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Design, Synthesis, Fluorescence Properties and Antibacterial Activities of New 8-Chloro-3-Alkyl-3H-Pyrazolo[4,3-a]acridine-11-Carbonitriles
Design, Synthesis, Fluorescence Properties and Antibacterial Activities of New 8-Chloro-3-Alkyl-3H-Pyrazolo[4,3-a]acridine-11-Carbonitriles
Bulletin of the Korean Chemical Society. 2014. Feb, 35(2): 551-556
Copyright © 2014, Korea Chemical Society
  • Received : August 28, 2013
  • Accepted : November 29, 2013
  • Published : February 20, 2014
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About the Authors
Zeynab Rahmani
Mehdi Pordel
Abolghasem Davoodnia

Abstract
The treatment of alkylated nitro derivatives of indazole with 2-(4-chlorophenyl)acetonitrile under basic conditions gave the new 8-chloro-3-alkyl-3 H -pyrazolo[4,3- a ]acridine-11-carbonitriles via the nucleophilic substitution of hydrogen which proceeds at room temperature with concomitant cyclisation in fairly good yields. The structures of all newly synthesized compounds were confirmed by IR, 1 H NMR, 13 C NMR and mass spectral data. Fluorescence experimental results of all newly synthesized compounds revealed remarkable photoluminescence properties and strong green fluorescence properties. Also, the new compounds exhibited potent antibacterial activity and their antibacterial activity (MIC) against Gram positive ( Staphylococcuse aureus methicillin resistant S. aureus and Bacillus subtilis ) and negative bacterial ( Pseudomonas aeruginosa and Escherichia coli ) species were determined.
Keywords
Introduction
Nitrogen heterocyclic compounds are of immense interests, because they constitute an important class of natural and non natural products, many of which exhibit useful biological activities and unique electrical and optical properties. 1 - 5 They can act as functional materials in the emitters of electroluminescence devices and in the molecular probes used for biochemical research, as well as in the traditional textile and polymer fields. 6 - 8 In particular, fluorescent dye materials whose fluorescence emission occur at a longer wavelength in the red light region play a leading role in full color electroluminescence displays. Heterocyclic fluorophores are useful materials in the search for new biologically active compounds and diagnostic methods. 9 Fluorescent chromophores are generally known to have planar and rigid 𝜋-conjugated systems, and many fluorescent chromophores are based on rigid ring systems such as stilbene, coumarin, naphthalimide, perylene, rodamine and etc .
Based on these aspects and in continuation with our research work on the synthesis of new fluorescent nitrogen heterocycles 10 - 15 and bioactive 16 - 21 nitrogen heterocyclic compounds, we now decided to examine the transformation of alkylated 5-nitro-1 H -indazoles and 2-(4-chlorophenyl) acetonitrile to new 8-chloro-3-alkyl-3 H -pyrazolo[4,3- a ]acridine-11-carbonitriles in basic media and to evaluate their spectroscopic properties and biological activities.
Experimental
Materials and Physical Measurement . Methanol, N , N -Dimethylformamide (DMF), ethyl bromide, n -propyl bromide, n -butyl bromide, iso-butyl bromide, 2-(4-chlorophenyl)-acetonitrile, 2-(4-methylphenyl)acetonitrile and 2-(4-methoxyphenyl) acetonitrile were purchased from Merck. Potassium hydroxide was purchased from Sigma–Aldrich. All solvents were dried according to standard procedures. Compounds 1a-e were synthesized as in literature. 22 The microorganisms S . aureus ATCC 1112, Bacillus subtilis ATCC 6633, Pseudomonas aeruginosa ATCC 27853 and Escherichia coli ATCC 25922 were purchased from Pasteur Institute of Iran and S. aureus methicillin resistant was isolated from different specimens which were referred to the Microbiological Laboratory of Ghaem Hospital of Medical University of Mashhad, Iran and its methicillin resistance was tested according to the NCCLS guidelines. 23 Absorption and fluorescence spectra were recorded on Varian 50-bio UV-Visible spectrophotometer and Varian Cary Eclipse spectrofluorophotometer. UV–vis and fluorescence scans were recorded from 350 to 700 nm. Melting points were measured on an Electrothermaltype-9100 melting-point apparatus. The IR (as KBr discs) spectra were obtained on a Tensor 27 spectrometer and only noteworthy absorptions are listed. The 13 C NMR (100 MHz) and the 1 H NMR (400 MHz) were recorded on a Bruker Avance DRX-400 FT spectrometer in CDCl 3 . Chemical shifts are reported in ppm downfield from TMS as internal standard; coupling constant J is given in Hz. The mass spectra were recorded on a Varian Mat, CH-7 at 70 eV. Elemental analysis was performed on a Thermo Finnigan Flash EA microanalyzer. All measurements were carried out at room temperature.
