CN111166743B - Anti-infection application of thiazole structure-containing compound - Google Patents

Anti-infection application of thiazole structure-containing compound Download PDF

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CN111166743B
CN111166743B CN202010001376.XA CN202010001376A CN111166743B CN 111166743 B CN111166743 B CN 111166743B CN 202010001376 A CN202010001376 A CN 202010001376A CN 111166743 B CN111166743 B CN 111166743B
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benzamide
gram
sulfonylamino
methylphenyl
thiazol
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CN111166743A (en
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游雪甫
董立民
张友文
李聪然
杨信怡
王秀坤
胡辛欣
聂彤颖
李国庆
李雪
卢芸
庞晶
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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
    • A61K31/41—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
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • 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
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
    • C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The application discloses anti-infection application of thiazole structure-containing compounds, the thiazole structure-containing compounds have an inhibiting effect on gram-negative bacteria pseudomonas aeruginosa virulence factors and gram-positive bacteria staphylococcus aureus virulence factors, and ML364 can respectively improve the survival rates of carbapenem drug-resistant pseudomonas aeruginosa and methicillin drug-resistant staphylococcus aureus-induced systemic infection mice by 60%.

Description

Anti-infection application of thiazole structure-containing compound
Technical Field
The application relates to the field of medicines, in particular but not limited to anti-infection application of a compound containing a thiazole structure.
Background
Pseudomonas aeruginosa (Pseudomonas aeruginosa) and Staphylococcus aureus (Staphylococcus aureus) are common pathogenic bacteria of nosocomial infection, and both are very susceptible to drug resistance. In a list of important pathogens for the development of novel antibiotics issued by the World Health Organization (WHO) in 2017, Carbapenem drugs resistant Pseudomonas aeruginosa (CRPA), Methicillin resistant, vancomycin mediated and resistant Staphylococcus aureus (Methicillin-resistant, vancomycin intermediate and resistant Staphylococcus aureus) are in the positions of paramount importance (class 1 emphasis) and paramount importance (class 2 emphasis), respectively. In order to alleviate the public health crisis caused by antibiotic resistance, it is particularly urgent to develop a novel treatment strategy different from the conventional antibacterial drugs. The traditional antibacterial treatment plays a role by bacteriostasis or sterilization, so that the survival pressure of bacteria is high, and drug resistance is easy to generate. The method controls the pathogenicity of bacteria, reduces the virulence of the bacteria, ensures that the bacteria are easy to be eliminated by the immune system of a human host, and is a hotspot for the research and development of novel medicaments. The strategy has low selective pressure on drug resistance of the strain and has the advantage of delaying or reducing the generation of drug resistance.
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 claims.
Pyocin (pyocyanin) is an important virulence factor produced by pseudomonas aeruginosa, and can cause changes in the redox balance of host cells, leading to cell damage and death. Pyocyanin with certain concentration can be detected at sputum, ear secretion and wound of a patient infected by pseudomonas aeruginosa. The literature reports that compared with a wild strain, the strain with the pyocin generation defect has obviously weakened toxicity to mice. After entering a human body, staphylococcus aureus can secrete a large number of virulence factors in order to adapt to the blood environment of the human body and avoid and weaken the immune invasion of host cells. The staphyloxanthin is a specific virulence factor of staphylococcus aureus, has a direct relation with the pathogenicity of bacteria, can help pathogenic bacteria to resist immune killing of human bodies, and can accelerate necrosis of human organs and tissues. In conclusion, the drug targeting pyocin or golden yellow pigment can not only reduce the pathogenicity of pseudomonas aeruginosa or golden yellow staphylococcus, but also effectively reduce the generation of drug resistance.
The reported medicines targeting bacterial virulence factors have narrow action range, and no compound which can act on gram-negative bacteria and gram-positive bacteria exists. Therefore, the development of a novel broad-spectrum antibacterial drug which is safe and effective and targets the virulence factors of bacteria is still necessary.
The compound related by the application has an inhibiting effect on gram-negative bacteria pseudomonas aeruginosa virulence factors and gram-positive bacteria staphylococcus aureus virulence factors. And ML364(2- ((4-methylphenyl) sulfonylamino) -N- (4-phenylthiazole-2-yl) -4- (trifluoromethyl) benzamide) has better in-vivo curative effect, 3mg/kg is continuously administrated three times, and the survival rates of mice with systemic infection caused by carbapenem drug-resistant pseudomonas aeruginosa and methicillin drug-resistant staphylococcus aureus can be respectively improved by 60 percent. Is expected to become a novel broad-spectrum antibacterial drug targeting bacterial virulence factors.
The application provides the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment or prevention of a bacterial infection
Figure BDA0002353625510000021
Wherein Ar is substituted phenyl, unsubstituted phenyl, substituted heterocycle, or unsubstituted heterocycle;
w is-C (O) -or-S (O)2-；
R1And R2Each independently selected from: hydrogen, unsubstituted alkyl, substituted alkyl, alkoxy, unsubstituted phenyl, substituted phenyl, unsubstituted naphthyl, substituted naphthyl, unsubstituted heterocycle, substituted heterocycle, or alkoxyacyl;
y is optionally present, and when Y is present, Y is
Figure BDA0002353625510000031
In that
Figure BDA0002353625510000032
Wherein Z is-NH-S (O)2-or-S (O)2-NH-，R3Is unsubstituted alkyl, substituted alkyl or halogen.
In the present application, Ar may be substituted phenyl, unsubstituted phenyl, substituted heterocycle or unsubstituted heterocycle, preferably phenyl substituted with one or more substituted or unsubstituted alkyl groups, phenyl substituted with one or more halogen, phenyl substituted with one halogen and one unsubstituted alkyl group, phenyl substituted with one or more alkoxy groups, phenyl or thienyl; halogen may preferably be fluorine or chlorine, alkoxy may preferably be methoxy, substituted alkyl may preferably be trifluoromethyl, and alkyl may preferably be methyl.
