CN113135958B - Application of nitrogen heterocyclic carbene selenium-gold compound in preparation of carbapenem-resistant acinetobacter baumannii resistant medicine - Google Patents
Application of nitrogen heterocyclic carbene selenium-gold compound in preparation of carbapenem-resistant acinetobacter baumannii resistant medicine Download PDFInfo
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- CN113135958B CN113135958B CN202110378013.2A CN202110378013A CN113135958B CN 113135958 B CN113135958 B CN 113135958B CN 202110378013 A CN202110378013 A CN 202110378013A CN 113135958 B CN113135958 B CN 113135958B
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 title claims abstract description 15
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
- C07F9/6503—Five-membered rings
- C07F9/6506—Five-membered rings having the nitrogen atoms in positions 1 and 3
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
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- Communicable Diseases (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract
An application of a nitrogen heterocyclic carbene selenium-gold compound in preparing a novel antibacterial drug for resisting carbapenems acinetobacter baumannii infection belongs to the technical field of drug preparation. The azacyclo-carbene selenium-gold compound uses imidazole azacyclo-carbene selenium containing selenium to replace a thiosugar ligand in a auranofin structure, the reaction activity of Au-Se in the azacyclo-carbene selenium-gold compound is higher than that of Au-S bond, and the problem that the Au-S bond in the auranofin structure is easily damaged by reductive mercaptan and is metabolized to generate toxic and side effects before reaching a target point can be avoided to a certain extent. In vitro antibacterial activity shows that compounds H7 and H8 inhibit IC of carbapenems resistant acinetobacter baumannii50At 3.34 and 4.67. mu.M, MIC were 10. mu.M, and MBC was 20. mu.M. The drug administration in the animal body also shows good drug-resistant bacterium resistance, can obviously prolong the survival time of the mice infected by the drug-resistant bacterium, and has important practical application value.
Description
Technical Field
The invention relates to an application of a nitrogen heterocyclic carbene selenium-gold compound in preparing a novel antibacterial drug for resisting carbapenems acinetobacter baumannii, belonging to the technical field of drug preparation.
Background
Acinetobacter baumannii is an important pathogenic bacterium of human, belongs to gram-negative bacteria, is a conditional pathogenic bacterium for strict aerobic and non-lactose fermentation, and can cause a plurality of serious infections clinically. It is ubiquitous in nature and found in air, water, dust, and human and animal excreta. Thus, the chance of contamination of the food is high. At present, nearly 70 million people die globally every year from drug-resistant bacterial infections, and scholars predict that the number of global deaths will rise to 1000 million people by 2050 without efforts to reduce drug resistance or develop new antibiotics. Antibiotics are the main drugs for treating acinetobacter baumannii infection at present, but antibiotic abuse is a worldwide problem, and the result of antibiotic abuse is the generation of a large number of drug-resistant bacteria. The carbapenems-resistant acinetobacter baumannii is a common and significant drug-resistant bacterium in clinical drug-resistant bacteria. Nowadays, carbapenems resistant acinetobacter baumannii infection is very common and is a main pathogenic bacterium for nosocomial and community infection. The world health organization in 2017 issued a list of 12 drug-Resistant bacteria that urgently needed the development of new antibiotics, wherein the carbapenem-Resistant enterobacteriaceae was listed as the first line, and is the highest in the urgency for the development of new antibiotics, while carbapenem-Resistant Acinetobacter Baumannii (CRAB) was listed as the first most urgent pathogen, carbapenem antibiotics were considered as the last line of defense for the treatment of gram-negative bacilli, and the emergence of carbapenem-Resistant bacteria further limited the choice of clinical treatment, which also made the clinical need for new antibacterial drugs urgent.