General Procedure for the Synthesis of 3a-e and 4a-d . To a solution of KOH (13.3 g, 238 mmol) in methanol (50 mL) the appropriate 1-alkyl-5-nitro-1 H -indazoles (10 mmol) and arylacetonitrile (12 mmol) were added with stirring. The mixture was stirred at rt for 24 h. After concentration at reduced pressure, the precipitate was collected by filtration, washed with water, following with EtOH, and then air dried to give crude 3a-e and 4a-d .
8-Chloro-3-methyl-3H-pyrazolo[4,3-a]acridine-11 carbonitrile (3a) : Compound 3a was obtained as shiny yellow needles (EtOH), yield (60%), mp 317-319 ℃; 1 H NMR (CDCl 3 ) δ 4.27 (s, 3H), 7.76 (dd, J = 9.1 Hz, J ' = 2.1 Hz, 1H), 7.90 (d, J = 9.6 Hz, 1H), 8.06 (d, J = 9.6 Hz, 1H), 8.31 (d, J = 2.1 Hz, 1H), 8.35 (d, J = 9.1 Hz, 1H), 9.10 (s, 1H) ppm; 13 C NMR (CDCl 3 ) δ 35.18, 110.62, 115.80, 116.22, 117.59, 122.16, 124.22, 125.63, 128.28, 129.75, 130.89, 134.51, 135.76, 137.50, 145.94, 148.21 ppm; IR (KBr disk): 𝑣 2223 cm -1 (CN). MS ( m / z ) 294 (M + +2). Anal. Calcd for C 16 H 9 ClN 4 (292.7): C, 65.65; H, 3.10; N, 19.14, found: C, 66.02; H, 3.16; N, 18.90.
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Synthesis of new compounds 3a-e.
8-Chloro-3-ethyl-3H-pyrazolo[4,3-a]acridine-11 carbonitrile (3b) : Compound 3b was obtained as shiny yellow needles (EtOH), yield (65%), mp 295-297 ℃; 1 H NMR (CDCl3) δ 1.61 (t, J = 7.2 Hz, 3H), 4.59 (q, J = 7.2 Hz, 2H), 7.76 (dd, J = 8.9 Hz, J ' = 2.1 Hz, 1H), 7.92 (d, J = 9.6 Hz, 1H), 8.06 (d, J = 9.6 Hz, 1H), 8.34 (d, J = 2.1 Hz, 1H), 8.36 (d, J = 8.9 Hz, 1H), 9.15 (s, 1H) ppm; 13 C NMR (CDCl 3 ) δ 15.52, 44.63, 115.62, 115.80, 116.76, 117.75, 122.54, 124.34, 125.87, 128.09, 129.26, 130.51, 132.51, 135.12, 137.20, 145.64, 148.88 ppm; IR (KBr disk): 𝑣 2225 cm -1 (CN). MS ( m / z ) 308 (M + +2). Anal. Calcd for C 17 H 11 ClN 4 (306.7): C, 66.56; H, 3.61; N, 18.26, found: C, 66.23; H, 3.55; N, 18.07.
8-Chloro-3-propyl-3H-pyrazolo[4,3-a]acridine-11 carbonitrile (3c) : Compound 3c was obtained as shiny yellow needles (EtOH), yield (70%), mp 273-275 ℃; 1 H NMR (CDCl 3 ) δ 1.01 (t, J = 7.2 Hz, 3H), 2.04-2.13 (m, 2H), 4.52 (t, J = 7.2 Hz, 2H), 7.76 (dd, J = 8.9 Hz, J ' = 2.1 Hz, 1H), 7.92 (d, J = 9.6 Hz, 1H), 8.05 (d, J = 9.6 Hz, 1H), 8.32 (d, J = 2.1 Hz, 1H), 8.36 (d, J = 8.9 Hz, 1H), 9.14 (s, 1H) ppm; 13 C NMR (CDCl 3 ) δ 13.50, 23.49, 56.55, 113.67, 115.34, 116.89, 117.13, 122.55, 124.20, 125.98, 128.10, 129.25, 130.57, 132.87, 135.19, 137.45, 145.98, 148.50 ppm; IR (KBr disk): 𝑣 2225 cm -1 (CN). MS ( m / z ) 322 (M + +2). Anal. Calcd for C 18 H 13 ClN 4 (320.8): C, 67.40; H, 4.08; N, 17.47, found: C, 67.18; H, 4.01; N, 17.73.