In this application, R1And R2May each be independently selected from: hydrogen, unsubstituted alkyl, substituted alkyl, unsubstituted phenyl, substituted phenyl, unsubstituted naphthyl, substituted naphthyl, unsubstituted heterocycle, substituted heterocycle, or alkoxyacyl; unsubstituted alkyl groups may preferably be methyl or tert-butyl; substituted alkyl is preferably trifluoroethyl; the substituted phenyl group may preferably be one or more of fluoro, chloro, methyl, isopropyl, tert-butyl, methoxy orNitro-substituted phenyl; the heterocyclic ring may preferably be pyridine, thiophene or pyrrole; the alkoxyacyl group may preferably be an ethoxyacyl group.
In this application, R2May be unsubstituted alkyl, substituted alkyl, unsubstituted phenyl, substituted phenyl, unsubstituted naphthyl, substituted naphthyl, unsubstituted heterocycle, substituted heterocycle or alkoxyacyl; unsubstituted alkyl groups may preferably be methyl or tert-butyl; substituted alkyl is preferably trifluoroethyl; the substituted phenyl group may preferably be one or more fluoro, chloro, methyl, isopropyl, tert-butyl, methoxy or nitro substituted phenyl groups; the heterocyclic ring may preferably be pyridine, thiophene or pyrrole; the alkoxyacyl group may preferably be an ethoxyacyl group. R1Preferably hydrogen.
In the present application, when Y is present, Z is-NH-S (O)2When-is, W may be-C (O) -;
y may be
Figure BDA0002353625510000041
Ar may be substituted phenyl, unsubstituted phenyl, substituted or unsubstituted heterocyclic, preferably phenyl substituted with one or more substituted or unsubstituted alkyl, phenyl substituted with one or more halogen, phenyl substituted with one halogen and one unsubstituted alkyl, phenyl substituted with one or more alkoxy, phenyl or thienyl; halogen may preferably be fluorine or chlorine, alkoxy may preferably be methoxy, substituted alkyl may preferably be trifluoromethyl, alkyl may preferably be methyl;
R1and R2May each be independently selected from: hydrogen, unsubstituted alkyl, substituted alkyl, unsubstituted phenyl, substituted phenyl, unsubstituted naphthyl, substituted naphthyl, unsubstituted heterocycle, substituted heterocycle, or alkoxyacyl; unsubstituted alkyl groups may preferably be methyl or tertiaryA butyl group; substituted alkyl is preferably trifluoroethyl; the substituted phenyl group may preferably be one or more fluoro, chloro, methyl, isopropyl, tert-butyl, methoxy or nitro substituted phenyl groups; the heterocyclic ring may preferably be pyridine, thiophene or pyrrole; the alkoxyacyl group may preferably be an ethoxyacyl group, R1Preferably hydrogen;
R3it may be hydrogen or chlorine or trifluoromethyl.
In the present application, when Y is present, Z is-S (O)2when-NH-, W may be-C (O) -;
y may be
Figure BDA0002353625510000042
R3May be hydrogen or methyl;
ar may be substituted phenyl, unsubstituted phenyl, substituted or unsubstituted heterocycle, preferably phenyl substituted with one or more substituted or unsubstituted alkyl, phenyl substituted with one halogen and one substituted alkyl; halogen may preferably be chlorine, substituted alkyl may preferably be trifluoromethyl, and alkyl may preferably be methyl.
In the present application, W may be-C (O) -;
R2may be methyl or tert-butyl; a trifluoroethyl group; unsubstituted phenyl; phenyl substituted by fluorine, chlorine, methyl, isopropyl, tert-butyl, methoxy or nitro, phenyl substituted by two fluorines or two chlorines; unsubstituted naphthyl; pyridyl, thienyl or pyrrolyl; or an ethoxyacyl group;
R1may be hydrogen;
y may be
Figure BDA0002353625510000051
Ar may be phenyl substituted by one or two or three methyl groups, isopropylPhenyl substituted by a group, phenyl substituted by ethoxy, phenyl substituted by two fluorines or methoxy, phenyl substituted by trifluoromethyl, phenyl substituted by fluorine, phenyl substituted by one fluorine and one methyl, or thienyl; r3And may be chloro or trifluoromethyl.
In the present application, W may be-C (O) -;
R2may be unsubstituted phenyl;
R1may be hydrogen;
y may be
Figure BDA0002353625510000052
Ar can be phenyl substituted with chloro and trifluoromethyl, phenyl substituted with methyl, phenyl substituted with trifluoromethyl, phenyl substituted with two methyl groups;
R3may be a methyl group.
In the present application, when Y is absent, W may be-S (O)2-；
Ar may be phenyl substituted by trifluoromethyl, R2May be in ortho position to the nitrogen atom in the thiazole ring, R2May be unsubstituted phenyl;
R1may be hydrogen.
In the present application, the term "alkyl" refers to a linear or branched alkyl or cycloalkyl group having 6 or less carbon atoms.
In the present application, the term "substituted phenyl" refers to phenyl substituted with alkoxy, halogen, nitro or alkyl.
In the present application, the term "heterocycle" refers to an aromatic heterocycle containing one or more heteroatoms.
In the present application, the term "substituted heterocycle" refers to a heterocycle substituted with alkoxy, halogen, nitro or alkyl.
In this application, the term "halogen" refers to fluorine, chlorine, bromine and iodine.
