WO2015115924A1 - Pentapeptides contenant 3- [2- (2-quinolinyl) benzoxazol -5-yl] alanine, composition pharmaceutique et leur application - Google Patents

Pentapeptides contenant 3- [2- (2-quinolinyl) benzoxazol -5-yl] alanine, composition pharmaceutique et leur application Download PDF

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WO2015115924A1
WO2015115924A1 PCT/PL2015/000011 PL2015000011W WO2015115924A1 WO 2015115924 A1 WO2015115924 A1 WO 2015115924A1 PL 2015000011 W PL2015000011 W PL 2015000011W WO 2015115924 A1 WO2015115924 A1 WO 2015115924A1
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leu
pentapeptides
aia
lle
application
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Katarzyna GUZOW
Michał OBUCHOWSKI
Wiesław WICZK
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Medical Uniwersity of Gdansk
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Medical Uniwersity of Gdansk
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics

Definitions

  • the present invention relates to novel pentapeptides, a pharmaceutical composition and their application for the manufacture of a therapeutic agent intended for the treatment of diseases caused by bacterial and/or fungal activity.
  • l alkyl or aryl or functional group
  • the benzoxazoie ring is found in the naturally occurring biologically active compounds, such as: calcimycin (an antibiotic produced by Streptomyces chartreusensis) and cesomycin (an antibiotic of the calcimycin class that has been isolated from Frankia, a genus within Actinomycetales); UK-1, UK-2 and UK-3 (respectively, a cytotoxic and two antifungal metabolites from Streptomyces sp. 517- 02); and antituberculous and/or antifungal and bacteriocidal alkaloids isolated from the coral species Pseudopterogorgia elisabethae or from the sea sponges of the Dysidea genus.
  • calcimycin an antibiotic produced by Streptomyces chartreusensis
  • cesomycin an antibiotic of the calcimycin class that has been isolated from Frankia, a genus within Actinomycetales
  • UK-1, UK-2 and UK-3 respectively, a cyto
  • MIC 6.25 ⁇ / ⁇
  • MIC 6.25 ⁇ / ⁇
  • penicillin 25 g/ml
  • Tuberculosis is one of the most prevalent infectious diseases. It is caused by Mycobacterium tuberculosis. Many people are carriers of the latent form of the bacterium, which is a dangerous source of remission after completion of treatment. There is therefore an unmet need for novel classes of antituberculous drugs that would be capable of providing complete cure without the need to undergo many months of antibiotic treatment. Benzoxazoie derivatives are good candidates for such drugs, given the fact that the 2-substituted lipophilic 5,7-di-tert-butylbenzoxazole derivatives have been shown to be active against M.
  • tuberculosis and several non- tuberculous opportunistic mycobacterial strains (Mycobacterium kansasii, Mycobacterium avium 80/72 and 152/74), against which the first antituberculous drug isoniazid was inactive.
  • compound lipophilicity plays a very important role, given the very low permeability of the cell membrane and the very thick and compacted cell wall in these bacteria.
  • benzoxazoie derivatives the presence of tert-butyl groups in the molecule increases its lipophilicity, although it has been observed that their activity is more affected by their chemical structure than by their lipophilicity.
  • tuberculosis CNCTC My 331/88 Mycobacterium kansasii CNCTC My 235/80 i 6509/96 and Mycobacterium avium CNCTC My 330/88 have also been demonstrated for 2-benzylsulfanylbenzoxazole derivatives, with the activity increasing when the phenyl ring contains substituents, particularly two nitryl groups or one thioamide group. It has also been demonstrated that compounds with the substituent at position 4 of the phenyl ring display higher activity than their analogues with the substituent at position 3.
