Synthesis and?antimicrobial activity of?new (E)-4-[piperidino (4'-methylpiperidino-, morpholino-) N-alkoxy]stilbenes

Article abstract of DOI:10.1016/j.ejmech.2005.11.010

The synthesis of twenty-one new (E)-4-[piperidino-(4`-methylpiperidino-, morpholino-)N-alkoxy] stilbenes is reported. The compounds were tested for antimicrobial activities against Gram-negative, Gram-positive bacteria, and fungi. In particular, compounds

Full text of DOI:10.1016/j.ejmech.2005.11.010

European Journal of Medicinal Chemistry 41 (2006) 519–525
http://france.elsevier.com/direct/ejmech
Short communication
Synthesis and antimicrobial activity of new (E)-4-[piperidino
(4’-methylpiperidino-, morpholino-) N-alkoxy]stilbenes
Elżbieta Wyrzykiewicz a,*, Monika Wendzonka a, Bogdan Kędzia b
a Faculty of Chemistry, Adam Mickiewicz University, Grunwaldzka 6, 60-780 Poznań, Poland
b Institute of Medicinal Plants, Libelta 27, 61-707 Poznań, Poland
Received 30 June 2005; received in revised form 16 November 2005; accepted 28 November 2005
Available online 03 March 2006
Abstract
The synthesis of twenty-one new (E)-4-[piperidino-(4`-methylpiperidino-, morpholino-)N-alkoxy] stilbenes is reported. The compounds were
tested for antimicrobial activities against Gram-negative, Gram-positive bacteria, and fungi. In particular, compounds 3b, 3c, 3f, 3g, 3h, 3k, 3l
showed good antibacterial activity against Staphylococcus aureus and 3h, 3k, 3m, 3n also against Bacillus subtilis, as well as 3h, 3n also against
Streptococcus faecalis.
© 2006 Elsevier SAS. All rights reserved.
Keywords: (E)-stilbenes; Piperidines; Morpholines; Antimicrobial activity
1. Introduction
that on the other hand N-substituted derivatives of piperidine
and morpholine showed a rather significant antimicrobial activ-
ity [19–24].
(E)-stilbenes, hydroxylated at two to five positions, and
their oligomers, are natural compounds, found in various fa-
milies of plants. Hydroxylated stilbenes have been widely in-
vestigated because of their biological role in plant defense
against pathogens and for their pharmacological properties
[1–10]. Previously published results have shown that grape-
wines synthesize antimicrobial compounds in response to fun-
gal infection. These compounds, which are referred to as phy-
toalexins, belong to the family of stilbenes [11–14]. Taking
into regard the biological properties of (E)-stilbenols, the
synthesis and antimicrobial activity of (E)-acetoxystilbenes
[15] and (E)-azastilbenols and their derivatives have been stu-
died previously in our laboratory [16–18]. In view of the fact
that the substitution of acetyl group with hydroxy substituent
of (E)-stilbenols, as well as that the N-substititution of benzyl
and haloalkyl group with annular nitrogen atom of (E)-azastil-
benols influences the antimicrobial activity, it may be of inter-
est to direct further synthetic work towards new, yet unde-
scribed (E)-4-[piperidino-(4`-methylpiperidino-, morpholino-)
N-alkoxy] stilbenes 3a-3n, 5a-5g. It ought to be pointed out
The purpose of this investigation was to elucidate the influ-
ence of the presence of the piperidine, 4-methylpiperidine, and
morpholine ring, and the effect of the length of the alkyloxy
bridge between the (E)-stilbene skeletone and piperidine (4`-
methylpiperidine, morpholine) ring on the antimicrobial activ-
ity of 3a-3n and 5a-5g in order to acquire information on the
structural characteristic enhancing this activity. This paper pre-
sents the synthesis and characteristics of twenty-one new (E)-4-
(piperidino-N-alkoxy)stilbenes 3a-3g, (E)-4-(4`-methylpiperi-
dino-N-alkoxy) stilbenes 3h-3n, (E)-4-(morpholino-N-alkoxy)
stilbenes 5a-5g and the in vitro estimation of their antimicro-
bial activity against such microorganismus as Gram-positive
and Gram-negative bacteria, yeast, dermatophytes and moulds.
