CN102675211A - Synthetization of secnidazole cinnamate derivative, and applications of secnidazole cinnamate derivative on antibacterial agent - Google Patents
Synthetization of secnidazole cinnamate derivative, and applications of secnidazole cinnamate derivative on antibacterial agent Download PDFInfo
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- CN102675211A CN102675211A CN2011100637586A CN201110063758A CN102675211A CN 102675211 A CN102675211 A CN 102675211A CN 2011100637586 A CN2011100637586 A CN 2011100637586A CN 201110063758 A CN201110063758 A CN 201110063758A CN 102675211 A CN102675211 A CN 102675211A
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- secnidazole
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- styracin
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- -1 secnidazole cinnamate derivative Chemical class 0.000 title claims abstract description 34
- 239000003242 anti bacterial agent Substances 0.000 title 1
- 238000002360 preparation method Methods 0.000 claims abstract description 44
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- 238000006243 chemical reaction Methods 0.000 claims description 19
- NQBWNECTZUOWID-UHFFFAOYSA-N (E)-cinnamyl (E)-cinnamate Natural products C=1C=CC=CC=1C=CC(=O)OCC=CC1=CC=CC=C1 NQBWNECTZUOWID-UHFFFAOYSA-N 0.000 claims description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- NQBWNECTZUOWID-QSYVVUFSSA-N cinnamyl cinnamate Chemical class C=1C=CC=CC=1\C=C/C(=O)OC\C=C\C1=CC=CC=C1 NQBWNECTZUOWID-QSYVVUFSSA-N 0.000 claims description 18
- WBYWAXJHAXSJNI-VOTSOKGWSA-M trans-cinnamate Chemical compound [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 claims description 15
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a secnidazole cinnamate derivative which has the following general formula, wherein R in the formula is shown in the description. The secnidazole cinnamate derivative can obviously inhibit the growth of gram positive bacteria and gram negative bacteria, thus being applicable in preparation of antibacterial drugs. The invention discloses a preparation method for the secnidazole cinnamate derivative.
Description
Technical field
The present invention relates to the synthetic and application aspect antibacterials of secnidazole cinnamate derivates.
Background technology
Bacterial infection is a modal type in the infection, if lack treatment timely and effectively, can cause high mortality when serious.For example just bring enormous economic loss and life to threaten by Campylobacter, Salmonellas, O157 intestinal bacteria and the microbial food origin disease of monocytosis Li Site every year to the mankind.
Microbiotic is considered to treat the best weapon of bacterial infection disease, yet along with antibiotic abuse phenomenon is serious day by day, the drug-resistance of bacteria problem is increasingly sharpened, the speed that the speed of new antibiotic research and development produces well below resistant organism.Research shows, has produced resistance many streptococcus pneumoniaes of national 25% at present; The infectation of bacteria of the U.S. 75% can produce resistance to one or more microbiotic; The staphylococcus strain isolated of Japan more than 50% has multi-drug resistant.And can be used as alternate novel type microbiotic for counting seldom, cause a lot of clinically severe infections persons dead because of drug-fast bacteria infection.The superbacteria (tolerating multiple antibiotic intestinal bacteria and bacillus canalis capsulatus) of Lancet report has caused that especially the universe queries the height of traditional antibiotic therapy recently.Therefore it is very urgent to seek new antibiotic preparation.
Styracin (Cinnamic acid) is that 3-cinnamic acid (3-phenyl-2-propenoic acid) is the effective constituent of Chinese traditional medicine cinnamon (Cinnamomum cassia); Experiment in vivo and vitro shows that styracin has the activity of antitumor, antibiotic, antiinflammation and inhibition XOD, at present in medicine (being used to make local anesthetic, sterilant and styptic etc.) and agricultural (being used as the sanitas of growth stimulant, long-acting fungicide, fruit and vegetable using etc.) extensive application.There is the mixture of bibliographical information styracin and pasteurize auxiliary agent to have sterilization, preservative activity.But the fungistatic effect of styracin itself is not satisfactory, has the people that styracin is carried out molecular structure alteration, finds that its bacteriostatic action strengthens through after bromo or the esterification.Therefore can styracin be initiator, synthetic than styracin more low toxicity, efficient and economic antibacterials.
Secnidazole belongs to the 5-nitroimidazoles medicine, is mainly used in anaerobe resistant and anti-trichomonal effect.Characteristics such as secnidazole is compared with metronidazole, tinidazole, ornidazole, has long half time, and effect is strong, and is easy to use are so clinical application is more extensive.But secnidazole is easy to generate oral cavity metal peculiar smell when oral administration, and can cause functional gastrointestinal disorder, feel sick, untoward reaction such as vomiting, be easy to cause patient's repulsion psychology be unfavorable for medication.For reducing its untoward reaction, it is carried out the prodrug modification is very necessary.Present domestic secnidazole only is applied to the treatment of gynecological infectious diseases, does not also see the treatment that is used for bacterial infection disease.For further understanding secnidazole to the susceptibility of bacterial isolates and based on the understanding to styracin, the present invention is with secnidazole grafting styracin and studied their antibacterial activity in vitro, and expectation can obtain the better compound of biological activity.