  • the present invention comprises five novel pentapeptides, each containing the non-proteinogenic amino acid 3-[2-(2-quinolinyl)benzoxazol-5-yl]alanine in their sequence (Fig. 1). These compounds show antimicrobial activity at concentrations ranging from several to less than 100 micrograms per millilitre (Table 2). One of them, H-Box(2Q)-His-lle-His-Met-NH 2 , shows selective activity against a single yeast species, Pichia pastoris.
  • the other four pentapeptides display antimicrobial activity against Gram-positive bacteria (Bacillus subtilis 168), including pathogenic strains (Enterococcus faecalis ATCC 29212, Staphylococcus aureus ATCC 29213, Staphylococcus aureus ATCC 25923), and against yeast (Pichia pastoris).
  • pathogenic strains Enterococcus faecalis ATCC 29212, Staphylococcus aureus ATCC 29213, Staphylococcus aureus ATCC 25923
  • yeast Pichia pastoris
  • the pentapeptides do not show any significant cytotoxicity in the healthy human embryonic kidney cell line Hek293 or the neoplastic mouse fibroblast cell line A9 within the concentration ranges at which they display antimicrobial activity, which suggests that it will be possible to safely use these compounds in living organisms.
  • the non-proteinogenic fragment used in the pentapeptides (the benzoxazole ring) is relatively common in various types of biologically active compounds and also in this case it is biologically active, as previously demonstrated in microbiological assays using 3-[2-(2-quinolinyl)benzoxazol-5-yl]alanine methyl ester.
  • Combining a benzoxazole derivative with a peptide chain increases the biological activity of the former, which consists in inhibiting the growth of both prokaryotic and eukaryotic microorganisms.
  • the present invention relates to novel pentapeptides whose general formula is as follows:
  • H-Box(2Q) is 3-[2-(2-quinolinyl)benzoxazol-5-yl]alanine
  • AiA 2 A 3 A 4 is His-Leu-His-lle (1)
  • AiA 2 A 3 A 4 is His-Leu-His-Phe (2)
  • AiA 2 A 3 A 4 is Leu-Arg-Trp-Phe (3)
  • AiA 2 A 3 A 4 is His-lle-His-Ala (4)
  • a pharmaceutical composition which contains a novel pentapeptide described above and at least one pharmaceutically acceptable carrier and/or diluent.
  • composition has antibacterial and/or antifungal application.
  • aureus including multidrug resistant strains— potential application of the compounds to combat the so-called nosocomial infections
  • Fig. 1 depicts the structures of the pentapeptides containing 3-[2-(2- quinolinyl)benzoxazol-5-yl]alanine.
  • Fig. 2 depicts a diagram of the synthetic pathway of N-(tert-butoxycarbonyl)-3-[2-(2- quinolinyl)benzoxazol-5-yl]alanine.
  • Fig. 3 depicts a simplified diagram of the synthetic pathway of the pentapeptides.
  • Fig. 5 depicts examples of Petri dishes after incubation of multidrug resistant strains of Staphylococcus aureus (435 (A), 128/0 (B), 1322 (C), 1863 (D)) with solutions of the pentapeptides in 96% ethanol
  • (12 H-Box(2Q)-Leu-Arg-Trp-Phe-NH 2
  • 210 H-Box(2Q)- His-Leu-His-lle-NH 2
  • 111 H-Box(2Q) ⁇ His-Leu-His-Phe-NH 2
  • Each dot represents the place where 1 pi of the solution of a specific compound of a specific concentration was applied (in decreasing order from right to left in individual rows— Z2 [6 mg/ml; 0.6 mg/ml; 0.06 mg/ml; 0.006 mg/ml], Z10 [8 mg/ml; 0.8 mg/ml; 0.08 mg/ml; 0.008 mg/ml], and for 111 [5 mg/ml; 0.5 mg/ml; 0.05 mg/ml; 0.005 mg/ml]).
  • Fig. 6 depicts Petri dishes after incubation of the multidrug resistant strain of Staphylococcus aureus 435 with solutions of the pentapeptides in DMSO
  • Z2 H- Box(2Q)-Leu-Arg-Trp-Phe-NH 2
  • Z10 H-Box(2Q)-His-Leu-His-lle-NH 2
  • Zll H-Box(2Q)- i His-Leu-His-Phe-NH 2
