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WO2017106950A1 - Composition pharmaceutique, utilisation de cette composition pharmaceutique, méthode de traitement de maladies associées à des infections microbiennes et procédé de préparation d'un composé - Google Patents

Composition pharmaceutique, utilisation de cette composition pharmaceutique, méthode de traitement de maladies associées à des infections microbiennes et procédé de préparation d'un composé Download PDF

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Publication number
WO2017106950A1
WO2017106950A1 PCT/BR2016/050338 BR2016050338W WO2017106950A1 WO 2017106950 A1 WO2017106950 A1 WO 2017106950A1 BR 2016050338 W BR2016050338 W BR 2016050338W WO 2017106950 A1 WO2017106950 A1 WO 2017106950A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
compound
polymyxin
tobramycin
composition according
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/BR2016/050338
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English (en)
Portuguese (pt)
Inventor
Sílvia DIAS DE OLIVEIRA
André ARIGONY SOUTO
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Uniao Brasileira de Educacao e Assistencia Mantenedora da PUCRS
Original Assignee
Uniao Brasileira de Educacao e Assistencia Mantenedora da PUCRS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication of WO2017106950A1 publication Critical patent/WO2017106950A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/702—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates

Definitions

  • the present invention describes antimicrobial action of azostilbenoids.
  • the present invention is in the fields of Microbiology and Organic Chemistry.
  • carbapenemic resistance is currently widely described in several countries, including Brazil, and requires the use of other drugs such as polymyxins and tigecycline, or even inhaled tobramycin as adjuvant in respiratory infections (Levin et al., 1999; Villegas & Hartstein, 2003; Manchanda et al., 2010; Rossi, 2011; Kempf & Rolain, 2012).
  • efflux pump inhibitors may be important adjuvants in the treatment of infections caused by Acinetobacter spp. resistant to multiple drugs.
  • Resveratrol is a polyphenolic phytoalexin produced by plants in response to unfavorable environmental conditions, which has antioxidant, anti-inflammatory, cardioprotective, neuroprotective, chemoprotective, antiviral, antifungal and antibacterial action (Docherty et al., 2005; Jung et al. ., 2005; Aggarwal & Shishodia, 2006; Baur & Sinclair, 2006; Pezzuto, 2008; Paulo et al., 2010; Martini et al., 201 1; Nawrocki et al., 2013; Zetterström et al., 2013).
  • Resveratrol has been shown to inhibit bacterial biofilm formation, which has been attributed to inhibitory action on quorum sensing (Augustine et al. 2013; Lee et al., 2013), as well as been associated with inhibition of swarmin expression and virulence in Proteus mirabilis (Wang et al., 2006).
  • Membrane potential disruption and / or inhibition of DNA replication by inhibition of DNA gyrase have also been indicated as resveratrol action mechanisms in various microorganisms (Subramanian et al., 2014; Mora-Pale et al., 2015).
  • Figure 1 shows graphs with the minimum inhibitory concentration (MIC) ( ⁇ / ⁇ ) of Azoresilbenoid RedresvOOl in isolates of A. calcoaceticus-baumannii (B34, B48 and C146).
  • Figure 2 shows graphs of the association of Azoresilbenoides RedresvOO1 with polymyxin B in isolate A. calcoaceticus-baumannii B48, expressed as MIC ( ⁇ g / ml).
  • Figure 3 shows graphs of the association of Azoresilbenoides RedresvOO1 with polymyxin B in isolate A. calcoaceticus-baumannii C146, expressed as MIC ( ⁇ g / ml).
  • Figure 4 shows graphs of the association of Azostilbenoides RedresvOOl with tobramycin in isolate A. calcoaceticus-baumannii C146, values are expressed as MICs ⁇ g / ml_) required to inhibit growth of Acinetobacter calcoaceticus-baumannii strain 146.
  • the present invention features a pharmaceutical composition, characterized in that it comprises: - at least one compound of formula:
  • R1, R2 and R3 are OH
  • At least one pharmaceutically acceptable carrier at least one pharmaceutically acceptable carrier.
  • the pharmaceutical composition further comprises at least one antimicrobially acting drug.
  • the antimicrobially acting drug is selected from the group consisting of: Polymyxin B, Polymyxin E and tobramycin or a combination thereof.
  • the compound is at a concentration between 2 and 30 ⁇ g / mL.
  • the antimicrobially acting drug is in a concentration between 2 and 100 ⁇ g / mL.
  • the use of said pharmaceutical composition is for the preparation of a drug with antimicrobial action.
  • said pharmaceutical composition is for the preparation of a medicament with antimicrobial action against a selected microorganism of the genus Acinetobacterspp.
  • the microorganism is Acinetobacter calcoaceticus-baumannii.
  • the method of treating diseases associated with microbial infections comprises applying said pharmaceutical composition.
  • the process of preparing said compound comprises condensing a suitable phenol with sodium nitrite.
  • Redresv001 stilbenoid showed inhibitory action against three isolates of A. calcoaceticus-baumannii (B34, B48 and C146) ( Figure 1), as well as interacting with antimicrobial drugs.
  • polymyxin B polymyxin E (colistin), tobramycin and meropenem.
  • the active Redresv001 showed adjuvant activity with the antimicrobial drugs polymyxin B, polymyxin E and tobramycin.
  • the Resistance Phenotype Reversal of the isolates occurs.
  • the compound Redresv 001 is not being used as a therapeutic agent, but in subtherapeutic doses, decreasing the minimum inhibitory concentrations (MIC) of the therapeutic doses of antibiotics that were previously used and that the isolates had resistance profile to them.
  • A. calcoaceticus-baumannii B48 and C146 isolates are resistant to polymyxin B, with minimum inhibitory concentrations (MIC) of 8 and 4 ⁇ g / mL, respectively.
  • MIC minimum inhibitory concentrations
