WO2017106950A1 - Pharmaceutical composition, use of the pharmaceutical composition, method for treating diseases associated with microbial infections and method for preparing a compound - Google Patents

Pharmaceutical composition, use of the pharmaceutical composition, method for treating diseases associated with microbial infections and method for preparing a compound Download PDF

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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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pharmaceutical composition
compound
polymyxin
tobramycin
composition according
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PCT/BR2016/050338
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French (fr)
Portuguese (pt)
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Sílvia DIAS DE OLIVEIRA
André ARIGONY SOUTO
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Uniao Brasileira De Educacao E Assistencia
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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
    • A61K31/70—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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Abstract

The present invention describes the antimicrobial action of azo-stilbenoids. The present invention pertains to the fields of microbiology and organic chemistry.

Description

Relatório Descritivo de Patente de Invenção  Patent Invention Descriptive Report
COMPOSIÇÃO FARMACÊUTICA, USO DA COMPOSIÇÃO FARMACÊUTICA, MÉTODO DE TRATAMENTO DE DOENÇAS ASSOCIADAS A INFECÇÕES PHARMACEUTICAL COMPOSITION, USE OF PHARMACEUTICAL COMPOSITION, METHOD OF TREATMENT OF DISEASES ASSOCIATED WITH INFECTIONS
MICROBIANAS E PROCESSO DE PREPARAÇÃO DE UM COMPOSTO Campo da Invenção MICROBIANAS AND A COMPOUND PREPARATION PROCESS Field of the Invention
[0001] A presente invenção descreve ação antimicrobiana de azoestilbenoides. A presente invenção se situa nos campos da Microbiologia e Química Orgânica.  The present invention describes antimicrobial action of azostilbenoids. The present invention is in the fields of Microbiology and Organic Chemistry.
Antecedentes da Invenção Background of the Invention
[0002] Infecções associadas à assistência em saúde causadas por Acinetobacter calcoaceticus-baumannii têm sido bastante prevalentes nas últimas décadas, tornando-se motivo de preocupação mundial nas unidades de saúde. Estes microrganismos são considerados patógenos oportunistas responsáveis por causar infecções do trato respiratório, quadros de pneumonias associados à ventilação mecânica, infecções de feridas e bacteremia em pacientes internados em unidades de terapia intensiva (Manchanda et al., 2010).  Healthcare-associated infections caused by Acinetobacter calcoaceticus-baumannii have been quite prevalent in recent decades, becoming a cause of worldwide concern in health facilities. These microorganisms are considered opportunistic pathogens responsible for causing respiratory tract infections, mechanical ventilation-associated pneumonia, wound infections and bacteremia in patients admitted to intensive care units (Manchanda et al., 2010).
[0003] O uso indiscriminado de antimicrobianos aliado ao fato de que esses microrganismos possuem capacidade de se manter por longos períodos em ambientes hospitalares e adquirirem facilmente determinantes de resistência culminou em um quadro disseminado de resistência aos principais antimicrobianos utilizados na terapia contra infecções causadas por esta bactéria (Peleg et al., 2008; Manchanda et al., 2010). Desde a década de 1970, têm sido relatados inúmeros casos de resistência associados a aminoglicosídeos, fluoroquinolonas e cefalosporinas em Acinetobacter spp., o que levou ao uso dos carbapenêmicos. Entretanto, atualmente, a resistência aos carbapenêmicos é amplamente descrita em vários países, inclusive no Brasil, e obriga o uso de outros fármacos, como as polimixinas e a tigeciclina, ou mesmo a tobramicina inalatória como adjuvante em quadros de infecções respiratórias (Levin et al., 1999; Villegas & Hartstein, 2003; Manchanda et al., 2010; Rossi, 201 1 ; Kempf & Rolain, 2012). The indiscriminate use of antimicrobials combined with the fact that these microorganisms are able to sustain themselves for long periods in hospital settings and easily acquire resistance determinants has culminated in a widespread picture of resistance to the main antimicrobials used in therapy against infections caused by it. bacteria (Peleg et al., 2008; Manchanda et al., 2010). Since the 1970s, numerous cases of resistance associated with aminoglycosides, fluoroquinolones and cephalosporins have been reported in Acinetobacter spp., Which led to the use of carbapenemics. However, 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).
[0004] Muitos mecanismos de resistência a antimicrobianos têm sido descritos em A. calcoaceticus-baumannii, tais como redução da permeabilidade da membrana externa, perda de porinas, alterações nos sítios de ligação dos antimicrobianos, produção de β-lactamases e hiperexpressão de bombas de efluxo (Manchanda et al., 2010; Rumbo et al., 2013). As bombas de efluxo AdeABC, AdeFGH, AdelJK,CraA, AmvA, AbeM e AbeS têm sido associadas à resistência a um amplo espectro de antimicrobianos, tais como cloranfenicol, trimetoprim, aminoglicosídeos, fluoroquinolonas, β-lactâmicos e tetraciclinas (Coyne et al., 201 1 ). Desta forma, os inibidores de bomba de efluxo podem ser importantes adjuvantes no tratamento de infecções causadas por Acinetobacter spp. resistentes a múltiplos fármacos.  Many antimicrobial resistance mechanisms have been described in A. calcoaceticus-baumannii, such as reduction of outer membrane permeability, loss of porins, changes in antimicrobial binding sites, β-lactamases production, and hyperexpression of blood pumps. efflux (Manchanda et al., 2010; Rumbo et al., 2013). AdeABC, AdeFGH, AdelJK, CraA, AmvA, AbeM and AbeS efflux pumps have been linked to resistance to a broad spectrum of antimicrobials such as chloramphenicol, trimethoprim, aminoglycosides, fluoroquinolones, β-lactams and tetracyclines (Coyne et al., 201 1). Thus, efflux pump inhibitors may be important adjuvants in the treatment of infections caused by Acinetobacter spp. resistant to multiple drugs.
[0005] Desta forma, a indústria farmacêutica não tem desenvolvido novos fármacos na mesma velocidade em que os microrganismos têm se mostrado resistentes àqueles já existentes. Assim, tem sido necessária a investigação de alternativas terapêuticas, considerando compostos já disponíveis no mercado e validados para a utilização em seres humanos, bem como a síntese de novos compostos para serem utilizados isoladamente ou associados com fármacos antimicrobianos para o tratamento de infecções causadas por bactérias caracterizadas como resistentes aos antibióticos.  Thus, the pharmaceutical industry has not developed new drugs at the same rate that microorganisms have been resistant to existing ones. Thus, research into therapeutic alternatives has been necessary, considering compounds already available on the market and validated for use in humans, as well as the synthesis of new compounds to be used alone or in combination with antimicrobial drugs to treat infections caused by bacteria. characterized as antibiotic resistant.