In the present application, preferably, the compound of formula (I) may include:
2- ((4-methylphenyl) sulfonylamino) -N- (4-phenylthiazol-2-yl) -4- (trifluoromethyl) benzamide;
2- ((4-methylphenyl) sulfonamido) -N- (4- (2, 5-dichlorophenyl) thiazol-2-yl) benzamide;
2- ((4-methylphenyl) sulfonylamino) -N- (4- (2-thienyl) thiazol-2-yl) benzamide;
2- ((4-fluorophenyl) sulfonylamino) -N- (4- (4-methylphenyl) thiazol-2-yl) benzamide;
4- ((2, 5-dimethylphenyl) sulfonylamino) -N- (4-phenylthiazol-2-yl) benzamide;
2- ((4-ethoxyphenyl) sulfonamido) -N- (4- (4-fluorophenyl) thiazol-2-yl) benzamide;
2- ((4-methylphenyl) sulfonylamino) -N- (4-ethoxyacylthiazol-2-yl) benzamide;
2- ((2-thienyl) sulfonamido) -N- (4- (4-methylphenyl) thiazol-2-yl) benzamide;
2- ((4-fluorophenyl) sulfonylamino) -N- (4-phenylthiazol-2-yl) benzamide;
2- ((4-fluorophenyl) sulfonylamino) -N- (4- (4-isopropylphenyl) thiazol-2-yl) benzamide;
2- ((3, 4-difluorophenyl) sulfonamido) -N- (4- (4-methoxyphenyl) thiazol-2-yl) benzamide;
2- ((2-thienyl) sulfonamido) -N- (4-phenylthiazol-2-yl) benzamide;
2- ((4-methylphenyl) sulfonylamino) -N- (4-tert-butylthiazol-2-yl) benzamide;
2- ((4-methylphenyl) sulfonylamino) -N- (4- (3-nitrophenyl) thiazol-2-yl) benzamide;
2- ((4-methylphenyl) sulfonylamino) -N- (4- (4-methoxyphenyl) thiazol-2-yl) benzamide;
2- ((2,4, 6-trimethylphenyl) sulfonamido) -N- (4- (4-tert-butylphenyl) thiazol-2-yl) benzamide;
2- ((3, 4-dimethoxyphenyl) sulfonylamino) -N- (4- (4-fluorophenyl) thiazol-2-yl) benzamide;
2- ((3-trifluoromethylphenyl) sulfonylamino) -N- (4-phenylthiazol-2-yl) benzamide hydrobromide;
2- ((4-fluorophenyl) sulfonylamino) -N- (4-methylthiazol-2-yl) benzamide;
2- ((3-trifluoromethylphenyl) sulfonylamino) -N- (4-methylthiazol-2-yl) benzamide;
2- ((4-fluorophenyl) sulfonylamino) -N- (4- (4-pyridyl) thiazol-2-yl) benzamide;
2- ((4-methylphenyl) sulfonylamino) -N- (4- (3-pyridinyl) thiazol-2-yl) benzamide;
2- ((4-fluoro-3-methylphenyl) sulfonylamino) -N- (4- (4-pyridinyl) thiazol-2-yl) benzamide;
2- (phenylsulfonylamino) -N- (4- (3-pyridyl) thiazol-2-yl) -4-chlorobenzamide;
2- ((4-methylphenyl) sulfonylamino) -N- (4-naphthylthiazol-2-yl) benzamide;
2- ((4-methylphenyl) sulfonylamino) -N- (4-methylthiazol-2-yl) benzamide;
2- ((4-methylphenyl) sulfonylamino) -N- (4- (2-pyrrolyl) thiazol-2-yl) benzamide;
2- ((4-methylphenyl) sulfonylamino) -N- (4-trifluoroethylthiazol-2-yl) benzamide;
2-methyl-5- (N- (3-methylphenyl) sulfamoyl) -N- (4-phenylthiazol-2-yl) benzamide;
3- (N- (2-chloro-5- (trifluoromethyl) phenyl) sulfamoyl) -N- (4-phenylthiazol-2-yl) benzamide;
3- (N- (2, 4-dimethylphenyl) sulfamoyl) -N- (4-phenylthiazol-2-yl) benzamide;
3- (N- (3-trifluoromethylphenyl) sulfamoyl) -N- (4-phenylthiazol-2-yl) benzamide;
4- (N- (4-methylphenyl) sulfamoyl) -N- (4-phenylthiazol-2-yl) benzamide hydrochloride;
n- (4-phenylthiazol-2-yl) -3-trifluoromethylbenzenesulfonamide;
and N- (4-phenylthiazol-2-yl) -4-trifluoromethylbenzenesulfonamide.
Further preferably, the compound of formula (I) may include:
2- ((4-methylphenyl) sulfonylamino) -N- (4-phenylthiazol-2-yl) -4- (trifluoromethyl) benzamide (ML 364);
2- ((2-thienyl) sulfonamido) -N- (4- (4-methylphenyl) thiazol-2-yl) benzamide;
2- ((4-fluorophenyl) sulfonylamino) -N- (4- (4-isopropylphenyl) thiazol-2-yl) benzamide;
2- ((4-fluorophenyl) sulfonylamino) -N- (4- (4-methylphenyl) thiazol-2-yl) benzamide;
2- ((4-fluorophenyl) sulfonylamino) -N- (4-phenylthiazol-2-yl) benzamide;
and 2-methyl-5- (N- (3-methylphenyl) sulfamoyl) -N- (4-phenylthiazol-2-yl) benzamide.
In this application, reference books and references relating to chemical reactions, such as: basic organic chemistry, third edition, from chen shi, Shiwei, Xurui autumn, Shi shi; SYNTHETIC ORGANIC CHEM (John Wiley & Sons, Inc., NY); sandler et al, ORGANIC FUNCTIONAL GROUP precursors (2 nd edition, Acad. Press, NY, 1983); house, MODERN synthitic REACTIONS (2 nd edition, w.a. benjamin, inc., Menlo Park, CA, 1972); gilchrist, HETEROCYCLIC CHEM. (2 nd edition, John Wiley & Sons, NY, 1992); march, adv. organic chem.: REACTIONS, MECH. & stroture (4 th edition, Wiley-intersci., NY, 1992); fuhrhop & Penzlin, ORGANIC SYNTHESIS: CONCEPTS, METHOD, STARTING MATERIALS: second, revised and supplementations (John Wiley & Sons ISBN: 3-527-; hoffman, ORGANIC CHEM., AN INTERMEDIATE TEXT (Oxford Univ. Press, ISBN 0-19-509618-; larock, composition ORGANIC TRANSFORMATIONS, GUIDE TO FUNCTION GROUP PREPARATIONS (2 nd edition, Wiley-VCH, ISBN: 0-471-.
Specific and similar reactants can also be identified by indexes of known chemicals made by Chemical abstracts Service of the American Chemical Society available in most public libraries and college libraries and by online databases. References for the preparation and selection OF pharmaceutically acceptable SALTS OF the compounds described herein are Stahl & CG Wermuth, HANDBOOK OF PHARMACEUTICAL SALTS (Verlag Helvetica Chimica Acta, Zurich, 2002).