The auranofin is taken as an oral antirheumatic medicament containing gold, and is discovered to have the effects of resisting tumors, bacteria and the like in recent years. Auranofin is a selective TrxR inhibitor, can competitively bind with TrxR in eukaryote, and binds with Sec498 selenol residue at the C terminal of the aureofin to play an irreversible inhibiting role. However, Au-S bond in the auranofin structure is easily destroyed by reductive thiol, and the drug is easy to be metabolized before reaching the target point, thereby generating toxic and side effects.
Disclosure of Invention
In order to solve the problem that auranofin is easy to reduce and damage to generate toxic and side effects, the imidazole nitrogen heterocyclic carbene selenium containing selenium is used for replacing a thiosugar ligand in the auranofin structure, the reaction activity of Au-Se is higher than that of an Au-S bond, and the problem can be avoided to a certain extent. The two N-heterocyclic carbene selenium-gold compounds H7 and H8 have good antibacterial activity on carbapenem-resistant acinetobacter baumannii, the minimum inhibitory concentration reaches 10 mu M, and the compounds H7 and H8 can obviously treat the infection caused by carbapenem-resistant acinetobacter baumannii at the animal level, increase the wound healing speed and simultaneously increase the pathological survival period of mice under severe infection.
The technical scheme adopted by the invention is as follows: preparation of two nitrogen heterocyclic carbene selenium-gold compounds for effectively treating carbapenems-resistant acinetobacter baumannii and in-vivo and in-vitro antibacterial effects of the two compounds on carbapenems-resistant acinetobacter baumannii. Compared with auranofin, the compounds H7 and H8 obtained by substituting the sulfur sugar ligand in the auranofin structure with the imidazole nitrogen heterocyclic carbene selenium containing selenium have better stability, show good in-vivo and in-vitro antibacterial activity to carbapenems-resistant acinetobacter baumannii, and can obviously prolong the survival period of mice after bacterial infection. The structural formulae of compounds H7 and H8 are as follows:
the N-heterocyclic carbene selenium-gold compound H7 or H8 is applied to the preparation of novel antibacterial drugs for carbapenem-resistant acinetobacter baumannii.
The invention has the beneficial effects that: the compounds H7 and H8 have good antibacterial effect on carbapenems-resistant acinetobacter baumannii, the minimum antibacterial concentration is 10 mu M, and the compound H7 and H8 can obviously inhibit the infection lesion of the carbapenems-resistant acinetobacter baumannii on mice after being administered with 10mM of the compounds H7 and H8 in the level of an animal body, promote the wound healing of the infected mice more quickly, and simultaneously improve the survival rate of the mice under severe infection and increase the survival time. The N-heterocyclic carbene selenium-gold compound has the advantages of reliable curative effect, no toxic or side effect, simple preparation, low price and the like.
Drawings
FIG. 1 shows the structural formulas of N-heterocyclic carbene selenium-gold compounds H7 and H8.
FIG. 2 is a hydrogen spectrum of N-heterocyclic carbene selenium-gold compound H7.
FIG. 3 is a carbon spectrum diagram of N-heterocyclic carbene selenium-gold compound H7.
FIG. 4 is a hydrogen spectrum of N-heterocyclic carbene selenium-gold compound H8.
FIG. 5 is a carbon spectrum diagram of N-heterocyclic carbene selenium-gold compound H8.
FIG. 6 is the in vitro bacteriostatic IC of Compound H750And a minimum inhibitory concentration.
FIG. 7 is in vitro bacteriostatic IC of Compound H850And a minimum inhibitory concentration.
FIG. 8 is a graph of the in vivo antibacterial wound infections in mice with Compound H7 and Compound H8.
Fig. 9 is a graph of the change in body weight of mice infected with wounds under the in vivo antibacterial effect of compound H7 and compound H8.
FIG. 10 is a graph of the wound changes of the mouse wound infection under in vivo antibacterial effect of compound H7 and compound H8.
FIG. 11 shows immunohistochemistry results for compound H7 and compound H8 under in vivo antibacterial conditions.
FIG. 12 is a graph showing the effect of compound H7 and compound H8 on survival rates in 0-72H in mice resistant to carbapenems of Acinetobacter baumannii infection.
