H16FN3NaO3[M+Na]+, 376.1068, found, 376.1067.
example 16 preparation of N1- (4-fluorophenyl) -N4Synthesis of (1o) - (2-oxo-1, 2,3, 4-tetrahydroquinolin-3-yl) fumaramide
The synthesis of compound 1o is as above, and the physical constants and spectral data for 1o are as follows:
1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H CONH), 10.41 (s, 1H CONH), 9.06(d, J = 7.5 Hz, 1H CONH), 7.64 (dd,J= 8.9, 5.0 Hz, 2H Ar-H ), 7.24 - 7.13(m, 4H Ar-H ), 6.95 (t,J= 7.4 Hz, 1H Ar-H ), 6.89 (d,J= 7.8 Hz, 1H Ar-H),6.43- 6.34 (m, 2H CH=CH ), 4.59-4.48 (m, 1H quinoline-CH ), 3.16-3.07 (m, 1H ),2.97-2.85 (m, 1H ).13C NMR (101 MHz, DMSO-d6) δ168.66, 164.94, 163.99, 137.90,135.69, 133.90, 130.42, 128.62, 128.06, 122.78, 122.71, 121.68, 121.61,115.91, 115.69, 115.63, 48.62, 31.67. HRMS (ESI): calcd for C19H16FN3NaO3[M+Na]+, 376.1068, found, 376.1069。
example 17N1- (3, 4-difluorophenyl) -N4Synthesis of- (2-oxo-1, 2,3, 4-tetrahydroquinolin-3-yl) fumaramide (1p)
The synthesis of compound 1p is as above, and the physical constants and spectral data of 1p are as follows:
1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H CONH ), 10.40 (s, 1H CONH ),9.03 (s, 1H CONH ), 7.85-7.77 (m, 1H Ar-H ), 7.44-7.35 (m, 1H Ar-H ), 7.30(d,J= 8.9 Hz, 1H Ar-H ), 7.23-7.15 (m, 2H Ar-H), 6.98-6.92 (m, 1H Ar-H),6.89 (d,J= 7.7 Hz, 1H Ar-H ), 6.44- 6.36 (m, 2H CH=CH ), 4.57-4.45 (m, 1Hquinoline-CH ), 3.15-3.05 (m, 1H), 2.97-2.84 (t,J= 14.6 Hz, 1H ).13C NMR(101 MHz, DMSO-d6) δ 168.68, 164.76, 164.61, 137.89, 136.52, 133.88, 130.19,128.62, 128.06, 122.78, 122.70, 118.00, 117.83, 116.18, 115.62, 108.91,108.70, 48.58, 31.69. HRMS (ESI): calcd for C19H15F2N3NaO3[M+Na]+, 394.0974,found, 394.0972。
example 18N1- (2-oxo-1, 2,3, 4-tetrahydroquinolin-3-yl) -N4Synthesis of (1q) phenylfumaramide
The synthesis of compound 1q was as above, with the physical constants and spectral data for 1q as follows:
1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H CONH), 10.42 (s, 1H CONH ), 9.15(d,J= 6.1 Hz, 1H CONH ), 7.63 (d,J= 7.9 Hz, 2H Ar-H ), 7.31 (t,J= 7.7Hz, 2H Ar-H ), 7.24-7.15 (m, 2H Ar-H), 7.07 (t,J= 7.3 Hz, 1H Ar-H), 6.99-6.86 (m, 2H Ar-H), 6.45-6.34 (m, 2H CH=CH), 4.60- 4.49 (m, 1H quinoline-CH ),3.16-3.07 (m, 1H), 2.98-2.87 (m, 1H ).13C NMR (101 MHz, DMSO-d6) δ168.65,165.05, 163.95, 139.27, 137.92, 133.98, 129.20, 128.61, 128.05, 124.02,122.77, 122.72, 119.89, 115.64, 48.63, 31.65. HRMS (ESI): calcd forC19H17N3NaO3[M+Na]+, 358.1162, found, 358.1163。
example 19N1- (Naphthalen-1-yl) -N4Synthesis of- (2-oxo-1, 2,3, 4-tetrahydroquinolin-3-yl) fumaramide (1r)
The synthesis of compound 1r was as above, and the physical constants and spectral data for 1r were as follows:
1H NMR (400 MHz, DMSO-d6) δ 11.38 (s, 1H CONH), 10.43 (s, 1H CONH ), 9.23(d,J= 7.5 Hz, 1H CONH ), 8.21 (d,J= 5.8 Hz, 1H Ar-H ), 7.98-7.91 (m, 1HAr-H ), 7.87 (d,J= 7.3 Hz, 1H Ar-H ), 7.77 (d,J= 8.1 Hz, 1H Ar-H), 7.59-7.46 (m, 3H Ar-H ), 7.26-7.13 (m, 2H Ar-H ), 7.00- 6.83 (m, 2H Ar-H ), 6.60-6.43 (m, 2H CH=CH ), 4.68-4.56 (m, 1H quinoline -CH ), 3.19-3.09 (m, 1H),3.01-2.88 (m, 1H ).13C NMR (101 MHz, DMSO-d6) δ 168.60, 165.25, 164.46,137.91, 134.83, 134.16, 133.67, 130.36, 128.61,128.09, 127.90, 126.49,126.46, 126.05, 125.75, 123.13, 122.80, 122.67, 121.47, 115.64, 48.67, 31.63.
