Synthesis of selenium-containing amino acid analogues and their biological study

Article abstract of DOI:10.1134/S1068162011030034

Synthesis of selenium-containing amino acid analogues is described. These compounds were prepared in a concise and short synthetic route in good yields by nucleophilic substitution reaction of pyridineselenol and quinolineselenol derivatives with N-phthaloylglycyl chloride followed by hydrazinolysis. The newly synthesized compounds were screened against different strains of bacteria and fungi.

Full text of DOI:10.1134/S1068162011030034

ISSN 1068ꢀ1620, Russian Journal of Bioorganic Chemistry, 2011, Vol. 37, No. 3, pp. 261–269. © Pleiades Publishing, Ltd., 2011.
Synthesis of SeleniumꢀContaining Amino Acid Analogues
and Their Biological Study1
,
b
,
c
, d
Sh. H. AbdelꢀHafeza , 2, H. A. Saada , M. R. E. Alya
aChemistry Department, Faculty of Science, Taif University, 888, Alhawiya, Taif University,
Taif, Kingdom of Saudi Arabia
bChemistry Department, Faculty of Applied Science, Assiut University,
Assiut, Egypt
cChemistry Department, Faculty of Applied Science, Zagazig University,
Zagazig, Egypt
dChemistry Department, Faculty of Applied Science,
Port Said University, Egypt
Received November 29, 2010; in final form, December 29, 2010
Abstract—Synthesis of seleniumꢀcontaining amino acid analogues is described. These compounds
were prepared in a concise and short synthetic route in good yields by nucleophilic substitution reaction
of pyridineselenol and quinolineselenol derivatives with
Nꢀphthaloylglycyl chloride followed by
hydrazinolysis. The newly synthesized compounds were screened against different strains of bacteria
and fungi.
Keywords: pyridineselenol, quinolineselenol, amino acid, antiꢀbacterial activities, antiꢀfungal activities
DOI: 10.1134/S1068162011030034
1 2
In recent years, the interest in organoselenium of seleniumꢀcontaining sulfa drugs [12], we decided to
chemistry increased remarkably due to its pivotal expand our interest to the introduction of an orgaꢀ
role in the synthesis of a large number of biologiꢀ
cally active compounds and important therapeutic
products ranging from anticancer, antioxidant and
antifungal to naturally occurring food supplements
[1–7].
noselenium compounds in the amino acid analogues
framework. To accomplish this task, we sought to
functionalize the pyridineselenol and quinolineseleꢀ
nol derivatives with
Nꢀphthaloylglycyl chloride folꢀ
lowed by hydrazinolysis by hydrazine hydrate followed
by treatment with HCl.
Moreover, selenium is an essential micronutrient
for animals and humans: to date, its bioavailability
seems to depend upon the naturally occurring seleꢀ
niumꢀcontaining amino acids selenocysteine, seleꢀ
nomethionine, other seleno amino acids, such as seleꢀ
nocystathionine, are also involved in seleno amino
acid metabolic pathways [8, 9].
To accomplish and attend our plan, firstly we
started with compound (
7,9ꢀdimethylpyrido[3',2':4,5]selenolo[3,2ꢀ
idine (II as described previously [13].
I
) and prepared 4ꢀhydrazinoꢀ
d
]pyrimꢀ
)
Compound (II) reacted with chloroacetyl chloꢀ
ride to furnish 2ꢀchloroꢀ 'ꢀ(7,9ꢀdimethylpyꢀ
rido[3',2':4,5]selenolo[3,2ꢀ ]pyrimidinꢀ4ꢀyl)aceꢀ
tohydrazide (III , which, when allowed to react
with piperidine or morpholine, afforded compound
II) instead of (IVa), (IVb). This cleavage of the
N
In our previous work, we described the synthesis of
d
pyrimidoselenolo[2,3ꢀb]quinoline [10], pyrimidoseꢀ
)
lenolo[2,3ꢀ ]pyridazine [11] and demonstrated that
c
certain compounds manifest significant antiꢀinflamꢀ
matory and analgesic activities with strong fungicidal
effects. Stimulated by our recent work on the synthesis
(
amide linkage in compound (III) by amines instead
of nucleophilic substitution is due to enhancement
of the sensitivity of the carbonyl group to nucleoꢀ
philes induced by the electronegativity of the
1
The article is published in the original.
Corresponding author: phone: 00966 552453944; eꢀmail:
2
sabdel68@yahoo.co.uk; shams@aun.edu.eg.
β
ꢀchlorine atom (Scheme 1).
261

262
ABDELꢀHAFEZ et al.
CH3
N
CH3
N
N
N
a
N
N
NH2
Cl
NH
Se
Se
II
H3C
H3C
(
I)
(
)
b
CH3
N
CH3
N
c
N
N
N
NH
NH
NH
Se
NH
H3C
Se
H3C
N
N
Cl
O
O
(IVa, b
)
(
III)
X
(IVa), X = H
(b) X = O
Reagents and conditions: (a) NH2NH2, reflux; (b) ClCOCH2Cl, room temperature; (c) piperidine/morpholine, reflux
Scheme 1.