Detailed Description
The present invention will be described in detail with reference to the following embodiments. It should be understood that the summary of the detailed description section is illustrative and not restrictive, i.e., does not set forth any limitations on the summary of the invention. Defining: carbapenems resistant in carbapenems resistant acinetobacter means: acinetobacter baumannii was tested with carbapenem antibiotics according to the CLSI method (paper sheet method or dilution method), and the results were judged as drug resistance (resistance) according to the CLSI-M100 standard. Carbapenem antibiotics are atypical beta-lactam antibiotics with the widest antibacterial spectrum and the strongest antibacterial activity, and have become one of the most important antibacterial drugs for treating severe bacterial infection due to the characteristics of stability to beta-lactamase, low toxicity and the like; has broad spectrum, strong antibacterial activity and high stability to beta-lactamase.
IC50 was 50% inhibitory concentration, B/B0The half inhibition is the lower the half inhibition used to measure the sensitivity of the antibody at the concentration corresponding to 50%, indicating the higher the sensitivity of the antibody.
MIC is the minimum inhibitory concentration, is an index for measuring the antibacterial activity of the antibacterial drug, and is the minimum drug concentration capable of inhibiting the growth of pathogenic bacteria in a culture medium after bacteria are cultured in vitro for 18 to 24 hours.
MBC is the lowest bactericidal concentration, which is the lowest concentration capable of killing bacteria in a culture medium, namely 99.9 percent of test microorganisms are killed, and the lowest drug concentration required by the test microorganisms with 3 orders of magnitude is reduced.
Example 1 Synthesis of N-heterocyclic carbene selenium-gold Compounds H7 and H8 and the structural formulas thereof
1. Structural formula (xvi):
the preparation method comprises the steps of substituting imidazole nitrogen heterocyclic carbene selenium containing selenium for a thiosugar ligand in a auranofin structure, wherein the reaction activity of Au-Se is higher than that of an Au-S bond, obtaining the compound H7 and the compound H8 by a chemical synthesis method, and determining the structures by NMR nuclear magnetic analysis.
H7 and H8 synthesis steps: para-substituted benzaldehyde is used as an initial raw material, a benzoin condensation reaction is carried out under the catalysis of thiamine hydrochloride, the obtained para-substituted benzoin compound and formamide are refluxed, a 4, 5-diaryl substituted imidazole compound is obtained through ring closure, the para-substituted benzoin compound and bromoethane are subjected to substitution reaction to generate a single N-ethyl substituted 4, 5-diaryl substituted imidazole compound, and finally the mono-N-ethyl substituted 4, 5-diaryl substituted imidazole compound and corresponding halohydrocarbon are reacted to generate a ligand.
The synthetic routes of the compounds H7 and H8 are as follows:
the specific synthetic steps of compound H8 were:
(i) weighing thiamine hydrochloride (2.00g and 5.94mmol), dissolving the thiamine hydrochloride in a mixed solution of 10mL of water and 20mL of ethanol, stirring, adding a proper amount of 2M sodium hydroxide solution to enable the pH of the solution to be 9-10, adding 4-bromobenzaldehyde (17.2g and 93.2mmol), reacting at normal temperature for 3 days, concentrating by using a rotary evaporator after the reaction is finished, removing the ethanol as far as possible, extracting the obtained aqueous solution by using dichloromethane, drying an organic layer by using anhydrous sodium sulfate, filtering, spin-drying to obtain a crude product, and separating and purifying by using a silica gel column to obtain white solid p-bromobenzoin 2 a.
(ii) Weighing 2a (8.5g,23mmol), dissolving in 30mL formamide, refluxing at 210-220 ℃ for 2-3 h, cooling the reaction solution to below 100 ℃, slowly adding 100mL pure water while stirring, filtering the precipitated solid, washing with a small amount of diethyl ether (5mL × 3), and drying to obtain 4, 5-bis (4' -fluorophenyl) imidazole 3a as a white solid.