[0006] O resveratrol é uma fitoalexina polifenólica produzida por plantas em resposta a condições ambientais desfavoráveis, que apresenta ação antioxidante, anti-inflamatória, cardioprotetora, neuroprotetora, quimioprotetora, antiviral, antifúngica e antibacteriana (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; Zetterstrõm et al., 2013). O resveratrol tem se mostrado capaz de inibir a formação de biofilme bacteriano, o que tem sido atribuído à ação inibitória no quorum sensing (Augustine et al., 2013; Lee et al., 2013), bem como tem sido associado à inibição da expressão do "swarminçf e da virulência em Proteus mirabilis (Wang et al., 2006). A ruptura do potencial de membrana e/ou a inibição da replicação do DNA através da inibição da DNA girase também têm sido indicados como mecanismos de ação do resveratrol em diversos microrganismos (Subramanian et al., 2014; Mora-Pale et al., 2015). Foi atribuída a este composto a capacidade de inibir o crescimento de Escheríchia coli pela supressão da expressão de FtsZ e da formação do anel Z, implicado na divisão da célula bacteriana (Hwang & Lim, 2015). A divisão celular também foi descrita como alvo da ação do resveratrol em Arcobater spp., onde este composto agiu como inibidor de bomba de efluxo (Ferreira et al., 2014), o que indica a possibilidade de utilização do resveratrol como adjuvante em terapias antimicrobianas. Entretanto, o resveratrol não tem sido avaliado em associação a fármacos antimicrobianos que poderiam ser utilizados para o tratamento de infecções causadas por bactérias multirresistentes. Desta forma, a associação do resveratrol, que possivelmente possa atuar como inibidor de sistemas de efluxo, com antibióticos que poderiam ser excluídos da célula bacteriana por efluxo, poderia constituir uma opção terapêutica. 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). This compound has been attributed the ability to inhibit the growth of Escheríchia coli by suppressing FtsZ expression and Z-ring formation implicated in bacterial cell division (Hwang & Lim, 2015) Cell division has also been described as a target for resveratrol action in Arcobater spp. efflux pump inhibitor (Ferreira et al., 2014), indicating the possibility of using resveratrol as an adjuvant in antimicrobial therapies.However, resveratrol has not been evaluated in combination with antimicrobial drugs. s that could be used to treat infections caused by multi-resistant bacteria. Thus, the association of resveratrol, which may possibly act as an inhibitor of efflux systems, with antibiotics that could be excluded from the bacterial cell by efflux, could be a therapeutic option.
[0007] Assim, do que se depreende da literatura pesquisada, não foram encontrados documentos antecipando ou sugerindo os ensinamentos da presente invenção, de forma que a solução aqui proposta possui novidade e atividade inventiva frente ao estado da técnica.  Thus, from what is clear from the researched literature, no documents were found anticipating or suggesting the teachings of the present invention, so that the solution proposed here has novelty and inventive activity in relation to the state of the art.
Sumário da Invenção Summary of the Invention
[0008] A presente declaração de invenção visa proteger o achado de que o estilbenoide Redresv001 apresentou ação inibitória frente a três isolados de A. calcoaceticus-baumannii (B34, B48 e C146) (Figura 1 ), bem como apresentou interação com os fármacos antimicrobianos polimixina B, polimixina E (colistina), tobramicina e meropenem. [0009] Estes e outros objetos da invenção serão imediatamente valorizados pelos versados na arte e pelas empresas com interesses no segmento, e serão descritos em detalhes suficientes para sua reprodução na descrição a seguir. [0008] This declaration aims to protect the finding that 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. These and other objects of the invention will be immediately appreciated by those skilled in the art and companies having an interest in the segment, and will be described in sufficient detail for their reproduction in the following description.
Breve Descrição das Figuras Brief Description of the Figures
[0010] Com o intuito de melhor definir e esclarecer o conteúdo do presente pedido de patente, são apresentadas as presentes figuras:  In order to better define and clarify the contents of this patent application, the following figures are presented:
[0011] A figura 1 mostra gráficos com a concentração inibitória mínima (CIM) (μς/ιηί) do Azoestilbenoide RedresvOOl em isolados de A. calcoaceticus-baumannii (B34, B48 e C146). [0011] Figure 1 shows graphs with the minimum inhibitory concentration (MIC) (μς / ιηί) of Azoresilbenoid RedresvOOl in isolates of A. calcoaceticus-baumannii (B34, B48 and C146).
[0012] A figura 2 mostra gráficos da associação do Azoestilbenoides RedresvOOl com polimixina B no isolado A. calcoaceticus-baumannii B48, expressas como CIM ^g/ml_).  Figure 2 shows graphs of the association of Azoresilbenoides RedresvOO1 with polymyxin B in isolate A. calcoaceticus-baumannii B48, expressed as MIC (µg / ml).
[0013] A figura 3 mostra gráficos da associação do Azoestilbenoides RedresvOOl com polimixina B no isolado A. calcoaceticus-baumannii C146, expressas como CIM ^g/ml_).  Figure 3 shows graphs of the association of Azoresilbenoides RedresvOO1 with polymyxin B in isolate A. calcoaceticus-baumannii C146, expressed as MIC (µg / ml).
[0014] A figura 4 mostra gráficos da associação do Azoestilbenoides RedresvOOl com tobramicina no isolado A. calcoaceticus-baumannii C146, os valores são expressos como CIMs ^g/ml_) necessárias para inibir o crescimento de Acinetobacter calcoaceticus-baumannii cepa 146. (1 ) somente tobramicina; (2) tobramicina na presença do inibidor de bomba de efluxo CCCP nas concentrações de 20, 10 e 5 μg/mL; (3) tobramicina na presença de CCCP na concentração de 2,5 μg/mL; (4) tobramicina na presença de redresvOOl nas concentrações de 12 e 6 μg/mL; (5) tobramicina na presença de redresvOOl na concentração de 3 μg/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. (1 ) tobramycin only; (2) Tobramycin in the presence of the CCCP efflux pump inhibitor at concentrations of 20, 10 and 5 μg / mL; (3) tobramycin in the presence of 2.5 μg / mL CCCP; (4) tobramycin in the presence of redresvOOl at concentrations of 12 and 6 μg / mL; (5) Tobramycin in the presence of 3 µg / mL redresvOOl.
Descrição Detalhada da Invenção Detailed Description of the Invention
[0015] Em um primeiro objeto, a presente invenção apresenta uma composição farmacêutica, caracterizada por compreender: - pelo menos um composto de fórmula: In a first object, the present invention features a pharmaceutical composition, characterized in that it comprises: - at least one compound of formula:
Figure imgf000006_0001
Figure imgf000006_0001
em que R1 , R2 e R3 são OH; e  wherein R1, R2 and R3 are OH; and
- pelo menos um veículo farmaceuticamente aceitável.  at least one pharmaceutically acceptable carrier.
[0016] Em uma concretização, a composição farmacêutica adicionalmente compreende pelo menos um fármaco com ação antimicrobiana In one embodiment, the pharmaceutical composition further comprises at least one antimicrobially acting drug.