In an attempt to introduce amino acid analogues methylpyrimido[4',5':4,5]selenolo[2,3ꢀ
into organoselenium compounds, we tested the quinoline 4ꢀyl)acetohydrazide (VII . Its reaction with piperiꢀ
derivative instead of that with the pyridine nucleus. dine or morpholine afforded compound VI rather
The reaction of 4ꢀhydrazinoꢀ11ꢀmethylpyrimꢀ than compounds (VIIIa), (VIIIb) and the reason for
ido[4',5':4,5]selenolo[2,3ꢀ ]quinoline (VI [11] with that seems to be the same as mentioned above
b]quinolinꢀ
)
(
)
b
)
chloroacetyl chloride afforded 2ꢀchloroꢀ
N
'ꢀ(11ꢀ
(Scheme 2).
CH3
N
CH3
N
N
a
N
N
NH2
Cl
NH
Se
Se
N
(
V
)
(
VI
)
b
CH3
N
N
CH3
N
N
c
N
NH
NH
Se
NH
NH
Se
VII
N
N
O
O
(
(
b
VIIIa, b
VIIIa), X = H
, X = O
)
(
)
X
Cl
Reagents and conditions: (a) NH2NH2, reflux; (b) ClCOCH2Cl, room temperature; (c) piperidine/morpholine, reflux
Scheme 2.
Yet another putative precursor, 4,6ꢀdimethylquinoꢀ
The reaction of derivatives (IXa) and (IXb) with
lineꢀ2ꢀselenol (IXa), was prepared by the reaction of chloroacetamide in refluxing ethanol in the presence
2ꢀchloroꢀ4,6ꢀdimethylquinoline with sodium hydroꢀ of sodium borohydride afforded 2ꢀ[(4,6ꢀdimethꢀ
genselenide in ethanol in low yield (10%); diquinoliꢀ ylquinolinꢀ2ꢀyl)selanyl]acetamide (X), which allowed
nyl diselenide derivative (IXb) formed in high yield to react with chloroacetyl chloride to yield (XI).
(90%) due to self oxidation of (IXa) in air accelerated Again, the reaction with piperidine or morpholine
by heating [14]. Compounds (IXa) and (IXb) were isoꢀ afforded compound (X) instead of (XIIa), (XIIb)
lated by fractional crystallization. (Scheme 3).
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 37
No. 3
2011

SYNTHESIS OF SELENIUMꢀCONTAINING AMINO ACID ANALOGUES
CH3
263
H3C
CH3
N
SeH
H3C
a
(IXa
)
NH2
N
Se
CH3
O
(X)
H3C
b
N
Se
2
(IXb
)
CH3
H3C
CH3
c
H3C
NH
N
Se
XI
Cl
NH
O
O
N
Se
N
(
)
O
O
X
(XIIa, b)
(
b
XIIa), X = H
, X = O
Reagents and conditions: (a) ClCH2CONH2, NaBH4, reflux; (b) ClCOCH2Cl, room temperature;
(c) piperidine/morpholine, reflux
Scheme 3.
Secondly, to accomplish our target we started with imido)glycyl]pyridineꢀ2ꢀselenol
another precursor, viz., ꢀphthaloylglycyl chloride hydrazinolysis with NH2NH2 followed by treatment
XIV), which has been prepared long ago [15], and with 2 N HCl gave the corresponding 3ꢀcyanoꢀSeꢀglyꢀ
(XV), which on
N
(
allowed to react with organoselenium compound cylꢀ4,6ꢀdimethylpyridineꢀ2ꢀselenol
hydrochloride
(
XIII) to yield 3ꢀcyanoꢀ4,6ꢀdimethylꢀSeꢀ[(
Nꢀphthalꢀ
(XVI) (Scheme 4).
CH3
N
O
O
CH3
CN
O
Cl
CN
a
O
+
N
N
H3C
Se
XV
H3C
N
Se
O
XIV
2
O
(
XIII
)
(
)
(
)
b
CH3
N
CN
O
NH2HCl
H3C
Se
(XVI)
Reagents and conditions: (a) NaBH4, EtOH, reflux; (b) (i) NH2NH2/reflux, (ii) 2M HCl, 40°C, 5 min
Scheme 4.
Under similar conditions, compound (XVII) reacted lineꢀ2ꢀselenol (XVIII), which on hydrazinolysis furnished
with (XIV) to form 3ꢀcyanoꢀ4ꢀmethylꢀSeꢀ[( ꢀphthalimꢀ the corresponding 3ꢀcyanoꢀSeꢀglycylꢀ4ꢀmethylquinoꢀ
ido)glycyl]quinolineꢀ2ꢀ[(Nꢀphthalimido)glycyl]quinoꢀ lineꢀ2ꢀselenol hydrochloride (XIX) (Scheme 5).
N
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 37
No. 3
2011

264
ABDELꢀHAFEZ et al.
O
CH3
N
O
CH3
N
O
Cl
CN
CN
Se
a
O
+
N
N
Se
2
O
O
(
XVII
)
(
XIV
)
(XVIII)
b
CH3
CN
O
NH2HCl
N
Se
(XIX)
Reagents and conditions: (a) NaBH4, EtOH, reflux; (b) (i) NH2NH2/reflux, (ii) 2M HCl, 40°C, 5 min
Scheme 5.