The following scheme can be used for the synthesis of compounds of formula (I):
Figure BDA0002353625510000081
scheme 1
Wherein W is-S (O)2Ar is substituted phenyl, unsubstituted phenyl, substituted heterocycle or unsubstituted heterocycle, R2Is unsubstituted alkyl, substituted alkyl, alkoxy, unsubstituted phenyl, substituted phenyl, unsubstituted naphthyl, substituted naphthyl, unsubstituted heterocycle, substituted heterocycle or alkoxyacyl, R1Is hydrogen.
Figure BDA0002353625510000091
Scheme 2
Wherein Ar is substituted phenyl, unsubstituted phenyl, substituted heterocycle or unsubstituted heterocycle, R3Is unsubstituted alkyl, substituted alkyl or halogen, R2Is unsubstituted alkyl, substituted alkyl, alkoxy, unsubstituted phenyl, substituted phenyl, unsubstituted naphthyl, substituted naphthyl, unsubstituted heterocycle, substituted heterocycle or alkoxyacyl, R1Is hydrogen.
TABLE 1 Mass Spectrometry data for some of the compounds of the present application
Figure BDA0002353625510000092
Figure BDA0002353625510000101
In the present application, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof may inhibit a gram-negative or gram-positive virulence factor, or both a gram-negative and a gram-positive virulence factor.
In the present application, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof may achieve an anti-infective effect by inhibiting a gram-negative or gram-positive virulence factor, or both.
In the present application, the gram-negative bacterial virulence factors may include, but are not limited to, any one or more of pyocin (Pyocyanin), fluorosiderophore (Pyoverdine), Elastase (Elastase), and Rhamnolipid (Rhamnolipid).
In the present application, the gram-negative bacterial virulence factor may be selected from any one or more of pyocin, a fluorescent siderophore, elastase and rhamnolipids.
In the present application, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof can inhibit the biosynthesis of pyocins.
In the present application, the gram-positive bacterial virulence factors may include, but are not limited to, any one or more of, aureochrome (Staphyloxanthin), haemotoxin (Hemoysin), plasma Coagulase (coagulose) and Enterotoxin (Enterotoxin).
In the present application, the gram-positive virulence factor may be selected from any one or more of the group consisting of golden yellow pigment, haemotoxin, plasma coagulase and enterotoxin.
In the present application, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof may inhibit the biosynthesis of golden yellow pigment.
In the present application, the bacteria may be gram-negative bacteria or gram-positive bacteria, or gram-negative bacteria and gram-positive bacteria.
In the present application, the gram-negative bacteria may include, but are not limited to, gram-negative bacteria susceptible bacteria and gram-negative bacteria resistant bacteria.
In the present application, the gram-negative bacteria resistant bacteria may include, but are not limited to, carbapenem drug-resistant pseudomonas aeruginosa, carbapenem drug-resistant acinetobacter baumannii, and carbapenem drug-resistant extended-spectrum beta-lactamase (ESBL) enterobacter.
In the present application, the gram-negative bacteria resistant bacteria may be selected from any one or more of carbapenem drug-resistant pseudomonas aeruginosa, carbapenem drug-resistant acinetobacter baumannii, and carbapenem drug-resistant extended-spectrum beta-lactamase (ESBL) enterobacter.
In the present application, the gram-positive bacteria may include, but are not limited to, gram-positive bacteria sensitive bacteria and gram-positive bacteria resistant bacteria.
In the present application, the gram-positive bacteria resistant bacteria may include, but are not limited to, Methicillin-resistant Staphylococcus Epidermidis (MRSE), Methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Staphylococcus aureus (VRSA), vancomycin-resistant enterococcus faecium/enterococcus faecalis (VRE), and Penicillin-insensitive Streptococcus Pneumoniae (PNSSP).
In the present application, the gram-positive bacteria resistant bacteria may be selected from any one or more of methicillin-resistant staphylococcus epidermidis, methicillin-resistant staphylococcus aureus (MRSA), vancomycin-resistant staphylococcus aureus (VRSA), vancomycin-resistant enterococcus faecium/enterococcus faecalis (VRE), and penicillin-insensitive streptococcus pneumoniae.
In the present application, the compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof can inhibit infection by pseudomonas aeruginosa or staphylococcus aureus.
Use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, in combination with one or more of a sulfonamide, quinolone antibacterial, beta-lactam antibiotic, aminoglycoside antibiotic, lincosamide, streptogramin, oxazolidinone, polypeptide, macrolide antibiotic and tetracycline antibiotic for the treatment or prevention of a bacterial infection.
The compounds of the present application or pharmaceutical compositions comprising the active compounds may be administered to a subject by any convenient route of administration, whether systemically/peripherally or locally. Routes of administration include, but are not limited to: orally (e.g., by ingestion); taking orally; under the tongue; transdermal (including, for example, via a patch, plaster, etc.); transmucosal (including, for example, through patches, plasters, etc.); intranasally (e.g., by nasal spray); ophthalmic (e.g., via eye drops); lung (e.g., by using inhalation or insufflation therapy, e.g., via aerosol, e.g., through the mouth or nose); rectally (e.g., by suppository or enema); the vagina (e.g., through a pessary); parenterally, for example, by injection, including subcutaneous injection, intradermal injection, intramuscular injection, intravenous injection, intraarterial injection, intracardiac injection, intrathecal injection, intraspinal injection, intracapsular injection, subcapsular injection, intraorbital injection, intraperitoneal injection, intratracheal injection, subcuticular injection, intraarticular injection, subarachnoid injection, and intrasternal injection.
The compounds described herein may be formed into and/or used as pharmaceutically acceptable salts. Types of pharmaceutically acceptable salts include, but are not limited to: (1) an acid addition salt formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid: such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 2-naphthalenesulfonic acid, 3-phenylpropionic acid, trimethylacetic acid, t-butylacetic acid, laurylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; (2) salts are formed when an acidic proton present in the parent compound is replaced with a metal ion, such as an alkali metal ion (e.g., lithium, sodium, potassium), alkaline earth metal ion (e.g., magnesium, or calcium), or aluminum ion, or is coordinated with an organic base. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.
The compound can inhibit virulence factors of strains such as pseudomonas aeruginosa PAO1, pseudomonas aeruginosa ATCC27853, carbapenem drug-resistant pseudomonas aeruginosa clinical isolates 16-2, pseudomonas aeruginosa clinical isolates 16-17, staphylococcus aureus ATCC29213, methicillin drug-resistant staphylococcus aureus ATCC33591, methicillin drug-resistant staphylococcus aureus N315, methicillin drug-resistant staphylococcus aureus clinical isolates 08-50 and the like.