[0017] Em uma concretização da composição farmacêutica, o fármaco com ação antimicrobiana é selecionado do grupo consistindo de: Polimixina B, Polimixina E e tobramicina ou combinação dos mesmos. In one embodiment of the pharmaceutical composition, the antimicrobially acting drug is selected from the group consisting of: Polymyxin B, Polymyxin E and tobramycin or a combination thereof.
[0018] Em uma concretização da composição farmacêutica, o composto está em uma concentração entre 2 e 30 μg/mL. In one embodiment of the pharmaceutical composition, the compound is at a concentration between 2 and 30 μg / mL.
[0019] Em uma concretização da composição farmacêutica, o fármaco com ação antimicrobiana está em uma concentração entre 2 e 100 μg/mL.  In one embodiment of the pharmaceutical composition, the antimicrobially acting drug is in a concentration between 2 and 100 μg / mL.
[0020] Em um segundo objeto, o uso da dita composição farmacêutica é para a preparação de um medicamento com ação antimicrobiana.  [0020] In a second object, the use of said pharmaceutical composition is for the preparation of a drug with antimicrobial action.
[0021] Em uma concretização do uso da dita composição farmacêutica, é para a preparação de um medicamento com ação antimicrobiana contra um microrganismo selecionado do género Acinetobacterspp.  In one embodiment of the use of said pharmaceutical composition, it is for the preparation of a medicament with antimicrobial action against a selected microorganism of the genus Acinetobacterspp.
[0022] Em uma concretização do uso da dita composição farmacêutica, o microrganismo é Acinetobacter calcoaceticus-baumannii.  In one embodiment of the use of said pharmaceutical composition, the microorganism is Acinetobacter calcoaceticus-baumannii.
[0023] Em um terceiro objeto, o método de tratamento de doenças associadas a infecções microbianas compreende a aplicação da dita composição farmacêutica.  In a third object, the method of treating diseases associated with microbial infections comprises applying said pharmaceutical composition.
[0024] Em um quarto objeto, o processo de preparação do dito composto compreende a condensação de um fenol adequado com um nitrito de sódio. Exemplos - Concretizações In a fourth object, the process of preparing said compound comprises condensing a suitable phenol with sodium nitrite. Examples - Embodiments
[0025] Os exemplos aqui mostrados têm o intuito somente de exemplificar uma das inúmeras maneiras de se realizar a invenção, contudo sem limitar, o escopo da mesma.  The examples shown herein are intended solely to exemplify one of the numerous ways of carrying out the invention, but without limiting the scope thereof.
[0026] A presente declaração de invenção visa proteger o achado de que o estilbenoide Redresv001 apresentou ação inibitória frente a três isolados de A. calcoaceticus-baumannii (B34, B48 e C146) (Figura 1 ), bem como apresentou interação com os fármacos antimicrobianos polimixina B, polimixina E (colistina), tobramicina e meropenem. Além disso, o ativo Redresv001 apresentou atividade adjuvante com os fármacos antimicrobianos polimixina B, polimixina E e tobramicina.  [0026] This declaration aims to protect the finding that 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. In addition, the active Redresv001 showed adjuvant activity with the antimicrobial drugs polymyxin B, polymyxin E and tobramycin.
[0027] Ao associar o composto ao fármaco antimicrobiano, ocorre a Reversão do Fenótipo de Resistência dos isolados. Dessa forma, o composto Redresv 001 não está sendo utilizado como agente terapêutico, e sim em doses subterapêuticas, diminuindo as concentrações inibitórias mínimas (CIM) das doses terapêuticas dos antibióticos que antes já eram utilizados e que os isolados tinham perfil de resistência a eles.  By combining the compound with the antimicrobial drug, the Resistance Phenotype Reversal of the isolates occurs. Thus, 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.
[0028] Os isolados de A. calcoaceticus-baumannii B48 e C146 são resistentes à polimixina B, com concentrações inibitórias mínimas (CIM) de 8 e 4 μg/mL, respectivamente. Entretanto, a associação de Azoestilbenoides RedresvOOl em concentrações inibitórias (24 μg/mL) e sub-inibitórias (3, 6 e 12 μg/mL) com a polimixina B diminuiu a CIM para 0,75 μg/mL, tornando-os sensíveis a este fármaco (Figuras 2 e 3). Cabe ressaltar que a polimixina B tem sido amplamente utilizada para o tratamento de infecções causadas por estes microrganismos, uma vez que eles têm se mostrado resistentes a todos os outros fármacos disponíveis. Logo, quando A. calcoaceticus-baumannii é resistente à polimixina B, as opções de tratamento ficam bastante limitadas. Desta forma, é possível que o Azoestilbenoides RedresvOOl , mesmo em concentrações tão baixas quanto 3 μg/mL, possa ser clinicamente importante para o tratamento de infecções causadas por A. calcoaceticus-baumannii resistentes à polimixina B. O isolado A. calcoaceticus-baumannii B34 não foi avaliado por ser sensível à polimixina B. A. calcoaceticus-baumannii B48 and C146 isolates are resistant to polymyxin B, with minimum inhibitory concentrations (MIC) of 8 and 4 μg / mL, respectively. However, the combination of Azoresilbenoides RedresvOOl in inhibitory (24 μg / mL) and sub-inhibitory (3, 6 and 12 μg / mL) concentrations with polymyxin B decreased the MIC to 0.75 μg / 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 μg / 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.
[0029] O isolado A. calcoaceticus-baumannii C146 com CIM de 24 μg/mL para redresvOOl e com CIM 64 μg/mL para tobramicina, foi submetido à associação de tobramicina com redresvOOl nas concentrações de 12 e 6 μ9/ιτιΙ_, tendo reduzido a CIM de tobramicina para 8 μς/ιη.-, e a associação da tobramicina com redresvOOl na concentração de 3 μg/mL reduziu a CIM de tobramicina para 16 μg/mL (Figura 4).  The isolate A. calcoaceticus-baumannii C146 with 24 µg / mL MIC for redresvOOl and with 64 µg / mL MIC for tobramycin was subjected to the combination of tobramycin and redresvOOl at concentrations of 12 and 6 μ9 / ιτιΙ_. tobramycin MIC to 8 μς / ιη.-, and the combination of tobramycin with redresvOOl at a concentration of 3 μg / mL reduced the tobramycin MIC to 16 μg / mL (Figure 4).
[0030] O isolado A. calcoaceticus-baumannii C146 com CIM de 24 μg/mL para redresvOOl e com CIM > 8 μg/mL para polimixina E (colistina), foi submetido à associação de polimixina E com redresvOOl nas concentrações de 12 e 6 μς/ιη.-, tendo reduzido a CIM para polimixina E para 4 μς/ιτι.-.  Isolate A. calcoaceticus-baumannii C146 with MIC of 24 μg / mL for redresvOOl and MIC> 8 μg / mL for polymyxin E (colistin) was combined with polymyxin E with redresvOOl at concentrations 12 and 6. μς / ιη.-, having reduced the CIM for polymyxin E to 4 μς / ιτι.-.