The present invention prepares corresponding ester cpds with cinnamic acid derivative grafting secnidazole; Gram-positive and gram negative bacterium growth all there is the obvious suppression effect; Therefore the secnidazole cinnamate derivates is as very potential antibacterials, and its prospect extremely merits attention.Along with deepening continuously to secnidazole cinnamate derivative drug research; On the basis that its anti-microbial effect mechanism is constantly understood, carry out effective structure of modification and modification and molecular designing; Be used for clinically with having increasing secnidazole cinnamate derivative antibacterials efficient, low toxicity, promote the well-being of mankind.
Summary of the invention
The object of the present invention is to provide one type of secnidazole cinnamate derivates and their preparation method and purposes.
Technical scheme of the present invention is following:
One type of secnidazole cinnamate derivates is characterized in that it has following general formula:
R is in the formula:
A kind of method for preparing above-mentioned secnidazole cinnamate derivates is characterized in that it is made up of the following step:
Step 1. is with substituted phenyl aldehyde of a series of differences and propanedioic acid reaction, and consumption is phenyl aldehyde 3.2mmol, and propanedioic acid 3.87mmol adds the 0.387mmol piperidines and makes catalyzer, adds an amount of pyridine simultaneously and makes solvent in the 50mL round-bottomed flask, in 80-90 ℃ of reaction down;
Step 2. is followed the tracks of reaction with thin-layer chromatography (TLC) in the solution that step 1 obtains, reflux is until reacting completely;
Step 3. is cooled to room temperature, in round-bottomed flask, adds a large amount of anhydrous diethyl ethers, and the vibration rear overhang is done; Adding a small amount of tap water is that the adularescent particle generates, and filters and with a large amount of tap water washing leaching cakes, washes some times with normal hexane more at last; Obtain the substituted styracin of a series of differences, for use.
Styracin and secnidazole reaction that step 4. obtains step 3, consumption is secnidazole (0.5mmol), styracin (0.5mmol) adds DCC (0.5mmol) and DMAP (0.5mmol) as catalyzer, in 50-60 ℃ of reaction down.
Step 5. is followed the tracks of reaction with thin-layer chromatography (TLC) in the solution that step 4 obtains, reflux is until reacting completely;
Step 6. is cooled to room temperature, uses saturated NaHCO
3Respectively extract three times and collected organic layer with EtOAc, it is suspended from the back adds a small amount of EtOAc vibration filtration, collect the filtrating evaporate to dryness, use EtOH/CHCl
3Recrystallization obtains solid, i.e. title product.Wherein used elutriant is EtOAc.
Secnidazole cinnamate derivates of the present invention has the obvious suppression effect to Gram-positive and gram negative bacterium growth, and therefore the secnidazole cinnamate derivates of invention can be applied to prepare antibacterials.
Embodiment
Through following examples further explain the present invention, but scope of the present invention does not receive any restriction of these embodiment.
Embodiment one: (E)-and the preparation of 1-(2-methyl-5-nitro-1H-imidazoles-1-yl)-2-propyl group laurate (compound 3a)
With phenyl aldehyde and propanedioic acid reaction, consumption is phenyl aldehyde 3.2mmol, and propanedioic acid 3.87mmol adds the 0.387mmol piperidines and makes catalyzer, adds an amount of pyridine simultaneously and makes solvent in the 50mL round-bottomed flask, in 80-90 ℃ of reaction down; Follow the tracks of reaction with thin-layer chromatography (TLC), reflux is until reacting completely; Reaction solution is cooled to room temperature, in round-bottomed flask, adds a large amount of anhydrous diethyl ethers, the vibration rear overhang is done, and adding a small amount of tap water is that the adularescent particle generates, and filters and with a large amount of tap water washing leaching cakes, washes some times with normal hexane more at last, obtains styracin, for use.Styracin and secnidazole that back is obtained react; Consumption is secnidazole (0.5mmol); Styracin (0.5mmol); Add DCC (0.5mmol) and DMAP (0.5mmol) as catalyzer, under 50-60 ℃, react and react with thin-layer chromatography (TLC) tracking, reflux is until reacting completely; Reaction solution is cooled to room temperature, uses saturated NaHCO
3Respectively extract three times and collected organic layer with EtOAc, filter, collect the evaporate to dryness of filtrating, use EtOH/CHCl adding a small amount of EtOAc vibration after its outstanding doing
3Recrystallization obtains solid, i.e. title product.Wherein used elutriant is EtOAc.Light grey powder, productive rate 61%, m.p.:136-139 ℃.
1H NMR (300MHz, CDCl
3, δ ppm): 1.42 (d, J=4.62Hz, 3H), 2.49 (s, 3H), 3.76-3.78 (m; 1H), 4.10-4.14 (m, 2H), 6.75 (d, J=9.24Hz, 1H), 7.02 (s; 1H), and 7.37-7.39 (m, 3H), 7.48-7.50 (m.2H), 7.67 (s, 1H) .ESI-MS:316.1 (C
16H
18N
3O
4, [M+H]
+) .Anal.Calcd for C
16H
17N
3O
4: C, 60.94%; H, 5.43%; N, 13.33%.Found:C, 60.67%; H, 5.56%; N, 13.45%.