The compounds of the present application may be used to treat tumors, such as breast cancer; pneumonia; urinary tract infections; infectious endocarditis; skin soft tissue infections; bacteremia, sepsis, etc.
The present application also provides the following compounds:
2- ((4-methylphenyl) sulfonamido) -N- (4- (2, 5-dichlorophenyl) thiazol-2-yl) benzamide;
2- ((4-methylphenyl) sulfonylamino) -N- (4- (2-thienyl) thiazol-2-yl) benzamide;
4- ((2, 5-dimethylphenyl) sulfonylamino) -N- (4-phenylthiazol-2-yl) benzamide;
2- ((4-ethoxyphenyl) sulfonamido) -N- (4- (4-fluorophenyl) thiazol-2-yl) benzamide;
2- ((4-methylphenyl) sulfonylamino) -N- (4-ethoxyacylthiazol-2-yl) benzamide;
2- ((3, 4-difluorophenyl) sulfonamido) -N- (4- (4-methoxyphenyl) thiazol-2-yl) benzamide;
2- ((2-thienyl) sulfonamido) -N- (4-phenylthiazol-2-yl) benzamide;
2- ((4-methylphenyl) sulfonylamino) -N- (4-tert-butylthiazol-2-yl) benzamide;
2- ((4-methylphenyl) sulfonylamino) -N- (4- (3-nitrophenyl) thiazol-2-yl) benzamide;
2- ((4-methylphenyl) sulfonylamino) -N- (4- (4-methoxyphenyl) thiazol-2-yl) benzamide;
2- ((2,4, 6-trimethylphenyl) sulfonamido) -N- (4- (4-tert-butylphenyl) thiazol-2-yl) benzamide;
2- ((3, 4-dimethoxyphenyl) sulfonylamino) -N- (4- (4-fluorophenyl) thiazol-2-yl) benzamide;
2- ((3-trifluoromethylphenyl) sulfonylamino) -N- (4-phenylthiazol-2-yl) benzamide hydrobromide;
2- ((4-fluorophenyl) sulfonylamino) -N- (4-methylthiazol-2-yl) benzamide;
2- ((3-trifluoromethylphenyl) sulfonylamino) -N- (4-methylthiazol-2-yl) benzamide;
2- ((4-fluorophenyl) sulfonylamino) -N- (4- (4-pyridyl) thiazol-2-yl) benzamide;
2- ((4-methylphenyl) sulfonylamino) -N- (4- (3-pyridinyl) thiazol-2-yl) benzamide;
2- ((4-fluoro-3-methylphenyl) sulfonylamino) -N- (4- (4-pyridinyl) thiazol-2-yl) benzamide;
2- (phenylsulfonylamino) -N- (4- (3-pyridyl) thiazol-2-yl) -4-chlorobenzamide;
2- ((4-methylphenyl) sulfonylamino) -N- (4-naphthylthiazol-2-yl) benzamide;
2- ((4-methylphenyl) sulfonylamino) -N- (4-methylthiazol-2-yl) benzamide;
2- ((4-methylphenyl) sulfonylamino) -N- (4- (2-pyrrolyl) thiazol-2-yl) benzamide;
2- ((4-methylphenyl) sulfonylamino) -N- (4-trifluoroethylthiazol-2-yl) benzamide;
3- (N- (2-chloro-5- (trifluoromethyl) phenyl) sulfamoyl) -N- (4-phenylthiazol-2-yl) benzamide;
3- (N- (2, 4-dimethylphenyl) sulfamoyl) -N- (4-phenylthiazol-2-yl) benzamide;
3- (N- (3-trifluoromethylphenyl) sulfamoyl) -N- (4-phenylthiazol-2-yl) benzamide;
4- (N- (4-methylphenyl) sulfamoyl) -N- (4-phenylthiazol-2-yl) benzamide hydrochloride;
n- (4-phenylthiazol-2-yl) -3-trifluoromethylbenzenesulfonamide;
and N- (4-phenylthiazol-2-yl) -4-trifluoromethylbenzenesulfonamide.
The application provides a novel antibacterial drug, which can obviously reduce biosynthesis of virulence factor pyocin of gram-negative bacteria pseudomonas aeruginosa and virulence factor golden yellow pigment of gram-positive bacteria staphylococcus aureus. Wherein, the compound has better inhibiting effect on pyocin and golden yellow pigment. The compound ML364 can obviously improve the survival rate of mice infected systemically by pseudomonas aeruginosa (including sensitive strains and carbapenem drug-resistant strains) and staphylococcus aureus (including sensitive strains and methicillin drug-resistant strains).
The application finds the inhibitory effect of the USP2 inhibitor ML364 on virulence factors of gram-negative and gram-positive bacteria.
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 the practice of the application. The objectives and 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 a further understanding of the claimed subject matter and are incorporated in and constitute a part of this specification, illustrate embodiments of the subject matter and together with the description serve to explain the principles of the subject matter and not to limit the subject matter.
FIG. 1 is a graph of ML364 inhibition of Pseudomonas aeruginosa PAO1 and 16-2 pyocin. P <0.01, P <0.001, P <0.0001, compared to control.
FIG. 2 is a graph of the effect of ML364(3mg/kg) on the survival of mice in a model of systemic infection with Pseudomonas aeruginosa (A) and Staphylococcus aureus (B). P <0.01, compared to model group.
FIG. 3 is a scheme showing the preparation of N- (4-phenylthiazol-2-yl) -3-trifluoromethylbenzenesulfonamide1H-NMR spectrum.
FIG. 4 is a scheme of the synthesis of 2- ((2-thienyl) sulfonamido) -N- (4-phenylthiazol-2-yl) benzamide1H-NMR spectrum.
FIG. 5 is a scheme showing the synthesis of 2- ((4-ethoxyphenyl) sulfonamido) -N- (4- (4-fluorophenyl) thiazol-2-yl) benzamide1H-NMR spectrum.