[0031] Entretanto, o azoestilbenoide RedresvOOl não foi capaz de reverter a resistência dos isolados de A. calcoaceticus-baumannii ao meropenem, mas o meropenem nas concentrações de 16 e 32 μg/mL foi capaz de inibir a ação do Azoestilbenoides RedresvOOl nos três isolados analisados (Tabelas 1 e 2), sugerindo alguma interação entre os compostos. However, RedresvOOl azostilbenoid was not able to reverse the resistance of A. calcoaceticus-baumannii isolates to meropenem, but meropenem at 16 and 32 μg / 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.
Tabela 1 - Influência da associação de meropenem com Azoestilbenoides RedresvOOl no crescimento dos isolados B48 e C146 de A. calcoaceticus- baumannii. Table 1 - Influence of the association of meropenem with Azoresilbenoides RedresvOOl on the growth of isolates B48 and C146 of A. calcoaceticus baumannii.
Meropenem Azoestilbenoides RedresvOl ^g/ml_)  Meropenem Azostilbenoides RedresvOl (g / ml)
(MQ mL) 6 8 10 12 (MQ mL) 6 8 10 12
32 Crescimento Crescimento Crescimento Crescimento 16 Crescimento Crescimento Crescimento Crescimento32 Growth Growth Growth Growth 16 Growth Growth Growth Growth
8 a 0,25 Ausência de crescimento 8 to 0.25 No growth
Tabela 2 - Influência da associação de meropenem com AzoestilbenoidesTable 2 - Influence of meropenem association with Azostilbenoids
RedresvOOl no crescimento do isolado B34 de A. calcoaceticus-baumannii.Redresorb on growth of A. calcoaceticus-baumannii isolate B34.
Meropenem Azoestilbenoides RedresvOl ^g/ml_) Meropenem Azostilbenoides RedresvOl (g / ml)
(MQ mL) 20 22 24 32 Crescimento Crescimento Crescimento (MQ mL) 20 22 24 32 Growth Growth Growth
16 Crescimento Crescimento Crescimento 16 Growth Growth Growth
8 a 0,25 Ausência de crescimento  8 to 0.25 No growth
[0032] Em ensaios preliminares, a associação de AzoestilbenoidesIn preliminary trials, the Azostylbenoids Association
Redresv001 , em concentrações sub-inibitórias, não alterou a CIM de ciprofloxacina nos três isolados avaliados. Redresv001 at sub-inhibitory concentrations did not alter the ciprofloxacin MIC in the three isolates evaluated.
[0033] Todas as composições utilizadas foram preparadas em meio de cultura Mueller-Hinton com veículo DMSO e antibiótico solúvel em água, quando utilizado.  All compositions used were prepared in Mueller-Hinton culture medium with DMSO vehicle and water soluble antibiotic when used.
Tolerância de células persisters  Persistent cell tolerance
[0034] O efeito em células persisters da associação de tobramicina na concentração de 10xCIM com redresv001 na concentração de 0,5xCIM foi avaliado no isolado A. calcoaceticus-baumannii Ac2 em cultivo planctonico. O isolado Ac2 foi capaz de produzir células persisters após 24 h de exposição à tobramicina associada ao redresv001 , após a adição imediata de ambos os compostos, bem como após a adição tardia do redresv001 , apresentando frações de células sobreviventes semelhantes: 5.6905% e 5.3452%, respectivamente. Paralelamente, foi observado que Ac2 também foi capaz de apresentar células persisters após 24 h de exposição aos compostos quando avaliados individualmente, sendo que 0.41 14% da fração inicial de células foi capaz de sobreviver à exposição à tobramicina e 4.210% ao redresv001 . Desta forma, observou-se que a fração de células persisters detectada a partir da associação do redresv001 com a tobramicina foi 10X maior do que a fração obtida a partir da exposição somente ao fármaco, o que, diferentemente do que era esperado, indicou que o redresv001 atuou favorecendo a formação de células tolerantes ao fármaco. Também foi observado que não houve diferença na fração de células persisters após a exposição imediata e tardia do redresv001 . Citotoxicidade do RedresvOOI em fibroblastos The effect on persister cells of the combination of tobramycin at 10xCIM concentration with redresv001 at 0.5xCIM concentration was evaluated in isolate A. calcoaceticus-baumannii Ac2 in planktonic culture. The Ac2 isolate was able to produce persister cells after 24 h of exposure to redresv001-associated tobramycin after the immediate addition of both compounds as well as after the late addition of redresv001, with similar surviving cell fractions: 5,6905% and 5,3452%. respectively. At the same time, it was observed that Ac2 was also able to present persister cells after 24 h of exposure to the compounds when evaluated individually, with 0.41 14% of the initial cell fraction surviving exposure to tobramycin and 4,210% to redresv001. Thus, it was observed that the persister cell fraction detected from the association of redresv001 with tobramycin was 10X higher than the fraction obtained from drug exposure alone, which, unlike expected, indicated that redresv001 acted by favoring drug-tolerant cell formation. It was also observed that there was no difference in the persister cell fraction after immediate and late exposure of redresv001. RedresvOOI cytotoxicity in fibroblasts
[0035] Foi realizado ensaio de citotoxicidade com Redresv001 em linhagem MRC-7 (fibroblasto de pulmão humano). Em 24h de ensaio, não houve morte celular. Após 72 horas, a dose IC50 de Redresv001 para a linhagem celular foi de 13,34 ug/mL. Esses dados corroboram com os ensaios realizados com Redresv001 em associação com polimixina B, colistina e tobramicina, nas concentrações de 6 e 12ug, reduzindo as MICs dos fármacos e mantendo viabilidade celular nestas concentrações.  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 µg / mL. These data corroborate the assays performed with Redresv001 in combination with polymyxin B, colistin and tobramycin at concentrations of 6 and 12ug, reducing drug MICs and maintaining cell viability at these concentrations.
Atividade biológica dos azoestilbenoides Azostilbenoids biological activity
[0036] Em estudos anteriores, análogos do resveratrol foram sintetizados pela modificação de substituintes em ambos os anéis, não alterando a dupla ligação entre eles: um pela fusão de benzeno e outros dois pela fusão de um anel heterocíclico; esses análogos recentemente sintetizados apresentaram atividade antineoplásica, vasodilatadora e anti-tirosinase (Song et al., 2012). O aumento dos efeitos anti-tirosinase, bem como antioxidante e outras atividades, foram relatados por Song e colaboradores em 2012, para o azo-oxiresveratrol e o azo-resveratrol. Segundo esses autores, os dois compostos são potenciais inibidores da atividade agonista da tirosinase em cogumelos, por apresentarem inibição de 41 ,46% a 50 μΜ e de 72,75% na mesma concentração, respectivamente. O azo-resveratrol (IC50=36,28 ± 0,72μΜ) exibiu atividade inibitória equipotente ao resveratrol e os autores sugerem a possibilidade de mais fácil absorção na pele por apresentar um Log P maior (3,03 para resveratrol e 3,30 para azo-resveratrol), indicando o uso externo para tratamento de várias doenças associadas com a hiperpigmentação.  In previous studies, resveratrol analogs have been synthesized by modifying substituents on both rings, not altering the double bond between them: one by the fusion of benzene and the other by the fusion of a heterocyclic ring; These recently synthesized analogues showed antineoplastic, vasodilatory, and anti-tyrosinase activity (Song et al., 2012). Increased anti-tyrosinase effects as well as antioxidant and other activities were reported by Song and colleagues in 2012 for azo-oxiresveratrol and azo-resveratrol. According to these authors, both compounds are potential inhibitors of tyrosinase agonist activity in mushrooms, as they have inhibition of 41, 46% at 50 μΜ and 72.75% at the same concentration, respectively. Azo-resveratrol (IC50 = 36.28 ± 0.72μΜ) exhibited equipotent inhibitory activity to resveratrol and the authors suggest the possibility of easier skin absorption by presenting a higher Log P (3.03 for resveratrol and 3.30 for azo-resveratrol), indicating external use for the treatment of various diseases associated with hyperpigmentation.