Embodiment two: (E)-and the preparation of 1-(2-methyl-5-nitro-1H-imidazoles-1-yl)-2-propyl group-3-(2-fluorophenyl) propenoate (compound 3b)
The preparation method is with embodiment one.Replace phenyl aldehyde with adjacent fluorobenzaldehyde, get target compound.White powder, productive rate 66%, m.p.:106-107 ℃.
1H NMR (300MHz, CDCl
3, δ ppm): 1.42 (d, J=4.62Hz, 3H), 2.54 (s, 3H), 4.29-4.37 (m; 1H), and 4.64-4.71 (m, 1H), 5.38-5.43 (m, 1H), 6.39 (d, J=16.08Hz; 1H), and 7.08-7.19 (m, 2H), 7.34-7.41 (m, 1H), 7.49 (t, J=7.50Hz; 1H), 7.71 (d, J=16.26Hz, 1H), 7.93 (s, 1H) .ESI-MS:334.1 (C
16H
17FN
3O
4, [M+H]
+) .Anal.Calcdfor C
16H
16FN
3O
4: C, 57.65%; H, 4.84%; N, 12.61%.Found:C, 56.37%; H, 4.86%; N, 12.87%.
Embodiment three: (E)-and the preparation of 1-(2-methyl-5-nitro-1H-imidazoles-1-yl)-2-propyl group-3-(2-chloro-phenyl-) propenoate (compound 3c)
The preparation method is with embodiment one.Replace phenyl aldehyde with o-chlorobenzaldehyde, get target compound.White powder, productive rate 61%, m.p.:125-127 ℃.
1H NMR (300MHz, CDCl
3, δ ppm): 1.44 (d, J=6.42Hz, 3H), 2.55 (s, 3H), 4.30-4.38 (m; 1H), and 4.64-4.70 (m, 1H), 5.38-5.43 (m, 1H), 6.27 (d, J=16.08Hz; 1H), and 7.25-7.35 (m, 2H), 7.40-7.43 (m, 1H), 7.55-7.58 (m; 1H), 7.93 (s, 1H), 8.00 (d, J=16.08Hz, 1H) .ESI-MS:350.1 (C
16H
17ClN
3O
4, [M+H]
+) .Anal.Calcd forC
16H
16ClN
3O
4: C, 54.94%; H, 4.61%; N, 12.01%.Found:C, 54.69%; H, 4.81%; N, 12.45%.
Embodiment four: (E)-and the preparation of 1-(2-methyl-5-nitro-1H-imidazoles-1-yl)-2-propyl group-3-(2-bromophenyl) propenoate (compound 3d)
The preparation method is with embodiment one.Replace phenyl aldehyde with adjacent bromobenzaldehyde, get target compound.White powder, productive rate 57%, m.p.:112-115 ℃.
1H NMR (300MHz, CDCl
3, δ ppm): 1.44 (d, J=6.39Hz, 3H), 2.55 (s, 3H), 4.09 (d, J=8.40Hz; 1H), and 4.30-4.38 (m, 1H), 4.64-4.70 (m, 1H), 5.36-5.44 (m, 1H); 6.23 (d, J=15.99Hz, 1H), 7.21-7.26 (m, 1H), 7.33 (t, J=7.13Hz; 1H), and 7.54-7.57 (m, 1H), 7.59-7.62 (m, 1H), 7.93 (s, 1H) .ESI-MS:394.0 (C
16H
17BrN
3O
4, [M+H]
+) .Anal.Calcd for C
16H
16BrN
3O
4: C, 48.75%; H, 4.09%; N, 10.66%.Found:C, 48.61%; H, 4.51%; N, 11.15%.
Embodiment five: (E)-and the preparation of 1-(2-methyl-5-nitro-1H-imidazoles-1-yl)-2-propyl group-3-(2-methoxyphenyl) propenoate (compound 3e)
The preparation method is with embodiment one.Replace phenyl aldehyde with the O-methoxy phenyl aldehyde, get target compound.White powder, productive rate 59%, m.p.:158-162 ℃.
1H NMR (300MHz, CDCl
3, δ ppm): 1.59 (d, J=7.21Hz, 3H), 1.98 (s, 3H), 3.76-3.80 (m; 1H), 3.84 (s, 3H), 4.03-4.17 (m, 2H), 6.75 (d, J=15.36Hz; 1H), 6.92-6.96 (m, 2H), 7.02 (s, 1H), 7.10 (d, J=7.68Hz; 1H), and 7.28-7.34 (m, 1H), 7.66 (d, J=15.36Hz, 1H) .ESI-MS:346.1 (C
17H
20N
3O
5, [M+H]
+) .Anal.Calcd for C
17H
19N
3O
5: C, 59.12%; H, 5.55%; N, 12.17%.Found:C, 58.8l%; H, 5.75%; N, 11.95%.
