Bis(2-aminophenyl) diselenide derivatives with amino acids moieties as potential antivirals and antimicrobials

Article abstract of DOI:10.1080/10426500801901194

The seleno-organic compounds based on bis(2-aminophenyl) diselenide-1 are potential antiviral, antibacterial and antifungal agents.1 In this work, we reported synthesis of bis(2-aminophenyl) diselenide derivatives 2, 3 having amino acid and dipeptide moieties. This process was realized by acylation of amine groups in 1 with N-blocked amino acids, using the active esters method (with DCC and HOBT). After removing protective groups successive N-blocked amino acids were added the same way as previously. All compounds have been tested against broad spectrum of pathogenic microorganisms (Staphylococcus aureus, Staphylococcus simulans, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Candida albicans, Aspergillus niger) and viruses (HSV-1, EMCV, VSV), in vitro. Most of them exhibited high activity against EMCV. Some of tested compounds were active against gram-positive bacteria species (Staphylococcus aureus, Staphylococcus simulans) and yeast Candida albicans.

Full text of DOI:10.1080/10426500801901194

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Bis(2-aminophenyl) Diselenide
Derivatives with Amino Acids
Moieties as Potential Antivirals
and Antimicrobials
Ewa Dąbrowska a , Magdalena Pįętka-Ottlik a & Jerzy
Palus a
a Faculty of Chemistry, Wrocław University of
Technology, Wrocław, Poland
Published online: 03 Dec 2008.
To cite this article: Ewa Dbrowska , Magdalena Ptka-Ottlik & Jerzy Palus (2008) Bis(2-
aminophenyl) Diselenide Derivatives with Amino Acids Moieties as Potential Antivirals
and Antimicrobials, Phosphorus, Sulfur, and Silicon and the Related Elements, 183:4,
1082-1086, DOI: 10.1080/10426500801901194
To link to this article: http://dx.doi.org/10.1080/10426500801901194
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Phosphorus, Sulfur, and Silicon, 183:1082–1086, 2008
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500801901194
Bis(2-aminophenyl) Diselenide Derivatives with Amino
Acids Moieties as Potential Antivirals and Antimicrobials
Ewa Dabrowska, Magdalena Pietka-Ottlik,
ꢀ
ꢀ ꢀ
and Jerzy Palus
Faculty of Chemistry, Wroclꢀaw University of Technology, Wroclꢀaw,
Poland
The seleno-organic compounds based on bis(2-aminophenyl) diselenide-1 are po-
1
tential antiviral, antibacterial and antifungal agents. In this work, we reported
synthesis of bis(2-aminophenyl) diselenide derivatives 2, 3 having amino acid and
dipeptide moieties. This process was realized by acylation of amine groups in 1 with
N-blocked amino acids, using the active esters method (with DCC and HOBT). After
removing protective groups successive N-blocked amino acids were added the same
way as previously.
All compounds have been tested against broad spectrum of pathogenic microor-
ganisms (Staphylococcus aureus, Staphylococcus simulans, Escherichia coli, Pseu-
domonas aeruginosa, Klebsiella pneumoniae, Candida albicans, Aspergillus niger)
and viruses (HSV-1, EMCV, VSV), in vitro. Most of them exhibited high activity
against EMCV. Some of tested compounds were active against gram-positive bacte-
ria species (Staphylococcus aureus, Staphylococcus simulans) and yeast Candida
albicans.
Keywords Antimicrobial activity; bis(2-aminophenyl) diselenide derivatives; seleno-
amino acids; seleno-dipeptides; antivirals
INTRODUCTION
Many organoselenium compounds have a very interesting spectrum of
chemical or biological activities.1 Among them are natural and syn-
thetic seleno derivatives of aminoacids, peptides, or enzymes.2 Some
of them have been tested as a kidney-selective pro-drugs,3 glutathion
peroxidase (GPx) mimetics,4 or play an important role in elucidation of
both the local and global structures of many enzymes and proteins.5
Recently it has been described that bis(2-aminophenyl) diselenide
1 and its simple derivatives were potential antiviral, antibacte-
rial and antifungal agents.6 In this work, we report synthesis of
Address correspondence to Ewa Dabrowska, Department of Bioorganic Chemistry,
ꢀ
Faculty of Chemistry, Wroclꢀaw University of Technology, Wybrzez˙e Wyspian´skiego 27,
50-370 Wroclꢀaw, Poland. E-mail: ewa.dabrowska@pwr.wroc.p
1082