[0037] Além desses análogos, outros azoestilbenoides estão envolvidos em numerosas reações biológicas como a inibição de DNA, RNA e síntese de proteínas, carcinogênese e fixação de nitrogénio (Gini et al., 201 1 ). In addition to these analogues, other azostylbenoids are involved in numerous biological reactions such as DNA inhibition, RNA and protein synthesis, carcinogenesis and nitrogen fixation (Gini et al., 201 1).
[0038] Em 1994, Stevens e colaboradores sintetizaram benzotiazóis hidroxi-substituídos com a finalidade de comparar as citotoxicidades e propriedades farmacológicas com a genisteína e quercetina (Stevens et al., 1994), que são inibidores competitivos do sítio de ligação de Adenosina Trifosfato (ATP) de quinases, como a tirosina quinase. As proteínas tirosina quinases ocupam posição central no controle da proliferação celular e quando estão superexpressas mostram associação com a promoção e manutenção de doenças malignas. Os resultados in vitro desse estudo mostram que a citotoxicidade dos compostos sintetizados em linhagens de células MCF-7 (carcinoma de mama humano) e WiDr (células de tumor de cólon humano), em ratos, foram relevantes, principalmente do azocomposto, que apresentou IC50 de 7,0 e 27,0 μΜ para as respectivas linhagens, se comparado ao IC50 de 15,1 e 27,7 μΜ para genisteína e 24,0 e 40,2 μΜ para quercetina. Além das duas linhagens já citadas, os autores utilizaram também a HN5 (carcinoma de células escamosas), na qual o azo composto sintetizado apresentou IC50 de 58,0 μΜ e a quercetina de 190,0 μΜ. In 1994, Stevens and colleagues synthesized hydroxy-substituted benzothiazoles for the purpose of comparing cytotoxicities and pharmacological properties with genistein and quercetin (Stevens et al., 1994), which are competitive inhibitors of the adenosine triphosphate (ATP) kinase binding site, such as tyrosine kinase. Protein tyrosine kinases occupy a central position in the control of cell proliferation and when overexpressed show association with the promotion and maintenance of malignant diseases. The in vitro results of this study show that the cytotoxicity of compounds synthesized in MCF-7 (human breast carcinoma) and WiDr (human colon tumor cell) cell lines in rats were relevant, mainly from azocompound, which showed IC50. of 7.0 and 27.0 μΜ for the respective strains compared to the IC50 of 15.1 and 27.7 μΜ for genistein and 24.0 and 40.2 μΜ for quercetin. In addition to the two strains already mentioned, the authors also used HN5 (squamous cell carcinoma), in which the synthesized azo compound presented IC50 of 58.0 μΜ and quercetin of 190.0 μΜ.
[0039] Piotto e colaboradores, em 2013, sintetizaram derivados de pequenos azobenzenos com atividade antibacteriana e antifúngica (Piotto et al., 2013). A relevância desse estudo deve-se ao fato do aumento da resistência bacteriana à maioria das classes de antibióticos disponíveis. Os compostos sintetizados foram comparados com antimicrobianos estilbenos, sendo que os azoestilbenoides mostraram maior atividade antifúngica e antibacteriana, com menor toxicidade. A atividade antimicrobiana e a capacidade de destruir biofilmes, também demonstrada nesse estudo, são promissoras e aumentam o interesse do uso terapêutico dos azoestilbenoides. Estudos realizados no desenvolvimento molecular pré-síntese, indicaram que esses compostos podem inibir a ligação da ATP sintase (catalisa a formação de ATP) na interface entre as subunidades α e δ dessa enzima.  Piotto et al. In 2013 synthesized small azobenzene derivatives with antibacterial and antifungal activity (Piotto et al., 2013). The relevance of this study is due to the increased bacterial resistance to most classes of available antibiotics. The synthesized compounds were compared with stilbene antimicrobials, and azostilbenoids showed higher antifungal and antibacterial activity, with lower toxicity. The antimicrobial activity and the ability to destroy biofilms, also demonstrated in this study, are promising and increase the interest of therapeutic use of azostilbenoids. Studies performed on pre-synthesis molecular development indicated that these compounds may inhibit ATP synthase binding (catalyzes ATP formation) at the interface between α and δ subunits of this enzyme.
Síntese dos azoestilbenoides Azostylbenoids synthesis
[0040] Geralmente os azoestilbenoides são sintetizados pela oxidação de aminas aromáticas utilizando metais de transição ou pela redução de nitro aromáticos utilizando metais (Tedder & Theaker, 1958; Wermuth, 2008). A fim de preparar azoestilbenoides assimétricos, utilizamos o proposto por Tedder & Theaker (Tedder & Theaker, 1958): adição direta de um grupo diazônico num núcleo aromático (esquema 1 ). Hidroxi-ácidos aromáticos reagem com tampão de ácido nítrico em dois caminhos, ambos levando à produção de sais diazônicos, que serão total ou parcialmente resultados pela descarboxilação e à substituição do grupamento carboxila ejetado pelo grupo diazônico. Azostylbenoids are generally synthesized by oxidizing aromatic amines using transition metals or by reducing aromatic nitro using metals (Tedder & Theaker, 1958; Wermuth, 2008). In order to prepare asymmetric azostilbenoids, we use the one proposed by Tedder & Theaker (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.
Figure imgf000012_0001
Figure imgf000012_0001
Esquema 1. Adição direta de um grupo diazônico  Scheme 1. Direct addition of a diazonic group
Exemplo 1 Example 1
[0041] Neste trabalho, tentamos a modificação do ligante entre os dois anéis fenólicos do resveratrol pelo grupamento diazônico (esquema 2), através da condensação direta com o fenol e o nitrito de sódio. Em planejamento e desenvolvimento de potenciais fármacos por modificação molecular, a estratégica de mínimas modificações é muito bem aceita, na qual análogos são obtidos por pequenas modificações na estrutura do protótipo, podendo produzir aumento na potência ou na seletividade (Lee et al., 2003).  In this work, we try to modify the ligand between the two phenolic rings of resveratrol by the diazonic grouping (scheme 2) by direct condensation with phenol and sodium nitrite. In the planning and development of potential drugs by molecular modification, the minimal modification strategy is very well accepted, in which analogs are obtained by small modifications in the prototype structure, which may produce increase in potency or selectivity (Lee et al., 2003). .
