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WO2012036520A2 - Nouveau composé à action antibiotique et composition antibiotique le comprenant - Google Patents

Nouveau composé à action antibiotique et composition antibiotique le comprenant Download PDF

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Publication number
WO2012036520A2
WO2012036520A2 PCT/KR2011/006881 KR2011006881W WO2012036520A2 WO 2012036520 A2 WO2012036520 A2 WO 2012036520A2 KR 2011006881 W KR2011006881 W KR 2011006881W WO 2012036520 A2 WO2012036520 A2 WO 2012036520A2
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Prior art keywords
compound
composition
compounds
present
infection
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Ceased
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Korean (ko)
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WO2012036520A3 (fr
Inventor
강린우
김정구
안예진
이병무
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University Industry Cooperation Corporation of Konkuk University
Korea Rural Development Administration
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University Industry Cooperation Corporation of Konkuk University
Korea Rural Development Administration
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Publication of WO2012036520A2 publication Critical patent/WO2012036520A2/fr
Publication of WO2012036520A3 publication Critical patent/WO2012036520A3/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/60—Three or more oxygen or sulfur atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C335/04—Derivatives of thiourea
    • C07C335/24—Derivatives of thiourea containing any of the groups, X being a hetero atom, Y being any atom
    • C07C335/26—Y being a hydrogen or a carbon atom, e.g. benzoylthioureas
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D215/38—Nitrogen atoms

Definitions

  • the present invention relates to novel antibiotic compounds and antibiotic compositions comprising the compounds, and more particularly, to compounds that inhibit microbial lipid synthesis and the use of the compounds.
  • antibiotic resistance occurs when the bacteria causing the infection are not rescued by the antibiotics used to stop the infection. Bacteria survive and multiply and become more harmful.
  • Staphylococcus aureus is the main cause of infection from hospitals, which, epidemiologically, satisfactorily responds to vancomycin antibiotics.
  • many Staphylococcus aureus strains have recently been shown to be resistant to vancomycin.
  • the mortality rate of some infectious diseases is increasing again.
  • Antibiotics are used therapeutically to treat bacterial infections. Many types of antibiotics, classified according to their mechanism of action, are currently used. Known types of antibiotics include, for example, cell wall synthesis inhibitors, cell membrane inhibitors, protein synthesis inhibitors, and inhibitors that affect or bind to DNA or RNA synthesis.
  • Inhibitors of cell wall synthesis such as beta lactam antibiotics, generally inhibit some of the synthetic steps of bacterial peptidoglycan.
  • Penicillin is generally effective against non-resistant streptococcus, gonococcus and staphylococcus. Amoxicillin and ampicillin show a broad spectrum in Gram-negative bacteria. Cephalosporins are commonly used as surgical precautions and penicillin replacements for Gram-negative bacteria. Monobactam is generally useful for treating allergic subjects.
  • wisc.edu/clinsci/5amcg/amcg.html Introduction on the Use of the Antibiotics Guideline, of Specific Antibiotics Classes, Thomas Jefferson University, http://jeffiine.tju.edu/CWIS/OAC/antibiotics guide / intro.html And known in the art.
  • FabD Xoo0880
  • MCAT Malonyl-CoA-acyl carrier protein transacylase
  • This protein delivers the malonyl site to the holo-acyl transporter protein that forms the malonyl-ACP intermediate in bacterial type II fatty acid synthesis (Ruch, FE, and Vagelos, PR (1973)
  • the isolation and general properties of Escherichia coli malonyl) coenzyme A-acyl carrier protein transacylase J Biol Chem 248 , 8086-94.
  • This intermediate malonyl-ACP provides two carbons in the extension phase of fatty acid synthesis.
  • Fatty acid synthesis is essential for life's survival (Magnuson, K., Jackowski, S., Rock, CO, and Cronan, JE, Jr. (1993) Regulation of fatty acid biosynthesis in Escherichia coli.Micro biol Rev 57 , 522-42 .; White, SW, Zheng, J., Zhang, YM, and Rock (2005) The structural biology of type II fatty acid biosynthesis.Annu Rev Biochem 74 , 791-831. Helps to extend the length of the chain.
