CN110041368B - Organic phosphine clinafloxacin derivative and preparation method and application thereof - Google Patents
Organic phosphine clinafloxacin derivative and preparation method and application thereof Download PDFInfo
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom
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Abstract
The invention relates to an organic phosphine clinafloxacin derivative and a preparation method and application thereof, belonging to the technical field of chemical synthesis, wherein the organic phosphine clinafloxacin derivative is shown as a general formula I, and the compound has certain inhibitory activity on one or more of gram-positive bacteria, gram-negative bacteria and/or fungi, and can be used for preparing antibacterial and/or antifungal medicaments, thereby providing more efficient and safe candidate medicaments for clinical antimicrobial treatment, and being beneficial to solving clinical treatment problems of increasingly serious drug resistance, stubborn pathogenic microorganisms, newly-appeared harmful microorganisms and the like. In addition, the organic phosphine clinafloxacin derivative can also be used for preparing a DNA intercalator. The preparation raw materials are simple and easy to obtain, the synthetic route is short, and the application in the anti-infection aspect is of great significance.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to an organic phosphine clinafloxacin derivative, and a preparation method and application thereof.
Background
Clinafloxacin, an important member of the fluoroquinolone family, plays an irreplaceable role in fighting bacterial infections. Clinafloxacin has been proved to be more active than other fluoroquinolone antibacterial drugs on the market at present, and has higher biological activity on most gram-positive bacteria, gram-negative bacteria and anaerobic bacteria. Structural modifications based on clinafloxacin, particularly at its C-7 position, are currently the focus of attention of many researchers.
Phosphorus element is ubiquitous in nature and closely related to living bodies, and is one of the essential elements for life activities. Organic phosphines containing phosphorus phosphonate are not only important components of genetic information carriers DNA and RNA, but also important parts of "energy molecule" Adenosine Triphosphate (ATP) for storing and delivering energy. Organic phosphines are concerned by medicinal chemists due to their important physiological functions and unique chemical properties in vivo, and are widely used in the development and modification of antibacterial agents closely related to the health of human body. To date, a large number of antibacterial drugs based on organic phosphines have been successfully developed, such as fosfomycin, fosmidomycin, fosfomycin, and the like, which are widely used in clinical applications, and fosfluconazole, which is an antifungal drug. Research shows that the introduction of organic phosphine, especially phosphonate group, can greatly change the physicochemical property and biological activity of drug molecules, which makes organic phosphine derivatives based on phosphorus element show huge potential in antimicrobial aspect. Therefore, the structural modification of the C-7 position of clinafloxacin by using the organic phosphine fragment is a promising research topic, and a series of novel broad-spectrum antibacterial drugs with high activity are expected to be developed.
Disclosure of Invention
In view of the above, an object of the present invention is to provide an organophosphine clinafloxacin derivative and a pharmaceutically acceptable salt thereof; the second purpose is to provide a preparation method of the organic phosphine clinafloxacin derivative and the medicinal salt thereof; the third purpose is to provide the application of the organic phosphine clinafloxacin derivative and the medicinal salt thereof in the preparation of antibacterial and/or antifungal medicaments; the fourth purpose is to provide the application of the organic phosphine clinafloxacin derivative and the medicinal salt thereof in the preparation of the DNA intercalator.
In order to achieve the purpose, the invention provides the following technical scheme:
1. the organic phosphine clinafloxacin derivative and the medicinal salt thereof have the structure shown in the general formula I:
in the formula:
R1，R2is hydrogen, alkyl, cycloalkyl or aryl;
R3is hydrogen, alkyl, cycloalkyl, aryl or heterocyclyl.
Preferably, the first and second liquid crystal materials are,
R1，R2is hydrogen or ethyl;
r3 is methyl, n-propyl, cyclohexyl, thienyl, imidazolyl, phenyl, p-fluorophenyl, p-nitrophenyl, p-methoxyphenyl, benzimidazolyl or carbazolyl.
Preferably, it is any one of the following compounds:
preferably, the pharmaceutically acceptable salt is hydrochloride, nitrate or acetate.
2. The preparation method of the organic phosphine clinafloxacin derivative and the medicinal salt thereof comprises the following steps:
a. preparing organic phosphine clinafloxacin derivatives I-1-12: taking clinafloxacin and diethyl phosphite as starting materials, and respectively carrying out one-pot method with different aldehyde compounds to obtain organic phosphine clinafloxacin derivatives I-1-12;
b. preparing organic phosphine clinafloxacin derivatives I-13-14: and (b) taking the organic phosphine clinafloxacin derivatives I-7-8 prepared in the step a as raw materials, and hydrolyzing with concentrated hydrochloric acid to obtain the organic phosphine clinafloxacin derivatives I-13-14.
Preferably, the first and second liquid crystal materials are,
in the step a, the used solvent is toluene, the temperature of the reflux reaction is 120 ℃, and the time of the reflux reaction is 4-6 h; the mass ratio of the clinafloxacin, the diethyl phosphite and the aldehyde compound is 1:3: 1.5;
in the step b, the temperature of the reflux reaction is 80 ℃, and the time of the reflux reaction is 12 h.
