CN114617886B - Compound and antibacterial application of pharmaceutically acceptable salt thereof - Google Patents

Compound and antibacterial application of pharmaceutically acceptable salt thereof Download PDF

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CN114617886B
CN114617886B CN202210234383.3A CN202210234383A CN114617886B CN 114617886 B CN114617886 B CN 114617886B CN 202210234383 A CN202210234383 A CN 202210234383A CN 114617886 B CN114617886 B CN 114617886B
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antibacterial
formula
sensitive
resistant
staphylococcus aureus
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CN114617886A (en
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李雪
游雪甫
张友文
胡辛欣
王秀坤
聂彤颖
杨信怡
李聪然
李国庆
卢曦
庞晶
卢芸
孙琅
孟瑶
许春杰
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Institute of Medicinal Biotechnology of CAMS
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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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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

Abstract

The application discloses an antibacterial application of a compound shown in a general formula (I) and pharmaceutically acceptable salts thereof, wherein the meaning of groups in the general formula (I) is the same as that of the specification. The compound shown in the general formula (I) has better inhibition effect on various gram-positive bacteria causing clinical infection and can also show better antibacterial activity on drug-resistant gram-positive bacteria.

Description

Compound and antibacterial application of pharmaceutically acceptable salt thereof
Technical Field
The application relates to the technical field of medicines, in particular to an antibacterial application of a compound shown in a general formula (I) and pharmaceutically acceptable salts thereof.
Background
Staphylococcus aureus (Staphylococcus aureus, abbreviated as staphylococcus aureus hereinafter) is a clinically important pathogen that can cause a range of diseases from relatively minor skin infections to life threatening (e.g., endocarditis and osteomyelitis). It is also a symbiotic bacterium, about 30% of human nasal cavities bear staphylococcus aureus throughout the year, and when the immunity of the human body is reduced, the risk of generating staphylococcus aureus infection is greatly increased. At present, antibiotics such as penicillin, glycopeptides and the like are mainly used for clinically treating the staphylococcus aureus infection. However, bacterial resistance monitoring data shows that the resistance rate of staphylococcus aureus to antibiotics such as penicillin, methicillin, levofloxacin is higher. The glycopeptide drug vancomycin, which was the last line of defense against drug-resistant staphylococcus aureus, was reported in 1996 and 2002 as strains sensitive to it (VISA) and drug-resistant (VRSA), respectively. Currently, daptomycin (Daptomycin) in the marketed drugs can be used to inhibit vancomycin-resistant staphylococcus aureus, but Daptomycin-resistant staphylococcus aureus has also appeared in 2005. To date, almost every drug (including vancomycin, linezolid, daptomycin, and mupirocin) used to treat clinical staphylococcus aureus infections has emerged as a strain resistant to it.
Enterococci can cause a variety of infections including urinary tract infections, bacteremia, endocarditis, and meningitis. The national average drug resistance rates of enterococcus faecium and enterococcus faecalis to vancomycin are 1.0% and 0.2% respectively (national bacterial drug resistance monitoring report in 2020). In the new list of antibiotics developed and emphasized pathogens published by the world health organization (World Health Organization, WHO) in 2017, vancomycin-resistant enterococcus faecium (VRE) and methicillin-resistant (MRSA), vancomycin-mediated (VISA) and drug-resistant (VRSA) staphylococcus aureus were listed as very important (class 2 emphasis) strains with the most serious problem of gram-positive bacterial resistance. There is therefore an urgent need to develop new antibacterial agents, in particular agents active against resistant bacteria.
Disclosure of Invention
The following is a summary of the subject matter described in detail herein. This summary is not intended to limit the scope of the application.
The application provides an antibacterial application of a compound shown in a general formula (I) and pharmaceutically acceptable salts thereof,
wherein Ar is
R 1 、R 2 、R 3 Each independently is hydrogen, alkyl, haloalkyl, or hydroxy; r is R 4 、R 5 、R 6 、R 7 、R 9 、R 10 Each independently is-CF 3 、-NH 2 、-CO 2 H、-CO 2 Me、-CONHNH 2 -CO-piperazine, -CONH-glycine, -CH 2 CH 2 CO 2 Me、-CONH 2 、-CONHMe、-CH 2 CH 2 CONH-C1-C4 alkyl, -NHCO-C1-C4 alkyl, -NHCONH 2 、-NHSO 2 NH 2 、-NHSO 2 N(Me) 2 、-NHCO 2 -C1-C4 alkyl, six membered heterocycle substituted phenyl, aromatic ether or cyano; r is R 8 Is halogen.
