CN114748455B - Application of 5-substituted naphthoquinone compound in preparation of antibacterial drugs - Google Patents
Application of 5-substituted naphthoquinone compound in preparation of antibacterial drugs Download PDFInfo
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- CN114748455B CN114748455B CN202210500637.1A CN202210500637A CN114748455B CN 114748455 B CN114748455 B CN 114748455B CN 202210500637 A CN202210500637 A CN 202210500637A CN 114748455 B CN114748455 B CN 114748455B
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- staphylococcus aureus
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- resistant staphylococcus
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
- A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/336—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having three-membered rings, e.g. oxirane, fumagillin
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- 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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C46/00—Preparation of quinones
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C50/00—Quinones
- C07C50/26—Quinones containing groups having oxygen atoms singly bound to carbon atoms
- C07C50/32—Quinones containing groups having oxygen atoms singly bound to carbon atoms the quinoid structure being part of a condensed ring system having two rings
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D301/00—Preparation of oxiranes
- C07D301/02—Synthesis of the oxirane ring
- C07D301/03—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
- C07D303/32—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by aldehydo- or ketonic radicals
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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- C07B2200/07—Optical isomers
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
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- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
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Abstract
The invention discloses application of two 5-substituted naphthoquinone compounds in preparation of antibacterial drugs. The two 5-substituted naphthoquinone compounds have antibacterial activity on methicillin-resistant staphylococcus aureus, and provide a research direction for developing antibacterial infection medicaments with novel chemical structures, novel action mechanisms or novel action targets to effectively relieve the current bacterial drug resistance problem.
Description
Technical Field
The invention relates to the field of pharmacy, in particular to two 5-substituted naphthoquinone compounds and application thereof in preparation of antibacterial drugs.
Background
The clinical appearance of multi-drug resistant strains makes the research of novel antibiotics more and more difficult, and the problems of increased research and development difficulty, prolonged period, low action efficiency, shorter and shorter time for bacteria to generate drug resistance and the like make the drug resistance of bacteria become a serious worldwide problem. Therefore, antibiotic resistance has become a serious challenge for clinical anti-infective drug treatment, clinically, the existing effective antibiotics are insufficient to cope with pathogenic 'super bacteria' with broad-spectrum drug resistance, and research and development of antibacterial infective drugs with novel chemical structures, novel action mechanisms or novel action targets can effectively alleviate the current bacterial drug resistance problem, and are hot spots and difficulties in the current antibiotic research and development field.
Disclosure of Invention
The invention provides two compounds with antibacterial activity through mass screening in order to solve the problem of bacterial drug resistance at present. The structure is as follows:
in order to achieve the above purpose, the invention adopts the following technical scheme:
the invention solves the technical problem of researching the application of two 5-substituted naphthoquinone compounds in antibacterial activity.
The above 5-substituted naphthoquinone compounds are from the papers Shu X, chen CC, yu T, yang J, hu X.Enntioselective Total Synthesis of (-) -Spiroxins A, C, and D.Angew Chem Int Ed Engl.2021Aug 16;60 18514-18518 laboratory of author Cooperation, the synthetic procedure is as follows:
the invention provides an application of 5-substituted naphthoquinone compounds shown in a formula 1 or a formula 2 in preparing antibacterial drugs,
further, the bacterium is staphylococcus aureus, preferably methicillin-resistant staphylococcus aureus, more preferably methicillin-resistant staphylococcus aureus (MRSA) USA 300.
Preferably, the 5-substituted naphthoquinone compound is a compound represented by formula 2.
Methicillin-resistant staphylococcus aureus (MRSA) is an important pathogen causing nosocomial infections and community acquired infections, and causes different degrees of resistance to various antibacterial drugs, resulting in an annual rise in the incidence of the infections. Current medical MIC (Minimal Inhibitory Concentration) -based treatment protocols may lead to progressive development of mutant subgroups in bacteria into dominant populations, leading to bacterial resistance. Bacterial resistance monitoring has found that the Minimum Inhibitory Concentration (MIC) of some antibiotics against MRSA drifts upward and the bacteria become less sensitive to it. Therefore, research and development of antibacterial drugs having novel chemical structures and reduction of occurrence of bacterial resistance have been the focus of research by people. The MIC value of the 5-substituted naphthoquinone compound 2 of the invention to methicillin-resistant staphylococcus aureus is low and is 2.88 mug/mL, and the 5-substituted naphthoquinone compound can be used as a lead compound with antibacterial activity for further research.