3. The organic phosphine clinafloxacin derivative and the application of the medicinal salt thereof in preparing antibacterial and/or antifungal medicaments.
Preferably, the bacteria is one or more of methicillin-resistant staphylococcus aureus, enterococcus faecalis, staphylococcus aureus ATCC25923, staphylococcus aureus ATCC29213, klebsiella pneumoniae, escherichia coli, pseudomonas aeruginosa ATCC27853, escherichia coli ATCC25922 or acinetobacter baumannii; the fungi is one or more of Candida albicans, Candida tropicalis, Aspergillus fumigatus, Candida albicans ATCC90023 or Candida parapsilosis ATCC 20019.
4. The organic phosphine clinafloxacin derivative and the application of the medicinal salt thereof in the preparation of DNA intercalators.
Preferably, the DNA is calf thymus DNA.
The invention has the beneficial effects that: the invention provides an organic phosphine clinafloxacin derivative and a preparation method and application thereof, the invention utilizes a medicament design split principle, important structural fragment organic phosphine is introduced into C-7 position of clinafloxacin through Mannich reaction, a series of organic phosphine clinafloxacin derivatives with novel structures are designed and synthesized, and the compounds have certain inhibitory activity on gram positive bacteria (methicillin-resistant staphylococcus, enterococcus faecalis, staphylococcus aureus ATCC25923 and staphylococcus aureus ATCC29213), gram negative bacteria (Klebsiella pneumoniae, escherichia coli, pseudomonas aeruginosa ATCC27853, escherichia coli ATCC25922 and acinetobacter baumannii) and fungi (candida albicans, candida tropicalis, aspergillus fumigatus, candida albicans ATCC90023 and candida parapsilosis ATCC20019) through in-vitro antimicrobial activity detection, can be used for preparing antibacterial and/or antifungal drugs, thereby providing more efficient and safe candidate drugs for clinical antimicrobial treatment and being beneficial to solving the clinical treatment problems of increasingly serious drug resistance, stubborn pathogenic microorganisms, newly appeared harmful microorganisms and the like. In addition, the organic phosphine clinafloxacin derivative can also be used for preparing a DNA intercalator. The preparation raw materials are simple and easy to obtain, the synthetic route is short, and the application in the anti-infection aspect is of great significance.
Additional advantages, objects, and features of the invention will be set forth in part in the description which follows and in part will become apparent to those having ordinary skill in the art upon examination of the following or may be learned from practice of the invention. The objectives and other advantages of the invention may be realized and attained by the means of the instrumentalities and combinations particularly pointed out hereinafter.
Drawings
For the purposes of promoting a better understanding of the objects, aspects and advantages of the invention, reference will now be made to the following detailed description taken in conjunction with the accompanying drawings in which:
FIG. 1 is a graph showing the effects of compounds I-10 in competing with DNA of calf thymus, respectively (the concentrations of DNA and neutral red are 7.02X 10, respectively)-5mol/L and 2X 10-5mol/L, concentration of compound I-10 from 0 to 2X 10-5mol/L)。
Detailed Description
The embodiments of the present invention are described below with reference to specific embodiments, and other advantages and effects of the present invention will be easily understood by those skilled in the art from the disclosure of the present specification. The invention is capable of other and different embodiments and of being practiced or of being carried out in various ways, and its several details are capable of modification in various respects, all without departing from the spirit and scope of the present invention.
Example 1 preparation of Compound I-1