(iii) Weighing 3a (2.2g,5.85mmol), dissolving in 25mL of anhydrous tetrahydrofuran, adding 289mg of 60% sodium hydride, stirring for about 10min, adding bromoethane (0.528mL,7.02mmol), heating and refluxing for 2-3 h under the protection of nitrogen, after the reaction is finished, drying, and separating and purifying by a silica gel column to obtain 1-ethyl-4, 5-bis (4' -bromophenyl) imidazole 4a as a white solid.
(iv) Weighing 4a (200mg,0.49mmol), reacting with 4-fluorobenzeneboronic acid (144mg,1.18mmol) under the catalysis of potassium carbonate (138mg,4mmol) and tetrakis (triphenylphosphine) palladium (57mg,0.49mmol) for heating reflux reaction for 2 days, after the reaction is finished, carrying out spin drying to obtain a crude product, and separating and purifying by a silica gel column to obtain 1-ethyl-4, 5-bis (4 '-fluoro- [1,1' -biphenyl ] -4-yl) -1H-imidazole 5 a.
(v) Weighing 5a (1.8g,4.22mmol), dissolving with bromoethane (1.58mL,21.10mmol) in 20mL acetonitrile, heating and refluxing for reaction for 3 days, after the reaction is finished, performing spin drying to obtain a crude product, and separating and purifying by a silica gel column to obtain 1, 3-diethyl-4, 5-bis (4' -bromophenyl) -1H-imidazole bromide 6 a.
(vi) Weighing 6a (1.8g,0.83mmol) (452mg,0.83mmol) and dissolving in anhydrous THF (10mL), adding KOtBu (129mg,1.66mmol) and selenium powder (97mg,1.24mmol), stirring for 5 hours in ice bath, after the reaction is finished, spin-drying to obtain a crude product, and separating and purifying by a silica gel column to obtain the 1, 3-diethyl-4, 5-bis (4 '-fluoro- [1,1' -biphenyl ] -4-yl) -1, 3-dihydro-2H-imidazol-2-selenone compound 7 a.
(vii) Weighing 7a (26.0mg,0.048mmol) and triethylphosphine gold chloride (16.8mg,0.048mmol), adding into 4mL of anhydrous DCM, stirring at room temperature for 15-20min under the protection of nitrogen, filtering after TLC monitoring reaction is finished, and crystallizing filtrate in a dry weight rotary manner to obtain [1, 3-diethyl-4, 5-bis (4 '-fluoro- [1,1' -biphenyl ] -4-yl) -1, 3-dihydro-2H-imidazole-2-selenone ] [ triethylphosphine gold (I) ] chloride salt H8.
According to the synthetic route of the compound H7, the compound [1, 3-diethyl-4, 5-bis (4-methoxyphenyl) -1, 3-dihydro-2H-imidazole-2-selenone is synthesized][ gold triethyl phosphine (I)]Chloride salt, H7, white solid, 58% yield.1H NMR(500MHz,CDCl3)δ7.12(d,J＝8.7Hz,4H,ArPhH),6.86(d,J＝8.7Hz,4H,ArPhH),4.22(q,J＝7.1Hz,4H,NCH2CH3),3.80(d,J＝2.5Hz,6H,ArOCH3),1.86(dq,J＝10.2,7.6Hz,6H,PCH2CH3),1.28-1.18(m,15H,NCH2CH3,PCH2CH3).13C NMR(126MHz,CDCl3)δ159.93(Se＝C),131.88,131.54,120.36,114.10,113.89(ArPhC),129.63(NC＝CN),55.24(ArOCH3),42.55(NCH2CH3),18.26,17.97(PCH2CH3),14.48(NCH2CH3),8.99(PCH2CH3).MS-MOLDI-TOF(+)[m/z]:[M-Cl]+:731.170. See fig. 2-3.