Compared with the prior art, the invention has the beneficial effects that: the invention provides two compounds with stronger antibacterial effect, which have remarkable effect on inhibiting bacteria, especially methicillin-resistant staphylococcus aureus (MRSA) USA 300 with drug resistance, and the lowest effective inhibition concentration is respectively 2.88 mug/mL and 5.56 mug/mL, which are far lower than other naphthoquinone compounds.
Detailed description of the preferred embodiments
The invention is further described below by means of specific examples.
EXAMPLE 1 antibacterial Activity test
1. Material
1.1 pharmaceutical products and reagents
Methanol, shanghai Lingfeng chemical Co., ltd;
sodium chloride, shanghai trial four He Wei chemical Co., ltd;
sodium hydroxide, shanghai test four He Wei chemical Co., ltd;
peptone, BD difco;
yeast powder, BD difco;
agar powder, BD difco;
compound mother liquor: compounds 1 and 2 were dissolved in DMSO to prepare 5mM (i.e., 1390. Mu.g/mL and 1440. Mu.g/mL) stock solutions, which were stored in a-20deg.C refrigerator for use.
Culture medium:
(1) LB medium: mixing 10g/L NaCl, 10g/L peptone, 5g/L yeast powder and water as solvent, regulating pH to about 7.2+ -0.2 with 1mol/L NaOH solution at 25deg.C, packaging into 250mL conical flask, and sterilizing at 121deg.C under 1×105Pa for 20 min.
(2) LB agar medium: mixing NaCl 10g/L, peptone 10g/L, yeast powder 5g/L and water as solvent, adding agar powder with mass concentration of 1.5% -2.0%, adjusting pH to 7.2+ -0.2 at 25deg.C with 1mol/L NaOH solution, and adjusting pH to 121deg.C to 1X10) 5 Sterilizing under Pa for 20min, and pouring into a flat plate for standby.
1.2 instruments
SW-CJ-IFB purifying workbench (Suzhou purifying equipment Co., ltd.)
LS-B50L vertical pressure steam sterilizing pot (Shanghai Boxun medical biological instruments Co., ltd.)
SPX-250B-Z biochemical incubator (Shanghai Bo Xie medical equipment factory)
ZHWY-2102C constant temperature culture oscillator (Shanghai Zhi City analytical instruments manufacturing Co., ltd.)
YP202N electronic balance (Shanghai precision scientific instruments Co., ltd.)
RL203 electronic balance (Mei Te le Toli duo instrument (Shanghai) Co., ltd.)
DELTA320 bench pH meter (Mei Te le Tou Du instrument (Shanghai) Co., ltd.)
Multiskan MK3 microplate reader (Osseill Feishier science and technology Co., ltd.)
1.3 Experimental strains
Experimental strains: methicillin resistant staphylococcus aureus MRSA USA 300.