Finally, as the last example in our target plan, the phthalimido)glycyl]quinolineꢀ2ꢀselenol, which on
reaction of compound (IXb) with compound (XIV
)
hydrazinolysis furnished Seꢀglycylꢀ4,6ꢀdimethylquinꢀ
olineꢀ2ꢀselenol hydrochloride (XXI) (Scheme 6).
afforded derivative
(
XX), i.e
.
, 4,6ꢀdimethylꢀSeꢀ[(Nꢀ
CH3
O
O
CH3
O
H3C
Cl
H3C
a
O
+
N
N
N
Se
XX
N
Se
O
O
2
(
IXb
)
(
XIV
)
(
)
b
CH3
N
H3C
O
NH2HCl
Se
(XXI)
Reagents: (a) NaBH4, EtOH/ref.; (b) (i) NH2NH2/reflux, (ii) 2N HCl/heat 5 min/40°C
Scheme 6.
The structures of the synthesized compounds were test organism such as Candida albicans (418), Geotriꢀ
confirmed by their physical, analytical and spectral
data (Table 1).
chum candidum (226), Trichophyton rubrum (1804),
Fusarium oxysporum (5119), Scopulariopsis brevicaulis
(729), Aspergillus flavus (1276) were obtained from
Assiut University Mycological Center. Chloramꢀ
phenicol was used as an antibacterial standard, while
Clotrimazole was used as an antifungal standard.
DMSO was used as a blank, which exhibited no activꢀ
ity against any of the used organisms. The obtained
data revealed that most of the compounds selected
The antimicrobial screenings of the synthesized
compounds were undertaken using agar well diffusion
assay [16]. Table 2 lists the screening results of the
tested compounds against Gramꢀnegative and Gramꢀ
positive bacteria. Five bacterial test organisms such as
Staphylococcus aureus (Bꢀ54), Bacillus cereus (Bꢀ52),
Escherichia coli (Bꢀ53), Serratia marcescens (Bꢀ55),
and Pseudomonas aeruginosa (Bꢀ73) and seven fungi ((II), (IXb), (X), (XV), (XVI), (XVIII)–(XXI)) showed
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 37
No. 3
2011

SYNTHESIS OF SELENIUMꢀCONTAINING AMINO ACID ANALOGUES
265
Table 1. Physical and spectral data of compounds (III), (VII), (IXa), (IXb), (X), (XI), (XV), (XVI), (XVIII)–(XX) and (XXI)
Compd. Mol. formula
–1
1
Mp
°
C (yield %)
IR (cm
)
H NMR (δ, ppm)
no.
(W
/wt)
(III)
150–152 (60) C H ClN OSe 3250–3200 (NH), CDCl : 8.04 (s, 1H, CHꢀpyrimidine); 7.18 (s, 1H,
13 12
5
3
(368.68)
1650 (CO amide), CHꢀpyridine); 5.35 (br, 1H, NH, NHNHCO); 3.96
1610 (C=N)
(s, 2H, CH ) 2.81, 2.89 (2s, 6H, 2CH ); 1.13 (s, 1H,
NH, NHNHCO).
2
3
(VII
)
160–162 (72) C H ClN OSe 3400 (NH), 1660 DMSOꢀ
d
: 8.72 (s, 1H, CHꢀpyrimidine); 7.30–8.31
16 12
5
6
(404.71)
(CO amide), 1610 (m, 4H, ArꢀH); 4.45 (s, 2H, CH ); 4.30 (s, 1H, NH,
2
(C=N)
NHNHCO); 3.52 (s, 1H, NH, NHNH CO); 3.10 (s,
3H, CH ).
3
a
b
(
(
(
IXa
)
175–177 (10) C H NSe
1615 (C=N)
1615 (C=N)
DMSOꢀd : 7.42–7.78 (m, 4H, ArꢀH); 3.60 (br, 1H,
6
11 11
(236.17)
NH); 2.40 (s, 6H, 2CH ).
3
IXb
)
275–277 (90) C H N Se
DMSOꢀ
d
d
: 7.01–7.90 (m, 8H, ArꢀH); 2.43 (s, 12H,
: 7.46–7.87 (m, 4H, ArꢀH); 7.43 (s, 1H,
22 20
(470.33)
2
2
6
4CH ).
3
a
X)
180–182 (81) C H N OSe
3150–3370 (NH ); DMSOꢀ
1670 (COꢀamide); NH ); 3.82 (s, 2H, CH ); 2.53 (s, 3H, CH ); 2.50
13 14
(293.22)
2
2
6
2 2 3
1620 (CN)
170–172 (73) C H ClN O Se 3400 (NH); 1679 DMSOꢀd : 8.90 (br, 1H, NH); 7.38ꢀ7.95 (m, 4H,
6
(s, 3H, CH ).
3
a
(
(
(
(
(
(
(
XI
)
15 15
(369.70)
2
2
(COꢀamide); 1610 ArꢀH); 4.19 (s, 2H, COCH Cl); 3.95 (s, 2H,
2
(C=N)
100–102 (90) C H N O Se 2200 (CN); 1720, DMSOꢀd : 7.50–7.95 (m, 4H, ArꢀH); 7.42 (s, 1H,
6
SeCH CO); 2.64 (s, 3H, CH ); 2.60 (s, 3H, CH ).