  • 435(k) - control strain 435 Z2, Z10 and Zll - strains cultured in the presence of sublethal quantities of the pentapeptide Z2, Z10 and Zll, respectively).
  • Each dot represents the place where 1 ⁇ of the solution of a specific compound of a specific concentration was applied (in decreasing order from right to left in individual rows).
  • Fig. 7 depicts Petri dishes after incubation of the multidrug resistant strain of Staphylococcus aureus 128 with solutions of the pentapeptides in DMSO
  • Z2 H- Box(2Q)-Leu-Arg-Trp-Phe-NH 2
  • Z10 H-Box(2Q)-His-Leu-His-lle-NH 2
  • Zll H-Box(2Q)- His-Leu-His-Phe-NH 2
  • (k) - control strain 128 Z10 and 632 Z10 - strains cultured in the presence of sublethal quantities of the pentapeptide Z10).
  • Each dot represents the place where 1 ⁇ of the solution of a specific compound of a specific concentration was applied (in decreasing order from right to left in individual rows).
  • the first step of the synthesis involved the obtaining of a non-proteinogenic amino acid (/V-(iert-butoxycarbonyl)-3-[2-(2-quinolinyl)benzoxazol-5-yl]alanine) (Fig. 2) according to the procedure described in the literature which is based on the oxidative cyclisation of a Schiff base with lead tetraacetate in dimethylsulfoxide [Guzow et al., Tetrahedron 58 (2002) 2201].
  • A/-(terf-butoxycarbonyl)-3-nitrotyrosine (1 eq.) is used as the substrate and is dissolved in methanol and placed on a magnetic stirrer.
  • a suspension of palladium on activated charcoal (10%, but 5% is also acceptable) in methanol is then added. While the solution continues to be stirred, hydrogen gas is passed through the solution for about 3 hours.
  • the catalyst is filtered out using a hard fluted filter, and the filtrate is evaporated using a rotary evaporator, yielding /V-(tert-butoxycarbonyl)-3- aminotyrosine in the form of a brown oil which is dissolved in anhydrous ethanol and placed on a magnetic stirrer. While the solution is being stirred, a solution of quinoline- 2-carboxaldehyde (1 eq.) in anhydrous ethanol is added, as a result of which, several minutes later, a fine yellow precipitate of Schiff base precipitates.
  • the solvent is then evaporated using a rotary evaporator, yielding a yellow-brown solid which is dissolved in DMSO. While the Schiff base solution is being stirred by a magnetic stirrer, lead tetraacetate (1.5 eq.) is added to the solution, as a result of which the solution changes its colour from yellow to dark red.
  • the reaction mixture is then transferred to the separator, ethyl acetate and saturated aqueous sodium chloride solution are added, and the layers are separated.
  • the organic layer is washed three times with saturated aqueous sodium chloride solution and then it is dried with anhydrous magnesium sulfate.
  • the drying agent is then filtered out using a fluted filter of intermediate hardness, and the filtrate is evaporated using a rotary evaporator, yielding a dark brown oil, which is purified by column chromatography, using silica gel (Kieselgel 60, 0.040-0.063 mm, Merck) as the stationary phase and ethyl acetate-acetic acid (100:1, v/v) as the mobile phase.
  • the pentapeptides are produced through solid-phase peptide synthesis using the Fmoc/tBu protection scheme (Fig. 3).
  • An appropriate weighed-out amount of a polymer an amide resin, e.g. TentaGel S RAM [Rapp Polymere, Germany]
  • a polymer an amide resin, e.g. TentaGel S RAM [Rapp Polymere, Germany]
  • a reaction vessel a syringe equipped with a glass frit, a vessel for manual peptide synthesis or a column if an automated peptide synthesiser is used.
  • An unloaded amide resin may also be used for the synthesis, in which case it needs to be loaded with Fmoc-Ala, Fmoc-lle, Fmoc-Met or Fmoc-Phe, respectively, using an appropriate procedure and the resulting loading density must be determined.