FIG. 6 is a process for the preparation of 3- (N- (2-chloro-5- (trifluoromethyl) phenyl) aminosulfonyl) -N- (4-phenylthiazol-2-yl) benzamide1H-NMR spectrum.
FIG. 7 is a process for the preparation of 2- ((4-methylphenyl) sulfonylamino) -N- (4-ethoxyformylthiazol-2-yl) benzamide1H-NMR spectrum.
FIG. 8 is a drawing of 3- (N- (3-trifluoromethylphenyl) aminosulfonyl) -N- (4-phenylthiazol-2-yl) benzamide1H-NMR spectrum.
FIG. 9 is a process for preparing 4- ((2, 5-dimethylphenyl) sulfonylamino) -N- (4-phenylthiazol-2-yl) benzamide1H-NMR spectrum.
FIG. 10 is a process for the preparation of 2- ((4-methylphenyl) sulfonylamino) -N- (4- (4-methoxyphenyl) thiazol-2-yl) benzamide1H-NMR spectrum.
FIG. 11 is a process for the preparation of 2- ((4-methylphenyl) sulfonylamino) -N- (4- (2-thienyl) thiazol-2-yl) benzamide1H-NMR spectrum.
FIG. 12 is a preparation of 2- ((4-fluorophenyl) sulfonylamino) -N- (4-methylthiazol-2-yl) benzamide1H-NMR spectrum.
Detailed Description
To make the objects, technical solutions and advantages of the present application more apparent, embodiments of the present application will be described in detail below with reference to the accompanying drawings. It should be noted that the embodiments and features of the embodiments in the present application may be arbitrarily combined with each other without conflict.
Instruments and reagents
The instruments used in the examples: constant temperature incubator (Shanghai-Hengscientific instruments Co., Ltd., BPN-80RHP), shaking incubator (Shanghai Zhicheng analytical instruments manufacturing Co., ZWY-100H), enzyme labeling instrument (France HORIBA ABX, Enspire 2300); reagent: chloroform (Beijing chemical plant), hydrochloric acid (Beijing chemical plant), methanol (Tianjin Kemi European chemical reagent Co., Ltd.); phosphate buffered Saline (Phosphate Buffer Saline, PBS); culture medium: Luria-Bertani (LB) medium, Trypticase Soy Broth (TSB), MH (Murller-Hinton) agar medium; all compounds of the present application are available from Shanghai ceramic Biotechnology, Inc.
Instruments used in the quality control of the compounds: agilent liquid chromatograph-mass spectrometer (Agilent 1100Series LC/MSD, Agilent 1200Series LC/MSD), Zorbax SB-C18 column (PN 821975-. Mobile phase a was acetonitrile (containing 0.1% formic acid) and mobile phase B was water (containing 0.1% formic acid), and the gradient elution conditions were as follows: 0min 100% B,0.01min 100% B,1.5min 0% B,1.8min 0% B,1.81min 100% B; the sample volume was 1. mu.L, and the flow rate was 3 mL/min. The ionization mode is atmospheric pressure chemical ionization, the scanning voltage is 80-1000m/z, and all data adopt a positive ion detection mode and a negative ion detection mode. The deuterated solvent is DMSO-d6。
Example 1
Example 1.1 synthetic reference for compound ML364(2- ((4-methylphenyl) sulfonylamino) -N- (4-phenylthiazol-2-yl) -4- (trifluoromethyl) benzamide): mindyl I.Davis et al, Small molecular Inhibition OF THE Ubiquitin-specific Protease USP2 Accelenterates Cycle D1 deletion and Leads to Cell Cycle arm in color Cancer and Manual Cell Lymphoma Models, THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL 291, NO.47, pp.24628-24640, November 18,2016. The compounds in table 1 can all be synthesized in a similar manner.
Example 1.2 Synthesis of the compound 2- ((4-fluorophenyl) sulfonylamino) -N- (4- (4-isopropylphenyl) thiazol-2-yl) benzamide: the title compound was synthesized using the same procedure as in example 1.1.
Figure BDA0002353625510000171
Example 1.3 Synthesis of the compound 2- ((4-fluorophenyl) sulfonamido) -N- (4- (4-methylphenyl) thiazol-2-yl) benzamide: the same procedure was used to obtain the title compound using intermediate 5 and intermediate 6 obtained in example 1.2.
Figure BDA0002353625510000181
Example 1.4 Synthesis of the Compound 2- ((2-thienyl) sulfonamido) -N- (4- (4-methylphenyl) thiazol-2-yl) benzamide: the target compound was obtained in the same manner as in example 1.1, starting from intermediate 2.
Figure BDA0002353625510000182
Example 1.5 Synthesis of the Compound 2- ((4-fluorophenyl) sulfonamido) -N- (4-phenylthiazol-2-yl) benzamide: the title compound was obtained in the same manner as in example 1.3.
Figure BDA0002353625510000183
Example 1.6 Compound 2-methyl-5- (N- (3-methylphenyl) aminosulfonyl) -N- (4-phenylthiazol-2-yl) benzamide: the target compound was obtained in the same manner as in example 1.2, starting from intermediate 2.
Figure BDA0002353625510000184
Example 2 determination of the inhibitory Effect of Compounds on the biosynthesis of pyocins
According to the literature method, pyocin is extracted by chloroform-hydrochloric acid, and a compound A (2- ((4-methylphenyl) sulfonylamino) -N- (4-phenylthiazole-2-yl) -4- (trifluoromethyl) benzamide (ML364)), a compound B (2- ((2-thienyl) sulfonylamino) -N- (4- (4-methylphenyl) thiazole-2-yl) benzamide), a compound C (2- ((4-fluorophenyl) sulfonylamino) -N- (4- (4-isopropylphenyl) thiazole-2-yl) benzamide), a compound D (2- ((4-fluorophenyl) sulfonylamino) -N- (4- (4-methylphenyl) thiazole-2-yl) benzamide) and a compound C (4- ((4-fluorophenyl) sulfonylamino) -N- (4- (4-methylphenyl) thiazole-2-yl) benzamide) are selected, Compound E (2- ((4-fluorophenyl) sulfonylamino) -N- (4-phenylthiazol-2-yl) benzamide) and compound F (2-methyl-5- (N- (3-methylphenyl) sulfamoyl) -N- (4-phenylthiazol-2-yl) benzamide) (both available from shanghai ceramic biochemical science co. The compounds were all prepared in DMSO (dimethyl sulfoxide) at a concentration of 10mg/mL and stored at-20 ℃ until use. Adopting the same inoculation density, inoculating the pseudomonas aeruginosa to the glycerol-alanine culture medium containing the medicine and the glycerol-alanine culture medium not containing the medicine respectively, adding DMSO with the same volume into a blank group as a control, and culturing for 24 hours at 37 ℃ and 180 rpm. Taking 4mL of the bacterial culture solution, shaking and mixing with 3mL of trichloromethane for 30s, centrifuging 8000g for 5min, taking 2mL of blue-green trichloromethane layer solution, extracting with 2mL of 0.2M HCl, and centrifuging 8000g for 5min to obtain a pink liquid layer containing pyocyanin. The absorbance of the pink liquid layer was measured at 520nm and corrected for bacterial OD600 to calculate the concentration of pyocin. All strains used in the application are from American strain collection center (ATCC) and Chinese medical science institute pathogenic microorganism (virus) culture collection center (CAMS-CCPM-A) for medicinal microorganism-related culture collection.