Into a 150mL round-bottomed flask were added clinafloxacin (500mg,1.37mmol), diethyl phosphite (451.28mg,4.10mmol), acetaldehyde (90.25mg,2.05mmol) and toluene (50mL), and the mixture was refluxed with stirring at 120 ℃ for 4 hoursThe thin layer chromatography was followed until the reaction was complete. And concentrating, extracting, separating by column chromatography, recrystallizing, drying, etc. to obtain compound I-1(57198 mg). Yield: 78.9 percent; a white powder; melting point: 192.5 to 194.1 ℃;1H NMR(600MHz,CDCl3-d6)δ14.44(s,1H),8.90(s,1H),8.00(d,J＝11.6Hz,1H),4.37–4.33(m,1H),4.28–4.20(m,2H),4.19–4.11(m,2H),3.40(s,4H),3.08(dd,J＝27.6,6.5Hz,3H),2.87(s,2H),1.37(dt,J＝19.1,6.9Hz,9H),1.31(t,J＝7.1Hz,2H),0.96(d,J＝3.0Hz,2H)ppm。
example 2 preparation of Compound I-2
Clinafloxacin (500mg,1.37mmol), diethyl phosphite (451.28mg,4.10mmol), n-butyraldehyde (147.72mg,2.05mmol) and toluene (50mL) were added to a 150mL round-bottomed flask, and stirred at 120 ℃ under reflux for 4 hours, followed by thin layer chromatography until the reaction was complete. And then carrying out post-treatment such as concentration, extraction, column chromatography separation, recrystallization, drying and the like to obtain the compound I-2(580.91 mg). Yield: 76.1 percent; a white powder; melting point: 178.2 to 180.0 ℃;1H NMR(600MHz,CDCl3-d6)δ14.44(s,1H),8.89(s,1H),8.01(d,J＝11.6Hz,1H),4.37–4.31(m,1H),4.19(ddt,J＝32.1,14.6,7.5Hz,4H),3.36(s,4H),3.06(s,2H),2.92(d,J＝21.8Hz,3H),1.79(d,J＝9.6Hz,1H),1.70–1.59(m,2H),1.51–1.44(m,1H),1.40–1.32(m,6H),1.29(d,J＝7.2Hz,2H),0.96(t,J＝7.0Hz,5H)ppm。
example 3 preparation of Compound I-3
Clinafloxacin (500mg,1.37mmol), diethyl phosphite (451.28mg,4.10mmol), cyclohexanecarboxaldehyde (229.78mg,2.05mmol) and toluene (50mL) were added to a 150mL round bottom flask, stirred at 120 ℃ for reflux for 4 hours and followed by thin layer chromatography until the reaction was complete. Concentrating, extracting, separating by column chromatography, and repeatingAnd performing crystallization, drying and the like to obtain the compound I-3(611.19 mg). Yield: 74.7 percent; a white powder; melting point: 185.5 to 186.6 ℃;1H NMR(600MHz,CDCl3-d6)δ14.46(s,1H),8.89(s,1H),8.01(d,J＝11.5Hz,1H),4.37–4.31(m,1H),4.22(dd,J＝16.3,8.0Hz,1H),4.16(dd,J＝17.6,7.7Hz,3H),3.35(s,4H),3.14(s,2H),2.90(s,2H),2.66(s,1H),2.12(d,J＝12.0Hz,1H),1.95(d,J＝10.7Hz,1H),1.83(s,1H),1.75(s,3H),1.67(d,J＝11.5Hz,2H),1.39–1.34(m,6H),1.33–1.08(m,8H),0.95(s,2H)ppm。
example 4 preparation of Compound I-4
Clinafloxacin (500mg,1.37mmol), diethyl phosphite (451.28mg,4.10mmol), thiophenealdehyde (229.91mg,2.05mmol) and toluene (50mL) were added to a 150mL round bottom flask, stirred at 120 ℃ for reflux for 4 hours and followed by thin layer chromatography until the reaction was complete. And then carrying out post-treatment such as concentration, extraction, column chromatography separation, recrystallization, drying and the like to obtain the compound I-4(501.47 mg). Yield: 61.3 percent; a light yellow powder; melting point: 218.8-220.3 ℃;1H NMR(600MHz,CDCl3-d6)δ14.45(s,1H),8.89(s,1H),7.99(d,J＝11.3Hz,1H),7.34(d,J＝3.7Hz,1H),7.29(s,1H),7.08(s,1H),4.32(s,3H),4.29(s,1H),4.11–4.01(m,1H),3.99–3.85(m,1H),3.44(s,4H),3.14(s,2H),2.74(s,2H),1.96(s,1H),1.42(t,J＝6.5Hz,3H),1.28(d,J＝6.1Hz,2H),1.17(t,J＝6.6Hz,3H),0.94(s,2H)ppm。
example 5 preparation of Compound I-5
Clinafloxacin (500mg,1.37mmol), diethyl phosphite (451.28mg,4.10mmol), 2-n-butyl-4-chloro-5-formylimidazole (381.41mg,2.05mmol) and toluene (50mL) were added to a 150mL round-bottomed flask, stirred at 120 ℃ for reflux for 6 hours, and followed by thin layer chromatography until the reaction was complete. Then concentrating and extractingCollecting, separating by column chromatography, recrystallizing, drying, etc., and processing to obtain compound I-5(311.72 mg). Yield: 33.9 percent; a yellow powder; melting point: 250.0-251.7 ℃;1H NMR(600MHz,CDCl3-d6)δ14.36(s,1H),10.00(s,1H),8.89(s,1H),8.01(d,J＝11.6Hz,1H),5.30(s,1H),4.37(dt,J＝14.2,7.2Hz,2H),4.34–4.31(m,1H),4.20(d,J＝24.3Hz,1H),4.02–3.97(m,1H),3.92(d,J＝7.2Hz,1H),3.39(s,4H),3.10(s,2H),2.71(t,J＝7.7Hz,2H),2.62(s,2H),1.74–1.70(m,2H),1.46(t,J＝7.0Hz,3H),1.37(d,J＝6.9Hz,2H),1.29(d,J＝7.1Hz,2H),1.18(t,J＝6.6Hz,3H),0.93(td,J＝7.2,2.2Hz,5H)ppm。
example 6 preparation of Compound I-6