Embodiment six: (E)-and the preparation of 1-(2-methyl-5-nitro-1H-imidazoles-1-yl)-2-propyl group-3-(3-fluorophenyl) propenoate (compound 3f)
The preparation method is with embodiment one.Replace phenyl aldehyde with a fluorobenzaldehyde, get target compound.White powder, productive rate 66%, m.p.:133-136 ℃.
1H NMR (300MHz, CDCl
3, δ ppm): 1.41 (d, J=7.09Hz, 3H), 2.42 (s, 3H), 4.13-4.18 (m; 1H), and 4.34-4.36 (m, 1H), 4.61-4.66 (m, 1H), 6.56 (d, J=15.36Hz; 1H), 7.24-7.26 (m, 1H), 7.39 (d, J=8.24Hz, 1H), 7.56 (t; J=6.93Hz, 2H), 7.71 (s, 1H), 7.97 (s, 1H) .ESI-MS:334.1 (C
16H
17FN
3O
4, [M+H]
+) .Anal.Calcd forC
16H
16FN
3O
4: C, 57.65%; H, 4.84%; N, 12.61%.Found:C, 58.05%; H, 4.62%; N, 12.34%.
Embodiment seven: (E)-and the preparation of 1-(2-methyl-5-nitro-1H-imidazoles-1-yl)-2-propyl group-3-(3-bromophenyl) propenoate (compound 3g)
The preparation method is with embodiment one.Replace phenyl aldehyde with 3-bromobenzaldehyde, get target compound.Buff powder, productive rate 67%, m.p.:102-104 ℃.
1H NMR (300MHz, CDCl
3, δ ppm): 1.43 (d, J=6.57Hz, 3H), 2.54 (s, 3H), 4.09-4.16 (m; 1H), and 4.32-4.40 (m, 1H), 4.63-4.69 (m, 1H), 6.27 (d, J=15.90Hz; 1H), 7.26 (t, J=7.86Hz, 1H), 7.41 (d, J=7.68Hz, 1H); 7.51 (t, J=7.97Hz, 2H), 7.64 (s, 1H), 7.94 (s, 1H) .ESI-MS:394.0 (C
16H
17BrN
3O
4, [M+H]
+) .Anal.Calcdfor C
16H
16BrN
3O
4: C, 48.75%; H, 4.09%; N, 10.66%.Found:C, 48.89%; H, 3.98%; N, 11.12%.
Embodiment eight: (E)-and the preparation of 1-(2-methyl-5-nitro-1H-imidazoles-1-yl)-2-propyl group-3-(3-methoxyphenyl) propenoate (compound 3h)
The preparation method is with embodiment one.Replace phenyl aldehyde with NSC 43794, get target compound.White powder, productive rate 73%, m.p.:148-151 ℃.
1H NMR (300MHz, CDCl
3, δ ppm): 1.42 (d, J=6.66Hz, 3H), 2.40 (s, 3H), 3.82 (s; 3H), 4.04 (d, J=7.50Hz, 2H), 4.12-4.16 (m, 1H), 6.73 (d; J=15.39Hz, 1H), 6.91-6.94 (m, 2H), 7.00 (s, 1H), 7.09 (d; J=7.50Hz, 1H), 7.26-7.33 (m, 1H), 7.64 (d, J=15.36Hz, 1H) .ESI-MS:346.1 (C
17H
20N
3O
5, [M+H]
+) .Anal.Calcd forC
17H
19N
3O
5: C, 59.12%; H, 5.55%; N, 12.17%.Found:C, 59.33%; H, 4.98%; N, 12.52%.
Embodiment nine: (E)-and the preparation of 1-(2-methyl-5-nitro-1H-imidazoles-1-yl)-2-propyl group-3-(4-fluorophenyl) propenoate (compound 3i)
The preparation method is with embodiment one.Replace phenyl aldehyde with p-Fluorobenzenecarboxaldehyde, get target compound.White powder, productive rate 66%, m.p.:145-147 ℃.
1H NMR (300MHz, CDCl
3, δ ppm): 1.39 (d, J=8.69Hz, 3H), 2.04 (s, 3H); 3.48 (s, 1H), 3.71-3.81 (m, 1H), 4.08-4.15 (m, 1H); 6.66 (d, J=15.36Hz, 1H), 6.95 (s, 1H) .7.07 (t, J=8.68Hz; 2H), and 7.45-7.49 (m, 2H), 7.64 (d, J=15.18Hz, 1H) .ESI-MS:334.1 (C
16H
17FN
3O
4, [M+H]
+) .Anal.Calcd forC
16H
16FN
3O
4: C, 57.65%; H, 4.84%; N, 12.61%.Found:C, 57.23%; H, 5.01%; N, 12.49%.
Embodiment ten: (E)-and the preparation of 1-(2-methyl-5-nitro-1H-imidazoles-1-yl)-2-propyl group 3-(4-chloro-phenyl-) propenoate (compound 3j)
The preparation method is with embodiment one.Replace phenyl aldehyde with 4-chloro-benzaldehyde, get target compound.White powder, productive rate 56%, m.p.:217-219 ℃.
