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and/or in the noses of healthy people. Although it is usually harm-
References and notes
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infections. These infections may be serious such as infection of the
bloodstream, bones or joints. MRSA stands for methicillin-resistant
which is a type of S. aureus that is resistant to the antibacterial
activity of methicillin and other related antibiotics of the penicillin
class.29–31 The data (MICs) concerning the antimicrobial activity
against MRSA and MSSA of the compounds are summarized in Ta-
bles 3 and 4.
Among the compounds tested, only salinomycin A (2) as well as
three amide derivatives (3b, 3c and 3e) showed activity against
Gram-positive bacteria. Compounds (3a, 3d, 3f-3h) were practi-
cally inactive towards all micro-organisms tested (MIC P256
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lg/ml). Amides 3b and 3c, containing aromatic substituent benzyl
´
and benzo-15-crown-5 group respectively, show a considerably
better activity against Gram-positive bacteria than the correspond-
ing aliphatic amides. Amide 3a with benzyl substituent shows a
considerably better activity against hospital strains of MRSA and
MSSA than the corresponding active amides 3c and 3e indicating
that the benzyl substituent in the amide moiety has a strong influ-
ence on the antibacterial activity of salinomycin amides. Among
the compounds tested, only amide 3c showed relatively strong
activity against the series of clinical isolates of Staphylococcus:
11. Huczynski, A. Chem. Biol. Drug Des. 2012, 79, 235.
12. Riddell, F. G.; Tompsett, S. J. Tetrahedron 1991, 47, 10109.
13. Ivanova, J.; Pantcheva, I. N.; Mitewa, M.; Simova, S.; Tanabe, M.; Osakada, K.
Chem. Centr. J. 2011, 5. art. no. 52..
14. Kinashi, H.; Otake, N.; Yonehara, H.; Sato, S.; Saito, Y. Acta Cryst. 1975, B31,
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MRSA and MSSA (MIC = 2–4 lg/ml) and its activity is comparable
´
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with the activity of parent antibiotic. Salinomycin and its amide
derivatives are inactive against strains of Candida and Gram-nega-
tive bacteria.
To summarize, for the first time a simple and efficient one-pot
protocol for the synthesis of amides of anticancer antibiotic salino-
mycin has been described. The simplicity of this method, high
yields, easy work-up and purification of the products by flash chro-
matography and crystallization are key advantages. These results
are important for the development of molecules with dual poten-
tial anticancer and antibacterial activity.
We have provided evidence that the some of new derivatives of
salinomycin show antibacterial activity against human pathogenic
bacteria including drug resistant strains of Staphylococcus aureus.
From among the compounds tested, phenyl amide 3b was found
to be the most active derivative against clinical isolates of Staphy-
lococcus, being as effective against these organisms as the standard
ionophore antibiotic monensin A.
23. Salinomycin sodium salt (1) was isolated from SacoxÒ 120 micro Granulate an
anticoccidial feed additive distributed by Huvepharma Polska.100 g of permix
was dissolved in dichloromethane. The solvent was evaporated under reduced
pressure and the crude product obtained was purified by Dry Column Vacuum
Chromatography16 (gradient solvent mixture hexane/dichloromethane) giving
6 g pure SAL-Na. 1H NMR (600 MHz, DMSO-d6) d ppm 6.03 (d, J = 9.28 Hz, 1H),
5.75 (d, J = 10.71 Hz, 1H), 5.20 (s, 1H), 5.04 (s, 1H), 4.05 (d, J = 10.28 Hz, 1 H),
3.99 (t, J = 6.40 Hz, 1 H), 3.68 (dd, J = 10.55, 5.27 Hz, 1 H), 3.62 (d, J = 9.88 Hz, 1
H), 3.54 (d, J = 10.01 Hz, 1 H), 3.41 (d, J = 12.16 Hz, 1 H), 2.66 (t, J = 11.84 Hz,
1H), 2.18-2.07 (m, 2H), 1.91 (t, J = 9.96 Hz, 2H), 1.88-1.06 (m, 47 H, signals are
strongly overlapped), 0.85 (t, J = 6.72, Hz, 3 H), 0.82 (dd, J = 14.33, 7.35 Hz, 3H,)
0.73 (t, J = 8.18 Hz, 3H), 0.64 (t, J = 7.21 Hz, 3H), 13C NMR (75 MHz, DMSO-d6)d
ppm: 215.2, 181.4, 130.6, 122.0, 106.0, 98.4, 87.4, 75.7, 75.1,73.8, 70.4, 69.4,
66.7, 65.2, 54.8, 49.7, 48.4, 40.0, 38,1, 35.9, 35.7, 32.1, 31.9, 31.6, 28.7, 27.4,
26.8, 26.3, 23.1, 19.7, 19.3,17.4, 15.8, 15,7,14.5, 12.9, 12.5, 12.4, 10.9, 6.7, 6.2;
The NMR data is agreement with previously published assignments2; FT-IR
Acknowledgments
(KBr, cm–1), 3370 broad
m(O–H) band, 1716 m(C(11)@O), 1566 mas(COO–),
1406 s(COO–); Elemental analysis calc. for C42H69O11Na: C, 65.26; H, 9.00;
m
Found: 65.03; H, 9.29.