Preparing bacterial liquid: after the methicillin-resistant staphylococcus aureus (MRSA USA 300) preserved at the temperature of 80 ℃ below zero is thawed at room temperature, streaking and inoculating the methicillin-resistant staphylococcus aureus onto an LB agar medium, culturing the methicillin-resistant staphylococcus aureus at the temperature of 37 ℃ for 24 hours, taking single colonies which are well developed, inoculating the single colonies again, and culturing the single colonies at the temperature of 37 ℃ for 24 hours so as to ensure that the strain is in a growing period. Single colonies are selected and inoculated into LB culture medium, and cultured for 16 hours at 37 ℃ and 200r.p.m. Diluting 10000 times with fresh LB culture medium to obtain methicillin-resistant Staphylococcus aureus bacterial liquid, and determining its concentration as 2.6X10 by viable bacteria count 9 CFU/mL。
2. Experiment and content
2.1. Evaluation of antibacterial Activity:
the compounds in the experiment were dissolved in DMSO to prepare compounds 1 and 2 of formula (I) having molecular weights 278 and 288, respectively, at a concentration of 5 mM. Preparation of 96-well plates for antimicrobial activity test: the compounds were post-added to 96-well plates (flat bottom) column 2, with volumes of compounds added at columns 3-10 from high to low of 8, 7, 6, 5, 4, 3, 2, 1 μl, respectively, column 11 as growth control wells, and 8 μl DMSO was added. At 3 in parallel per group. 200 mu L of methicillin-resistant staphylococcus aureus bacterial liquid (2.6X10) is added to each of 1 to 12 rows of holes 9 CFU), to give a final concentration of compound 1 measured at 5.56, 4.87, 4.17, 3.44, 2.78, 2.09, 1.39, 0.70, 0 μg/mL, and a final concentration of compound 2 measured at 5.76, 5.04, 4.32, 3.60, 2.88, 2.16, 1.44, 0.72, 0 μg/mL. Placing the prepared 96-well plates in a constant temperature incubator at 37 ℃ for static culture for 24 hours, and measuring OD by using an enzyme-labeled instrument 600 And the results are recorded. All experiments were repeated three times.
2.2 evaluation method and result determination
2.2.1 percent antibacterial
The OD of each well was measured at 600nm using a microplate reader. The percent bacteriostasis of each well is expressed as:
3. results:
minimum effective antibacterial concentration of compounds 1 and 2 against methicillin-resistant staphylococcus aureus
The percentage of bacterial growth in each well was calculated as:
percentage of bacterial growth= (growth control well OD 600 Each well OD 600 ) Growth control well OD 600
The percentage of bacterial growth in each well of the plate was calculated according to the above formula, and the lowest combined drug concentration capable of inhibiting bacterial growth by 80% was taken as the endpoint of interpretation.
The results of the growth percentage experiment of methicillin-resistant staphylococcus aureus in 96-well plates when compounds 1 and 2 were applied respectively are shown in tables 1 and 2.
TABLE 1 percentage of growth of Compound 1 against methicillin-resistant Staphylococcus aureus (minimum effective inhibitory concentration: 5.56 μg/mL)
TABLE 2 percent growth of Compound 2 against methicillin-resistant Staphylococcus aureus (minimum effective inhibitory concentration: 2.88 μg/mL)
Experimental comparisons were made with the lowest effective inhibitory concentration of a compound having a similar structure against methicillin-resistant staphylococcus aureus, as shown in table 3. These compounds are from the papers Shu X, chen CC, yu T, yang J, hu X.Enntioselective Total Synthesis of (-) -Spiroxins A, C, and D.Angew Chem Int Ed Engl.2021Aug 16;60 (34) 18514-18518. Laboratory.
Table 3, 15 minimum effective inhibitory concentrations of exemplary compounds against methicillin-resistant staphylococcus aureus USA 300
In addition, the minimum effective inhibitory concentration MIC of fosfomycin sodium (positive control) on methicillin-resistant staphylococcus aureus is 14.56 mug/mL, and the antibacterial effect is far lower than that of compounds 1 and 2, which shows that the 5-substituted naphthoquinone compounds have better antibacterial effect and provide a feasible lead design for the development and synthesis of novel antibiotics with excellent antibacterial effect.
The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, simplifications, and applications without departing from the spirit and principles of the present invention should be made under equivalent substitution conditions, and are included in the scope of the present invention.
Claims (2)
1. An application of 5-substituted naphthoquinone compound shown in formula 2 in preparing antibacterial medicine,
the bacteria are methicillin-resistant staphylococcus aureus.
2. The use according to claim 1, wherein: the bacteria are methicillin-resistant staphylococcus aureus USA 300.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202210500637.1A CN114748455B (en) | 2022-05-09 | 2022-05-09 | Application of 5-substituted naphthoquinone compound in preparation of antibacterial drugs |
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| CN202210500637.1A CN114748455B (en) | 2022-05-09 | 2022-05-09 | Application of 5-substituted naphthoquinone compound in preparation of antibacterial drugs |
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| CN114748455A CN114748455A (en) | 2022-07-15 |
| CN114748455B true CN114748455B (en) | 2023-06-23 |
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