  • the resin is then prepared by shaking for 15 minutes in methylene chloride (DCM), as a result of which it swells. The solvent is then removed from the resin by filtration.
  • DCM methylene chloride
  • the next step involves Fmoc deprotection of the amino acid at position Xi, followed by acylation of the amino acid with the next residue, which is carried out according to the following procedure:
  • Resin pre-wash methylene chloride (DCM)-N,N-dimethylformamide (DMF) (1:1, v/v) 1 x 2 min ⁇ , ⁇ -dimethylformamide (DMF) 2 x 2 min
  • Fmoc-amino acid-HOBt-TBTU-DIPEA at a molar ratio of 1:1:1:2 is dissolved in DCM-DMF (1:1, v/v), added to the resin and shaken for about 1.5 hours at room temperature (HOBt - N-hydroxybenzotriazole; TBTU - O-UH-benzotriazol-la-y -N ⁇ N N'- tetramethyluronium tetrafluoroborate; DIPEA - N,N'-diisopropylethylamine).
  • Fmoc-His(Trt)-OH or Fmoc- Trp(Boc)-OH, respectively A 3-fold excess of Fmoc-amino acid (Fmoc-His(Trt)-OH or Fmoc- Trp(Boc)-OH, respectively) relative to the resin loading density is used for the reaction.
  • the procedure is repeated using a 2-fold excess of the Fmoc- amino acid and a different coupling method (e.g. the symmetrical anhydride method: Fmoc-amino acid-HOBt-N,N'- diisopropylcarbodiimide (DIPCI) 1:1:1 or the active ester method: Fmoc- amino acid-HOBt-HBTU (O-ilH-benzotriazol-la-y -N N ⁇ N'- tetramethyluronium hexafluoroborate)-DIPEA 1:1:1:2).
  • a different coupling method e.g. the symmetrical anhydride method: Fmoc-amino acid-HOBt-N,N'- diisopropylcarbodiimide (DIPCI) 1:1:1 or the active ester method: Fmoc- amino acid-HOBt-HBTU (O-ilH-benzotriazol-la-y -N N ⁇ N'-
  • next amino acid residues are added at positions X 3 (Fmoc-lle-OH, Fmoc-Leu-OH or Fmoc-Arg(Pbf)-OH), X 4 (Fmoc-His(Trt)-OH or Fmoc-Leu-OH) and X 5 (Boc-Box(2Q)-OH) using the same method as for the acylation at Xi, except that when a benzoxazolylalanine derivative is being added, a lower amount is used (i.e. equimolar amount relative to the resin loading density).
  • the final cleavage of the pentapeptide from the resin is performed. This is achieved by shaking the peptidyl- resin in trifluoroacetic acid-phenol-water-triisopropylsilane (88:5:5:2, v/v/v/v) for about 1.5 hours.
  • the polymer is then filtered off by washing it twice with a small amount of trifluoroacetic acid.
  • the resulting filtrate is concentrated on a rotary evaporator and the residue is treated with cold diethyl ether to precipitate the peptide.
  • the precipitated peptides are centrifuged or filtered off using a Schott funnel, dissolved in water (or in water with the addition of a small amount of acetic acid) and freeze-dried.
  • the testing is performed in sterile Mueller-Hinton Broth, which in the case of the yeast additionally contains 4% glucose .
  • Two batches of the same concentrations (2 runs) are prepared for each compound, with the wells filled with the culture medium containing specific concentrations of the test compounds being the negative control and the wells filled with the culture medium inoculated with the bacterial or yeast culture being the positive control.
  • the lowest concentration that inhibits the growth of bacteria or yeast is the minimum inhibitory concentration (MIC) (Table 2).
  • MIC minimal inhibitory concentration
  • Cytotoxicity of the compounds is assessed with in vitro methods on healthy cell lines (human embryonic kidney cell line Hek293) and on neoplastic cell lines (mouse fibroblast cell line A9).
  • the cells are cultured as monolayers in DMEM at a high glucose concentration with the addition of 1% solution of antibiotics (penicillin + streptomycin), 1% glutamine, NaHC0 3 (3.7 g/l) and 10% fetal bovine serum (FBS) in an incubator at 37°C in an atmosphere of 5% C0 2 .