Financial support from budget funds for science in years 2012–
2013 - grant ’’Iuventus Plus’’ of the Polish Ministry of Science and
Higher Education – Grant no. 0179/IP3/2011/71, is gratefully
24. Salinomycin acid (2). Salinomycin sodium salt (1) was dissolved in
dichloromethane and stirred vigorously with a layer of aqueous sulphuric
acid (0.015 mol dmÀ3) 3 times. The organic layer containing 2 was washed
with distilled water, and dichloromethane evaporated under reduced pressure
to dryness to produce the acid. The spectroscopic data of 2 data is agreement
with previously published assignments.13
´
acknowledged by Adam Huczynski.
25. Greenberg, A.; Breneman, C. M.; Liebman, J. F. The Amide Linkage: Structural
Significance in Chemistry Biochemistry and Materials Science; John Wiley & Sons:
USA, 2003.
Supplementary data
Supplementary data (exemplary NMR, FT-IR spectra and fig-
ures) associated with this article can be found, in the online ver-
sion. Details on data collection and refinement, fractional atomic
coordinates, anisotropic displacement parameters and full list of
bond lengths and angles in CIF format have been deposited at
the Cambridge Crystallographic Data Centre, No. CCDC 865743
for the 3a. Copies of this information may be obtained free of
charge from The Director, CCDC, 12 Union Road, Cambridge, CB2
1EZ, UK (fax: +44 1223 336 033; email: deposit@ccdc.cam.ac.uk
26. Valeur, E.; Bradley, M. Chem. Soc. Rev. 2009, 38, 606.
27. A solution of 2 (1000 mg, 1.33 mmol), 1,3-dicyclohexylcarbodiimide (140 mg,
2.03 mmol), and allylamine (150 mg, 2.33 mmol) in 50 cm3 of dich-
loromethane and 1-hydroxybenzotriazole hydrate (225 mg, 1.46 mmol)
dissolved in 15 cm3 of tetrahydrofuran were mixed together and stirred at
0 °C for 1 h. After this time, the reaction mixture was stirred at room
temperature for
a further 24 h. Then the solvents were distilled under
reduced pressure to dryness. The residue was suspended in hexane and
filtered off to remove the 1,3-dicyclohexylurea by-product. The filtrate was
evaporated under reduced pressure and purified by Dry Column Vacuum
Chromatography on silica gel (Fluka type 60) to give 3a as a colourless solid
(893 mg, 85% yield). Pure compound 3a was dissolved in acetonitrile. The
solution was allowed to evaporate at room temperature. After several days the
crystals were formed in 57% yield. 1H NMR (400 MHz, CD2Cl2) d ppm: 6.53 (t,
J = 5.71 Hz, 1H), 6.08 (dd, J = 10.74, 2.23 Hz, 1H), 5.94 (dd, J = 10.67, 1.47 Hz,