2. Chemistry
The synthetic approach to obtaining (E)-4-(piperidino-N-al-
koxy-)stilbenes 3a-3g, (E)-4-(4`-methylpiperidino-N-alkoxy-)
stilbenes 3h-3n, and (E)-4-(morpholino-N-alkoxy-) stilbenes
5a-5g followed the reactions shown in Scheme 1. We accom-
plished the synthesis of these compounds by the reaction of the
respective (E)-4-(bromoalkoxy) stilbenes 1a-1g with piperidine
* Corresponding author. Fax: + 48 61 86 58 008.
E-mail address: wyrzyk@amu.edu.pl (E. Wyrzykiewicz).
0223-5234/$ - see front matter © 2006 Elsevier SAS. All rights reserved.
doi:10.1016/j.ejmech.2005.11.010

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E. Wyrzykiewicz et al. / European Journal of Medicinal Chemistry 41 (2006) 519–525
2a (or 4`-methylpiperidine 2b, and morpholine 4) in DMF in
the presence of triethylamine at room temperature. By manip-
ulating the reaction time, it was found that after 10-25 hours
3a-3n and 5a-5g were the predominant products. (E)-4-(bro-
moalkoxy-)stilbenes 1a-1g were prepared according to a pre-
viously described procedure [25] by reacting equimolar
amounts of the respective (E)-stilbenol-4, [(E)-4`-nitrostilbe-
nol-4] and a proper dibromoalkane (1,2-dibromoethane; 1,3-di-
bromopropane; 1,4-dibromobutane; 1,5-dibromopentane) in
0.3 M NaOH solution of DMSO at room temperature. The
structures of all new compounds obtained were determined
by examining their UV/VIS, IR, 1H NMR and 13C NMR spec-
tra as well as on the basis of elemental analyses (Tables 1–5).
Assignments of the 1H NMR and 13C NMR resonances of
these compounds were deduced on the basis of the signal mul-
tiplicities, and by the concerted application of the two-dimen-
sional NMR technique HETCOR. The HETCOR results allow
unequivocal assignment of the 13C NMR spectra proposed on
the basis of chemical shift theory, additivity rules and by com-
paring the measured and calculated chemical shifts. (E) config-
uration in the stilbene part of the molecules of 3a-3n and 5a-5g
was determined on the basis of their UV/VIS and IR spectra. It
has been pointed out that in the UV/VIS spectra of 3a-3h λmax
are in the range 321-381 nm, as well as in the spectra of 5a-5g,
λmax in the range 321-379 nm (Table 1). According to literature
[26–28] (E)-stilbenes exhibit the values of λmax in the range
290-360 nm, and for (Z)-stilbenes the values of λmax are in
the range 260-280 nm. The infrared spectra of 3a-3h and 5a-
5g show a strong band in the range 964-970 cm−1 which, ac-
cording to literature [29,30], can be attributed to the out-of-
plane deformation vibration of the C-H bond of the (E)-ethy-
Scheme 1. Scheme of synthesis and structure of compounds 1a-1g, 2a-2b, 3a-
3n, 4 and 5a-5g.
Table 1
Chemical and physical data of compounds 3a-3n and 5a-5g
Compd.
Yield
[%]
M.p.