In embodiments of the application, R 1 May be CF 3 ，R 2 、R 3 May be hydrogen.
In embodiments of the application, R 1 、R 2 、R 3 Is hydrogen.
In embodiments of the application, R 1 Can be hydrogen, R 2 、R 3 May be a hydroxyl group.
In embodiments of the application, R 4 、R 5 、R 6 、R 7 、R 9 、R 10 Can each independently be-CH 2 CH 2 CONH-C1-C4 alkyl, six-membered heterocycle substituted phenyl, aromatic ether or cyano.
In embodiments of the application, R 4 Phenyl which may be substituted by piperazine, R 5 Can be-CH 2 CH 2 CONH-CH 3 。
In embodiments of the application, R 6 Phenyl which may be substituted by piperazine, R 7 Can be-CH 2 CH 2 CONH-CH 3 。
In embodiments of the application, R 8 Can be chlorine, R 9 M-carboxy para-methylanisole is possible.
In embodiments of the application, R 10 May be cyano.
In embodiments of the application, the compound of formula (I) may be an OSU-T315 meta-substituted isomer of formula (II), an OSU-T315 ortho-substituted isomer of formula (III), MK3903 of formula (IV), or MT63-78 of formula (V),
in an embodiment of the present application, the antibacterial use may be use in the preparation of antibacterial drugs.
In an embodiment of the present application, the antibacterial agent may include any one or more of a compound represented by general formula (I) and a pharmaceutically acceptable salt thereof.
In embodiments of the application, the antimicrobial uses may include antimicrobial uses against gram positive bacteria.
In embodiments of the application, the gram positive bacteria may include drug resistant bacteria and sensitive bacteria.
In embodiments of the application, the drug-resistant bacteria may include drug-resistant staphylococcus aureus, drug-resistant enterococcus faecium, and drug-resistant staphylococcus epidermidis.
In an embodiment of the application, the resistant bacteria may include methicillin-resistant staphylococcus aureus MRSA, vancomycin-moderately sensitive staphylococcus aureus VISA, vancomycin-resistant enterococcus faecium VRE, and methicillin-resistant staphylococcus epidermidis MRSE.
In an embodiment of the present application, the sensitive bacteria may include sensitive staphylococcus aureus, sensitive enterococcus faecium, sensitive enterococcus faecalis, and sensitive staphylococcus epidermidis.
In an embodiment of the application, the sensitive bacteria may include methicillin-sensitive staphylococcus aureus MSSA, vancomycin-sensitive enterococcus faecium VSE, vancomycin-sensitive enterococcus faecalis VSE, and methicillin-sensitive staphylococcus epidermidis MSSE.
At present, the literature report about the compound OSU-T315 shown in the formula (II) and the formula (III) is that the compound OSU-T315 is used as an inhibitor of Integrin-Linked Kinase (ILK), and the anti-tumor activity of the compound OSU-T315 shown in the formula (III) is also reported; the literature reports on compounds MK3903 and MT63-78 are useful in the fields of antidiabetic, obesity, and cancer. No report on the antibacterial field is made on the compounds OSU-T315 shown in the formula (II) and the formula (III), the compound MK3903 shown in the formula (IV) and the compound MT63-78 shown in the formula (V).
The inventors of the present application have found that, by accident, the meta-substituted isomer (CAS: 2070015-22-2) of OSU-T315 represented by formula (II), the ortho-substituted isomer (CAS: 1333146-24-9) of OSU-T315 represented by formula (III), the compound MK3903 (CAS: 1219737-12-8) represented by formula (IV) and the compound MT63-78 (CAS: 1179347-65-9) represented by formula (V) have a good inhibitory effect on various gram-positive bacteria causing clinical infections and also exhibit a good antibacterial activity against drug-resistant gram-positive bacteria.