  • the culture medium is replaced every two days. Confluent colonies are passaged and a cell suspension of a density of 5xl0 cells/ml is prepared for testing.
  • the suspension is then plated into 96-well EUSA plates and incubated for 24 hours.
  • Serial dilutions of the test compounds in DMSO are then prepared to improve their solubility and added to the cell-containing plates (the addition of DMSO did not affect cell viability, as demonstrated experimentally).
  • the cells with the appropriate doses of the test substances are incubated for about 44 hours.
  • the cell viability and proliferation is quantified using the WST-1 assay, which is a sensitive and accurate colorimetric method based on the ability of mitochondrial dehydrogenases to convert a yellow substrate, namely WST-1 (4-[3-(4-iodophenyl)-2- (4-nitrophenyl)-2H-5-tetrazolium]-l,3-phenyl sodium disulfonate) into orange- coloured formazan, whose quantity in the aqueous solution is directly proportionate to the viable cell count.
  • WST-1 diluted four times in a phosphate buffer (PBS), are added to each well in the plate and incubated in an incubator at 37°C in an atmosphere of 5% C0 2 .
  • the rates at which the multidrug resistant bacteria (128/0, 435, 632, 659, 1863) acquire resistance to the test compounds are determined by growing the relevant bacterial strains in Mueller-Hinton Broth in the presence of sublethal quantities of these compounds (H-Box(2Q)-His-Leu-His-lle-NH 2 - 10 ⁇ g/ml, H-Box(2Q)-His-Leu-His- Phe-NH 2 and H-Box(2Q)-Leu-Arg-Trp-Phe-NH 2 - 30 ⁇ g/ml).
  • the bacteria are grown for about 150 generations and the measurement of activity of each of the compounds against these strains and against the control strains, using the method of antimicrobial susceptibility testing, is repeated. 1 ⁇ of individual concentrations of the solutions of the test compounds in DMSO are transferred onto plates with Mueller Hinton broth solidified with agar onto which an appropriate bacterial strain treated with the compound or the control strain was spread plated. The plates are incubated overnight at 37°C, and the size of the growth inhibition zone at the compound application site is determined. No significant decrease in activity, compared to the activity against the control strains, is observed for any of the compounds.
  • strain 435 in the case of which it has been observed that the activity of the compound H-Box(2Q.)-Leu-Arg-Trp-Phe-NH 2 decreases by about 50% compared to the control strain (Figs. 6 and 7).

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Abstract

La présente invention concerne de nouveaux composés, une composition pharmaceutique et l'application de ces nouveaux composés pour la fabrication d'un agent thérapeutique pour le traitement de maladies provoquées par une activité bactérienne et/ou fongique.
PCT/PL2015/000011 2014-01-31 2015-01-29 Pentapeptides contenant 3- [2- (2-quinolinyl) benzoxazol -5-yl] alanine, composition pharmaceutique et leur application Ceased WO2015115924A1 (fr)

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PL407032A PL226349B1 (pl) 2014-01-31 2014-01-31 Pentapeptydy zawierające 3-[2-(2-chinolilo)benzoksazol-5-ylo] alaninę, kompozycja farmaceutyczna oraz ich zastosowanie
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Citations (1)

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US20130338341A1 (en) * 2012-06-18 2013-12-19 Universiti Malaya Peptides Having Antimicrobial Activity

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Publication number Priority date Publication date Assignee Title
US20130338341A1 (en) * 2012-06-18 2013-12-19 Universiti Malaya Peptides Having Antimicrobial Activity

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