ISBN: 978-83-60043-10-3 - eurobic9

Eurobic9, 2-6 September, 2008, Wrocław, Poland
P128. Antimicrobial Activity of the Co(II), Zn(II) and Cd(II) Complexes
with N-benzyloxycarbonyl-S-phenylalanine
D. Mitić a , M. Milenković b , S. Milosavljević a , Z. Miodragović a , K. Anđelković a and
Dj. Miodragović a
a
Faculty of Chemistry, University of Belgrade, Studentski trg 12-16, 11000 Belgrade, Serbia
e-mail: dmiodrag@chem.bg.ac.yu
b
Department of Microbiology and Immunology, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe
450, Serbia
There is a pressing need for new antifungal agents because of the fast development of resistance of
microorganisms to the state-of-the-art drugs currently used to treat different fungal infections. For this reason, the
elaboration of new types of antifungal agents is presently a very real task. A promising field for this search is
metal-based drugs. Metal-based drugs have a different mode of action compared to the commonly used
commercial polyene and azole antifungal drugs. Treatment of fungal cells with, for example, Cu(II) and Ag(I)
complexes [1] resulted in a reduced amount of ergosterol in the cell membrane and a subsequent increase in its
permeability.
In spite of interesting biological activities, only a few complexes with N-Boc amino acids have been described. As
N-benzyloxycarbonylglycine has favorable membrane penetration properties [2], in our previous paper the
preparation of neutral complexes of this ligand with various metal ions was described [3]. The antimicrobial
activity of the obtained metal complexes was also determined and it was established that among the investigated
strains, the Zn(II) and Co(II) complexes were selective, acting only against the yeast Candida albicans. In a
further investigation, the complex of Zn(II) with N-benzyloxycarbonyl-S-alanine was synthesized and was shown
to possess the same selectivity against Candida albicans [4].
In this study, new complex compounds of Zn(II), Cd(II) and Co(II) with N-benzyloxycarbonyl-S-phenylalanine
(1-3) were synthesized and characterized. As N-benzyloxycarbonyl-S-phenylalanine is more hydrophobic (and
more lipophilic) than N-Boc-glycine and N-Boc-S-alanine, it was supposed that these complexes could have
better antimicrobial activities than the previously investigated ones.
MIC values obtained for complexes are lower than MIC values obtained for ligand and simple metal salts. The
comparison of MIC value of complex 2 with MIC value of complex with N-Boc-gly indicates that substitution of
N-Boc-gly with N-Boc-S-phe ligand resulted in a more than twelve fold increase in the anti-Candida activity,
from 1.11 to 0.09 mM. The increase in activity was also observed for complexes 1 and 3 [5]. The increase in the
lipophilicity of N-benzyloxycarbonyl–S-phenylalaninato ligand is probably the reason for the better penetration
of the complexes with this ligand in comparison to the complexes with N-Boc-glycine or N-Boc-S-alanine.
It is interesting to note that Hitherto investigated complexes with N-benzyloxycarbonyl-amino acids exhibited
the best activity against the yeast Candida albicans of the until now investigated bacterial and fungal strains.
Complex 2 has MIC value almost the same as that of the standard drug nystatin in the case of Candida albicans
ATCC 24433.
Acknowledgement: This investigation was supported by the Ministry of Science of the Republic of Serbia,
Grant No. 142010.
References:
[1] D.M. Lambert, G.K.E. Scriba, J.H. Poupaert, P. Dumont, Eur. J. Pharm. Sci. 4, 159 (1996).
[2] B.S. Creaven, D. A. Egan, D. Karcz, K. Kavanagh, M. McCann, M. Mahon, A. Noble, B. Thati, M. Walsh, J.
Inorg. Biochem. 101, 1108 (2007).
[3] D.U. Miodragović, D.M. Mitić, Z.M. Miodragović, G.A. Bogdanović, Ž.J. Vitnik, M. D. Vitorović, M.Đ.
Radulović, B.J. Nastasijević, I.O. Juranić, K.K. Anđelković, Inorg. Chim. Acta 361, 86 (2008).
[4] D.M. Mitić, Đ.U. Miodragović, D.M. Sladić, Ž.J. Vitnik, Z.M. Miodragović, K.K.
Anđelković, M.Đ. Radulović, N.O. Juranić, J. Serb. Chem. Soc. (2008), in press.
[5] D. Mitić, M. Milenković, S. Milosavljević, D. Gođevac, Z. Miodragović, K. Anđelković, Dj. Miodragović,
submited for Eur. J. Med. Chem.
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