Wherein, the MIC of meta-substituted isomer of the compound OSU-T315 shown in the formula (II) to the staphylococcus aureus is 8-16 mug/mL; MIC for enterococcus faecium is 4 mug/mL, which is obviously better than that of the contrast medicine levofloxacin; MIC for enterococcus faecalis was 2-4. Mu.g/mL. The MIC of the ortho-substituted isomer of staphylococcus aureus of the compound OSU-T315 shown in the formula (III) is 8 mug/mL; MIC for enterococcus faecium was 4. Mu.g/mL; MIC for enterococcus faecalis was 4. Mu.g/mL. The minimum inhibitory concentration MIC of the compound MK3903 shown in the formula (IV) on staphylococcus aureus is 4-8 mug/mL; the MIC for enterococcus faecium is 4 mug/mL, which is obviously better than that of the contrast medicine levofloxacin; MIC for enterococcus faecalis was 4-8. Mu.g/mL. The MIC of the compound MT63-78 shown in the formula (V) on the staphylococcus aureus is 16 mug/mL; MIC for enterococcus faecium and enterococcus faecalis is 16-32 mug/mL.
Additional features and advantages of the application will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by practice of the application. Other advantages of the application may be realized and attained by the structure particularly pointed out in the written description and drawings.
Drawings
The accompanying drawings are included to provide an understanding of the principles of the application, and are incorporated in and constitute a part of this specification, illustrate embodiments of the application and together with the description serve to explain, without limitation, the principles of the application.
FIG. 1 (A) is a plot of colony count of MRSA standard strain ATCC33591 over time under the action of OSU-T315 (CAS: 2070015-22-2) at various concentrations;
FIG. 1 (B) is a plot of colony count of MRSA clinical strain 16-173 over time under the influence of varying concentrations of OSU-T315 (CAS: 2070015-22-2).
Detailed Description
For the purpose of making the objects, technical solutions and advantages of the present application more apparent, embodiments of the present application will be described in detail hereinafter with reference to the accompanying drawings. It should be noted that, without conflict, the embodiments of the present application and features of the embodiments may be arbitrarily combined with each other.
In the description of the present application, the term "alkyl" includes both straight chain groups and branched groups. Alkyl groups containing 4 or fewer carbon atoms may also be referred to as lower alkyl groups. Alkyl groups may also be mentioned by the number of carbon atoms they contain (i.e., C1-C4 alkyl is an alkyl group containing 1-4 carbon atoms).
In the description of the present application, the term "haloalkyl" includes groups substituted with one or more halogen atoms, including perfluorinated groups. Examples of suitable haloalkyl groups are chloromethyl, trifluoromethyl and the like. Halogenated moieties include chlorine, bromine, fluorine and iodine.
In the description of the present application, the minimum inhibitory concentration (Minimum Inhibitory Concentration, MIC) is an index for determining the magnitude of antimicrobial activity of an antimicrobial agent, which refers to the minimum concentration of the agent that inhibits the growth of pathogenic bacteria in a culture medium after 18 to 24 hours of in vitro culture of the bacteria.
The embodiment of the application provides an antibacterial application of a compound shown in a general formula (I) and pharmaceutically acceptable salts thereof,
wherein Ar is
R 1 、R 2 、R 3 Each independently is hydrogen, alkyl, haloalkyl, or hydroxy; r is R 4 、R 5 、R 6 、R 7 、R 9 、R 10 Each independently is-CF 3 、-NH 2 、-CO 2 H、-CO 2 Me、-CONHNH 2 -CO-piperazine, -CONH-glycine, -CH 2 CH 2 CO 2 Me、-CONH 2 、-CONHMe、-CH 2 CH 2 CONH-C1-C4 alkyl, -NHCO-C1-C4 alkyl, -NHCONH 2 、-NHSO 2 NH 2 、-NHSO 2 N(Me) 2 、-NHCO 2 -C1-C4 alkyl, six membered heterocycle substituted phenyl, aromatic ether or cyano; r is R 8 Is halogen.
In embodiments of the application, R 1 May be CF 3 ，R 2 、R 3 May be hydrogen.
In embodiments of the application, R 1 、R 2 、R 3 Is hydrogen.