1H NMR (300MHz, CDCl
3, δ ppm): 1.43 (d, J=8.23Hz, 3H), 1.92 (s, 3H), 3.36 (s; 1H), and 3.71-3.78 (m, 1H), 4.08-4.15 (m, 1H), 6.66 (d, J=15.36Hz; 1H), 6.84 (s, 1H), 7.35 (d, J=8.58Hz, 2H); 7.41 (d, J=8.61Hz, 2H), 7.62 (d, J=15.39Hz, 1H) .ESI-MS:350.1 (C
16H
17ClN
3O
4, [M+H]
+) .Anal.Calcd forC
16H
16ClN
3O
4: C, 54.94%; H, 4.61%; N, 12.01%.Found:C, 53.83%; H, 4.91%; N, 12.45%.
Embodiment 11: (E)-and the preparation of 1-(2-methyl-5-nitro-1H-imidazoles-1-yl)-2-propyl group-3-(4-bromophenyl) propenoate (compound 3k)
The preparation method is with embodiment one.Replace phenyl aldehyde with p-bromobenzaldehyde, get target compound.White powder, productive rate 62%, m.p.:220-222 ℃.
1H NMR (300MHz, CDCl
3, δ ppm): 1.40 (d, J=7.98Hz, 3H), 2.05 (s, 3H), 3.74-3.76 (m; 1H), 4.08-4.13 (m, 2H), 6.54 (d, J=15.00Hz, 1H); 6.80 (s, 1H), 7.01-7.06 (m, 1H), 7.23-7.26 (m, 2H); 7.62 (d, J=5.13Hz, 1H), 7.80 (d, J=15.00Hz, 1H) .ESI-MS:394.0 (C
16H
17BrN
3O
4, [M+H]
+) .Anal.Calcd forC
16H
16BrN
3O
4: C, 48.75%; H, 4.09%; N, 10.66%.Found:C, 48.87%; H, 4.31%; N, 10.49%.
Embodiment 12: (E)-and the preparation of 1-(2-methyl-5-nitro-1H-imidazoles-1-yl)-2-propyl group-3-(4-tolyl) propenoate (compound 3l)
The preparation method is with embodiment one.Replace phenyl aldehyde with p-tolyl aldehyde, get the target compound white powder, productive rate 63%, m.p.:194-195 ℃.
1H NMR (300MHz, CDCl
3, δ ppm): 1.42 (d, J=8.12Hz, 3H), 2.03 (s, 3H), 2.37 (s; 3H), and 3.44-3.51 (m, 1H), 3.70-3.76 (m, 1H), 4.07-4.1 (m, 1H) 6.70 (d; J=15.36Hz, 1H), 7.08 (s, 1H), 7.18 (d, J=7.89Hz, 2H); 7.38 (d, J=8.22Hz, 2H), 7.65 (d, J=15.36Hz, 1H) .ESI-MS:330.1 (C
17H
20N
3O
4, [M+H]
+) .Anal Calcd forC
17H
19N
3O
4: C, 62.00%; H, 5.81%; N, 12.76%.Found:C, 61.87%; H, 5.36%; N, 12.49%.
Embodiment 13: (E)-and the preparation of 1-(2-methyl-5-nitro-1H-imidazoles-1-yl)-2-propyl group-3-(4-methoxyphenyl) propenoate (compound 3m)
The preparation method is with embodiment one.Replace phenyl aldehyde with aubepine, get target compound.White powder, productive rate 68%, m.p.:146-148 ℃.
1H NMR (300MHz, CDCl
3, δ ppm): 1.41 (d, J=6.79Hz, 3H), 2.33 (s, 3H), 3.48 (s; 3H), and 3.72-3.74 (m, 1H), 4.09-4.13 (m, 2H), 6.54 (d, J=15.00Hz; 1H), and 6.80-6.91 (m, 1H), 7.01-7.06 (m, 1H), 7.23-7.26 (m, 2H); 7.35 (d, J=5.13Hz, 1H), 7.80 (d, J=15.00Hz, 1H) .ESI-MS:346.1 (C
17H
20N
3O
5, [M+H]
+) .Anal.Calcd for C
17H
19N
3O
5: C, 59.12%; H, 5.55%; N, 12.17%.Found:C, 59.31%; H, 5.30%; N, 11.79%.
Embodiment 14: (E)-and the preparation of 1-(2-methyl-5-nitro-1H-imidazoles-1-yl)-2-propyl group-3-(4-xenyl) propenoate (compound 3n)
The preparation method is with embodiment one.So that the phenyl phenyl aldehyde is replaced phenyl aldehyde, get target compound.White powder, productive rate 59%, m.p.:221-223 ℃.