  • the combination of Azoresilbenoides RedresvOOl in inhibitory (24 ⁇ g / mL) and sub-inhibitory (3, 6 and 12 ⁇ g / mL) concentrations with polymyxin B decreased the MIC to 0.75 ⁇ g / mL, making them sensitive to this drug ( Figures 2 and 3). It is noteworthy that polymyxin B has been widely used to treat infections caused by these microorganisms, as they have been resistant to all other drugs available. Thus, when A.
  • calcoaceticus-baumannii is resistant to polymyxin B, treatment options are very limited. Thus, it is possible that Azostilbenoides RedresvOOl, even at concentrations as low as 3 ⁇ g / mL, may be clinically important for the treatment of infections caused by A. calcoaceticus-baumannii. resistant to polymyxin B. Isolate A. calcoaceticus-baumannii B34 has not been evaluated as being sensitive to polymyxin B.
  • the isolate A. calcoaceticus-baumannii C146 with 24 ⁇ g / mL MIC for redresvOOl and with 64 ⁇ g / mL MIC for tobramycin was subjected to the combination of tobramycin and redresvOOl at concentrations of 12 and 6 ⁇ 9 / ⁇ _. tobramycin MIC to 8 ⁇ / ⁇ .-, and the combination of tobramycin with redresvOOl at a concentration of 3 ⁇ g / mL reduced the tobramycin MIC to 16 ⁇ g / mL ( Figure 4).
  • Isolate A calcoaceticus-baumannii C146 with MIC of 24 ⁇ g / mL for redresvOOl and MIC> 8 ⁇ g / mL for polymyxin E (colistin) was combined with polymyxin E with redresvOOl at concentrations 12 and 6. ⁇ / ⁇ .-, having reduced the CIM for polymyxin E to 4 ⁇ / ⁇ .-.
  • RedresvOOl azostilbenoid was not able to reverse the resistance of A. calcoaceticus-baumannii isolates to meropenem, but meropenem at 16 and 32 ⁇ g / mL was able to inhibit the action of RedresvOOl azostilbenoids in the three isolates. analyzed (Tables 1 and 2), suggesting some interaction between the compounds.
  • Redresv001 at sub-inhibitory concentrations did not alter the ciprofloxacin MIC in the three isolates evaluated.
  • compositions used were prepared in Mueller-Hinton culture medium with DMSO vehicle and water soluble antibiotic when used.
  • Redresv001 cytotoxicity assay was performed in MRC-7 (human lung fibroblast) strain. In the 24h trial, there was no cell death. After 72 hours, the IC50 dose of Redresv001 for the cell line was 13.34 ⁇ g / mL.
  • both compounds are potential inhibitors of tyrosinase agonist activity in mushrooms, as they have inhibition of 41, 46% at 50 ⁇ and 72.75% at the same concentration, respectively.
  • azostylbenoids are involved in numerous biological reactions such as DNA inhibition, RNA and protein synthesis, carcinogenesis and nitrogen fixation (Gini et al., 201 1).
  • Azostylbenoids are generally synthesized by oxidizing aromatic amines using transition metals or by reducing aromatic nitro using metals (Tedder & Theaker, 1958; Wermuth, 2008).
  • Tedder & Theaker, 1958 Direct addition of a diazonic group to an aromatic nucleus (scheme 1).
  • Aromatic hydroxy acids react with nitric acid buffer in two ways, both leading to the production of diazonic salts, which will be wholly or partially results by decarboxylation and replacement of the epoxy carboxyl group by the diazonic group.
  • the redresolving molecule was obtained by dissolving phenol (0.01 mol) in a mixture of acetone and water (1: 2).
  • the solution was treated with excess sulfamic acid and neutralized with sodium bicarbonate.
  • this compound was obtained by solubilizing Redresv001 (4.38 mmol) in Acetone (20 mL). After solubilization, was added potassium carbonate (5,45g) and kept under stirring for 5 min at a temperature of 25 Q C protected from light. At the end of the time, methyl lodetum (3 mL) was added dropwise for approximately 5 min. Agitation Q maintained at 25 C for 24h. To the solution was added Methyl iodide (3 ml) and stirring proceeded as previously continued for another 24 hours at 25 Q C. Saturated ammonium chloride added (25 mL) and the product was extracted with ethyl acetate (3 x 30 ml ).
  • this compound was obtained from agitation by the 80 Q C until complete solubilization of Redresv001 (0.9 mmol) in dimethylformamide (5 ml) and potassium carbonate (25 mmol). Methyl iodide was added (5.2 mmol) dropwise while stirring for 24 hours under reflux at 40 Q C. The product was extracted with saturated ammonium chloride increase (25 mL) and ethyl acetate ( 3 x 30 mL). The organic phase was washed with distilled water (5 x 30 mL), 1 M sodium hydroxide solution (6 x 30 mL) and Saturated sodium chloride (3 x 30 mL).
  • this compound was obtained from the solubilization of RedresvOO1 (4.38 mmol) in Acetic Anhydride (120 mL) under stirring at room temperature. Pyridine (1 mL) was added one drop every 5 min and stirred for 30 min after all addition.
  • this compound was obtained from the addition of anhydrous Dimethylsulfoxide (10mL) with Redresvol (500 mg) and kept under stirring in a closed system until solubilization. Then Triethylamine (306 ⁇ ) was added and stirring was continued for 20 minutes by adding Acetic Anhydride (206 ⁇ ) and stirring for a further 1h.
  • redresv002, redresv003, redresv004 and redresvOO6 were tested at concentrations of 5, 10, 20, 40, 80, 160, 320 and 640 ⁇ g / mL against Acinetobacter sp. and Escher ⁇ chia coli without showing antimicrobial activity.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • General Health & Medical Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne l'action antimicrobienne d'azo-stilbénoïdes. La présente invention relève des domaines de la microbiologie et de la chimie organique.
PCT/BR2016/050338 2015-12-21 2016-12-20 Composition pharmaceutique, utilisation de cette composition pharmaceutique, méthode de traitement de maladies associées à des infections microbiennes et procédé de préparation d'un composé Ceased WO2017106950A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
BR102015032162A BR102015032162A2 (pt) 2015-12-21 2015-12-21 composto, composição farmacêutica, uso da composição farmacêutica, método de tratamento de doenças associadas a infecções microbianas e processo de preparação de um composto
BR102015032162-7 2015-12-21