2 3 3
a,b
XV
)
18 13
(398.27)
3
3
1680,1660 (3 CO) CHꢀpyridine); 4.40 (s, 2H, CH ); 2.60 (s, 3H, CH );
2 3
2.40 (s, 3H, CH ).
3
a
XVI
)
>300 (76)
C H ClN OSe 3310–3190 (NH ); TFA: 8.30 (s, 2H, NH HCl); 8.21 (s, 1H, CHꢀpyriꢀ
(304.63)
10 12
3
2
2
2200 (CN); 1690
(CO)
dine); 4.70 (s, 2H, CH ); 3.45 (s, 3H, CH ); 3.20
2 3
(s, 3H, CH ).
3
a,b
XVIII
)
110–112 (75) C H N O Se 2200 (CN);
DMSOꢀd : 7.20–8.10 (m, 8H, ArꢀH); 4.50 (s, 2H,
6
21 13
(434.31)
3
3
1720,1670,1660 (3 CH ); 2.81 (s, 3H, CH ).
CO)
2 3
a
XIX
)
>300 (76)
C H ClN OSe 3330–3140 (NH ); TFA: 8.10–8.60 (m, 4H, ArꢀH); 7.55 (s, 2H,
(340.67)
13 12
3
2
2200 (CN); 1680 NH HCl); 4.40 (s, 2H, CH ); 3.01 (s, 3H, CH ).
2 2 3
(CO)
140–142 (70) C H N O Se 1710,1670,1660 (3 DMSOꢀd : 7.27–7.71 (m, 7H, ArꢀH); 7.26 (s, 1H,
6
a,b
XX
)
21 16
(423.32)
2
3
CO); 1620 (C=N) CHꢀpyridine); 3.92 (s, 2H, CH ); 2.67 (s, 3H,
2
CH ); 2.60 (s, 3H, CH ).
3
3
a
XXI
)
>300 (74)
C H ClN OSe 3320–3120 (NH ); TFA: 7.48–7.89 (m, 3H, ArꢀH); 7.20 (s, 1H, CHꢀ
(329.68)
13 15
2
2
1670 (CO)
pyridine); 7.42 (s, 2H, NH HCl); 3.76 (s, 2H, CH );
2 2
2.61 (s, 3H, CH ); 2.34 (s, 3H, CH ).
3
3
a
Notes: MS (see experimental Section).
b 13
C NMR of compounds (XV), (XVIII) and (XX) (see Section 4).
no activity against all organisms used except for comꢀ two compounds is presumably due to the presence of
pounds (II) and (XVIII), which showed remarkably
broadꢀspectrum potency against Staphylococcus
either the cyano group or quinoline nucleus in comꢀ
pound (XVIII) or amino group in addition to the pyriꢀ
dine nucleus in compound (II). These compounds
seem to be good bactericidal and fungicidal candidates
against all species of bacteria and fungi. Generally, it
was noticed that the activities of the tested compounds
are less than those of standard antifungal and antibacꢀ
terial agents used.
aureus, Bacillus cereus, Escherichia coli
, and
Pseudomonas aeruginosa with inhibition zone of 13,
12, 10, 8 mm for compound (XVIII) at concentration
of 20 mg/ml and inhibition zone at 9, 9 and 12 mm for
compound (II) at concentration of 20 mg/ml with
minimum inhibition concentration (MIC) values of 8
and 12 mg/ml, respectively. Of the synthesized comꢀ
pounds, only compounds (II) and (XVIII) showed
strong fungicidal effect against all species of fungi. The
MIC of these compounds was 11, 10 mg/ml (50%).
Thus, a new series of seleniumꢀcontaining amino
acid analogues were prepared in a concise and short
synthetic route in good yields by a nucleophilic substiꢀ
The strong fungicidal and bactericidal effect of these tution reaction. Organoselenium compounds (XVI),
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 37
No. 3
2011

266
ABDELꢀHAFEZ et al.
Table 2. Antibacterial activity (inhibition zone in mm)
(
XVIII
)
(II)
(
IX)*
Sample No.
Organisms
20 10
5
2.5 1.25 20 10
5
2.5 20 10
5
2.5 1.25 0.6 0.3
Staphylococcus aureus
(+ve) AUMC No. Bꢀ54
13 13 10
8
0
9
8
8
0
17 17 15 13 12 12 10
34 34 32 30 28 25 18
30 26 26 20 16 14 12
41 40 38 34 28 26 20
16 14 12 12 10 10 10
Bacillus cereus (+ve)
AUMC No Bꢀ52
12 12
8
0
0
–
0
–
–
–
Escherichia coli (–ve)
AUMC No. Bꢀ53
10
0
8
–
–
–
–
9
8
0
–
–
–
Serratia marcescens (–ve)
AUMC No. Bꢀ55
–
–
–
–
0
–
–
–
Pseudomonas aeruginosa
8
8
0
12
0
(–ve) AUMC No. Bꢀ73
Note: (IX)* = Chloramphenicol as antibacterial standard. AUMC = Assiut University Mycological Center.
Table 2. Continued: Antifungal activity (inhibition zone in mm)
(
XVIII
)
(
II)
(IX)**
Sample No.