Nuclear magnetic data of H8 compound: [1, 3-diethyl-4, 5-bis (4 '-fluoro- [1,1' -biphenyl)]-4-yl) -1, 3-dihydro-2H-imidazol-2-selenone][ gold triethyl phosphine (I)]Chloride salt, H8, white solid, yield 45%.1H NMR(500MHz,DMSO-d6)δ7.78-7.69(m,8H，ArPhH),7.51(d,J＝8.2Hz,4H，ArPhH),7.28(t,J＝8.8Hz,4H，ArPhH),4.14(dd,J＝13.9,6.9Hz,4H，NCH2CH3),1.99-1.88(m,6H，PCH2CH3),1.20-1.03(m,15H，NCH2CH3,PCH2CH3).13C NMR(126MHz,CDCl3)δ154.02(Se＝C),163.70,161.74,140.73,135.98,135.95,130.99,128.65,128.58,127.19,127.03,115.90,115.73(ArPhC),129.63(NC＝CN),42.74(NCH2CH3),18.25,17.96(PCH2CH3),14.53(NCH2CH3),9.00(NCH2CH3).MS-MOLDI-TOF(+)[m/z]:[M-Cl]+:859.620. See fig. 4-5.
2. Drugs and reagents:
in vitro Activity measurement of bacteria from ATCC platform carbapenems-resistant A.baumannii (
BAA-3035TM) (ii) a The animal experiment bacteria are clinically separated carbapenems-resistant acinetobacter baumannii, and are presented to the Japanese friendship hospital (with whole gene sequencing) of Jilin university; the animal experimental bacteria are clinically separated carbapenems-resistant acinetobacter baumannii, and are presented to the Japanese friendship hospital (complete gene sequencing) of Jilin university. The nutrient broth, the beef powder and the peptone are all products of Beijing Ooboxin Biotechnology Limited liability company. Yeast extract, tryptone, are all products of OXOID, England.
Example 2: in vitro antibacterial activity of N-heterocyclic carbene selenium-gold compounds H7 and H8 on carbapenems-resistant acinetobacter baumannii
Antibacterial activity and minimum inhibitory concentration were determined for compounds H7 and H8, by reference to CLSI (American society for clinical standards) M07-A9 broth microdilution. And (3) diluting the bacterial liquid with the OD value of 1 of 600nm to 0.5 McLeod turbidity by using a McLeod tube, and continuously diluting by 1000 times to obtain experimental bacterial liquid for later use. The antibacterial activity analysis was continued by adding the monomeric compound to the 96-well plate at columns 4-7 to give final concentrations of 1. mu.M, 2. mu.M, 5. mu.M and 10. mu.M, respectively. And arranging a negative control group in the 2 nd to 3 rd columns, adding LB culture medium into the other holes to be used as a blank control, culturing for 24 hours at 37 ℃, and considering the lowest concentration of the monomeric compound for completely clarifying the bacterial liquid as the lowest bacteriostatic concentration.
TABLE 1 bacteriostatic IC of Compounds H7 and H850And Minimum Inhibitory Concentration (MIC)
Solid medium plate bacteriostasis experiment
Respectively culturing each tested bacterium in a 37 ℃ bacterium shaking box until the OD value of 600nm is 1, and then diluting 10 times of the original bacterium liquid in a gradient way by 10 times-11Double-layer and double-layer bedPreparing 96-well plate, 200 μ L per well, sequentially adding diluted 10-1-10-11Culturing the bacterial solution with the concentration at 37 ℃ for 18-24h, and observing. The minimum concentration at which bacteria can normally grow is the concentration of the bacteria liquid in the drug screening experiment. Then preparing a nutrient broth solid culture medium, taking 100 mu L of bacterial liquid with the concentration of experimental bacterial liquid, respectively adding compounds H7 and H8 with the final concentrations of 0, 2, 5, 10 and 20 mu M, uniformly mixing, then respectively coating on agar plate culture media, and simultaneously setting a non-dosing group for simultaneous coating; finally, the growth of the bacteria was observed after 24h incubation at 37 ℃. As can be seen from FIGS. 6 and 7, the minimum bactericidal concentration MBC of compounds H7 and H8 was 20. mu.M.