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WO2017106950A1 true WO2017106950A1 (fr) 2017-06-29

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BR (1) BR102015032162A2 (fr)
WO (1) WO2017106950A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002033005A2 (fr) * 2000-10-19 2002-04-25 Trans Photonics, L.L.C. Nouveaux composants chromophoriques polyaryl-substitues
BRPI0705511A (pt) * 2006-12-14 2008-08-12 Oreal artigo cosmético, processo de coloração de matérias queratìnicas e uso do artigo cosmético
WO2013187167A1 (fr) * 2012-06-11 2013-12-19 関東化学株式会社 Inhibiteur enzymatique

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002033005A2 (fr) * 2000-10-19 2002-04-25 Trans Photonics, L.L.C. Nouveaux composants chromophoriques polyaryl-substitues
BRPI0705511A (pt) * 2006-12-14 2008-08-12 Oreal artigo cosmético, processo de coloração de matérias queratìnicas e uso do artigo cosmético
WO2013187167A1 (fr) * 2012-06-11 2013-12-19 関東化学株式会社 Inhibiteur enzymatique

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
MALCOLM F. G. STEVENS ET AL.: "Structural Studies on Bioactive Compounds. 23. Synthesis of Polyhydroxylated 2- Phenylbenzothiazoles and a Comparison of Their Cytotoxicities and Pharmacological Properties with Genistein and Quercetin", J. MED. CHEM., vol. 37, 1994, pages 1689 - 1695, XP002950252, [retrieved on 19940501] *
NADER NOROOZI PESYAN ET AL.: "New tetrazolic azo dyes linked to (thio)barbiturate and electron-rich aromatics as potential antimicrobial agents", TURK J CHEM, vol. 39, 2015, pages 998 - 1011, XP055393217, [retrieved on 20150322] *

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