Organisms
20 10
5
2.5 1.25 0.6 20 10
5
2.5 20 10
5
2.5 1.25 0.6 0.3
Candida albicans AUMC 12 12 10
No. 418
8
0
8
–
–
0
0
14 13
16 13
8
0
–
–
–
0
30 30 30 26 26 26 26
24 22 22 22 22 22 22
35 34 34 34 34 34 34
22 22 22 22 18 18 18
26 24 23 23 20 20 20
27 27 27 25 25 25 25
Geotrichum candidum
10 10
14 11
9
0
–
–
–
–
–
0
–
–
8
AUMC No. 226
Trichophyton rubrum
AUMC No. 1804
–
8
14
0
p.i.
Fusarium oxysporum
AUMC No. 5119
13 11 10
0
–
Scopulariopsis brevicaulis
AUMC No. 729
18
p.i.
0
–
–
0
–
–
14 10
Aspergillus flavus AUMC
No. 1276
15 15 11
18 14 10
0
Note: (IX)** = Clotrizmazole as antifungal standard. AUMC = Assiut University Mycological Center.
Table 2. Continued: Antibacterial activity (inhibition zone in mm and MICs given in brackets of chemical compounds tested,
Chloramphenicol (CHL) used as standard
Staphylococcus
aureus (+ve)
Bacillus cereus
Escherichia
coli (–ve)
Serratia
Pseudomonas
Sample No.
(+ve)
marcescens (–ve) aeruginosa (–ve)
(
(
(
II
)
8(5)
–
8(10)
8(10)
–
12(20)
8(10)
XVIII
)
8(2.5)
10(0.3)
8(5)
–
IX)*
18(0.3)
12(0.3)
20(0.3)
10(0.3)
Table 2. Continued: Antifungal activity ( inhibition zone in mm and MICs given in brackets of chemical compounds tested,
Clotrimazole (CLO) used as standard
Candida
albicans
Geotrichum
candidum
Trichophyton
rubrum
Fusarium
oxysporum
Scopulariopsis
brevicaulis
Aspergillus
flavus
Sample No.
II
(
(
(
)
8(5)
13(10)
9(5)
14 p.i.(20)
11(10)
–
8(5)
10(5)
XVIII
)
8(1.25)
26(0.3)
8(2.5)
18(0.3)
18 p.i.(20)
20(0.3)
11(5)
IX)**
22(0.3)
34(0.3)
25(0.3)
The authors have declared no conflict of interest.
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 37
No. 3
2011

SYNTHESIS OF SELENIUMꢀCONTAINING AMINO ACID ANALOGUES
267
(
XIX) and (XX) that contain glycyl moiety did not have Cl, 9.29. C15H15ClN2O2Se. Calcd., %: C, 48.73;
antimicrobial activity against the tested organisms.
H, 4.09; N, 7.58; Cl, 9.59.
It seems obvious that quinolineselenol and
4,6ꢀDimethylquinolineꢀ2ꢀselenol (IXa). A mixture
pyridineselenol derivatives in which the quinoline ring of 4,6ꢀdimethylꢀ2ꢀchloroquinoline (1.8 g, 10 mmol),
is bearing cyano and phthalimido groups (compound metallic selenium (1 g, 12 mmol) and sodium borohyꢀ
XVIII), as well as pyridine nucleus carrying hydrazino dride (1.2 g, 32 mmol) were refluxed in 50 ml ethanol
group (compound II) demonstrated the best results in for 2 h. The mixture was cooled and poured onto iceꢀ
the biological screening.
cold HCl. The solid thus separated which contain a
mixture of compounds (IXa), (IXb) was filtered off,
dried and recrystallized from ethanol to give the title
compound as yellow crystals. Yield 0.2 g (10%); the
mass spectrum of compound (IXa) exhibited molecuꢀ
EXPERIMENTAL CHEMISTRY
Melting points were determined using a Kofler
melting point apparatus and are uncorrected. IR specꢀ
tra were recorded on a PyeꢀUnicam SP3ꢀ100 instruꢀ
ment in KBr wafer. The mass spectra (EI, 70 eV, ion
source temperature 210°C) were recorded on a Jeol
lar ion peak at m/z (Irel, %) 236 ([M
]+, 100) and other
important fragments were observed at m/z 155.7 (41),
140.7 (13), 75.9 (3). Found, %: C, 55.78; H, 4.47;
N, 5.85. C11H11NSe. Calcd., %: C, 55.94; H, 4.69;
N, 5.93.
1
JMS600 instrument. H NMR spectra were obtained
on a Varian spectrometer (90 MHz) using tetramethꢀ
ylsilane as the internal reference. 13C NMR spectra
were recorded on a JNMꢀLA spectrometer (400 MHz)
at Assiut University. Elemental analyses were obtained
on an Elementar Vario EL 1150C analyser. Purity of
the compounds was checked by TLC using silica gel
plates.
2,2'ꢀBis(4,6ꢀdimethylquinolinyl) diselenide (IXb)
was not dissolved during the crystallization from ethaꢀ
nol. The solid was dried and recrystallized from dioxꢀ
ane to give (IXb) as an orange crystals; Yield (0.39 g,
90%).