In embodiments of the application, R 1 Can be hydrogen, R 2 、R 3 May be a hydroxyl group.
In embodiments of the application, R 4 、R 5 、R 6 、R 7 、R 9 、R 10 Can each independently be-CH 2 CH 2 CONH-C1-C4 alkyl, six-membered heterocycle substituted phenyl, aromatic ether or cyano.
In embodiments of the application, R 4 Phenyl which may be substituted by piperazine, R 5 Can be-CH 2 CH 2 CONH-CH 3 。
In embodiments of the application, R 6 Phenyl which may be substituted by piperazine, R 7 Can be-CH 2 CH 2 CONH-CH 3 。
In embodiments of the application, R 8 Can be chlorine, R 9 M-carboxy para-methylanisole is possible.
In embodiments of the application, R 10 May be cyano.
In embodiments of the application, the compound of formula (I) may be an OSU-T315 meta-substituted isomer of formula (II), an OSU-T315 ortho-substituted isomer of formula (III), MK3903 of formula (IV), or MT63-78 of formula (V),
in an embodiment of the present application, the antibacterial use may be use in the preparation of antibacterial drugs.
In an embodiment of the present application, the antibacterial agent may include any one or more of a compound represented by general formula (I) and a pharmaceutically acceptable salt thereof.
In embodiments of the application, the antimicrobial uses may include antimicrobial uses against gram positive bacteria.
In embodiments of the application, the gram positive bacteria may include drug resistant bacteria and sensitive bacteria.
In embodiments of the application, the drug-resistant bacteria may include drug-resistant staphylococcus aureus, drug-resistant enterococcus faecium, and drug-resistant staphylococcus epidermidis.
In an embodiment of the application, the resistant bacteria may include methicillin-resistant staphylococcus aureus MRSA, vancomycin-moderately sensitive staphylococcus aureus VISA, vancomycin-resistant enterococcus faecium VRE, and methicillin-resistant staphylococcus epidermidis MRSE.
In an embodiment of the present application, the sensitive bacteria may include sensitive staphylococcus aureus, sensitive enterococcus faecium, sensitive enterococcus faecalis, and sensitive staphylococcus epidermidis.
In an embodiment of the application, the sensitive bacteria may include methicillin-sensitive staphylococcus aureus MSSA, vancomycin-sensitive enterococcus faecium VSE, vancomycin-sensitive enterococcus faecalis VSE, and methicillin-sensitive staphylococcus epidermidis MSSE.
In embodiments of the present application, a "pharmaceutically acceptable salt" of a compound of formula (I) refers to the relatively non-toxic, inorganic and organic acid addition salts of a compound of formula (I). These salts may be prepared in situ during the final isolation and purification of the compounds of formula (I) and their derivatives, or by separately reacting the purified compounds of formula (I) and their derivatives with a suitable counterion, depending on the nature of the compounds of formula (I), and isolating the salts so formed. Representative counterions include chloride, bromide, nitrate, ammonium, sulfate, tosylate, phosphate, tartrate, maleate, and the like.
In the description of the present application, the term "antibacterial agent" refers to a drug that can be prepared or used to prevent bacterial infection.
In embodiments of the present application, the antimicrobial drug may be a solid formulation, a liquid formulation, or a semisolid formulation; the route of administration may be oral, injectable or topical; the dosage form may be injection (injectable solution or lyophilized preparation for injection), tablet, capsule, solid granule for oral administration, eye drop for eye, gel, ointment, skin cream, ointment, patch, spray, inhalant for oral or nasal cavity, etc.
In the embodiment of the application, the antibacterial drug can also contain auxiliary materials. The auxiliary materials can be selected according to the administration route, the type of preparation and the like.
In embodiments of the present application, the effective antimicrobial administration amount of the compounds of formula (I) and pharmaceutically acceptable salts thereof may vary from 50 to 5000 mg/day, and may be administered in single or multiple doses.
theclinicalisolatesusedinthefollowingexampleswerestoredintheChinamedicalsciencecenterfortypecultureCollection(CAMS-CCPM-A)ofpathogenicmicroorganisms(toxic)andrelatedmicroorganisms(toxic)andtheaccessionnumbersofthestrainsareshowninthetable.