[oC]
TLC
[Rf]
IR (KBr)
[cm−1
UV/VIS
Anal
]
CH=CH
967
967
969
966
966
967
963
966
967
967
966
967
968
968
968
968
964
966
971
967
970
λmax (lg ε)
321 (4.47)
321 (4.46)
321 (4.47)
322 (4.44)
377 (4.40)
375 (4.41)
378 (4.35)
321 (4.46)
321 (4.39)
321 (4.37)
321 (4.43)
378 (4.51)
379 (4.20)
381 (4.41)
321 (4.45)
322 (4.46)
322 (4.47)
321 (4.42)
378 (4.42)
379 (4.41)
379 (4.42)
3a
3b
3c
3d
3e
3f
3g
3h
3i
78
78
76
72
42
59
56
25
13
21
27
65
40
42
58
56
75
49
55
38
56
80-2
0.57a
0.32a
0.24a
0.21a
0.30a
0.24a
0.22a
0.71b
0.67b
0.68b
0.69b
0.51b
0.50b
0.43b
0.74a
0.74a
0.75a
0.76a
0.77a
0.77a
0.76a
(C21H25NO) C, H, N
(C22H27NO) C, H, N
(C23H29NO) C, H, N
(C24H31NO) C, H, N
(C22H26N2O3) C, H, N
(C23H28N2O3) C, H, N
(C24H30N2O3) C, H, N
(C22H27NO) C, H, N
(C23H29NO) C, H, N
(C24H31NO) C, H, N
(C25H33NO) C, H, N
(C23H28N2O3) C, H, N
(C24H30N2O3) C, H, N
(C25H32N2O3) C, H, N
(C20H23NO2) C, H, N
(C21H25NO2) C, H, N
(C22H27NO2) C, H, N
(C23H29NO2) C, H, N
(C21H24N2O4) C, H, N
(C22H26N2O4) C, H, N
(C23H28N2O4) C, H, N
108-9
87-90
82-3
50-2
75-8
83-6
73-4
73-5
75-7
3j
3k
3l
82-3
86-8
3m
3n
5a
5b
5c
5d
5e
5f
78-80
79-80
108-110
100-1
59-61
74-8
45-8
85-7
69-71
5g
a
CH3OH: CHCl3 (3:1).
CH3OH: CHCl3 (1:5).
b

E. Wyrzykiewicz et al. / European Journal of Medicinal Chemistry 41 (2006) 519–525
521
Table 2
1H NMR data of compounds 3a-3n and 5a-5g
Compd t1
t2
t3
t4
k1
k2
k3
k4
k5
q1
q2
d
Ar, m
3a
3h
5a
3b
3e
3i
4.13
2.79
2.79
2.81
2.10
2.45
2.53
2.47
2.47
2.49
2.39
2.39
2.42
2.40
2.42
2.48
2.38
2.45
2.34
2.32
2.43
2.47
2.52
2.96
2.59
2.47
2.53
2.96
2.93
2.53
2.53
2.42
2.42
2.96
2.91
2.49
2.50
2.29
2.90
2.90
2.91
2.35
2.35
–
–
3.74
–
–
–
–
3.72
3.76
–
–
–
–
3.76
3.75
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
1.61
–
–
1.60
1.60
–
–
–
–
1.62
1.61
–
–
–
1.45
–
–
1.45
1.44
–
–
–
–
1.44
1.46
–
–
–
–
1.64
–
–
–
1.66
1.61
–
–
–
–
1.29
–
–
–
1.29
1.25
–
–
–
–
0.92
–
–
–
0.93
0.95
–
–
–
6.87–7.50
6.87–7.49
6.87–7.50
6.86–7.49
6.94–8.20
6.86–7.48
6.90–8.20
6.86–7.49
6.90–8.20
6.86–7.50
6.83–8.21
6.85–7.49
6.89–8.20
6.86–7.50
6.84–8.29
6.47–7.50
6.68–8.50
6.85–7.72
6.88–8.21
6.80–7.49
6.89–8.20
4.12
4.13
4.00
4.03
4.00
4.00
4.00
4.06
3.99
4.04
3.98
4.00
4.00
4.02
3.97
4.03
3.96
3.98
3.95
3.99
2.00
2.04
2.00
1.97
1.98
1.99
2.00
2.00
1.97
1.94
1.96
1.99
1.90
1.87
1.90
1.88
1.80
1.84
3l
5b
5e
3c
3f
–
1.88
1.87
1.77
1.78
1.83
1.82
1.77
1.79
1.80
1.84
1.80
1.84
–
–
–
3j
1.65
1.66
–
–
–
1.32
1.25
–
–
–
0.93
0.92
–
–
–
3m
5c
5f
3d
3g
3k
3n
5d
5g
–
–
1.46
1.45
1.46
1.46
1.52
1.54
1.57
1.56
1.28
1.22
–
1.43
1.43
–
–
–
–
–
–
1.59
1.59
–
1.28
1.30
–
0.91
0.92
–
–
3.71
3.73
–
–
–
–
–
Table 3
13C NMR data of 3a-3g
Carbon atom
3a
Compd
3b
3c
3d
3e
3f
3g
C-1
137.56
137.58
126.40
128.52
127.07
126.13
127.57
129.91
128.14
114.67
158.66
66.62
56.01
26.92
–
137.60
127.00
128.53
127.00
126.14
127.59
129.94
128.20
114.70
158.66
66.06
56.00
27.20
23.00
–
137.70
127.47
128.62
127.15
126.23
127.68
129.95