MS of compound (IXb) exhibited a molecular ion
peak at m/z
important fragments were observed at m/z
390.1 (16), 236.4 (100), 155.7 (41), 140.7 (13), 75.9 (3).
(Irel, %) 472.4 ([M
+ 2]+, 13) and other
Compounds (
were prepared as previously described [11, 13, 14].
ꢀChloroacetylation (general procedure). Chloroꢀ
acetyl chloride (10 mmol) was added dropwise to a
solution of compounds (II), (VI) or ( ) (10 mmol) in
I), (II), (V), (VI), (XIII), and (XVII)
(Irel, %)
Found, %: C, 56.00; H, 4.11; N, 5.69. C22H20N2Se2
.
N
Calcd., %: C, 56.18; H, 4.29; N, 5.96.
X
2ꢀ[(4,6ꢀDimethylquinolinꢀ2ꢀyl)selanyl]acetamide (X).
A mixture of compounds (IXa) and (IXb) as obtained
from the reaction mixture (7.05 g, 15 mmol), sodium
borohydride (0.63 g, 17 mmol) and chloroacetamide
(1.40 g, 15 mmol) in 30 ml of ethanol was heated
under reflux for 2 h, the reaction mixture allowed to
cool and poured onto 50 ml ice water. The solid prodꢀ
uct was collected by filtration and recrystallized from
dioxane as yellow crystals. Yield 8.7 g (80%); MS of
dioxane (20 ml) and the reaction mixture was stirred
for 3 h at room temperature, then poured into cold
water. The precipitate was collected and recrystallized
from ethanol to give yellow crystals of compound
(
III), red crystals of compound (VII) and yellow crysꢀ
tals of compound (XI).
2ꢀChloroꢀ 'ꢀ(7,9ꢀdimethylpyrido[3',2':4,5]selenolo
[3,2ꢀ ]pyrimidinꢀ4ꢀyl)acetohydrazide (III). MS of
compound (III exhibited molecular ion peak at m/z
rel, %) 368.22 ([
]+, 12) and other important fragꢀ
N
d
compound (
rel, %) 294.3 ([
ments were observed at m/z
249.54 (15), 190.92 (100), 155.94 (40), 127.95 (20).
Found, %: C, 53.10; H, 4.66; N, 9.33. C13H14N2OSe
X
) exhibited a molecular ion peak at m/z
+ 2]+, 13) and other important fragꢀ
rel, %) 293.73 (10),
(I
M
(
I
M
(I
ments were observed at m/z 364.19 (7), 353.27 (17),
327.18 (22), 198.19 (9), 80.66 (100), 79.86 (34).
Found, %: C, 42.20; H, 3.00; N, 18.88; Cl, 9.45.
C13H12ClN5OSe. Calcd., %: C, 42.35; H, 3.28; N, 19.00;
Cl, 9.62.
.
Calcd., %: C, 53.25; H, 4.81; N, 9.55.
SeꢀAcylation (general procedure). A mixture of a
2ꢀChloroꢀ
[2,3ꢀ ]quinolinꢀ4ꢀyl)acetohydrazide (VII). MS of
compound (VII) exhibited molecular ion peak at m/z loylglycyl chloride (2.2 g, 10 mmol) in 30 ml of ethaꢀ
rel, %) 404 ([
+, 2) and other important fragments nol was heated under reflux for 1 h, the reaction mixꢀ
were observed at m/z 368 (44), 326 (100), 284 (18), ture allowed to cool and poured onto 50 ml ice water.
The solid product was collected by filtration and
Cl, 8.45. C16H12ClN5OSe. Calcd., %: C, 47.48; recrystallized from petroleum ether (60–80°C) (XV
N'ꢀ(11ꢀmethylpyrimido[4',5':4,5]selenolo diselenide (XIII), (XVII) and (IXb) (10 mmol),
sodium borohydride (0.44 g, 12 mmol) and Nꢀphthaꢀ
b
(I
M]
73 (24). Found, %: C, 47.13; H, 2.77; N, 17.10;
)
H, 2.99; N, 17.30; Cl, 8.76.
or ethanol ((XVIII) and (XX)).
2ꢀChloroꢀ ꢀ(2ꢀ(4,6ꢀdimethylquinolinꢀ2ꢀylselanyl)
N
3ꢀCyanoꢀ4,6ꢀdimethylꢀSeꢀ[(Nꢀphthalimido)glycyl]
acetyl)acetamide (XI). MS of compound (XI exhibited pyridineꢀ2ꢀselenol (XV), pale yellow crystals.
molecular ion peak at m/z 6, 75 MHz) 20.4, 24.3 (2CH3),
rel, %) 368.85 ([M – 1]+, 13C NMR (DMSOꢀ
and other important fragments were observed at 38.5 (CH2), 108.2, 114.1, 123.2, 123.5, 131.7, 134.2,
m/z 293.49 (57), 249.57 (100), 246.56 (43), 235.56 (17), 152.1, 154.4, 162.5, 167.3, 170.7 (C N, 7 C=C, C=N,
155.77 (43). Found, %: C, 48.44; H, 3.88; N, 7.32; 2 C=O); MS of compound (XV) exhibited molecular
(
I
d
δ
≡
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 37
No. 3
2011

268
ABDELꢀHAFEZ et al.
ion peak at m/z
(I
rel, %) 399.96 ([
M
+ 1]+, 4) and other 294.03 (6), 237.01 (100), 157.09 (18), 143.07 (14),
important fragments were observed at m/z 250.99 (7), 119.07 (11), 109.00 (10). Found, %: C, 47.11; H, 4.38;
227.93 (33), 165.94 (18), 129.98 (17), 68.97 (39). N, 8.30; Cl, 10.66. C13H15ClN2OSe. Calcd., %:
Found, %: C, 54.01; H, 3.11; N, 10.28. C18H13N3O3Se
.