Bis(2-aminophenyl) Diselenide Derivatives
1083
FIGURE 1 Diselenide derivatives of aminoacids and peptides.
bis(2-aminophenyl) diselenide derivatives 2, 3 having amino acid and
dipeptide moieties (Figure 1). This process was realized by acylation
of amine groups in 1 with N-blocked amino acids, using the active es-
ters method (with DCC and HOBT). After removing protective groups,
subsequent N-blocked amino acids were added in the same manner
as previously. All compounds have been tested against broad spec-
trum of pathogenic microorganisms (Staphylococcus aureus, Staphylo-
coccus simulans, Escherichia coli, Pseudomonas aeruginosa, Klebsiella
pneumoniae, Candida albicans, Aspergillus niger) and viruses (HSV-1,
EMCV, VSV), in vitro.
EXPERIMENTAL
Synthesis of Bis(2-aminophenyl) Diselenide 1
The key substrate, bis(2-aminophenyl) diselenide 1 has been ob-
tained in a two steps synthesis, starting from 2-chloronitrobezene 4,
same way as reported.6 Its selenylation using lithium diselenide in
hexamethylphosphoramide-tetrahydrofurane solution produced bis (2-
nitrophenyl) diselenide 5 in 84% yield (ref.6 86%). In the next step,
dinitro compound was transformed into amine 1 by reduction using
hydrazine monohydrate in the presence of Raney nickel as a catalyst
(Scheme 1). We observed that yield and products of this reaction were
strongly dependent on activity of used catalyst and solvent. When fresh,
commercially available catalyst in boiling n-propanol mixture was used,
aniline 6 as a product of deselenylation was obtained in high yield.
Amine 1 was obtained in the same conditions in yields up to 69% (lit.6
71%) when catalyst dried overnight on air was used. At the same time
in case of using isopropanol as a solvent, bis(2-aminophenyl) selenide
7 was produced in 15% yield.

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E. Dabrowska et al.
ꢀ
SCHEME 1
Synthesis of Amino Acid Derivatives 2
Active esters method (with hydroxybenzotriazole (HOBT) and dicyclo-
heksyl carbodiimide (DCC)) as a route of coupling carboxylic group of
N-Boc-protected natural amino acids 8 a–f and both amino group in
diselenide 1 was used. Reactions were carried out in dichloromethane
in temperature −14◦C and N-Boc protected diselenides 9a–f with 55
to 96% yield were produced. Free amines 2a–f were obtained by re-
moving protective groups by saturation of 1,4-dioxane solution of 9a–f
with gaseous hydrochloride and then by neutralization obtained this
way hydrochlorides 10a–f in reaction with N-methylmorpholine in
dichlorometane solution. Yields of these both procedures were 56–73%
and 64–94%, respectively (Scheme 2).
SCHEME 2

Bis(2-aminophenyl) Diselenide Derivatives
1085
Synthesis of Dipeptide Derivatives 3
Active esters method was also used to preparation of dipeptide deriva-
tives 3a–f. Hydrochlorides 10a, b were converted in situ to amines 2a,b
in presence of N-methylmorpholine and then it was coupled with N-Boc
protected L-amino acids 8a,c, d, f in presence of HOBT and DCC. Re-
actions were carried out in dichlorometane-dimethylformamide solu-
tion in temperature −14◦C and N-Boc protected diselenides 11a-f with
22–68% yield were produced. Hydrochlorides 12a–f were prepared the
same way as it was described for compounds 10 with 63–86% yield.
Free amine 3b,c,d,f were involved in reaction with propylene oxide in
anhydrous ethanol with 73–80% yield (Scheme 3).
SCHEME 3
CONCLUSIONS
New derivatives of bis(2-aminophenyl)diselenide 1 with aminoacids
and dipeptides moieties has been designed and synthesized using
the active esters method (with DCC and HOBT). All compound were
tested against selected viruses and microbes. The majority of tested
compounds exhibited high activity against EMCV. However, high cy-
totoxicity of these compounds resulted in undesirable low I values.
Some of tested compounds were weakly active Staphylococcus aureus,

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E. Dabrowska et al.
ꢀ
Staphylococcus simulans, Escherichia coli, Candida albicans and
Aspergillus niger.
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