  • MCAT has also been reported to be involved in the polyketide biosynthesis that produces acyl-ACP thioesters, producing one of the largest segments of secondary products such as tetracyclines and erythromycins (Keatinge-Clay, AT, Shelat).
  • MCAT is considered an essential enzyme in bacterial metabolic activity among the enzymes involved in the FAS process and is used as a potential drug target for the development of antibacterial drugs
  • the present invention solves the above problems, and it is an object of the present invention to provide a compound having an anti-living property.
  • Another object of the present invention is to provide a composition comprising the compound.
  • the above object of the present invention provides a compound of any one of formulas (1) to (3) or a pharmaceutically acceptable salt thereof.
  • the compound preferably inhibits malonyl-CoA: acyl carrier protein transacylase (MCAT) activity, but is not limited thereto.
  • MCAT acyl carrier protein transacylase
  • the present invention also provides a pharmaceutical composition for preventing or treating infection by a pathogen comprising the compound of any one of Formulas 1 to 3 of the present invention and a pharmaceutically acceptable carrier.
  • the present invention provides a feed composition for preventing or treating infection by a pathogen comprising the compound of any one of Formulas 1 to 3 of the present invention and a physiologically acceptable carrier.
  • the present invention provides a pesticide composition for infection prevention or treatment comprising the compound of any one of Formulas 1 to 3 of the present invention and a pharmaceutically acceptable carrier.
  • the composition preferably has microbial lipid synthesis inhibitory activity, but is not limited thereto.
  • composition of the present invention may further include a pharmaceutically acceptable excipient, carrier, diluent and the like.
  • Carriers usable in the present invention include macromolecules that are slowly metabolized, such as liposomes, polysaccharides, polylactic acid, polyglycolic acid, polymeric amino acids, and amino acid copolymers.
  • Salts of inorganic acids such as, for example, hydrochloride, hydrobromide, phosphate and sulfate;
  • Pharmaceutically acceptable salts such as salts of organic acids such as acetates, propionates, malonates and benzoates;
  • Liquids such as water, saline, glycerol and ethanol, and auxiliary substances such as wetting agents, emulsifiers or pH buffering materials can be used.
  • composition may be formulated in a unit dosage form suitable for intrabody administration of a patient according to a conventional method in the pharmaceutical field, preferably in the form of a formulation useful for the administration of a compound pharmaceutical product, and is commonly used in the art.
  • Oral or skin, intravenous, intramuscular, intraarterial, intramedullary, intramedullary, intraventricular, lung, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal tract, topical, sublingual, intravaginal or rectal Administration may be by parenteral administration routes including, but not limited to, routes.
  • Compound doses effective for bacterial treatment are from about 1 to 50 mg or 1 to 20 mg per kg body weight of receptor per day, more generally from 0.1 to about 100 mg per kg body weight of receptor per day.
  • Effective dose ranges of pharmaceutically acceptable salts and prodrugs can be calculated based on the weight of the parent compound to be delivered. If the salt or prodrug exhibits activity by itself, the effective dose can be estimated using the weight of the salt or prodrug, as mentioned above, or by other means known to those skilled in the art.
  • the active compounds can be used in the form of tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like, in combination with one or more excipients.
  • Tablets, troches, pills, capsules, and the like may contain one or more of the following ingredients: binders, for example microcrystalline cellulose, tragacanth gum, acacia, corn starch or gelatin; Excipients such as dicalcium phosphate, starch or lactose; Disintegrants such as corn starch, potato starch, alginic acid, Primogel and the like; Lubricants, eg magnesium stearate or Steotes; Glidants such as colloidal silicon dioxide; Sweeteners such as sucrose, fructose, lactose, saccharin or aspartame; Flavoring agents such as peppermint, methylsalicylate, wintergreen oil or cherry flavor; And peptide antimicrobials such as Enbuvirtide (Fuzeon TM).
  • binders for example microcrystalline cellulose, tragacanth gum, acacia, corn starch or gelatin
  • Excipients such as dicalcium phosphate, starch or lactose
  • the unit dosage form is a capsule, it may contain, in addition to substances of this type, a liquid carrier such as vegetable oil or polyethylene glycol. Various other materials may be present as coatings or to alter the physical form of the solid unit dosage form.