Example 3: in vivo anti-infection assessment of Compound H7 and Compound H8
The compounds H7 and H8 both showed better antibacterial activity by the determination of the minimum inhibitory concentration. Thus, we performed a systematic assessment of the anti-infective activity of H7 and H8 in vivo at the mouse animal level, as follows:
feeding 22-25g Balb/c mice for 1 week, cutting 1.2 × 1.2cm wound on back skin of the mice by using surgical scissors, and injecting 2 × 10 on wound surface6Establishing a wound infection model by using 200 mu L of CFU/ml bacterial liquid, randomly dividing the CFU/ml bacterial liquid into five groups, wherein each group comprises 6 bacteria, and after 24 hours of infection, the control group is externally applied to the wound by using normal saline; h2O2Group (positive control) was given 10mM concentration hydrogen peroxide for external application to the wound; the AF group (positive control) was given auranofin at 10mM concentration for external application to the wound; h710 mM concentration was given to H7 group for external application to the wound; the H8 group was given H810 mM concentration topical wounds, and mice were observed for 14 days of continuous wound infection (fig. 8), and the mice were recorded for weight (fig. 9) and wound (fig. 10) changes.
The healing effect of the H7 group wound is obviously higher than that of the control group and the H2O2The group, and better than the auranofin group, demonstrated a stronger anti-infective ability in vivo. H8 has wound infection resisting effect obviously superior to that of Control group and H2O2Group, but no significant difference with auranofin. Immunohistochemistry results also suggested that the H7 group expressed inflammatory factors at a lower level than the other four groups (fig. 11).
Example 4: effect of Compound H7 and Compound H8 on survival of mice resistant to carbapenems and Acinetobacter baumannii infection
The antibacterial activity of the compounds H7 and H8 is very good by measuring the minimum inhibitory concentration, and the minimum inhibitory concentration is 10 mu M. Patients who are resistant to carbapenem acinetobacter baumannii infection often have lower survival rates, so we evaluated the effect of compounds H7 and H8 on survival time of mice after carbapenem acinetobacter baumannii infection. 22-25g Balb/c mice were adaptively fed for 1 week, and were intraperitoneally injected with 200. mu.L of 2X 107CFU/ml bacterial suspension to establish an intraperitoneal infection model, which was randomly divided into 4 groups (control group, Auranofin group, H7 group, H8 group). Injecting the bacteria solution for 1hr, and treating with saline, Auranofin, H7 and H8 by intraperitoneal injection for control group, Auranofin group, H7 and H8. The survival was observed for 72 h. The survival time of the mice treated by H7 and H8 is obviously longer than that of the control group, and H7 and H8 also have treatment advantages compared with the auranofin group (figure 12).
The N-heterocyclic carbene selenium-gold compounds H7 and H8 are obtained by substituting a sulfur sugar ligand in a auranofin structure with imidazole N-heterocyclic carbene selenium containing selenium, and have better stability and antibacterial activity compared with auranofin. The antibacterial agent has good antibacterial activity on carbapenems-resistant acinetobacter baumannii, the minimum inhibitory concentration in vitro is 10 mu M, the in vivo effect is obvious, and the survival time of the infected mouse can be obviously prolonged.
Claims (2)
1. A nitrogen heterocyclic carbene selenium-gold compound is characterized in that: the structures of the N-heterocyclic carbene selenium-gold compounds H7 and H8 are as follows:
2. the application of the N-heterocyclic carbene selenium-gold compound is characterized in that: the N-heterocyclic carbene selenium-gold compound H7 or H8 is applied to the preparation of carbapenem-resistant acinetobacter baumannii antibacterial drugs.
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