HRMS (ESI): calcd for C23H19FN3NaO3[M+Na]+, 408.1319, found, 408.1313。
example 20:
N1- (3, 5-dimethylphenyl) -N4Synthesis of- (2-oxo-1, 2,3, 4-tetrahydroquinolin-3-yl) fumaramide (1s)
The synthesis of compound 1s was as above, with the physical constants and spectral data for 1s as follows:
1H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H CONH), 10.41 (s, 1H CONH ), 9.14(d,J= 7.7 Hz, 1H CONH ), 7.27-7.16 (m, 4H Ar-H), 6.95 (t,J= 7.4 Hz, 1HAr-H ), 6.89 (d,J= 7.8 Hz, 1H Ar-H ), 6.72 (s, 1H Ar-H ), 6.36 (s, 2H CH=CH ),4.61-4.52 (m, 1H quinoline -CH ), 3.16-3.08 (m, 1H), 2.98-2.88 (m, 1H)), 2.23(s, 6H Ar-CH3).13C NMR (151 MHz, DMSO-d6) δ168.60, 165.16, 139.02, 138.22,137.90, 134.38, 130.58, 128.62, 128.07, 125.67, 122.80, 122.69, 117.69,115.66, 48.69, 40.57, 40.45, 40.31, 40.17, 40.04, 39.90, 39.76, 39.62, 31.67,21.52.HRMS (ESI): calcd for C21H21N3NaO3[M+Na]+, 386.1475, found, 386.1475。
example 21N1- (2-oxo-1, 2,3, 4-tetrahydroquinolin-3-yl) -N4Experiment on chitinase inhibitory activity of (E) -phenyl fumaramide compound
Chitin synthase is derived from beer yeast cell membranes, the enzyme and a substrate are incubated together on a micropore plate, the produced chitin is combined with WGA coated on the plate and fixed, then WGA-HRP is added, the WGA-HRP can be combined with the chitin fixed on the plate, redundant reagents are washed away by distilled water, then TMB substrate solution is used for detecting the activity of the HRP, and the OD is detected at 450 nm after the reaction is stopped by 2M sulfuric acid. The results of the test compounds at a concentration of 300. mu.g/ml for their inhibition of chitin synthase are shown in FIG. 1 of the specification. As can be seen from fig. 1: most compounds have certain inhibition effect on chitin synthetase, and when the concentration of the compounds 1B and 1d is 300 mu g/ml, the inhibition rates are respectively 78.3 percent and 82.3 percent, the inhibition effect is equivalent to that of polyoxin B, and the inhibition effect of most compounds is more than 40 percent.