The results are shown below, and compared with the control group, 64 mug/mL ML364 can inhibit the biosynthesis of Pseudomonas aeruginosa wild strain PAO1 and carbapenem drug clinical drug-resistant strain 16-2 pyocyanin, and the higher the ML364 concentration is, the stronger the inhibition effect on pyocyanin is (FIG. 1). Compound B, C, E at 64 μ g/mL reduced pyocin biosynthesis levels to 61.73%, 51.86%, 62.87%, respectively, compared to the control (table 1).
Inhibition of pyocin biosynthesis by the compounds of Table 1 (64. mu.g/mL)
Figure BDA0002353625510000191
EXAMPLE 3 assay of inhibitory Effect of Compounds on biosynthesis of golden yellow pigment
According to the literature method, staphylococcus aureus is inoculated into TSB culture solutions containing and not containing medicaments respectively by using the same inoculation density and cultured for 48 hours at 37 ℃ and 180 rpm. 2.5mL of bacterial liquid was collected, centrifuged at 10000g for 3min and the supernatant was discarded, and the liquid was washed twice with 1 XPBS buffer. Adding 0.6mL of methanol into the bacterial thallus, shaking for 10min at 58 ℃, extracting for three times, centrifuging for 3min at 10000g, taking the supernatant, measuring the light absorption value of the obtained golden yellow pigment methanol solution at 450nm, and correcting by OD 600.
TABLE 2 inhibitory Effect of ML364 (32. mu.g/mL) on the biosynthesis of golden yellow pigment
Figure BDA0002353625510000201
TABLE 3 inhibitory Effect of the Compounds (64. mu.g/mL) on the biosynthesis of golden yellow pigment
Figure BDA0002353625510000202
As shown in Table 2, 32. mu.g/mL ML364 reduced ATCC29213 golden yellow to 14.54% and MRSA 08-50 golden yellow production to 21.43%. As shown in Table 3, 64. mu.g/mL. The compound can reduce the biosynthesis amount of the golden yellow pigment to 20.76% -54.16%.
Example 4ML 364 experiments on the resistance of mice to systemic infection by Pseudomonas aeruginosa and Staphylococcus aureus
Inoculating a pseudomonas aeruginosa wild strain PAO1, a carbapenem drug clinical resistant strain 16-2, staphylococcus aureus ATCC29213 and an MRSA clinical strain 08-50 frozen bacteria into 3mL of enrichment broth, performing static culture at 37 ℃ for 6h, diluting the bacteria solution 1:50 into 10mL of enrichment broth, and performing static culture at 37 ℃ for 18 h. Diluting the obtained bacterial liquid with 5% dry active yeast solution to prepare infectious bacterial liquid for later use. Infection amount: pseudomonas aeruginosa PAO 17.5X 103CFU/mouse, Pseudomonas aeruginosa 16-21.2X 104CFU/mouse, Staphylococcus aureus ATCC 292135.6X 105CFU/mouse, MRSA 08-504.55X 105CFU/mouse. Meanwhile, 0.85 percent NaCl is used for diluting the suspension to 10^ of the original bacterial solution-6～10^-7The concentration is 10 mu L of pseudomonas aeruginosa drops respectivelyFlow on LB agar plate, take 10 u L staphylococcus aureus drip on MH agar plate, after drying in the air, inverted culture for colony count. Randomly grouping SPF female mice (18-20g) according to body weight, and each group comprises 10 mice; after the abdomen is disinfected by iodine, the mouse is slightly inverted and injected with 0.5mL of bacteria liquid through the abdominal cavity. A10 mg/mL ML364 stock solution (containing 10% absolute ethanol and 10% polyoxyethylene castor oil, v/v) was prepared from a 5% glucose injection and diluted to a concentration of 0.3mg/mL, and 0.2mL was administered intraperitoneally at 0, 12, and 24 hours after infection of mice, respectively, to give a dose of about 3 mg/kg. Survival of each group of mice was observed and recorded over 7 days.
As shown in FIG. 2, intraperitoneal injection of 3mg/kg ML364 significantly increased the survival rate of mice. Wherein, the PAO1 infected model group mice die in 30 hours, and ML364 can improve the survival rate of the mice by 70%; the survival rate of the mouse infected by the carbapenem drug-resistant pseudomonas aeruginosa 16-2 is improved by 60 percent; the survival rate of the staphylococcus aureus ATCC29213 infected mouse is improved by 30 percent; the survival rate of mice infected by methicillin-resistant staphylococcus aureus 08-50 is improved by 60 percent.
Although the embodiments disclosed in the present application are described above, the descriptions are only for the convenience of understanding the present application, and are not intended to limit the present application. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the disclosure as defined by the appended claims.

Claims (11)

1. Use of a compound, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of a bacterial infection:
2- ((4-methylphenyl) sulfonylamino) -N- (4-phenylthiazol-2-yl) -4- (trifluoromethyl) benzamide;
2- ((2-thienyl) sulfonamido) -N- (4- (4-methylphenyl) thiazol-2-yl) benzamide;
2- ((4-fluorophenyl) sulfonylamino) -N- (4- (4-isopropylphenyl) thiazol-2-yl) benzamide; or
2- ((4-fluorophenyl) sulfonylamino) -N- (4-phenylthiazol-2-yl) benzamide;
wherein the compound inhibits a gram-negative bacterial virulence factor, and the gram-negative bacterial virulence factor is pyocin, the bacterial infection is caused by pseudomonas aeruginosa.