Clinafloxacin (500mg,1.37mmol), diethyl phosphite (451.28mg,4.10mmol), allyl-modified imidazole aldehyde (464.74mg,2.05mmol) and toluene (50mL) were added to a 150mL round bottom flask, stirred at 120 ℃ for 4 hours under reflux and followed by thin layer chromatography until the reaction was complete. And then carrying out post-treatment such as concentration, extraction, column chromatography separation, recrystallization, drying and the like to obtain the compound I-6(348.47 mg). Yield: 35.8 percent; a yellow powder; melting point: 108.0 to 110.0 ℃;1H NMR(600MHz,CDCl3-d6)δ14.40(s,1H),8.91(s,1H),8.03(d,J＝11.6Hz,1H),5.77(d,J＝17.6Hz,1H),4.72(d,J＝18.2Hz,1H),4.39–4.34(m,1H),4.20(dt,J＝22.0,7.3Hz,2H),4.12(d,J＝18.6Hz,1H),3.88(dd,J＝15.9,7.1Hz,1H),3.57(d,J＝6.8Hz,1H),3.50(d,J＝3.4Hz,2H),3.45(d,J＝12.0Hz,2H),3.00(s,2H),2.84–2.71(m,4H),2.39(s,1H),1.81(dt,J＝15.5,7.7Hz,2H),1.46(dt,J＝14.8,7.2Hz,2H),1.39(t,J＝7.0Hz,3H),1.30(dd,J＝17.9,11.8Hz,3H),1.16(t,J＝7.0Hz,3H),0.99–0.93(m,5H)ppm。
example 7 preparation of Compound I-7
Clinafloxacin (500mg,1.37mmol), diethyl phosphite (451.28mg,4.10mmol), benzaldehyde (217.55mg,2.05mmol) and toluene (50mL) were added to a 150mL round bottom flask, stirred at 120 ℃ for reflux for 6 hours and followed by thin layer chromatography until the reaction was complete. And then carrying out post-treatment such as concentration, extraction, column chromatography separation, recrystallization, drying and the like to obtain the compound I-7(318.17 mg). Yield: 39.4 percent; a white powder; melting point: 197.2 to 198.6 ℃;1H NMR(600MHz,CDCl3-d6)δ14.37(s,1H),8.88(s,1H),7.99(d,J＝11.5Hz,1H),7.60(s,2H),7.41(d,J＝6.5Hz,3H),4.32–4.25(m,2H),4.22(dd,J＝15.6,8.3Hz,1H),4.01(s,2H),3.81(s,1H),3.48(s,4H),3.16(s,2H),2.86(s,2H),1.38(t,J＝7.0Hz,3H),1.27(d,J＝6.9Hz,2H),1.10(t,J＝6.5Hz,3H),0.93(d,J＝2.8Hz,2H)ppm。
example 8 preparation of Compound I-8
Clinafloxacin (500mg,1.37mmol), diethyl phosphite (451.28mg,4.10mmol), p-fluorobenzaldehyde (254.43mg,2.05mmol) and toluene (50mL) were added to a 150mL round bottom flask, stirred at 120 ℃ for reflux for 6 hours and followed by thin layer chromatography until the reaction was complete. And then carrying out post-treatment such as concentration, extraction, column chromatography separation, recrystallization, drying and the like to obtain the compound I-8(305.39 mg). Yield: 36.7 percent; a white powder; melting point: 235.4-236.5 ℃;1H NMR(600MHz,CDCl3-d6)δ14.41(s,1H),8.88(s,1H),7.98(d,J＝11.7Hz,1H),7.54–7.47(m,2H),7.08(t,J＝8.5Hz,2H),4.33–4.27(m,2H),4.27–4.22(m,1H),4.00–3.91(m,2H),3.81–3.73(m,1H),3.41(s,4H),3.02(s,2H),2.69(s,2H),1.39(t,J＝7.1Hz,3H),1.27(q,J＝6.6Hz,2H),1.10(t,J＝7.1Hz,3H),0.93(q,J＝6.7Hz,2H)ppm。
example 9 preparation of Compound I-9
In a 150mL round bottom flaskClinafloxacin (500mg,1.37mmol), diethyl phosphite (451.28mg,4.10mmol), p-nitrobenzaldehyde (309.80mg,2.05mmol) and toluene (50mL) were added thereto, and the mixture was stirred at 120 ℃ for reflux for 6 hours and followed by thin layer chromatography until the reaction was complete. And then carrying out post-treatment such as concentration, extraction, column chromatography separation, recrystallization, drying and the like to obtain the compound I-9(331.09 mg). Yield: 38.1 percent; a white powder; melting point: 135.6-136.7 ℃;1H NMR(600MHz,DMSO-d6)δ14.37(s,1H),8.88(s,1H),8.25(d,J＝8.5Hz,2H),8.00(d,J＝11.6Hz,1H),7.74(d,J＝8.2Hz,2H),4.31(dt,J＝7.3,4.0Hz,2H),4.28–4.22(m,1H),4.07(d,J＝21.7Hz,1H),4.04–3.99(m,1H),3.91–3.85(m,1H),3.43(s,4H),3.02(s,2H),2.78(s,2H),1.40(t,J＝7.1Hz,3H),1.27(d,J＝7.1Hz,2H),1.15(t,J＝7.1Hz,3H),0.93(q,J＝6.6Hz,2H)ppm。
example 10 preparation of Compound I-10
Clinafloxacin (500mg,1.37mmol), diethyl phosphite (451.28mg,4.10mmol), p-methoxybenzaldehyde (279.10mg,2.05mmol) and toluene (50mL) were added to a 150mL round bottom flask, stirred at 120 ℃ for reflux for 6 hours, and followed by thin layer chromatography until the reaction was complete. And then carrying out post-treatment such as concentration, extraction, column chromatography separation, recrystallization, drying and the like to obtain the compound I-10(315.65 mg). Yield: 37.2 percent; a white powder; melting point: 113.4-114.4 ℃;1H NMR(600MHz,DMSO-d6)δ14.43(s,1H),8.87(s,1H),7.98(d,J＝11.7Hz,1H),7.40(s,2H),6.89(s,2H),4.32–4.26(m,2H),4.23(dd,J＝15.6,8.3Hz,1H),3.96(dd,J＝9.7,7.7Hz,3H),3.83(s,3H),3.40(s,4H),3.02(s,2H),2.68(s,2H),1.38(t,J＝7.0Hz,3H),1.27(s,2H),1.09(t,J＝7.0Hz,3H),0.92(q,J＝6.6Hz,2H)ppm。
example 11 preparation of Compound I-11