3-Butyl-8-chloro-3H-pyrazolo[4,3-a]acridine-11-carbonitrile (3d) : Compound 3d was obtained as shiny yellow needles (EtOH), yield (57%), mp 261-264 ℃; 1 H NMR (CDCl 3 ) δ 1.01 (t, J = 7.1 Hz, 3H), 1.38-1.47 (m, 2H), 1.00- 2.07 (m, 2H), 4.56 (t, J = 7.1 Hz, 2H), 7.76 (dd, J = 8.9 Hz, J ' = 2.1 Hz, 1H), 7.92 (d, J = 9.6 Hz, 1H), 8.06 (d, J = 9.6 Hz, 1H), 8.32 (d, J = 2.1 Hz, 1H), 8.36 (d, J = 8.9 Hz, 1H), 9.14 (s, 1H) ppm; 13 C NMR (CDCl 3 ) δ 13.65, 20.05, 32.34, 49.44, 110.09, 115.34, 116.66, 117.62, 122.26, 124.08, 125.70, 128.80, 129.34, 130.31, 134.94, 135.97, 137.53, 145.79, 148.02 ppm; IR (KBr disk): 𝑣 2225 cm -1 (CN). MS ( m / z ) 336 (M + +2). Anal. Calcd for C 19 H 15 ClN 4 (334.8): C, 68.16; H, 4.52; N, 16.73, found: C, 67.92; H, 4.45; N, 16.49.
8-Chloro-3-isobutyl-3H-pyrazolo[4,3-a]acridine-11-carbonitrile (3e) : Compound 3e was obtained as shiny yellow needles (EtOH), yield (63%), mp 245-247 ℃; 1 H NMR (CDCl 3 ) δ 1.02 (d, J = 6.8 Hz, 6H), 2.41-2.51 (m, 1H), 4.36 (d, J = 7.2 Hz, 2H), 7.78 (dd, J = 8.8 Hz, J ' = 2.0 Hz, 1H), 7.93 (d, J = 9.6 Hz, 1H), 8.04 (d, J = 9.6 Hz, 1H), 8.35 (d, J = 2.0 Hz, 1H), 8.39 (d, J = 8.8 Hz, 1H), 9.19 (s, 1H) ppm; 13 C NMR (CDCl 3 ) δ 20.50, 32.01, 55.20, 116.62, 116.80, 117.26, 117.93, 122.45, 124.94, 125.83, 128.26, 129.32, 130.77, 132.92, 135.18, 137.19, 145.32, 148.24 ppm; IR (KBr disk): 𝑣 2223 cm -1 (CN). MS ( m / z ) 336 (M + +2). Anal. Calcd for C 19 H 15 ClN 4 (334.8): C, 68.16; H, 4.52; N, 16.73, found: C, 67.90; H, 4.47; N, 16.48.
8-Methoxy-3-methyl-3H-pyrazolo[4,3-a]acridin-11-carbonitrile (4a) : Compound 4a was obtained as pale yellow needles (EtOH), yield (69%), mp 327-329 ℃, [lit. 13 325-327 ℃].
3-Ethyl-8-methoxy-3H-pyrazolo[4,3-a]acridin-11-carbonitrile (4b) : Compound 4b was obtained as pale yellow needles (EtOH), yield (65%), mp 310-312 ℃, [lit. 13 310-312 ℃].
3,8-Dimethyl-3H-pyrazolo[4,3-a]acridin-11-carbonitrile (4c) : Compound 4c was obtained as pale yellow needles (EtOH), yield (65%), mp 263-265 ℃, [lit. 13 261-264 ℃].
3-Ethyl-8-methyl-3H-pyrazolo[4,3-a]acridin-11-carbonitrile (4d) : Compound 4d was obtained as pale yellow needles (EtOH), yield (63%), mp 253-255 ℃, [lit. 13 255-256 ℃].