2. Use of a compound, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of a bacterial infection:
2- ((4-methylphenyl) sulfonylamino) -N- (4-phenylthiazol-2-yl) -4- (trifluoromethyl) benzamide;
2- ((2-thienyl) sulfonamido) -N- (4- (4-methylphenyl) thiazol-2-yl) benzamide;
2- ((4-fluorophenyl) sulfonylamino) -N- (4- (4-isopropylphenyl) thiazol-2-yl) benzamide; or
2- ((4-fluorophenyl) sulfonylamino) -N- (4-phenylthiazol-2-yl) benzamide;
wherein the compound inhibits a gram-positive bacterial virulence factor, and the gram-positive bacterial virulence factor is aureochrome, and the bacterial infection is caused by staphylococcus aureus.
3. Use of a compound, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of a bacterial infection:
2- ((4-methylphenyl) sulfonylamino) -N- (4-phenylthiazol-2-yl) -4- (trifluoromethyl) benzamide;
2- ((2-thienyl) sulfonamido) -N- (4- (4-methylphenyl) thiazol-2-yl) benzamide;
2- ((4-fluorophenyl) sulfonylamino) -N- (4- (4-isopropylphenyl) thiazol-2-yl) benzamide; or
2- ((4-fluorophenyl) sulfonylamino) -N- (4-phenylthiazol-2-yl) benzamide;
the compound inhibits gram-negative bacteria virulence factors and gram-positive bacteria virulence factors, the gram-negative bacteria virulence factors are pyocins, the gram-positive bacteria virulence factors are golden yellow pigments, and the bacterial infection is caused by pseudomonas aeruginosa and staphylococcus aureus.
4. The use of claim 1 or 3, wherein the gram-negative bacteria comprise gram-negative bacteria susceptible bacteria and gram-negative bacteria resistant bacteria.
5. The use according to claim 4, wherein the gram-negative bacteria resistant bacteria is carbapenem-drug-resistant Pseudomonas aeruginosa.
6. Use according to claim 2 or 3, wherein the gram-positive bacteria comprise gram-positive bacteria-susceptible bacteria and gram-positive bacteria-resistant bacteria.
7. The use of claim 6, wherein the gram-positive bacteria resistant bacteria are methicillin-resistant Staphylococcus aureus and vancomycin-resistant Staphylococcus aureus.
8. The use of any one of claims 1-3, wherein the compound or pharmaceutically acceptable salt thereof is administered orally, rectally, transdermally, intranasally, topically, or parenterally.
9. The following compounds:
2- ((4-methylphenyl) sulfonylamino) -N- (4-phenylthiazol-2-yl) -4- (trifluoromethyl) benzamide;
2- ((2-thienyl) sulfonamido) -N- (4- (4-methylphenyl) thiazol-2-yl) benzamide;
2- ((4-fluorophenyl) sulfonylamino) -N- (4- (4-isopropylphenyl) thiazol-2-yl) benzamide; or
Use of 2- ((4-fluorophenyl) sulfonamido) -N- (4-phenylthiazol-2-yl) benzamide, or a pharmaceutically acceptable salt thereof, in combination with one or more of sulfonamides, quinolone antibacterials, beta-lactam antibiotics, aminoglycoside antibiotics, lincosamides, streptogramins, oxazolidinones, polypeptides, macrolide antibiotics and tetracycline antibiotics for the manufacture of a medicament for the treatment or prophylaxis of a bacterial infection,
wherein the compound inhibits a gram-negative bacterial virulence factor, and the gram-negative bacterial virulence factor is pyocin, the bacterial infection is caused by pseudomonas aeruginosa.
10. The following compounds:
2- ((4-methylphenyl) sulfonylamino) -N- (4-phenylthiazol-2-yl) -4- (trifluoromethyl) benzamide;
2- ((2-thienyl) sulfonamido) -N- (4- (4-methylphenyl) thiazol-2-yl) benzamide;
2- ((4-fluorophenyl) sulfonylamino) -N- (4- (4-isopropylphenyl) thiazol-2-yl) benzamide; or
Use of 2- ((4-fluorophenyl) sulfonamido) -N- (4-phenylthiazol-2-yl) benzamide, or a pharmaceutically acceptable salt thereof, in combination with one or more of sulfonamides, quinolone antibacterials, β -lactam antibiotics, aminoglycoside antibiotics, lincosamides, streptogramins, oxazolidinones, polypeptides, macrolide antibiotics and tetracycline antibiotics for the manufacture of a medicament for the treatment or prophylaxis of a bacterial infection, wherein said compound inhibits a gram positive virulence factor and said gram positive virulence factor is aureochrome, said bacterial infection being caused by staphylococcus aureus.
11. The following compounds:
2- ((4-methylphenyl) sulfonylamino) -N- (4-phenylthiazol-2-yl) -4- (trifluoromethyl) benzamide;
2- ((2-thienyl) sulfonamido) -N- (4- (4-methylphenyl) thiazol-2-yl) benzamide;
2- ((4-fluorophenyl) sulfonylamino) -N- (4- (4-isopropylphenyl) thiazol-2-yl) benzamide; or
Use of 2- ((4-fluorophenyl) sulfonamido) -N- (4-phenylthiazol-2-yl) benzamide, or a pharmaceutically acceptable salt thereof, in combination with one or more of sulfonamides, quinolone antibacterials, β -lactam antibiotics, aminoglycoside antibiotics, lincosamides, streptogramins, oxazolidinones, polypeptides, macrolide antibiotics, and tetracycline antibiotics for the manufacture of a medicament for the treatment or prevention of a bacterial infection, wherein said compound inhibits a gram-negative virulence factor and a gram-positive virulence factor, and said gram-negative virulence factor is pyocyanamide, said gram-positive virulence factor is aureochrome, and said bacterial infection is caused by pseudomonas aeruginosa and staphylococcus aureus.
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