In a 150mL round bottom flaskClinafloxacin (500mg,1.37mmol), diethyl phosphite (451.28mg,4.10mmol), benzimidazole-2-carbaldehyde (299.40mg,2.05mmol) and toluene (50mL) were added thereto, and the mixture was stirred at 120 ℃ under reflux for 6 hours and followed by thin layer chromatography until the reaction was complete. And then carrying out post-treatment such as concentration, extraction, column chromatography separation, recrystallization, drying and the like to obtain the compound I-11(297.46 mg). Yield: 34.4 percent; a yellow powder; melting point: 129.9-131.2 ℃;1H NMR(600MHz,DMSO-d6)δ14.32(s,1H),8.87(s,1H),7.96(d,J＝11.2Hz,1H),7.83(dd,J＝5.9,3.0Hz,2H),7.48–7.44(m,2H),6.39(s,1H),4.51–4.42(m,2H),4.31–4.27(m,1H),4.11(ddd,J＝21.1,11.3,5.0Hz,3H),3.44(s,4H),3.22(s,2H),2.89(s,2H),1.34(t,J＝6.4Hz,3H),1.27(dd,J＝9.6,6.4Hz,2H),1.19(t,J＝7.0Hz,3H),0.94–0.88(m,2H)ppm。
example 12 preparation of Compound I-12
Clinafloxacin (500mg,1.37mmol), diethyl phosphite (451.28mg,4.10mmol), N-ethyl-carbazole-3-carbaldehyde (457.35mg,2.05mmol) and toluene (50mL) were added to a 150mL round bottom flask, stirred at 120 ℃ for reflux for 6 hours, followed by thin layer chromatography until the reaction was complete. And then carrying out post-treatment such as concentration, extraction, column chromatography separation, recrystallization, drying and the like to obtain the compound I-12(507.45 mg). Yield: 52.3 percent; a light yellow powder; melting point: 129.4-130.7 ℃;1H NMR(600MHz,DMSO-d6)δ8.86(s,1H),8.33(s,1H),8.18(d,J＝7.7Hz,1H),7.98(d,J＝11.6Hz,1H),7.73(d,J＝8.3Hz,1H),7.51(t,J＝7.6Hz,1H),7.47–7.43(m,2H),7.27(s,1H),4.40(q,J＝7.1Hz,2H),4.36–4.29(m,2H),4.26(td,J＝6.6,3.0Hz,1H),4.06(dd,J＝15.4,7.3Hz,2H),3.95(dt,J＝10.0,7.1Hz,1H),3.56(s,4H),3.29(s,2H),3.10(s,2H),1.47(t,J＝7.2Hz,3H),1.32(t,J＝7.0Hz,3H),1.24(d,J＝7.2Hz,2H),1.01(t,J＝7.0Hz,3H),0.90(q,J＝6.5Hz,2H)ppm。
example 13 preparation of Compound I-13
Compound I-7(200mg,0.34mmol) and concentrated hydrochloric acid (15mL) were added to a 50mL round bottom flask, stirred at 80 ℃ under reflux for 12 hours, followed by thin layer chromatography until the reaction was complete, neutralization with an alkaline solution of sodium hydroxide, and extraction with chloroform (5X 50 mL). And then carrying out post-treatment such as concentration, extraction, column chromatography separation, recrystallization, drying and the like to obtain the compound I-13(138.64 mg). Yield: 76.2 percent; a white powder; melting point:>250℃；1H NMR(600MHz,DMSO-d6)δ8.83(s,1H),7.90(d,J＝11.5Hz,1H),7.70(d,J＝7.0Hz,2H),7.49–7.41(m,3H),4.75(d,J＝16.4Hz,1H),4.40–4.35(m,1H),3.63(s,5H),3.26(s,2H),1.19(d,J＝6.2Hz,2H),0.98(d,J＝3.4Hz,2H)ppm。
example 14 preparation of Compound I-14
Compound I-8(200mg,0.33mmol) and concentrated hydrochloric acid (15mL) were added to a 50mL round bottom flask, stirred at 80 ℃ under reflux for 12 hours, followed by thin layer chromatography until the reaction was complete, neutralization with an alkaline solution of sodium hydroxide, and extraction with chloroform (5X 50 mL). And then carrying out post-treatment such as concentration, extraction, column chromatography separation, recrystallization, drying and the like to obtain the compound I-14(130.69 mg). Yield: 71.6 percent; a white powder; melting point:>250℃；1H NMR(600MHz,DMSO-d6)δ8.82(s,1H),7.86(d,J＝10.6Hz,1H),7.58(d,J＝12.7Hz,1H),7.47–7.40(m,1H),7.18(t,J＝8.5Hz,1H),7.12(t,J＝8.7Hz,1H),5.12(d,J＝13.1Hz,1H),4.71(d,J＝13.5Hz,1H),4.36(s,2H),3.54(s,5H),3.12(s,2H),1.18(d,J＝5.8Hz,2H),0.97(s,2H)ppm。
example 15 in vitro antimicrobial Activity of organophosphine clinafloxacin derivatives
The organic phosphine clinafloxacin derivatives prepared in examples 1 to 14 were evaluated for the Minimal Inhibitory Concentration (MIC) against gram-positive bacteria (methicillin-resistant Staphylococcus aureus, enterococcus faecalis, Staphylococcus aureus ATCC25923, Staphylococcus aureus ATCC29213), gram-negative bacteria (Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa ATCC27853, Escherichia coli ATCC25922, Acinetobacter baumannii) and fungi (Candida albicans, Candida tropicalis, Aspergillus fumigatus, Candida albicans ATCC90023, Candida parapsilosis ATCC20019) by a 96-well microdilution method in accordance with the Clinical Laboratory Standards Institute (CLSI) set by the American national Committee, the test compound was dissolved in a small amount of dimethyl sulfoxide, diluted with water to a solution having a concentration of 1.28mg/mL, and diluted to 512. mu.g/mL with a culture solution, after incubation at 35 ℃ for 24 hours and shaking the plates well on a shaker, MIC was measured at 490nm and the results are shown in tables 1-3.