Esquema 2. Modificação do protótipo resveratrol (adaptado de Roberti et al., 2003) Scheme 2. Modification of the resveratrol prototype (adapted from Roberti et al., 2003)
[0042] Conforme descrito por Tedder & Theaker (Tedder & Theaker, 1958), fenol foi dissolvido em uma mistura de acetona e água; nitrito de sódio foi adicionado à solução, seguido de ácido clorídrico e mantida agitação a 0QC por 24h. A solução foi tratada com excesso de ácido sulfâmico e neutralizada com bicarbonato de sódio antes da adição de excesso de resorcinol solubilizado em solução de hidróxido de sódio. Após agitação por 2h à temperatura de 25 QC, o precipitado foi isolado por filtração e recristalizado, resultando em cristais de coloração avermelhada, sendo esse o redresvOOl . Outros Exemplos As described by Tedder & Theaker (Tedder & Theaker, 1958), phenol was dissolved in a mixture of acetone and water; Sodium nitrite was added to the solution, followed by hydrochloric acid and stirring maintained at 0 Q C for 24h. The solution was treated with excess sulfamic acid and neutralized with sodium bicarbonate before excess resorcinol was added. solubilized in sodium hydroxide solution. After stirring for 2h at a temperature of 25 Q C, the precipitate was isolated by filtration and recrystallized, resulting in reddish crystals, which is the redresvOOl. Another examples
[0043] Outros derivados podem ser sintetizados por acetilação ou metilação; para metilação podem ser seguidos os métodos descritos por Snyder e colaboradores (Snyder et al., 201 2) e Norikane (Norikane, 2014), e para a acetilação por Pujic e colaboradores (Pujic et al., 2008) e Acerson & Andrus (Acerson & Andrus, 2014). Todos os compostos sintetizados foram caracterizados por espectroscopia de infravermelho, determinação de massa e ponto de fusão, além de ressonância magnética nuclear (1 H e 13C RMN). Other derivatives may be synthesized by acetylation or methylation; for methylation can be followed the methods described by Snyder et al. (Snyder et al., 201 2) and Norikane (Norikane, 2014), and for acetylation by Pujic et al. (Pujic et al., 2008) and Acerson & Andrus ( Acerson & Andrus, 2014). All synthesized compounds were characterized by infrared spectroscopy, mass and melting point determination, and nuclear magnetic resonance ( 1 H and 13 C NMR).
Figure imgf000013_0001
Figure imgf000013_0001
Esquema 3. Síntese do azoestilbenoide redresvOOl Scheme 3. Synthesis of azostylbenoid redresorbed
[0044] A síntese do redresvOOl (R1 =R2=R3 = OH) foi através do método geral descrito na literatura (Tedder & Theaker, 1 958). A molécula redresvOOl foi obtida a partir da dissolução do Fenol (0,01 mol) em uma mistura de acetona e água (1 :2). Adicionado nitrito de sódio (0,145 mol) à solução, seguido de ácido clorídrico 2 N (0,1 mol) e agitação mantida a 0QC por 24h. A solução foi tratada com excesso de ácido sulfâmico e neutralizada com bicarbonato de sódio. Adicionado excesso de resorcinol solubilizado em solução de hidróxido de sódio 1 M. Após agitação por 2h à temperatura de 25QC adicionado ácido clorídrico p.a até precipitação. Após resfriamento, o composto foi isolado por filtração e recristalizado; rendimento: 72%; composto colorido; ponto de fusão: 220QC; IR (KBr): o = 3425,80, 3201 ,83, 1 592,1 9, 1 251 ,51 ; UV-vis: λ (acetonitrila/água) = 230nm; RMN 1 H (400 MHz, CD3OD): δ = 1 3.363 (s, 1 H, OH), 9.951 (s, 1 H, OH), 9.737 (s, 1 H, OH), 7.690-7.579 (m, 3H, Ar-H), 6.902-6.864 (m, 2H, Ar-H), 6.489-6.461 (m, 2H, Ar-H), 6.303-6.297 (m, 1 H, Ar-H); RMN 13C (1 00 MHz, CD3OD): δ = 163.03, 161 .16, 156.64, 145.30, 1 34.66, 133.45, 124.37, 1 1 6.94, 109.46, 1 04.02. The synthesis of redresvOO1 (R1 = R2 = R3 = OH) was by the general method described in the literature (Tedder & Theaker, 1958). The redresolving molecule was obtained by dissolving phenol (0.01 mol) in a mixture of acetone and water (1: 2). Added sodium nitrite (0.145 mol) to the solution followed by 2N hydrochloric acid (0.1 mol) and stirring maintained at 0 Q C for 24h. The solution was treated with excess sulfamic acid and neutralized with sodium bicarbonate. Added excess of resorcinol dissolved in sodium hydroxide solution 1M After stirring for 2h at a temperature of 25 Q C pa added hydrochloric acid until precipitation. After cooling, the compound was isolated by filtration and recrystallized; yield: 72%; colored compound; melting point: 220 C Q; IR (KBr): o = 3425.80, 3201, 83, 1 592.19, 1 251, 51; UV-vis: λ (acetonitrile / water) = 230nm; 1 H NMR (400 MHz, CD 3 OD): δ = 1,363 (s, 1H, OH), 9,951 (s, 1H, OH), 9,737 (s, 1H, OH), 7,690-7,579 (m , 3H, Ar-H), 6,902-6,864 (m, 2H, Ar-H), 6,489-6,461 (m, 2H, Ar-H), 6,303-6,297 (m, 1H, Ar-H); 13 C NMR (100 MHz, CD 3 OD): δ = 163.03, 161.16, 156.64, 145.30, 1334.66, 133.45, 124.37, 1194, 109.46, 10.02.