Example 22N1- (2-oxo-1, 2,3, 4-tetrahydroquinolin-3-yl) -N4Experiments on the antimicrobial Activity of the Compound (I) -Phenylfumaramides
Dissolving the compound in DMSO, preparing solution with autoclaved distilled water for later use, autoclaving the 96-well plate, penicillin bottle, gun head and other articles, transferring 100uL of diluted bacteria solution into the 96-well plate by using a liquid transfer gun, and using ofloxacin and streptomycin; fluconazole, polyoxin B as reference control. The bacteria and fungi were cultured at 37 ℃ for 24 hours, and the phenomenon was observed. The results are as follows:
N1- (2-oxo-1, 2,3, 4-tetrahydroquinolin-3-yl) -N4-antibacterial MIC value (ug/mL) of phenylfumaramids
Figure 695486DEST_PATH_IMAGE009
N1- (2-oxo-1, 2,3, 4-tetrahydroquinolin-3-yl) -N4Antifungal MIC values (ug/mL) of phenylfumaramides
Figure 979837DEST_PATH_IMAGE010
The experiments were performed with streptomycin, norfloxacin; fluconazole and polyoxin B are used as control drugs, belong to antibiotic drugs and are recognized antibiotics with strong antimicrobial activity, but the phenomenon of microbial resistance is already generated at present. The novel compound has no drug resistance, and the results of the activity data show that the novel compound has obvious bacteriostatic action, and the antifungal activity of the novel compound on candida albicans (ATCC 90023) and candida albicans (ATCC 76615) is higher than that of other fungus strains. The compound has more excellent antifungal activity against Candida albicans (ATCC 90023) than the polytoxin B with MIC of 4 ug/ml. The MICs of the compound 2n and 2o (GIMCC 3.19) resisting aspergillus fumigatus are 1ug/ml and 1ug/ml respectively, and the compound has more excellent antifungal activity compared with fluconazole. Compound 2a, 2o showed the strongest antifungal activity against candida albicans (ATCC 76615), with a MIC of 1ug/ml, similar to fluconazole. Compounds 2c, 2f, 2g and 2r, 2s had similar potency to c.neooformans (ATCC 32719) compared to the control drug. The MICs for anti-Candida albicans compounds 2b, 2d, 2e and 2l, 2s (ATCC 90023) were 1ug/ml, which is equal to the value for fluconazole. All of the above compounds showed moderate activity against Aspergillus flavus (ATCC 16870).
Description of the drawings: in the figure 1 of the specification, the inhibition rate of the compound on chitin synthetase at 300 ug/mL is shown.

Claims (7)

1.N1- (2-oxo-1, 2,3, 4-tetrahydroquinolin-3-yl) -N4The design synthesis and application of the-phenyl fumaric amide compound are characterized in that: the structure of the compound is shown as a general formula I:
Figure 575286DEST_PATH_IMAGE001
wherein R is hydrogen, methyl, ethyl, methoxy, halogen, amino, nitro, etc.
2. N as claimed in claim 11- (2-oxo-1, 2,3, 4-tetrahydroquinolin-3-yl) -N4The synthesis method of the phenyl fumaric amide compound comprises the following steps:
Figure 603285DEST_PATH_IMAGE002
a) taking the compound 2a-s as an initial raw material, and condensing with maleic anhydride through acid-amine condensation reaction to obtain a key intermediate compound 3 a-s;
b) the compound 3a-s and 3-amino-3, 4-dihydroquinoline-2 (1H) -ketone are condensed by acid amine to react to obtain a target product 1 a-s.
3. The synthesis method of claim 2, wherein the molar ratio of the compound 2a-s to the maleic anhydride is 1:1 ~ 2, preferably 1:1.2, the reaction is carried out at room temperature for 2 ~ 5h, preferably 2h, and ethyl acetate, acetone, dichloromethane, 1, 2-dichloroethane and the like are used as solvents, preferably dichloromethane.
4. The molar ratio of the compound 3a-s to the 3-amino-3, 4-dihydroquinolin-2 (1H) -one is 1:1 ~ 2, preferably 1:1.2, the reaction is carried out at 25 ~ 50 ℃ for 3 ~ 8H, preferably 25 ℃ for 3H, and dichloromethane, 1, 2-dichloroethane and the like are used as solvents, preferably dichloromethane, triethyl phosphite and elementary iodine are used as catalysts.
5. N as claimed in claim 11- (2-oxo-1, 2,3, 4-tetrahydroquinolin-3-yl) -N4Application of phenyl fumaramide compounds in medicaments of chitin synthase inhibitors.
6. N as claimed in claim 11- (2-oxo-1, 2,3, 4-tetrahydroquinolin-3-yl) -N4The use of phenylfumaramides for the preparation of a medicament against pathogenic bacteria or fungi, such as escherichia coli, staphylococcus aureus, methicillin-resistant staphylococcus aureus, bacillus subtilis, proteus vulgaris, pseudomonas aeruginosa; candida albicans, Cryptococcus neoformans, Aspergillus flavus, Aspergillus fumigatus, etc.
7. A pharmaceutical composition characterized by containing N according to claim 11- (2-oxo-1, 2,3, 4-tetrahydroquinolin-3-yl) -N4-a pharmaceutically acceptable carrier for the phenylfumaramide compound.
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