Example 1: antibacterial Spectrometry for OSU-T315 (CAS: 2070015-22-2)
The measuring method comprises the following steps:
the strain to be tested is taken out from a low-temperature refrigerator at-80 ℃ two days before the test, streaked and inoculated on Tryptic Soy Agar (TSA) for resuscitating culture for 18-24hr. Three colonies of consistent size and morphology were picked one day before the test and inoculated in 2mL of trypticase soy peptone medium (TSB) and statically cultivated at 37℃until the logarithmic growth phase.
Determination of the minimum of Compounds (OSU-T315, CAS: 2070015-22-2) for each Strain tested by microdilutionThe bacteriostasis concentration (Minimum Inhibitory Concentration, MIC) is as follows: drug stock solutions of the compounds were double diluted in 96-well plates to the desired concentration gradients of 128, 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125 μg/mL in a 96-well plate. Taking test bacterial liquid cultured overnight, adjusting bacterial liquid to 0.5 McFarland concentration by turbidimetry, diluting bacterial liquid with 0.85 mass% physiological saline 20 times (about 5×10) 6 CFU/ml), sucking 10 μl of diluted bacterial liquid, adding into the serial double diluted medicated CAMH broth culture medium, and setting no-dosing control tube at the same time in experiment; tapping the edge of the culture plate, mixing, and culturing at 37deg.C for 16-18hr; the 96-well plate is taken out, and whether colony deposition exists at the bottom of the well is observed visually, and the minimum concentration of the drug contained in the well for sterile growth is the MIC value (refer to CLSI standard). The test strains for each species contained ATCC standard strains and clinically isolated strains.
The measurement results are shown in Table 1.
TABLE 1 antibacterial Spectrometry results for OSU-T315 (CAS: 2070015-22-2)
Note that: MSSA, methicillin-sensitive staphylococcus aureus; MRSA, methicillin-resistant staphylococcus aureus; VISA, vancomycin, moderately sensitive staphylococcus aureus; VSE, vancomycin-sensitive fecal/enterococcus faecalis; VRE, vancomycin resistant faecium/enterococcus faecalis; MSSE, methicillin-sensitive staphylococcus epidermidis; MRSE, methicillin resistant Staphylococcus epidermidis; ESBL, ultra-broad spectrum beta-lactamase; CRE, carbapenem resistant enterobacteria; NDM-1, neodri-beta-lactamase; ND, undetected.
OSU-T315 (CAS: 2070015-22-2) can be seen to have better antimicrobial activity against sensitive and resistant gram-positive bacteria, including MRSA, VISA, VRE resistant bacteria.
OSU-T315 (CAS: 2070015-22-2) has a MIC for Staphylococcus aureus of 8-16 μg/mL; MIC for enterococcus faecium is 4 mug/mL, which is obviously better than that of the contrast medicine levofloxacin; MIC for enterococcus faecalis was 2-4. Mu.g/mL.
Example 2: determination of antibacterial Activity of OSU-T315 (CAS: 1333146-24-9)
The anti-gram-positive activity of OSU-T315 (CAS: 1333146-24-9) was determined by the microdilution method. The method of culturing the strain and the method of microdilution were the same as in example 1. The measurement results are shown in Table 2.
TABLE 2 antibacterial Activity determination of OSU-T315 (CAS: 1333146-24-9)
OSU-T315 (CAS: 1333146-24-9) can be seen to have better antimicrobial activity against drug-resistant gram-positive bacteria, wherein the MIC for drug-resistant Staphylococcus aureus is 8 μg/mL; MIC for enterococcus faecium was 4. Mu.g/mL; MIC for enterococcus faecalis was 4. Mu.g/mL.
Example 3: determination of antibacterial Activity of MK3903 (CAS: 1219737-12-8), MT63-78 (CAS: 1179347-65-9)
MK3903 (CAS: 1219737-12-8) and MT63-78 (CAS: 1179347-65-9) were assayed for their antibacterial activity against sensitive and drug-resistant gram-positive bacteria by microdilution. The method of culturing the strain and the method of microdilution were the same as in example 1. The measurement results are shown in Table 3.