C, 47.36; H, 4.59; N, 8.50; Cl, 10.75.
Calcd., %: C, 54.28; H, 3.29; N, 10.55.
3ꢀCyanoꢀ4ꢀmethylꢀSeꢀ[(Nꢀphthalimido)glycyllquinꢀ
BIOLOGICAL SCREENING ASSAY
olineꢀ2ꢀselenol (XVIII), pale yellow crystals. 13C NMR
(DMSOꢀ
116.9, 122.6, 123.8, 124.4, 127.1, 130.9, 131.6, 133.5,
145.8, 150.9, 153.8, 158.6, 166.4 (C N, 10 C=C,
C=N, 2 C=O); MS of compound (XVIII) exhibited
molecular ion peak at m/z rel, %) 434.30 ([
+ 1]+,
d6, 75 MHz) δ16.6, (CH3), 53.4, (CH2), 114.2,
Antibacterial Activity
≡
Five bacterial species representing both Gramꢀ
positive and Gramꢀnegative strains were used to test
the antibacterial activities of the target compounds
(I
M
and other important fragments were observed at 290.00
(9), 222.9 (30), 247.99 (15), 168.07 (11), 78.05 (39).
(
II), (IXa), (IXb), (
X), (XV), (XVI), (XVIII), (XIX),
(XX) and (XXI) in vitro, in comparison to Chloramꢀ
Found, %: C, 57.88; H,2.88; N, 9.56. C21H13N3O3Se
Calcd., %: C, 58.08; H, 3.02; N, 9.68.
4,6ꢀDimethylꢀSeꢀ[( ꢀphthalimido)glycyl]quinolineꢀ
2ꢀselenol (XX), pale yellow crystals. 13C NMR
(DMSOꢀ 6, 75 MHz) 18.6, 21.4 (2CH3), 43.7,
.
phenicol as a reference drug using the standard agar
paper disc diffusion method [16]: S. aureus (Bꢀ54),
B. cereus (Bꢀ52), E. coli (Bꢀ53), S. marcescens (Bꢀ55),
and P. aeruginosa (Bꢀ73). Cell suspensions of bacterial
stains were prepared from 48 h old cultures grown on
potato dextrose agar (PDA) or Sabouraud agar (SA)
media. One ml of the cell suspension was added to
Petri dishes of 9 cm in diameter, and then 15 ml of
nutrient agar was poured onto the plates. Plates were
shaken gently to homogenize the innoculum. Sterile
5 mm filter paper (Whatmann, UK) was saturated
with 10 mg ml–1 of the test compound, Chloramꢀ
phenicol solutions (200, 100, 50, 25, 15.5, 6 mg ml–1
concentrations) as reference drug or DMSO as negaꢀ
tive control. Impregnated discs were then dried for 1 h
and placed in the centre of each plate. The seeded
plates were incubated at 35 2°C for 24–48 h. The
radii of the inhibition zones in mm of triplicate sets
were measured and the results are given in Table 2.
N
d
δ
(CH2), 122.6, 122.0, 127.4, 129.0, 130.0, 132.1, 132.3,
135, 141.8, 146.0, 150.9, 153.8, 155.6, 166.5 (10 C=C,
C=N, 2 C=O); MS of compound (XX) exhibited
molecular ion peak at m/z
and other important fragments were observed at m/z
rel, %) 375.99 (5), 312.9 (16), 287.94 (11), 227.87
(Irel, %) 423.31 ([M
+ 1]+, 1)
(I
(54), 50.98 (100). Found, %: C, 59.35; H, 3.77;
N, 6.68. C21H16N2O3Se. Calcd., %: C, 59.58; H, 3.81;
N, 6.62.
Hydrazinolysis (general procedure). Compound
XV), (XVIII), (XX) (10 mmol) in ethanol (25 ml) was
(
refluxed with hydrazine hydrate (10 ml) for 1 h, and
the reaction mixture was concentrated to dryness. The
residue was heated at 40°C for 10 min with 2M HCl
(30 ml), allowed to stand at room temperature for
30 min and the precipitate of phthalohydrazide was
filtered off. The filtrate was concentrated and the resiꢀ
due was recrystallized from DMF–H2O to give pale
yellow crystals.