1H NMR (300MHz, CDCl
3, δ ppm): 1.42 (d, J=7.99Hz, 3H), 2.09 (s, 3H), 3.06 (s; 1H), and 3.76-3.78 (m, 1H), 4.10-4.17 (m, 1H), 6.79 (d, J=15.36Hz; 1H), 7.03 (s, 1H), 7.35-7.39 (m, 1H), 7.46 (t, J=7.41Hz; 2H), and 7.55-7.64 (m, 6H), 7.72 (d, J=15.36Hz, 1H) .ESI-MS:392.1 (C
22H
22N
3O
4, [M+H]
+) .Anal.Calcd forC
22H
21N
3O
4: C, 67.51%; H, 5.41%; N, 10.74%.Found:C, 67.31%; H, 5.20%; N, 10.99%.
Embodiment 15: (E)-and the preparation of 1-(2-methyl-5-nitro-1H-imidazoles-1-yl)-2-propyl group-3-(4-(benzyloxy) phenyl) propenoate (compound 30)
The preparation method is with embodiment one.So that Bian oxygen benzaldehyde is replaced phenyl aldehyde, get target compound.White powder, productive rate 53%, m.p.:185-188 ℃.
1H NMR (300MHz, CDCl
3, δ ppm): 1.40 (d, J=8.05Hz, 3H), 2.35 (s, 3H), 2.52 (s; 1H), 3.74-3.76 (m, 1H), 4.06-4.14 (m, 1H), 5.10 (s, 2H); 6.62 (d, J=15.36Hz, 1H), 6.91-7.00 (m, 2H), 7.13-7.15 (m; 1H), and 7.31-7.45 (m, 7H), 7.64 (d, J=15.36Hz, 1H) .ESI-MS:422.2 (C
23H
24N
3O
5, [M+H]
+) .Anal.Calcd forC
23H
23N
3O
5: C, 65.55%; H, 5.50%; N, 9.97%.Found:C, 65.36%; H, 5.78%; N, 9.65%.
Embodiment 16: (E)-and the preparation of 1-(2-methyl-5-nitro-1H-imidazoles-1-yl)-2-propyl group-3-(4-(dimethylamino) phenyl) propenoate (compound 3p)
The preparation method is with embodiment one.Replace phenyl aldehyde with paradimethy laminobenzaldehyde, get target compound.Light grey powder, productive rate 57%, m.p.:122-123 ℃.
1H NMR (300MHz, CDCl
3, δ ppm): 1.40 (d, J=3.84Hz, 3H), 2.53 (s, 3H), 3.02 (s, 6H); 4.32-4.36 (m, 1H), 4.62-4.65 (m, 1H), 5.36 (t, J=3.71Hz, 1H); 6.04 (d, J=9.42Hz, 1H), 6.65 (d, J=5.22Hz, 2H), 7.37 (d; J=5.22Hz, 2H), 7.52 (d, J=9.42Hz, 1H), 7.92 (s, 1H) .ESI-MS:359.1 (C
18H
23N
4O
4, [M+H]
+) .Anal.Calcd for C
18H
22N
4O
4: C, 60.32%; H, 6.19%; N, 15.63%.Found:C, 60.54%; H, 6.10%; N, 15.39%.
Embodiment 17: (E)-and the preparation of 1-(2-methyl-5-nitro-1H-imidazoles-1-yl)-2-propyl group-3-(2,4 dichloro benzene base) propenoate (compound 3q)
The preparation method is with embodiment one.Replace phenyl aldehyde with 2,4 dichloro benzene formaldehyde, get target compound.White powder, productive rate 57%, m.p.:165-169 ℃.
1H NMR (300MHz, CDCl
3, δ ppm): 1.43 (d, J=8.44Hz, 3H), 2.56 (s, 3H); 3.47-3.51 (m, 1H), 3.73-3.75 (m, 1H), 4.05-4.12 (m, 1H); 6.72 (d, J=9.24Hz, 1H), 6.96 (s, 1H), 7.23-7.26 (m; 1H), and 7.40-7.46 (m, 2H), 7.94 (d, J=9.24Hz, 1H) .ESI-MS:384.0 (C
16H
16Cl
2N
3O
4, [M+H]
+) .Anal.Calcd forC
16H
15Cl
2N
3O
4: C, 50.02%; H, 3.94%; N, 10.94%.Found:C, 50.43%; H, 4.10%; N, 10.77%.
Embodiment 18: (E)-and the preparation of 1-(2-methyl-5-nitro-1H-imidazoles-1-yl)-2-propyl group-3-(1-naphthyl) propenoate (compound 3r)
The preparation method is with embodiment one.Replace phenyl aldehyde with 1-naphthalene phenyl aldehyde, get target compound.White powder, productive rate 69%, m.p.:176-179 ℃.
1H NMR (300MHz, CDCl
3, δ ppm): 1.42 (d, J=7.21Hz, 3H), 2.12 (s, 3H), 3.72-3.81 (m, 2H); 4.11-4.20 (m, 1H), 6.83 (d, J=15.18Hz, 1H), 7.19 (s, 1H), 7.42-7.52 (m; 1H), 7.52-7.58 (m, 2H), 7.67 (d, J=7.29Hz, 1H), 7.87 (d, J=7.50Hz; 2H), 8.19 (d, J=7.50Hz, 1H), 8.51 (d, J=15.18Hz, 1H) .ESI-MS:366.1 (C
20H
20N
3O
4, [M+H]
+) .Anal.Calcd for C
20H
19N
3O
4: C, 65.74%; H, 5.24%; N, 11.50%.Found:C, 65.53%; H, 5.37%; N, 11.85%.