128.19
114.89
158.87
67.88
59.40
26.66
24.18
29.17
54.63
25.93
24.44
144.29
144.36
128.39
124.11
146.41
123.95
133.00
128.80
126.46
114.89
159.80
67.87
58.90
27.30
23.28
–
144.13
128.28
123.98
146.13
123.98
132.74
128.84
126.34
114.68
159.35
67.78
57.00
28.66
23.55
28.60
52.87
23.62
23.55
C-2,6
C-3,5
C-4
C-α
C-α’
127.09
128.53
127.58
126.15
127.70
130.08
128.13
114.76
158.47
66.09
57.96
–
128.36
124.08
146.37
123.93
132.93
128.81
126.42
114.87
159.25
68.80
55.73
26.50
–
C-1’
C-2’,6’
C-3’,5’
C-4’
C-I
C-II
C-III
C-IV
C-V
C-VI,X
C-VII,IX
C-VIII
–
–
–
–
55.12
26.04
24.28
54.70
26.06
24.52
54.58
25.91
24.46
54.45
25.60
24.20
54.49
25.76
24.30
lene bridge of the stilbene skeletone (Table 1). In the 1H NMR
spectra of 3a-3n and 5a-5g there are two triplets of O-CH2 (t1)
and N-CH2 (t2) protons of N-alkoxy chain linking (E)-stilbene
and piperidine (4-methylpiperidine, morpholine) rings. The va-
lues of the chemical shifts of the signals of these protons were
established in the range 3.95-4.06 δ and 2.39-2.81 δ, respec-
show two quintets (k4 and k5) of protons of methylene groups
of piperidine ring (Scheme 2, Table 2). The values of the che-
mical shifts of the signals of these protons fall in the range
1.56-1.62 δ and 1.43-1.46 δ, respectively. The presence of
1
these signals in the H NMR spectra of 3a-3g indicates the
occurrence of the piperidine ring in the molecules of these
1
1
tively (Scheme 2, Table 2). The H NMR spectra of 3a-3g
compounds. The H NMR spectra of 3h-3n show a dublet of

522
E. Wyrzykiewicz et al. / European Journal of Medicinal Chemistry 41 (2006) 519–525
Table 4
13C NMR data of 3h-3n
Carbon atom
3 h
Compd
3i
3j
3k
3l
3m
3n
C-1
137.58
137.47
127.02
128.47
127.52
126.07
128.64
129.84
128.08
114.59
158.52
66.43
55.58
26.85
–
137.51
127.03
128.49
127.55
126.09
127.35
129.84
128.11
114.57
158.57
67.71
58.93
27.41
23.45
–
137.61
127.11
128.58
127.63
126.17
128.58
129.89
128.20
114.60
158.76
67.79
58.97
26.74
24.16
29.14
54.02
34.22
30.76
21.87
144.23
128.36
124.11
146.34
129.81
132.82
129.03
128.77
115.06
159.19
68.81
55.54
26.74
–
144.27
128.35
124.08
146.27
123.84
132.91
130.84
128.74
114.78
159.68
67.71
58.54
27.29
23.47
–
144.28
128.35
124.08
146.27
123.82
132.92
128.65
126.40
114.77
159.74
67.86
59.03
26.24
24.15
29.10
54.10
34.32
30.81
21.89
C-2,6
C-3,5
C-4
C-α
C-α’
127.15
128.59
127.64
126.19
127.82
130.09
128.14
114.89
158.47
66.16
57.49
–
C-1’
C-2’,6’
C-3’,5’
C-4’
C-I
C-II
C-III
C-IV
C-V
C-VI,X
C-VII,IX
C-VIII
C-XI
–
–
–
–
54.48
34.19
30.52
21.86
54.09
34.19
30.79
21.89
54.90
34.13
30.79
21.87
54.07
34.17
30.78
21.89
53.93
34.29
30.71
21.83
Table 5
13C NMR data of 5a-5g
Carbon atom
5a
Compd
5b
5c
5d
5e
5f
5g
C-1
137.64
137.53
126.49
128.53
127.11
126.14
127.59
130.01
128.11
114.64
158.57
67.02
55.58
26.56
–
137.52
126.45
128.53
127.10
126.13
127.59
129.96
128.11
114.59
158.55
67.66
58.59
27.23
23.03
–
137.46
126.32
128.48
127.03
126.04
127.54