Antifungal Activity
Compounds (II), (IXa), (IXb), (
X), (XV), (XVI),
(XVIII)–(XX) and (XXI) were screened for their antiꢀ
fungal activity in vitro, in comparison to Clotrimazole as
a referencedrug using the standard agar paper disc difꢀ
fusion method against seven fungi: C. albicans (418),
G. candidum (226), T. rubrum (1804), F. oxysporum
(5119), S. brevicaulis (729), A. flavus (1276). A spore
suspension in sterile distilled water was prepared from
2–3 days old culture of the fungi growing on potato dexꢀ
trose agar (PDA) or Sabouraud agar (SA) media. The
final spore concentration was 56104 spores ml–1. About
15 ml of the growth medium was placed into sterile petri
dishes of 9 cm in diameter and incubated with 1 ml of the
3ꢀCyanoꢀSeꢀglycylꢀ4,6ꢀdimethylpyridineꢀ2ꢀselenol
hydrochloride (XVI). MS of compound (XVI) exhibꢀ
ited molecular ion peak at m/z (Irel, %) 302.00 ([M
– 2]+,
0.4) and other important fragments were observed at
m/z 163.06 (100), 148.07 (15), 135.09 (8), 114.98 (18),
78.97 (34). Found, %: C, 39.22; H, 3.88; N, 13.76; Cl,
11.44. C10H12ClN3OSe. Calcd., %: C, 39.43; H, 3.97;
N, 13.79; Cl, 11.64.
3ꢀCyanoꢀSeꢀglycylꢀ4ꢀmethylquinolineꢀ2ꢀselenol
hydrochloride (XIX). MS of compound (XIX) exhibꢀ
ited molecular ion peak at m/z (Irel, %) 340.70 ([M
]+,
spore suspension. Plates were shaken gently to 28
2°C
2%) and other important fragments were observed at
m/z 309.13 (2), 199.01 (44), 148.92 (95), 78.95 (86),
62.94 (100), 69.03 (27), 57.02 (38). Found, %:
for 7 days. The radii of the inhibition zones in mm of
triplicate sets were measured and the results had shown
in Table 2.
C, 45.66; H, 3.22; N, 12.02; Cl, 10.16. C13H12ClN3OSe
.
Calcd., %: C, 45.83; H, 3.55; N, 12.33; Cl, 10.41.
SeꢀGlycylꢀ4,6ꢀdimethylquinolineꢀ2ꢀselenol hydroꢀ
chloride (XXI). MS of compound (XXI) exhibited
ACKNOWLEDGMENTS
molecular ion peak at m/z
(Irel, %) 330.00 ([
M
+ 1]+,
This work was financial supported by Taif Univerꢀ
2) and other important fragments were observed at m/z sity, under the project number 1/431/823.
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 37
No. 3
2011

SYNTHESIS OF SELENIUMꢀCONTAINING AMINO ACID ANALOGUES
269
9. Caputa, R., Capone, S., Greca, M.D., Longobardo, L.,
and Pinto, G., Tetrahedron Lett., 2007, vol. 48,
p. 1425–1427.
REFERENCES
1. Mugesh, G., Du Mont, W.ꢀW., Sies, H., Chem. Rev.
,
2001, vol. 101, pp. 2125–2180.
10. AbdelꢀHafez, Sh.H., Eur. J. Med. Chem., 2008, vol. 43,
2. Gasparian, A.V., Yao, Y.J., Liu, J., Yemelyanov, A.Y.,
Lyakh, L.A., Slaga, J.T., and Budunova, I.V.,
Mol. Cancer Ther., 2002, vol. 1, p. 1079.
3. Fleming, J., Ghose, A., and Harrison, P.R., Nutr. Cancer
2001, vol. 40, p. 42.
4. Ghose, A., Fleming, J., ElꢀBayoumy, K., and Harriꢀ
son, P.R., Cancer Res., 2001, vol. 61, p. 7479.
5. Wu, W., Murakami, K., Koketsu, M., Yamada, Y., and
pp. 1971–1977.
11. AbdelꢀHafez, Sh.H. and Hussein, M.A., Arch. Pharm.
2008, vol. 341, pp. 240–246.
,
,
12. AbdelꢀHafez, Sh.H. and Russian, J., Bioorganic Chemisꢀ
try, 2010, vol. 36, pp. 370–376.
13. AbdelꢀHafez, Sh.H., Ahmed, R.A., AbdelꢀAzim, M.A.,
and Khairy, M.H., J. Chem. Res., 2007, vol. 10,
pp. 580–584.
Saiki, I., Anticancer Res., 1999, vol. 19, p. 5375.
6. Hu, C., Zhang, P., Li, H., Ji, Z., and Liu, B., Huaxue
Tongbao, 2002, vol. 65, p. 162; Chem. Abstr., 2002,
vol. 137, pp. 169–434.
7. Koketsu, M., Tanaka, K., Takenaka, Y., Kwong, C.D.,
and Ishihara, H., Eur. J. Pharm. Sci., 2002, vol. 15,
p. 307.
14. AbdelꢀHafez, Sh.H., AbdelꢀMohsen, Sh.A., and
ElꢀOssaily, Y.A., Phosphorus, Sulfur, Silicon Relat.
Elem., 2006, vol. 181, pp. 2297–2305.
15. Sheehan, J.C. and Frank, V.S., J. Am. Chem. Soc.
1949, vol. 71, p. 1856.
,
8. Kyoto Encyclopedia of Genes and Genomes, KEGG, 16. Perez, C., Paul, M., and Bazerque, P., Cta. Bio. Med.
Release 40.0, October 2006.
Exp., 1990, vol. 15, p. 113.
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 37
No. 3
2011