  • the pharmaceutical composition of the present invention may be prepared, packaged or sold in a formulation suitable for rectal administration. Such compositions may be, for example, in the form of suppositories, retention enema preparations and solutions for rectal or colonic washing.
  • the pharmaceutical compositions of the invention may also be prepared, packaged or sold in formulations suitable for vaginal administration. Such compositions may be, for example, in the form of suppositories, embedded or coated vaginal intercalating substances such as tampons, cleaning formulations, vaginal cleaning solutions.
  • compositions of the present invention may be prepared, packaged or sold in a formulation suitable for ophthalmic administration.
  • the compounds of the present invention may be applied in pure form, ie in liquids.
  • the compound may be administered to the skin as a composition or formulation in combination with a dermatologically acceptable carrier.
  • Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like.
  • Useful liquid carriers include water, alcohols, glycols, and two or more of these mixtures, wherein the compounds of the present invention may optionally be dissolved or dispersed at effective levels using non-toxic surfactants.
  • the pesticide composition according to the invention may further comprise other additional ingredients, such as agriculturally acceptable supports, carriers or fillers.
  • support refers to a natural or synthetic organic or inorganic material with which the active material is bound, in particular for ease of application to parts of the plant. Therefore, this support should generally be inert and agriculturally acceptable.
  • the retard can be a solid or a liquid.
  • suitable supports include clays, natural or synthetic silicates, silicas, resins, waxes, solid fertilizers, water, alcohols, in particular butanol, organic solvents, mineral oils and vegetable oils and derivatives thereof. Mixtures of such supports can also be used.
  • the pesticide composition may also contain other additional ingredients.
  • the pesticide composition may further contain a surfactant.
  • the surfactant may be an ionic or nonionic emulsifier, dispersant or wetting agent or a mixture of these surfactants.
  • the active substance and / or the inert support is water insoluble and the vector reagent for application is water, it is generally necessary to have at least one surfactant present.
  • the surfactant content may be 5 to 40% by weight of the composition.
  • Additional components may also include, for example, protective colloids, tackifiers, thickeners, thixotropic agents, penetrants, stabilizers, sequestrants. More generally, the active substance may be combined with any solid or liquid additive according to conventional formulation techniques.
  • the pesticide composition according to the present invention may contain 0.05 to 99% by weight, preferably 10 to 70% by weight of active substance.
  • the composition according to the invention is an aerosol dispenser, capsule suspension, cold mist concentrate, dustable powder, emulsifiable concentrate, oil-in-water emulsion, water-in-oil emulsion, encapsulated granules, fine granules, fluid concentrate for seed treatment, gas (under pressure) ), Gas-generating products, granules, radish concentrates, macrogranules, microgranules, oil dispersible powders, oil miscible fluid concentrates, oil miscible liquids, pastes, plant rodlets, powders for dry seed treatment Seeds coated with pesticides, soluble concentrates, soluble powders, solutions for seed treatment, suspension concentrates (fluid concentrates), ultra low volume (ulv) liquids, ultra volume suspensions, water dispersible granules or tablets, It can be used in various forms such as water dispersible powders for slurry treatment, water soluble granules or tablets, soluble powders for seed treatment and hydrating agents.
  • compositions include commercially available concentrated compositions that must be diluted before being applied to the crop, as well as compositions that are in direct application to the plant or seed to be treated using a suitable device such as a spraying or spreading device.
  • the pesticide composition of the present invention can be used for the therapeutic or prophylactic control of insects as well as the therapeutic or prophylactic control of phytopathogenic bacteria of crops.
  • an effective non-phytotoxic amount of a composition as defined above is seed treatment, leaf application, stem application, or the seed, plant and / or fruit of the plant or the plant is growing or growing therefrom.
  • Soil and / or inert substrates e.g., organic substrates (e.g. sand, rock wool, glass wool, expandable minerals (e.g. pearlite, vermiculite, zeolites, expandable clay)), pumice, coal rock material / tuff, synthetic organic Substrates (e.g. polyurethane), organic substrates (e.g. peat, compost, wood waste (e.g.