TABLE 1 in vitro gram-positive bacteria resistance data (MIC, μ g/mL) of organic phosphine clinafloxacin derivatives I-1 to 14
TABLE 2 in vitro gram-negative bacteria Activity data (MIC, μ g/mL) for organophosphine clinafloxacin derivatives I-1-14
The results of in vitro antibacterial activity in tables 1 and 2 indicate that the organophosphine clinafloxacin derivative of the present invention is more effective against gram-positive bacteria, particularly MRSA strains, to which all compounds exhibited relatively good biological activity (MIC of 0.5 to 32 μ g/mL) except for compound I-11(MIC of 256 μ g/mL).
Based on the structure-activity relationship (SAR) data in tables 1 and 2, the size of a conjugated system is found to have certain influence on the antibacterial activity of the compound, and particularly, the antibacterial activity of the compound is obviously reduced compared with the biological activity of the phenyl derivatives I-7-10 by introducing benzimidazole (I-11) and carbazole groups (I-12) with larger conjugated systems. Comparison shows that the electronic effect also has obvious influence on the biological activity of the compounds, and the biological activity of the phenyl derivative I-10 containing the electron-donating methoxy group on gram-positive bacteria is obviously better than that of the phenyl derivatives I-8 and I-9 with electron-withdrawing substituents.
TABLE 3 in vitro antifungal Activity data (MIC, μ g/mL) for organic Phosphoclinafloxacin derivatives I-1 to 14
As can be seen from Table 3, the compounds I-1 to 14 prepared in examples 1 to 14 of the present invention also exhibit a certain inhibitory effect on the fungi tested. Wherein the compound I-5 can completely inhibit the growth of Candida albicans ATCC90023 and Candida tropicalis, the MIC values are both 2 mug/mL, and the biological activity of the compound can be comparable to that of a reference drug fluconazole. In addition, compounds I-5 and I-10 also have relatively good activity against Aspergillus fumigatus, 32 and 128 times higher than the reference drug fluconazole, respectively.
Example 16 organophosphine clinafloxacin derivative as DNA intercalator
The compound I-10 prepared in example 10 of the present invention intercalates DNA effectively as an artificial intercalator. The embedding effect of the DNA probe Neutral red (Neutral red) is detected by using ultraviolet absorption spectrum, and the result is shown in figure 1. The results showed that the absorption spectrum near 530nm gradually decreased with increasing concentration of compound I-10, while the absorption peak at 275nm was observed to gradually increase, and these obvious spectral changes indicate that compound I-10 can effectively intercalate into the double helix of DNA by substituting NR in the DNA-NR complex, and further act with DNA, blocking the replication of bacterial DNA to exert its potent antibacterial activity.
Example 17 pharmaceutical application of organic phosphine clinafloxacin derivatives I-1-14
According to the antimicrobial activity evaluation result, the organic phosphine clinafloxacin derivative has better antibacterial and antifungal activity, and can be prepared into antibacterial and antifungal medicines for clinical use. The medicines can be single preparations, for example, the medicines are prepared from organic phosphine clinafloxacin derivatives with one structure and pharmaceutically acceptable auxiliary materials; or a compound preparation, for example, the compound preparation is prepared by organic phosphine clinafloxacin derivatives with one structure, existing antibacterial and antifungal active ingredients (such as sulfamethoxazole, fluconazole, phosphorus fluconazole, itraconazole and the like) and pharmaceutically acceptable auxiliary materials, or is prepared by several organic phosphine clinafloxacin derivatives with different structures and pharmaceutically acceptable auxiliary materials. The preparation types include, but are not limited to, tablets, capsules, powders, granules, dripping pills, injections, powder injections, solutions, suspensions, emulsions, suppositories, ointments, gels, films, aerosols, transdermal patches and other dosage forms, and various sustained-release and controlled-release preparations and nano preparations.