Composto Redresv002 Redresv002 Compound
[0045] Seguindo o método geral, esse composto foi obtido a partir da solubilização do Redresv001 (4,38 mmol) em Acetona (20 mL). Após solubilização, foi adicionado Carbonato de Potássio (5,45g) e mantido em agitação por 5 min a temperatura de 25QC, protegido da luz. Finalizado o tempo, adicionou-se lodeto de Metila (3 mL) gota a gota, por aproximadamente 5 min. Agitação mantida a 25QC por 24hs. À solução, adicionou-se lodeto de Metila (3 mL) conforme procedido anteriormente e agitação mantida por mais 24hs à 25QC. Acrescentado Cloreto de Amónio saturado (25 mL) e o produto foi extraído com Acetato de Etila (3 x 30 mL). A fase orgânica foi lavada com Água destilada (5 x 30 mL), solução de Hidróxido de Sódio 1 M (6 x 30 mL) e Cloreto de Sódio saturado (3 x 30 mL). Finalizado, Sulfato de Magnésio foi colocado em excesso na solução, sendo esta filtrada e concentrada; rendimento: 77%; composto colorido; ponto de fusão: 1 1 0-120°C; IR (KBr): o = 2928,37, 2930,46, 3306,50, 1580,93, 1 596,60, 1 250,90; UV-vis: λ (acetonitrila/água) = 226nm; RMN 1 H (400 MHz, CDCI3): δ = 13.352 (s, 1 H, OH), 7.795-7.736 (m, 3H, Ar-H), 7.003-6.981 (m, 2H, Ar-H), 6.61 0-6.582 (m, 1 H, Ar-H), 6.470-6.474 (m, 1 H, Ar- H), 3.983-3.857 (d, 6H, CH3); RMN 1 3C (1 00 MHz, CDCI3): δ = 163.21 , 161 .46, 1 55.67, 144.46, 134.09, 132.77, 1 23.36, 1 14.51 , 1 07.77, 101 .44, 55.64, 55.61 . Composto Redresv003 Following the general method, 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 ). 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). Finally, magnesium sulfate was placed in excess in the solution, which was filtered and concentrated; yield: 77%; colored compound; melting point: 110-120 ° C; IR (KBr): o = 2928.37, 2930.46, 3306.50, 1580.93, 1,596.60, 1,250.90; UV-vis: λ (acetonitrile / water) = 226nm; 1 H NMR (400 MHz, CDCl 3): δ = 13,352 (s, 1H, OH), 7,795-7,736 (m, 3H, Ar-H), 7,003-6,981 (m, 2H, Ar-H), 6,660 -6,582 (m, 1H, Ar-H), 6,470-6,474 (m, 1H, Ar-H), 3,983-3,857 (d, 6H, CH 3); 13 C-NMR (100 MHz, CDCl 3): δ = 163.21, 161.46, 15.56.67, 144.46, 134.09, 132.77, 11.36, 11.51, 107.77, 101.44, 55.64, 55.61. Redresv003 Compound
[0046] Seguindo o método geral, esse composto foi obtido a partir de agitação por à 80QC até solubilização completa do Redresv001 (0,9 mmol) em Dimetilformamida (5 mL) e Carbonato de Potássio (25 mmol). Foi Adicionado lodeto de Metila (5,2 mmol), gota a gota, mantendo a agitação por 24h, sob refluxo, à 40QC. O produto foi extraído com acréscimo de Cloreto de Amónio saturado (25 mL) e Acetato de Etila (3 x 30 mL). A fase orgânica foi lavada com Água destilada (5 x 30 mL), solução de Hidróxido de Sódio 1 M (6 x 30 mL) e Cloreto de Sódio saturado (3 x 30 mL). Finalizado, Sulfato de Magnésio foi colocado em excesso na solução, sendo esta filtrada e concentrada; rendimento: 66%; composto colorido; ponto de fusão: 190-200°C; IR (KBr): Ό = 3243,03, 1593,20, 1251,45; UV-vis: λ (acetonitrila/água) = 244nm; RMN 1H (400 MHz, CDCI3): δ = 7.863-7.545 (m, 3H, Ar-H), 7.135-7.082 (m, 2H, Ar-H), 6.773-6.768 (m, 1H, Ar-H), 6.636-6.602 (m, 1H, Ar-H), 4.125-3.325 (d, 9H, CH3); RMN 13C (100 MHz, CDCI3): δ = 163.12, 161.12, 158.26, 146.81, 135.81, 124.08, 124.08, 117.18, 114.58, 114.44, 106.07, 99.15, 56.07, 55.66, 55.55. [0046] Following the general method, 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). Finally, magnesium sulfate was placed in excess in the solution, which was filtered and concentrated; yield: 66%; colored compound; melting point: 190-200 ° C; IR (KBr): δ = 3243.03, 1593.20, 1251.45; UV-vis: λ (acetonitrile / water) = 244nm; 1H-NMR (400 MHz, CDCl3): δ = 7.863-7.545 (m, 3H, Ar-H), 7.135-7.082 (m, 2H, Ar-H), 6.773-6.768 (m, 1H, Ar-H), 6,636-6,602 (m, 1H, Ar-H); 4,125-3,325 (d, 9H, CH 3); 13 C-NMR (100 MHz, CDCl 3): δ = 163.12, 161.12, 158.26, 146.81, 135.81, 124.08, 124.08, 117.18, 114.58, 114.44, 106.07, 99.15, 56.07, 55.66, 55.55.
Composto Redresv004  Redresv004 Compound
[0047] Seguindo o método geral, esse composto foi obtido a partir da solubilização de RedresvOOl (4,38 mmol) em Anidrido Acético (120 mL) sob agitação a temperatura ambiente. Foi adicionado Piridina (1 mL) sendo uma gota a cada 5 min e agitado por 30 min após toda a adição. O produto foi precipitado após adição de Água Destilada a 10QC, filtrado e lavado com Água (3 x 30mL) e Ácido Clorídrico a 5% (500 mL); rendimento: 98,3%; composto colorido; ponto de fusão: 115-122°C; IR (KBr): o = 3065,77, 1760,37, 1588,21, 1191,01; UV-vis: λ (acetonitrila/água) = 355nm; RMN 1H (400 MHz, CDCI3): δ = 7.876-7.821 (m, 3H, Ar-H), 7.259-7.224 (m, 2H, Ar-H), 7.159-7.021 (m, 2H, Ar-H), 2.380-2.262 (m, 7H, COCH3); RMN 13C (100 MHz, CDCI3): δ = 169.12, 168.58, 153.21, 150.40, 149.44, 141.63, 124.16, 122.27, 119.74, 118.27, 116.80, 21.17, 20.69. Following the general method, 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. The product was precipitated after addition of distilled water at 10 Q C, filtered and washed with water (3 x 30mL) and 5% hydrochloric acid (500 ml); yield: 98.3%; colored compound; mp 115-122 ° C; IR (KBr): o = 3065.77, 1760.37, 1588.21, 1191.01; UV-vis: λ (acetonitrile / water) = 355nm; 1H-NMR (400 MHz, CDCl3): δ = 7.876-7.821 (m, 3H, Ar-H), 7.259-7.224 (m, 2H, Ar-H), 7.159-7.021 (m, 2H, Ar-H), 2,380-2,262 (m, 7H, COCH 3); 13 C NMR (100 MHz, CDCl 3): δ = 169.12, 168.58, 153.21, 150.40, 149.44, 141.63, 124.16, 122.27, 119.74, 118.27, 116.80, 21.17, 20.69.