  • coir wood fibers / chips, bark
  • liquid substrates e.g. suspended hydroponic systems, Nutrient Film Technique, A method for treating or preventing insects as well as therapeutically or prophylactically controlling insect phytopathogenic bacteria of crops, which is applied through irrigation / drip application (irrigation) to aeroponics). This is provided.
  • an effective non-phytotoxic amount is sufficient to control or eradicate pests and / or diseases present in or prone to crops, while the crops do not involve any significant phytotoxic symptoms. Means quantity. Such amounts can vary widely depending on the pests and diseases to be eradicated or controlled, the type of crop, the climatic conditions and the compounds included in the composition according to the invention. The amount can be determined by those skilled in the art and can be determined by systematic field experiments.
  • the treatment method according to the invention may be useful for the treatment of propagation materials, such as tubers or rhizomes, as well as for the treatment of seeds, seedlings or transplanted seedlings and plants or transplanted plants.
  • the treatment method may also be useful for the treatment of roots.
  • the treatment method according to the invention may also be useful for treating the ground parts of plants, such as the body, stems or sacks, leaves, flowers and fruits of related plants.
  • Plants that may be protected by the method of the present invention include cotton; maybe; Vine plants; Fruit or vegetable crops, seedlings, major crops such as Graminae sp. (E.g. corn, grass or wheat, rice, barley and wheat), flowers, horticulture and forest crops; As well as genetically modified homologs of these crops may be mentioned.
  • Graminae sp. E.g. corn, grass or wheat, rice, barley and wheat
  • flowers horticulture and forest crops;
  • genetically modified homologs of these crops may be mentioned.
  • the feed composition comprising the compound of the present invention or a salt thereof is used as a feed for animals such as mammals, birds, reptiles, amphibians, fish, preferably mammals.
  • animals such as mammals, birds, reptiles, amphibians, fish, preferably mammals.
  • the feed of the present invention is used as a pet food such as dogs, cats, mice, animal feed such as cattle and pigs, poultry feed such as chickens and turkeys, and fish feed such as sea bream and defense. , Preferably as pet food or animal feed.
  • the feed of the present invention can be made by appropriately blending a compound of the present invention or a salt thereof with a feed material.
  • the feed material include grains, algae, vegetable oils, animal feed materials, other feed materials, and refined products.
  • grains examples include mairo, wheat, barley, oats, rye, brown rice, buckwheat, crude, sorghum, blood, corn, soybean, and the like.
  • Examples of the crude rivers include rice bran, skim rice bran, bran, powder, wheat, embryo, barley bran, screening, pellets, corn bran, corn germ, and the like.
  • vegetable oils include soybean meal, soybean meal, flaxseed meal, cottonseed meal, peanut gourd, safflower foil, palm gourd, palm gourd, houma gourd, sunflower gourd, rapeseed gourd, kaypo gourd and mustard gourd.
  • animal feed materials for example, fish meal (North American wheat, imported wheat, whole wheat, coastal wheat), fish brush fire, meat meal, fish bone meal, blood meal, decomposing hair, bone meal, animal by-products, feather mill, silkworm, skim milk powder, Casein, dried whey, and the like.
  • feedstocks include plant foliage (alfalfa, haycube, alfalfa leaf powder, pseudo acacia powder, etc.), corn processing industrial by-products (corn gluten, wheat, corn gluten feed, corn staple, etc.), starch processed products, sugar, fermentation.
  • Industrial products yeast, beer foil, malt sprouts, alcohol foil, walnuts, etc.
  • agricultural production by-products citrus fruits, tofu, coffee, cocoa, etc.
  • others cassava, bean, guam, seaweed, Krill, spirulina, chlorella, minerals, etc.
  • Typical products include proteins (casein, albumin, etc.), amino acids, sugars (starch, cellulose, sucrose, glucose, etc.), minerals, vitamins, and the like.
  • the inventors found three lead compounds that inhibit bacterial cell growth in the range of ⁇ ug / ml and confirmed their direct binding to the target protein using NMR results.
  • Figure 1 shows the type II bacterial fatty acid synthesis pathway.
  • 2 is an SDS-PAGE photograph of purified fabD (Xoo0880)
  • 3 is a crystal photograph grown in 0.1 M CHES pH9.0, 1.5 M NH 4 SO 4 , and 0.2 M NaCl.