TABLE 3 determination of the antibacterial Activity of MK3903 and MT63-78
It can be seen that MK3903 and MT63-78 have good antibacterial activity against sensitive and resistant gram-positive bacteria (including MRSA, VISA, VRE resistant bacteria), and especially MK3903 has good activity. The minimum inhibitory concentration MIC of MK3903 on staphylococcus aureus is 4-8 mug/mL; the MIC for enterococcus faecium is 4 mug/mL, which is obviously better than that of the contrast medicine levofloxacin; MIC for enterococcus faecalis was 4-8. Mu.g/mL. MT63-78 has MIC of 16 mug/mL for staphylococcus aureus; MIC for enterococcus faecium and enterococcus faecalis is 16-32 mug/mL.
Example 4: determination of the Sterilization Curve (Time-kill Curve) (reference CLSI standard)
The strain to be tested is taken out from a low-temperature refrigerator at-80 ℃ two days before the test, streaked and inoculated on a TSA culture dish for resuscitating and culturing for 18-24hr. Three colonies with consistent size and morphology were picked one day before the test and inoculated in 2mL of TSB medium, and were stationary cultured at 37℃until the logarithmic growth phase.
Taking a strain to be tested cultured overnight, and diluting the bacterial liquid to about 10 6 Colony count unit (CFU/mL), different concentrations (0, 1, 2, 4, 8, 16, 32. Mu.g/mL) of the antibacterial agent (OSU-T315 (CAS: 2070015-22-2)) were added, mixed well and incubated at 37℃for stationary culture. Samples were taken at 0, 2, 4, 6, 8, and 24 hours, respectively, 10-fold serial dilutions were performed and plated on TSA dishes, incubated at 37℃for 16-18 hours, the average colony count of the dishes at each time point of each concentration was calculated, and the change curves of colony count with time were plotted as shown in FIG. 1 (A) and FIG. 1 (B). Wherein FIG. 1 (A) shows the colony count of MRSA standard strain ATCC33591 with time under the action of OSU-T315 (CAS: 2070015-22-2) at different concentrations, and FIG. 1 (B) shows the colony count of MRSA clinical strain CCPM (A) -P-0116173 with time under the action of OSU-T315 (CAS: 2070015-22-2) at different concentrations.
The results show that OSU-T315 (CAS: 2070015-22-2) has bactericidal effect on MRSA strain ATCC33591 and has dose-dependent bactericidal characteristics.
The results show that the compounds OSU-T315, MK3903 and MT63-78 have better inhibition effect on various gram-positive bacteria causing clinical infection and can also show better antibacterial activity on drug-resistant gram-positive bacteria.
Although the embodiments of the present application are described above, the embodiments are only used for facilitating understanding of the present application, and are not intended to limit the present application. Any person skilled in the art can make any modification and variation in form and detail without departing from the spirit and scope of the present disclosure, but the scope of the present disclosure is still subject to the scope of the present disclosure as defined by the appended claims.

Claims (14)

1. The antibacterial application of the compound shown in the general formula (I) and the pharmaceutically acceptable salt thereof,
wherein Ar is
R 1 、R 2 、R 3 Each independently is hydrogen, methyl, halomethyl, or hydroxy; r is R 4 、R 6 Phenyl substituted by piperazine, R 5 、R 7 is-CH 2 CH 2 CONH-CH 3 ，R 8 Is chlorine, R 9 Is meta-carboxy para-methylanisole, R 10 Is cyano;
the antibacterial uses include antibacterial uses against staphylococcus aureus, enterococcus faecium and enterococcus faecalis.
2. The antibacterial use according to claim 1, wherein,
R 1 is CF (CF) 3 ，R 2 、R 3 Is hydrogen; or alternatively, the process may be performed,
R 1 、R 2 、R 3 is hydrogen; or alternatively, the process may be performed,
R 1 is hydrogen, R 2 、R 3 Is hydroxyl.
3. The antibacterial use according to claim 1, wherein the compound of formula (I) is an OSU-T315 meta-substituted isomer of formula (II), an OSU-T315 ortho-substituted isomer of formula (III), MK3903 of formula (IV) or MT63-78 of formula (V),
4. an antibacterial use according to any one of claims 1 to 3, for use in the preparation of antibacterial medicaments.