Composto RedresvOOõ Redresolution Compound
[0048] Seguindo o método geral, esse composto foi obtido a partir da adição do Dimetilsulfóxido anidro (10mL) com RedresvOOl (500 mg) e mantido sob agitação em sistema fechado até solubilização. Após, adicionou- se Trietilamina (306 μΐ) e a agitação foi mantida por 20 minutos, acrescentando Anidrido Acético (206 μΐ) e agitação por mais 1h. O produto foi separado através de passagem por coluna cromatográfica com sílicagel 60 (0,2-0,5mm) empacotada e utilizando como solvente o clorofórmio; rendimento: 8%; composto colorido; ponto de fusão: 130-145°C; IR (KBr): o = 3495,94, 1760,37, 1371,79, 1191,01; UV-vis: λ (acetonitrila/água) = 272nm; RMN 1H (400 MHz, CDCI3): δ = 13.362 (s, 1H, OH), 13.156 (s, 1H, OH), 7.798-7.648 (m, 3H, Ar-H), 7.260-7.185 (m, 1H, Ar-H), 6.814-6.723 (m, 2H, Ar-H), 6.276-6.271 (m, 1H, Ar- H), 2.411-2.334 (d, 3H, CH3); RMN 13C (100 MHz, CDCI3): δ = 169.79, 158.85, 154.01, 152.98, 144.26, 133.59, 132.96, 123.83, 122.45, 116.16, 115.83, 113.43, 108.91, 21.24. Following the general method, 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 μΐ) was added and stirring was continued for 20 minutes by adding Acetic Anhydride (206 μΐ) and stirring for a further 1h. The product was separated by passing through packed silica gel 60 (0.2-0.5mm) chromatographic column and using chloroform as a solvent; yield: 8%; colored compound; melting point: 130-145 ° C; IR (KBr): o = 3495.94, 1760.37, 1371.79, 1191.01; UV-vis: λ (acetonitrile / water) = 272nm; 1H-NMR (400 MHz, CDCl3): δ = 13.362 (s, 1H, OH), 13.156 (s, 1H, OH), 7.798-7.648 (m, 3H, Ar-H), 7.260-7.185 (m, 1H, Ar-H), 6,814-6,723 (m, 2H, Ar-H), 6,276-6,271 (m, 1H, Ar-H), 2,411-2,334 (d, 3H, CH 3); 13 C NMR (100 MHz, CDCl 3): δ = 169.79, 158.85, 154.01, 152.98, 144.26, 133.59, 132.96, 123.83, 122.45, 116.16, 115.83, 113.43, 108.91, 21.24.
Antividade antimicrobiana Antimicrobial Activity
[0049] Para os derivados redresv002, redresv003, redresv004 e redresvOOõ foram testados nas concentrações de 5, 10, 20, 40, 80, 160, 320 e 640 μg/mL frente a Acinetobacter sp. e Escheríchia coli sem mostrar atividade antimicrobiana.  For derivatives redresv002, redresv003, redresv004 and redresvOO6 were tested at concentrations of 5, 10, 20, 40, 80, 160, 320 and 640 μg / mL against Acinetobacter sp. and Escheríchia coli without showing antimicrobial activity.
[0050] Os versados na arte valorizarão os conhecimentos aqui apresentados e poderão reproduzir a invenção nas modalidades apresentadas e em outras variantes, abrangidas no escopo das reivindicações anexas.  Those skilled in the art will enhance the knowledge presented herein and may reproduce the invention in the embodiments disclosed and in other embodiments within the scope of the appended claims.

Claims

Reivindicações Claims
1 . Composição farmacêutica, caracterizada por compreender:  1 . Pharmaceutical composition, comprising:
- pelo menos um composto de fórmula:  - at least one compound of formula:
Figure imgf000017_0001
Figure imgf000017_0001
em que R1 , R2 e R3 são OH; e  wherein R1, R2 and R3 are OH; and
- pelo menos um veículo farmaceuticamente aceitável.  at least one pharmaceutically acceptable carrier.
2. Composição farmacêutica de acordo com a reivindicação 1 , caracterizada por adicionalmente compreender pelo menos um fármaco com ação antimicrobiana  Pharmaceutical composition according to Claim 1, characterized in that it further comprises at least one antimicrobially acting drug.
3. Composição farmacêutica de acordo com a reivindicação 2, caracterizada pelo fármaco com ação antimicrobiana ser selecionado do grupo consistindo de: polimixina B, polimixina E, tobramicina, combinação dos mesmos.  Pharmaceutical composition according to Claim 2, characterized in that the antimicrobially acting drug is selected from the group consisting of: polymyxin B, polymyxin E, tobramycin, combination thereof.
4. Composição farmacêutica de acordo com qualquer uma das reivindicações 2 ou 3, caracterizada pelo fármaco com ação antimicrobiana ser selecionado do grupo consistindo de: polimixina B, polimixina E e tobramicina ou combinação dos mesmos.  Pharmaceutical composition according to either claim 2 or claim 3, characterized in that the antimicrobially acting drug is selected from the group consisting of: polymyxin B, polymyxin E and tobramycin or a combination thereof.
5. Composição farmacêutica de acordo com qualquer uma das reivindicações 1 a 4, caracterizada pelo composto estar em uma concentração entre 2 e 30 μg/mL.  Pharmaceutical composition according to any one of Claims 1 to 4, characterized in that the compound is in a concentration between 2 and 30 μg / mL.
6. Composição farmacêutica de acordo com qualquer uma das reivindicações 1 a 5, caracterizada pelo fármaco com ação antimicrobiana estar em uma concentração entre 2 e 100 μg/mL.  Pharmaceutical composition according to any one of Claims 1 to 5, characterized in that the antimicrobially acting drug is in a concentration between 2 and 100 μg / mL.
7. Uso da composição farmacêutica, conforme definida em qualquer uma das reivindicações 1 a 6 caracterizado por ser para a preparação de um medicamento com ação antimicrobiana. Use of the pharmaceutical composition as defined in any one of claims 1 to 6 for the preparation of an antimicrobially acting medicament.
8. Uso da composição farmacêutica, de acordo com a reivindicações 7, caracterizado por ser para a preparação de um medicamento com ação antimicrobiana contra um microrganismo selecionado do género Acinetobacter.Use of the pharmaceutical composition according to claim 7, characterized in that it is for the preparation of a medicament with antimicrobial action against a selected microorganism of the genus Acinetobacter.
9. Uso da composição farmacêutica, de acordo com a reivindicação 8 caracterizado pelo microrganismo ser Acinetobacter calcoaceticus-baumannii.Use of the pharmaceutical composition according to claim 8, characterized in that the microorganism is Acinetobacter calcoaceticus-baumannii.
10. Método de tratamento de doenças associadas a infecções microbianas, caracterizado por compreender a aplicação de uma composição farmacêutica, conforme definido em qualquer uma das reivindicações 1 a 6 em um paciente. A method of treating diseases associated with microbial infections, comprising applying a pharmaceutical composition as defined in any one of claims 1 to 6 to a patient.
1 1 . Processo de preparação de um composto conforme definido na reivindicação 1 , caracterizado por compreender a condensação de um fenol adequado com um nitrito de sódio.  1 1. A process for preparing a compound as defined in claim 1, characterized in that it comprises condensing a suitable phenol with sodium nitrite.
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