  • FIG. 6 is a schematic diagram of a VLS experiment to search for antagonist drugs for specific target proteins.
  • Figure 7 shows the procedure for bacterial cell growth inhibition assay with selected compounds derived from VLS.
  • FIG. 8 to 10 show 1D 1 H-NMR spectra of the chemical formulas 1 (FIG. 8), 2 (FIG. 9), and 3 (FIG. 10) of the present invention which are XoMCAT lead compounds. This spectrum shows the degree of affinity for the compound for XoMCAT.
  • the compounds used in the present invention were purchased from ChemBridge Corporation (16981 Via Tazon, Suite G, San Diego, Calif., 92127, USA), USA, and used by the company's web site: http://www.chembridge.com/ . .
  • Example 1 Xanthomona soryzae pv. Cloning , Expression, Purification, Crystallization, Crystal Structure Determination of XoMCAT from oryzae (Xoo)
  • the FAD coding sequence of Xoo0880 was amplified by polymerase chain reaction using a bacterial cell (Xoo KACC10331 strain) genome as a template.
  • Oligonucleotide primer sequences were designed based on previously reported gene sequences (Lee, BM, et al. (2005) Nucleic Acids Res 33 , 577-86.).
  • the forward and reverse primers are: 5'GGG GGG CAT ATG ACC GAA TCC ACT CTC GCC TTC A3 '(SEQ ID NO: 1) and 5'-GGG GGG GGA TCC TCA GTG GCC CCA CGC GTC GAG A-3' (SEQ ID NO: 2) )
  • NdeI and BamHI restriction sites are shown in bold.
  • the PCR amplicon was double-treated with Nde I and Bam HI and the residues of the tobacco etch virus (TEV) protease cleavage site and 6xHis in front of the Nde I site in the pET11a vector (Novagen) to facilitate purification of the expressed protein.
  • TMV tobacco etch virus
  • 6xHis 6xHis in front of the Nde I site in the pET11a vector (Novagen) to facilitate purification of the expressed protein.
  • His-TEV-pET11a expression vector comprising the coding sequence of Xoo0880 was loaded into E. coli BL21 (DE3). Cells were grown at 37 ° C. until OD 600 reached 0.5 in Luria-Bertani medium containing 50 ⁇ g / ml ampicillin. Protein expression was induced by adding 0.5 mM Isopropyl-beta-D-thiogalactopyranoside to the culture. After induction, the cells were incubated for an additional 16 hours at the same temperature. Cultured E. coli was collected by centrifugation (Vision VS24-SMTi V5006A rotor) for 20 minutes at 6,000 rpm at 277K. The collected E.
  • coli was then resuspended in a cold cell disruption buffer A [25 mM Tris-HCl pH 7.5, 150 mM NaCl, 10 mM Imidazole] and sonicated on ice (Sonomasher, S & T Science, Korea). By crushing. The lysate was then centrifuged at 277K, 12,000 rpm for 30 minutes to obtain cell extracts (Vision VS24-SMTi V508A rotor). Only 10% of the total expressed Xoo0880 was water soluble (not shown). Supernatants containing water-soluble fabD were loaded into Ni-NTA resin (Novagen) to use affinity purification. Affinity purification was performed at 4 ° C. according to the manufacturer's protocol.
  • the fabD protein with 6 ⁇ His-tag was then eluted with crushing buffer A containing 200 mM imidazole and treated overnight with TEV protease at 4 ° C. to remove 6 ⁇ His-tag.
  • the protein solution thus treated was dialyzed at 4 ° C. using Buffer B [25 mM Tris-HCl pH 7.5, 15 mM NaCl] for 6 hours, and further purified using a UNO6 Q column (Bio-Rad). The purity of the purified protein was analyzed using SDS-PAGE (FIG. 2).
  • the purified protein was concentrated to 7 mg ml -1 and used in the crystallization process.