Results and Discussion
Syntheses and Spectral Characterization . As depicted in Scheme 1 , the required starting materials 1-alkyl-5-nitro- 1 H -indazoles 1a-e were prepared by reaction of 5-nitro-1 H -indazole with different alkyl halides in DMF and KOH using a literature method. 22 The treatment of 1-alkyl-5-nitro-1 H -indazoles 1a-e with 2-(4-chlorophenyl) acetonitrile 2 led to the formation of the new 8-chloro-3-alkyl-3 H -pyrazolo[4,3- a ]acridine-11-carbonitriles 3a-e by way of the nucleophilic substitution of hydrogen 24 followed by the ring closure which proceeds via an electrocyclic pathway 10 - 15 in basic MeOH solution in good yields. The simple work-up procedure was performed by filtration of the precipitated product and washing with water and EtOH, respectively. The following mechanism is offered for the formation of compounds 3a-e . 25 10 - 15 Attack of the anion of 2 on 1a-e affords intermediate A and thus B ( Scheme 2 ). Subsequent prototropy to C initiates a 6𝜋-electrocyclisation to D and then products 3a-e result following dehydration ( Scheme 2 ).
The structure of compounds 3a-e was established by FT-IR, 1 H NMR, 13 C NMR and mass spectral data. For example, 1 H NMR of compound 3a revealed the presence of the doublet of doublet signal at δ 7.76 ppm ( J = 9.1 Hz and J ' = 2.1 Hz), the doublet signals at δ 7.92 (d, J = 9.6 Hz), δ 8.05 (d, J = 9.6 Hz), δ 8.32 (d, J = 2.1 Hz), and δ 8.36 (d, J = 9.1 Hz) ppm, and singlet signal at δ 9.14 ppm attributed to six protons of aromatic rings. 13 C NMR spectrum indicated that there are sixteen different carbons in compound 3a . Moreover, the FT-IR spectrum of 3a in KBr showed an absorption band at 2223 cm -1 corresponding to the cyanide group. All this evidence plus the molecular ion peak at m / z 294 (M+2 + ) and microanalytical data strongly support the tetracyclic structure of compound 3a .
All the newly synthesized compounds have been characterized by elemental analysis and spectroscopic data. The spectral details of all these are given in experimental section.
As an explanation for heterocyclization reaction demonstrated by Scheme 3 , there is another possible mode of cyclisation in this reaction. According to the expanded view (aromatic region) of 1 H NMR spectrum of compound 3e , two doublet signals at δ 7.93 ( J = 9.6 Hz, 1H), δ 8.07 ( J = 9.6 Hz, 1H) ppm are assignable to two protons of aromatic rings (H a , H b ) in 3e and thus the latter cyclisation has not occurred, since two singlet attributed to protons of aromatic rings (H c , H d ) aren’t observed in the 1 H NMR spectrum of compound 3e .
Fluorescence Spectra and Quantum Yields . The compounds 3a-e were characterized by using an UV-Vis spectrophotometer and a fluorescence spectrophotometer. The wavelength range of both spectrophotometers is 200 nm-1000 nm. The fluorescence absorption and emission spectra of 3a-e were recorded at concentrations of 2 × 10 -5 and 6 × 10 -6 mol L -1 in dichloromethane (DCM), respectively. Figure 1 shows the visible absorption and emission spectra of compounds 3a-e .
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Proposed reaction mechanism for the formation of compounds 3a-e.
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Two possible modes of cyclisation in the reaction of 1a-e with 2 and the expanded view of 1H NMR spectrum of compound 3e in downfield region.