1. Preparation of Compound I-2 tablets
Prescription: the tablet is prepared from 1000 tablets of compound I-210 g, 187g of lactose, 50g of corn starch, 3.0g of magnesium stearate and a proper amount of ethanol solution with the volume percentage concentration of 70%.
The preparation method comprises the following steps: drying corn starch at 105 deg.C for 5 hr; mixing compound I-2 with lactose and corn starch, making soft mass with 70% ethanol solution, sieving to obtain wet granule, adding magnesium stearate, and tabletting; each tablet weighs 250mg, and the content of active ingredients is 10 mg.
2. Preparation of Compound I-2 capsules
Prescription: compound I-225 g, modified starch (120 meshes) 12.5g, microcrystalline cellulose (100 meshes) 7.5g, low-substituted hydroxypropyl cellulose (100 meshes) 2.5g, talcum powder (100 meshes) 2g, sweetening agent 1.25g, orange essence 0.25g, proper amount of pigment and water, and prepared into 1000 granules.
The preparation method comprises the following steps: micronizing compound I-2 into superfine powder, mixing with modified starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, pulvis Talci, sweetener, orange essence and pigment, making into soft material with water, granulating with 12-14 mesh sieve, drying at 40-50 deg.C, sieving, grading, and making into capsule; each tablet weighs 50mg, and the content of active ingredient is 25 mg.
3. Preparation of Compound I-3 granules
Prescription: compound I-326 g, dextrin 120g and sucrose 280 g.
The preparation method comprises the following steps: mixing compound I-3, dextrin and sucrose uniformly, granulating by wet method, drying at 60 deg.C, and packaging.
4. Preparation of Compound I-4 injection
Prescription: 1000mL of the compound I-410 g, 500mL of propylene glycol and 500mL of water for injection were prepared in total.
The preparation method comprises the following steps: weighing the compound I-4, adding propylene glycol and injection water, stirring for dissolving, adding 1g of activated carbon, fully stirring, standing for 15 minutes, filtering with a 5-micron titanium rod for decarbonization, sequentially fine-filtering with microporous filter membranes with the pore diameters of 0.45 micron and 0.22 micron, finally encapsulating in a 10mL ampoule, and sterilizing with 100 ℃ circulating steam for 45 minutes to obtain the compound I-4.
5. Preparation of compound I-4 powder injection
The preparation method comprises the following steps: and subpackaging the sterile powder of the compound I-4 under the sterile condition to obtain the compound I-4.
6. Preparation of Compound I-6 eye drops
Prescription: compound I-63.78 g, sodium chloride 0.9g, appropriate amount of boric acid buffer solution, and distilled water to 1000 mL.
The preparation method comprises the following steps: weighing the compound I-6 and sodium chloride, adding into 500mL of distilled water, dissolving completely, adjusting pH to 6.5 with boric acid buffer solution, adding distilled water to 1000mL, stirring well, filtering with microporous membrane, bottling, sealing, and sterilizing with 100 deg.C flowing steam for 1 hr.
7. Preparation of Compound I-10 Liniment
Prescription: compound I-104 g, potassium soap 7.5g, camphor 5g, distilled water to 100 mL.
The preparation method comprises the following steps: dissolving camphor with 95 percent ethanol solution by volume percentage for later use; heating potassium soap to liquefy, weighing compound I-10, adding potassium soap solution and Camphora ethanol solution under stirring, gradually adding distilled water, emulsifying completely, and adding distilled water to full volume.
8. Preparation of suppository of compound I-10
Prescription: 100 metric samples of compound I-104 g, 14g of gelatin, 70g of glycerol and 100mL of distilled water.
The preparation method comprises the following steps: weighing gelatin and glycerol, adding distilled water to 100mL, heating in water bath at 60 deg.C to melt into paste, adding compound I-10, stirring, pouring into vaginal suppository mold when it is nearly solidified, and cooling to solidify.
9. Preparation of Compound I-10 ointment
Prescription: 100.5-2 g of compound I, 6-8 g of hexadecanol, 8-10 g of white vaseline, 8-19 g of liquid paraffin, 2-5 g of monoglyceride, 2-5 g of polyoxyethylene (40) stearate, 5-10 g of glycerol, 0.1g of ethylparaben and distilled water added to 100 g.
The preparation method comprises the following steps: heating cetyl alcohol, white vaseline, liquid paraffin, monoglyceride and polyoxyethylene (40) stearate to completely melt, mixing, and keeping the temperature at 80 deg.C to obtain oil phase; adding ethylparaben into glycerol and distilled water, heating to 85 deg.C for dissolving, adding oil phase under stirring, emulsifying, adding compound I-10, stirring, and cooling.
10. Preparation of compound I-5 and fluconazole compound powder injection
Prescription: the compound I-550 g, fluconazole 50g and sodium benzoate 1g are prepared into 100 bottles.