Embodiment 19: (E)-and the preparation of 1-(2-methyl-5-nitro-1H-imidazoles-1-yl)-2-propyl group-3-(2-naphthyl) propenoate (compound 3s)
The preparation method is with embodiment one.Replace phenyl aldehyde with the 2-naphthaldehyde, get target compound.White powder, productive rate 63%, m.p.:204-206 ℃.
1H NMR (300MHz, CDCl
3, δ ppm): 1.46 (d, J=9.04Hz, 3H), 2.35 (s, 3H), 3.43-3.49 (m, 1H); 3.71-3.80 (m, 1H), 4.00-4.15 (m, 1H), 6.69 (s, 1H), 6.74 (s; 1H), 6.80-6.82 (m, 2H), 7.26 (s, 1H), 7.34 (d, J=8.58Hz; 2H), 7.51 (d, J=8.40Hz, 2H), 7.60 (d, J=15.36Hz, 1H) .ESI-MS:366.1 (C
20H
20N
3O
4, [M+H]
+) .Anal.Calcd forC
20H
19N
3O
4: C, 65.74%; H, 5.24%; N, 11.50%.Found:C, 65.68%; H, 5.10%; N, 11.97%.
Embodiment 20: (E)-and the preparation of 1-(2-methyl-5-nitro-1H-imidazoles-1-yl)-2-propyl group 3-(2-thiophene) propenoate (compound 3t)
The preparation method is with embodiment one.Replace phenyl aldehyde with thiophene-2-formaldehyde, get target compound.Light grey powder, productive rate 73%, m.p.:164-168 ℃.
1H NMR (300MHz, CDCl
3, δ ppm): 1.40 (d, J=6.79Hz, 3H), 2.39 (s, 3H); 3.77-3.80 (m, 2H), 4.12-4.20 (m, 1H), 6.86 (d, J=15.36Hz; 1H), 6.96 (s, 1H), 7.50-7.53 (m, 1H), 7.60-7.63 (m; 1H), and 7.81-7.87 (m, 1H), 7.91 (s, 1H) .ESI-MS:322.1 (C
14H
16N
3O
4S, [M+H]
+) .Anal.Calcd for C
14H
15N
3O
4S:C, 52.33%; H, 4.70%; N, 13.08%.Found:C, 51.96%; H, 4.89%; N, 12.83%.
Embodiment 21: external resisting gram-positive of secnidazole cinnamate derivates and gram negative bacterium activity research
Adopt mtt assay to measure the minimum inhibition concentration of secnidazole cinnamate derivates, calculate MIC value (μ g/mL) bacterium.
1 materials and methods
1.1 material
Reagent: Kanamycin, DMSO, MTT (3-(4,5-dimethylthiazole-2)-2,5-phenylbenzene tetrazole bromine salt; Commodity are called tetrazolium bromide), Virahol, hydrochloric acid, be AR, synthetic compound 3a-3t, Mueller-Hinton substratum (beef extract powder 5g, casein hydrolysate 17.5g; Starch 1.5g, agar 12.5g adds in the 1000ml zero(ppm) water), PBS damping fluid (phosphate buffered saline buffer 0.01mol/L; PH 7.4, Na
2HPO
412H
2O 2.9g, KH
2PO
40.2g, NaCl 8.0g, KCl 0.2g, zero(ppm) water 1000mL).
Bacterial classification: intestinal bacteria (E.coli), streptococcus aureus (S.aureus), subtilis (B.subtilis), Pseudomonas aeruginosa (P.aeruginosa) provide by school of life and health sciences mikrobe teaching and research room of Nanjing University.
1.2 method
1.2.1 culture medium preparation
Get beef extract powder 5g, casein hydrolysate 17.5g, starch 1.5g adds in the 1000mL zero(ppm) water, the heated and boiled dissolving, packing, 121 ℃ of autoclaving 15min are subsequent use.
1.2.2 the cultivation of test organisms
In sterilisable chamber, get intestinal bacteria, streptococcus aureus; Four kinds of test strains of subtilis and Pseudomonas aeruginosa, under the spirit lamp with inoculating needle respectively on four kinds of test strain inclined-planes, scrape the inclined-plane lawn that takes a morsel; Process bacteria suspension with a certain amount of sterilized water, get a certain amount of being added to then and melt and be cooled in the MH substratum about 50 ℃, shake up; At once pour in the sterile petri dish, treat after the abundant condensation that with after the plug sealing, it is subsequent use to cultivate 18-24h in 37 ℃.Draw bacterium liquid 1mL, by dilution in 1: 1000, make bacterial concentration be about 10 with the MH substratum
5Cfu/mL.