The wavelengths of maximum absorbance (λ abs /nm), wavelengths of fluorescence excitation (λ ex /nm), wavelengths of fluorescence emission (λ flu /nm), values of extinction coefficient (ε) and fluorescence quantum yield (Φ F ) data are presented in Table 1 . Values of extinction coefficient (ε) were calculated as the slope of the plot of absorbance vs . concentration. The fluorescence excitation (λ ex ) wavelength at 390 nm (λ ex /nm) was used for all compounds 3a-e . The fluorescence quantum yields (Φ F ) of compounds 3a-e were determined via comparison methods, using fluorescein as a standard sample in 0.1 M NaOH and MeOH solution. 26 The fluorescence spectral properties ( Table 1 ) of compounds 3a-e are similar to each other and fluorescence intensity in compound 3d , with a butyl group, was the highest. It can be concluded from the data in Table 1 that these compounds are highly fluorescent. Intensity of fluorescence emission of compounds 3a-e can be explained by an efficient intramolecular charge transfer (ICT) states from the donor site (endocyclic N) to the acceptor moiety (CN group). Typical photoinduced charge transfer system consists of a donor (D) and acceptor (A) couple, which can be separate chromophores within a large molecule, leading to intramolecular charge transfer (ICT). In Scheme 4 , neutral and charge-separated mesomeric structures of 3a-e are presented. The fluorescence quantum yields (Φ F ) of the new compounds 3a-e are comparable with some fluorescent heterocyclic compounds which we have reported previously. A comparison of Φ F between 3d and some of them has been shown in Table 2 . Solvatochromic properties of compound 3e were studied in some solvents ( Fig. 2 ). As can be seen in these figures, the fluorescence absorption and emission spectra of 3e in polar solvents undergoes a bathochromic shift. Increasing solvent polarity stabilizes the ICT excited-state molecule relative to the ground-state molecule with the observed red shift of the absorption and the emission maximum ( Table 3 ). For example, λ flu shifts from 450 to 475 nm is observed as the solvent is changed from n-hexane to methanol.
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Visible absorption and emission spectra of compounds 3a-e in DCM solution.
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Neutral and charge-separated mesomeric structures of 3a-e.
Photophysical data for absorption (abs) and fluorescence (flu) of3a-e
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aWavelengths of maximum absorbance. bExtinction coefficient. cWavelengths of fluorescence excitation. dWavelengths of fluorescence emission. eFluorescence quantum yield
Comparing the fluorescence quantum yield of3dand some recently synthesized fluorescent heterocyclic compounds
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Comparing the fluorescence quantum yield of 3d and some recently synthesized fluorescent heterocyclic compounds
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Visible absorption and emission spectra of compound 3e in different solvents.
Spectroscopic data for3eat 298K in dependence of the solvent
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Spectroscopic data for 3e at 298K in dependence of the solvent
Antibacterial Studies. The antibacterial activity of our new products 3a-e as well as 4a-d which we have synthesized previously 13 ( Scheme 5 ), was tested against a panel of strains of Gram positive ( Staphylococcuse aureus methicillin resistant S. aureus (MRSA) clinical isolated and Bacillus subtilis (ATCC 6633)) and negative bacterial ( Pseudomonas aeruginosa (ATCC 27853) and Escherichia coli , (ATCC 25922)) species ( Table 4 ) using broth microdilution method as described previously. 27 Ampicillin, Penicillin G and Sulfamethoxazole were used as references. The lowest concentration of the antibacterial agent that prevents growth of the test organism, as detected by lack of visual turbidity (matching the negative growth control), is designated the minimum inhibitory concentration (MIC). Experimental details of the tests can be found in our earlier studies. 17 - 21
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8-Substituted-3-alkyl-3H-pyrazolo[4,3-a]acridine-11-carbonitriles 4a-d.
Antibacterial activity (MIC, μg mL-1) of references and compounds3a-eand4a-d
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Antibacterial activity (MIC, μg mL-1) of references and compounds 3a-e and 4a-d
The antimicrobial tests performed on compounds 3a-e and 4a-d confirmed that they are effective against both Gram-positive and Gram-negative bacteria and some showed greater inhibitory activity against a number of Gram-positive and Gram-negative bacteria than the well known antibacterial agents Ampicillin and Sulfamethoxazole.
Also, the results revealed that new compounds 3a-e which have chlorine substituents, displayed greater antibacterial activity against mentioned organism than 4a-d in most cases ( Table 4 ). Gratifyingly, compound 3d with a butyl group was the most potent of the tested compounds against Gram-positive and Gram-negative bacteria in this work and all biological research work that we have reported previously. 16 - 21 We propose that the chain lengths and chlorine substituent might change the binding characteristics of ligands to their respective receptors and, thereby, improve the biological activities. 18
Conclusion
The synthesis of five new 8-chloro-3-alkyl-3 H -pyrazolo-[4,3- a ]acridine-11-carbonitriles has been described through one pot reaction of 1-alkyl-5-nitro-1 H -indazoles with 2-(4-chlorophenyl) acetonitrile. All these compounds are hitherto unknown in literature and are observed to exhibit excellent fluorescence properties. This property, together with high antibacterial activity, can offer an excellent opportunity for the study of physiological functions of bacteria such as at single-cell level. 28
Acknowledgements
The publication cost of this paper was supported by the Korean Chemical Society.
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