5. The antibacterial use according to claim 4, wherein the antibacterial agent comprises any one or more of a compound represented by the general formula (I) and a pharmaceutically acceptable salt thereof.
6. The antibacterial use according to any one of claims 1 to 3, wherein the staphylococcus aureus is a drug-resistant bacterium or a sensitive bacterium, the enterococcus faecium is a drug-resistant bacterium or a sensitive bacterium, and the enterococcus faecalis is a sensitive bacterium.
7. The antibacterial use of claim 6, wherein the staphylococcus aureus comprises methicillin resistant staphylococcus aureus MRSA, vancomycin moderately sensitive staphylococcus aureus VISA, and methicillin sensitive staphylococcus aureus MSSA;
the enterococcus faecium comprises vancomycin-resistant enterococcus faecium VRE and vancomycin-sensitive enterococcus faecium VSE;
the enterococcus faecalis comprises vancomycin sensitive enterococcus faecalis VSE.
8. The antibacterial application of the compound shown in the general formula (I) and the pharmaceutically acceptable salt thereof,
wherein R is 1 Is halomethyl, R 2 、R 3 Is hydrogen, ar isR 4 Phenyl substituted by piperazine, R 5 is-CH 2 CH 2 CONH-CH 3 The method comprises the steps of carrying out a first treatment on the surface of the The antibacterial use is antibacterial use of staphylococcus epidermidis.
9. The antibacterial use according to claim 8, wherein R 1 Is CF (CF) 3 ，R 2 、R 3 Is hydrogen.
10. The antibacterial use according to claim 8, wherein the compound of formula (I) is an OSU-T315 meta-substituted isomer of formula (II),
11. the antibacterial use according to any one of claims 8 to 10, for use in the preparation of antibacterial medicaments.
12. The antibacterial use of claim 11, wherein the antibacterial agent comprises any one or more of a compound of formula (I) and pharmaceutically acceptable salts thereof.
13. The antibacterial use according to any one of claims 8 to 10, wherein the staphylococcus epidermidis is a drug resistant or sensitive bacterium.
14. The antibacterial use of claim 13, wherein the staphylococcus epidermidis comprises methicillin resistant staphylococcus epidermidis MRSE and methicillin sensitive staphylococcus epidermidis MSSE.
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CN108420814A (en) * 2017-02-15 2018-08-21 四川大学 A kind of NPS-2143 is used for the new application of antibacterial
CN110652512A (en) * 2018-12-28 2020-01-07 暨南大学 Application of crizotinib in preparation of anti-gram-positive-bacteria drugs
CN111166743A (en) * 2020-01-02 2020-05-19 中国医学科学院医药生物技术研究所 Anti-infection application of thiazole structure-containing compound
CN111870601A (en) * 2020-08-28 2020-11-03 广东工业大学 Application of 6-dimethylamino quinoline aromatic ethylene derivative in preparation of drug-resistant bacteria resistant drugs
CN113262214A (en) * 2021-03-12 2021-08-17 暨南大学 Application of cinacalcet hydrochloride in preparation of antibacterial drugs
CN113952339A (en) * 2020-07-21 2022-01-21 复旦大学 Use of compound FDEFA1 in preparation of gram-positive cocci inhibitor

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108420814A (en) * 2017-02-15 2018-08-21 四川大学 A kind of NPS-2143 is used for the new application of antibacterial
CN110652512A (en) * 2018-12-28 2020-01-07 暨南大学 Application of crizotinib in preparation of anti-gram-positive-bacteria drugs
CN111166743A (en) * 2020-01-02 2020-05-19 中国医学科学院医药生物技术研究所 Anti-infection application of thiazole structure-containing compound
CN113952339A (en) * 2020-07-21 2022-01-21 复旦大学 Use of compound FDEFA1 in preparation of gram-positive cocci inhibitor
CN111870601A (en) * 2020-08-28 2020-11-03 广东工业大学 Application of 6-dimethylamino quinoline aromatic ethylene derivative in preparation of drug-resistant bacteria resistant drugs
CN113262214A (en) * 2021-03-12 2021-08-17 暨南大学 Application of cinacalcet hydrochloride in preparation of antibacterial drugs

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