  • Crystallization of XoMCAT was performed via Hydra II e-drop (Matrix), an automated pipetting system using several screening kits such as Crystal screen HT, Index HT, and Salt Rx HT (Hampton Research), high throughput (HT)] crystal screening has begun. Initially very thin needle shaped crystals were obtained under Wizard G-5 conditions (0.1 M CHES pH9.5, 1.25 M NH 4 SO 4 , and 0.2 M NaCl) and modified conditions (0.1 M CHES pH9.0, 1.5 M NH). 4 SO 4 , and 0.2 M NaCl). It was regenerated using the hanging drops method, and crystals were made for a week.
  • the crystal structure of XoMCAT and its active site residues are shown in Figures 4-5.
  • the overall structure of XoMCAT consists of two domains, a larger domain and a smaller domain, and folds stably. Its active site is located in the canyon between these domains.
  • Larger domains program DSSP Kabsch, W. and Sander, C. (1983) Biopolymers 22, 2577-637.. 14 of the alpha with a surface area of the exciter three block 12585 ⁇ 2 calculated from a-helical structure, and eight beta -It is composed of linear structure.
  • the nucleophilic activating residue Ser-94 is located in the Sharpton located between the alpha-helix and beta-linear structures of the larger domain and the other active site residues Gln 13, Arg 119 and His 203 are located near the nucleophilic residue. Located.
  • Xoo0880 is one of the potential targeted genes for rice blight based on GlaxoSmithKline (GSK), it is antagonistic to substrate binding sites of the XoMCAT enzyme through high efficiency (HT) virtual library screening (VLS, Figure 6). Drug lead compounds were searched.
  • VLS For drug screening, VLS, a computer simulation, was performed using an 18 million compound database in the ICM Molsoft modeling suit. Substrates of each flexible structure present in the compound database found via Lipinski's formula in VLS were docked into the substrate binding pocket grid of XoMCAT using ICM and assigned scores reflecting the quality of the complex. Three checks were performed in parallel at the same time to check for regeneration of each substrate binding result. 1991 compounds with top scores were selected and each of its complexes examined by visualizing (numerical) coefficients such as shape complementarity, hydrogen bonding network and ligand flexibility. 500 compounds were obtained based on this final selection step for characterization through experimental analysis.
  • OD nc the negative control OD 600
  • OD tc OD 600 of the positive control (a known inhibitor): OD 600, OD pc of the test compound.
  • MIC 50 values were determined as the minimum compound concentration that inhibited bacterial cell growth of 50%.
  • Table 1 is a table of MICs of lead compounds from bacterial cell growth inhibition assays.
  • High purity purified protein stock solution (Xoo PDF) was prepared at 100 ⁇ M concentration in 25 mM Tris pH 7.5, 10 mM NaCl and 3 mM 2-ME buffer. Each inhibitor stock solution was prepared at 30 mM in 100% DMSO.
  • 20 ⁇ M protein and 0.1 mM inhibitor were made using the same buffer solution of 10% D 2 O and 25 mM Tris pH 7.5, 10 mM NaCl, 3 mM 2-ME.
  • the 1D NMR spectra of the inhibitor-only solution and the two samples containing the inhibitor and the PDF were measured, respectively.
  • the binding of the inhibitor to the target protein PDF was confirmed by a change in the 1D NMR spectrum of the inhibitor used in the experiment.
  • NMR spectra were recorded using a 500 MHz 1D NMR Bruker DRX from the Korea Basic Science Institute (KBSI) in Daejeon.

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Abstract

La présente invention concerne un nouveau composé actif sur le plan antibiotique et une composition antibiotique comprenant ledit composé. L'invention concerne plus spécifiquement un composé inhibant la synthèse des lipides des microorganismes, ainsi qu'une utilisation du composé.
PCT/KR2011/006881 2010-09-17 2011-09-16 Nouveau composé à action antibiotique et composition antibiotique le comprenant Ceased WO2012036520A2 (fr)

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KR1020100092040A KR101289461B1 (ko) 2010-09-17 2010-09-17 신규한 항생활성 화합물 및 그 화합물을 포함하는 항생 조성물

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* Cited by examiner, † Cited by third party
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KR101542454B1 (ko) * 2013-10-11 2015-08-06 건국대학교 산학협력단 신규한 항생활성 화합물 및 그 화합물을 포함하는 항생 조성물

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