1.2.3 antibacterial experiment
Medicine to be measured is dissolved in the solution that is mixed with 2mg/mL among the DMSO, with doubling dilution medicine is diluted among finite concentration gradient (50 μ g/mL, 25 μ g/mL, 12.5 μ g/mL, 3.125 μ g/mL) and the DMSO then.In sterilization microtiter plate article one, add the substratum of 100 μ L respectively, the positive contrast of second adds 100 μ L bacteria suspensions.Add the bacteria suspension of 90 μ L and the medicament solution of 10 μ L in remaining hole.Parallel 3 times of each medicament solution concentration.Indicate bacteria name in the microtiter plate bottom.The petridish of handling is cultivated 24h, observation in 37 ℃.
1.2.4 the mensuration of MIC
After each microtiter plate can be measured its MIC value intuitively, (phosphate buffered saline buffer 0.01mol/L, pH 7.4, Na in each hole of plate, to add 50 μ L PBS damping fluids
2HPO
412H
2O 2.9g, KH
2PO
40.2g, NaCl 8.0g, KCl 0.2g, zero(ppm) water 1000mL), wherein comprise 2mg MTT/mL.At room temperature continue to hatch 4-5h.Material in the hole is shifted out and add the Virahol that 100 μ L contain 5% 1mol/L HCl extract dyestuff.Continue at room temperature to compose to educate 12h, measure each hole photoabsorption (OD value), measure wavelength 550nm in ELIASA.Calculate the MIC of medicine based on each hole OD value to bacterial growth.
(minimum inhibitory concentration, MIC): under specific environment, hatch 24h, can suppress the lowest drug concentration that to rise appreciably appear in certain mikrobe is minimum inhibition concentration to minimum inhibition concentration.According to the optical density(OD) of measuring (OD value), make the typical curve of bacterial growth inhibiting rate, on typical curve, try to achieve its corresponding drug level.
The MIC that records sees shown in the table 1
The inhibition MIC value (μ g/mL) to bacterium of the listed secnidazole cinnamate derivates of table 1 the present invention
Kanamycin, positive control.
Claims (3)
1. one type of secnidazole cinnamate derivates is characterized in that it has following general formula:
R is in the formula:
2. method for preparing the described secnidazole cinnamate derivates of claim 1 is characterized in that it is made up of the following step:
Step 1. is with substituted phenyl aldehyde of a series of differences and propanedioic acid reaction, and consumption is phenyl aldehyde 3.2mmol, and propanedioic acid 3.87mmol adds the 0.387mmol piperidines and makes catalyzer, adds an amount of pyridine simultaneously and makes solvent in the 50mL round-bottomed flask, in 80-90 ℃ of reaction down;
Step 2. is followed the tracks of reaction with thin-layer chromatography (TLC) in the solution that step 1 obtains, reflux is until reacting completely;
Step 3. is cooled to room temperature, in round-bottomed flask, adds a large amount of anhydrous diethyl ethers, and the vibration rear overhang is done; If adding a small amount of tap water is that the adularescent particle generates, and filters and with a large amount of tap water washing leaching cakes, washes with normal hexane more at last ten times; Obtain the substituted styracin of a series of differences, for use.
Styracin and secnidazole reaction that step 4. obtains step 3, consumption is secnidazole (0.5mmol), styracin (0.5mmol) adds DCC (0.5mmol) and DMAP (0.5mmol) as catalyzer, in 50-60 ℃ of reaction down.
Step 5. is followed the tracks of reaction with thin-layer chromatography (TLC) in the solution that step 4 obtains, reflux is until reacting completely;
Step 6. is cooled to room temperature, uses saturated NaHCO
3Respectively extract three times and collected organic layer with EtOAc, its outstanding ten backs are added a small amount of EtOAc vibration filter, collect the filtrating evaporate to dryness, use EtOH/CHCl
3Recrystallization obtains solid, i.e. title product.Wherein used elutriant is EtOAc.
3. the application of the described secnidazole cinnamate derivates of claim 1 in the preparation antibacterials.
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Citations (3)
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| CN1370158A (en) * | 1999-08-23 | 2002-09-18 | 史密丝克莱恩比彻姆公司 | Fatty acid synthase inhibitors |
| US20030220392A1 (en) * | 2000-05-24 | 2003-11-27 | Leber Jack Dale | Fatty acid synthase inhibitors |
| US6723749B2 (en) * | 2000-08-02 | 2004-04-20 | Smithkline Beecham Corporation | Fatty acid synthase inhibitors |
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2011
- 2011-03-17 CN CN2011100637586A patent/CN102675211A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1370158A (en) * | 1999-08-23 | 2002-09-18 | 史密丝克莱恩比彻姆公司 | Fatty acid synthase inhibitors |
| US20030220392A1 (en) * | 2000-05-24 | 2003-11-27 | Leber Jack Dale | Fatty acid synthase inhibitors |
| US6723749B2 (en) * | 2000-08-02 | 2004-04-20 | Smithkline Beecham Corporation | Fatty acid synthase inhibitors |
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