The preparation method comprises the following steps: taking the compound I-5, the fluconazole and the sodium benzoate according to the prescription amount, uniformly mixing in a sterile state, and subpackaging 100 bottles to obtain the compound I-5.
11. Preparation of Compound I-10 Aerosol
Prescription: 102.5 g of compound I, 203 g of Span, 4g of talcum powder (100 meshes) and trichlorofluoromethane added to a proper amount.
The preparation method comprises the following steps: respectively placing the compound I-10, the Span20 and the talcum powder in a vacuum drying oven for drying for a plurality of hours, placing in a dryer for cooling to room temperature, crushing into micro powder by using an airflow crusher, uniformly mixing according to the prescription amount, filling into a closed container, and adding trichloromonofluoromethane to a specified amount to obtain the trichloromonofluoromethane.
Finally, the above embodiments are only intended to illustrate the technical solutions of the present invention and not to limit the present invention, and although the present invention has been described in detail with reference to the preferred embodiments, it will be understood by those skilled in the art that modifications or equivalent substitutions may be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions, and all of them should be covered by the claims of the present invention.
Claims (7)
1. The organic phosphine clinafloxacin derivative and the medicinal salt thereof are characterized by being any one of the following compounds:
2. the organic phosphine clinafloxacin derivative and the pharmaceutically acceptable salts thereof as claimed in claim 1, wherein the pharmaceutically acceptable salts are hydrochloride, nitrate or acetate.
3. The process for preparing the organophosphine clinafloxacin derivative and the pharmaceutically acceptable salt thereof according to claim 1, wherein the process comprises the steps of:
a. preparing organic phosphine clinafloxacin derivatives I-1-4 and I-7-12: taking clinafloxacin and diethyl phosphite as starting materials, and respectively carrying out one-pot method with different aldehyde compounds to obtain organic phosphine clinafloxacin derivatives I-1-4 and I-7-12;
b. preparing organic phosphine clinafloxacin derivatives I-13-14: and (b) taking the organic phosphine clinafloxacin derivatives I-7-8 prepared in the step a as raw materials, and hydrolyzing with concentrated hydrochloric acid to obtain the organic phosphine clinafloxacin derivatives I-13-14.
4. The method of claim 3,
in the step a, the used solvent is toluene, the temperature of the reflux reaction is 120 ℃, and the time of the reflux reaction is 4-6 h; the mass ratio of the clinafloxacin, the diethyl phosphite and the aldehyde compound is 1:3: 1.5;
in the step b, the temperature of the reflux reaction is 80 ℃, and the time of the reflux reaction is 12 h.
5. The use of the organophosphine clinafloxacin derivative and the pharmaceutically acceptable salts thereof as claimed in claim 1 or 2 for the preparation of antibacterial and/or antifungal medicaments, wherein the bacteria is one or more of enterococcus faecalis, staphylococcus aureus, escherichia coli 25922 or acinetobacter baumannii; the fungus is one or more of Candida albicans ATCC90023, Candida tropicalis or Aspergillus fumigatus.
6. Use of the organophosphine clinafloxacin derivative and the pharmaceutically acceptable salts thereof as defined in claim 1 or 2 for the preparation of DNA intercalators.
7. The use of claim 6, wherein the DNA is calf thymus DNA.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103396396A (en) * | 2013-08-12 | 2013-11-20 | 西南大学 | Amido alkyl acyl clinafloxacin and application thereof |
| CN105777807A (en) * | 2016-03-31 | 2016-07-20 | 贵州大学 | Chalcone phosphonate derivative containingquinazoline and preparation method and application of chalcone phosphonate derivative |
| CN106117268A (en) * | 2016-07-13 | 2016-11-16 | 广西师范学院 | α aminophosphonate compound with 2 amino 1,3,4 thiadiazoles structures and preparation method thereof and purposes |
| CN107459507A (en) * | 2016-06-03 | 2017-12-12 | 西南大学 | Clinafloxacin oxazolidine acyl derivative and its preparation method and application |
-
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103396396A (en) * | 2013-08-12 | 2013-11-20 | 西南大学 | Amido alkyl acyl clinafloxacin and application thereof |
| CN105777807A (en) * | 2016-03-31 | 2016-07-20 | 贵州大学 | Chalcone phosphonate derivative containingquinazoline and preparation method and application of chalcone phosphonate derivative |
| CN107459507A (en) * | 2016-06-03 | 2017-12-12 | 西南大学 | Clinafloxacin oxazolidine acyl derivative and its preparation method and application |
| CN106117268A (en) * | 2016-07-13 | 2016-11-16 | 广西师范学院 | α aminophosphonate compound with 2 amino 1,3,4 thiadiazoles structures and preparation method thereof and purposes |
Non-Patent Citations (1)
| Title |
|---|
| "噻唑类新化合物的设计与合成及其抗微生物活性研究";高巍伟;《中国博士学位论文全文数据库 工程科技I辑》;20190115(第1期);第284页，方案5，第300页第5.2.8节，第313页第5.4.2.1节，第317页第5.4.2.8节，第322页第5.4.2.18节，表5.1-5.5 * |
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