129.80
128.06
114.51
158.57
67.74
58.94
26.31
24.02
29.18
53.75
66.92
144.27
128.37
124.00
146.40
124.09
132.90
128.89
128.37
114.87
159.70
68.81
55.41
26.34
–
144.13
128.27
124.01
146.18
123.85
132.77
128.69
126.34
114.71
159.47
67.66
58.51
27.13
22.95
–
144.30
128.33
124.10
146.40
123.96
132.94
128.80
126.44
114.84
159.78
67.86
58.88
26.18
23.91
29.04
53.72
66.89
C-2,6
C-3,5
C-4
C-α
C-α’
127.25
128.66
127.72
126.27
127.27
130.38
128.16
114.84
158.47
66.69
57.42
–
C-1’
C-2’,6’
C-3’,5’
C-4’
C-I
C-II
C-III
C-IV
C-V
C-VI,X
C-VII,IX
–
–
–
–
54.10
65.94
53.80
66.19
53.64
66.81
53.70
66.92
53.58
66.73
groups of morpholine ring. These signals indicate the occur-
rence of the morpholine ring in the investigated molecules
(Scheme 2, Table 2).
The presence of piperidine (4-methylpiperidine, morpho-
line) ring in the molecules of 3a-3n and 5a-5g is also indicated
in the 13C NMR spectra of these compounds (carbons VI, X;
VII, IX and VIII - Tables 3–5).
3. Biology
Scheme 2. The numbering of protons of N-alkoxypiperidine, N-alkoxy-4-
methylpiperidine and N-alkoxymorpholine groups of 3a-3n; 5a-5g.
New (E)-4-[piperidino-]N-alkoxystilbenes 3a-3g, (E)-4-[4`-
methylpiperidino-]N-alkoxystilbenes 3h-3n and (E)-4-[mor-
pholino-]N-alkoxystilbenes 5a-5g were tested in vitro in order
to evaluate their antimicrobial effect. The potential antimicro-
bial activity of compounds 3a-3n and 5a-5g was estimated in
vitro by determining the MIC against a wide spectrum of mi-
croorganism: Gram-positive cocci (Staphylococcus aureous
protons of a methyl group in the range 0.91-0.95 δ. The pre-
sence of this signal in the 1H NMR spectra of 3h-3n proves the
occurrence of the 4-methylpiperidine ring in the molecules of
1
these compounds. The H NMR spectra of 5a-5g in the range
of 3.71-3.75 δ show a triplet of proton signals of O-CH2

E. Wyrzykiewicz et al. / European Journal of Medicinal Chemistry 41 (2006) 519–525
523
Table 6
Antimicrobial activity of 3a-3n and 5a-5g
Compd
Minimal inhibitory concentration (MIC) μg/cm3 *
SF BS EC CA MG AF
100 100 100
SA
10
5
KP
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
PA
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
3a
3b
3c
3d
3e
3f
3g
3h
3i
50
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
50
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
5.0
–
100
100
50
–
5
100 100
–
–
–
–
100 100 100
100 100 100
7.5
10
7.5
–
100 100
100 100
7.5
–
–
100
100 100
100 10
7.5
–
–
–
–
–
–
–
5.0
–
–
–
50
50
50
50
10
100
10
50
–
5
–
–
5
50
50
50
50
–
100
–
–
–
–
–
–
3j
3k
3l
–
7.5
7.5
10
10
–
3m
3n
5a
5b
5c
5d
5e
5f
5g
A
10
–
–
–
–
–
–
–
5.0
–
Scheme 3. The numbering of carbons of (E)-stilbene, N-alkoxypiperidine, N-
alkoxy-4-methylpiperidine and N-alkoxymorpholine groups of 3a-3n; 5a-5g.
–
–
100
100
100
100
100
5.0
–
50
50
50
50
50
–
209P FDA, Streptococcus faecalis ATCC 8040), aerobic bacilli
(Bacillus subtilis ATCC 1633), Gram-negative rods (Escheri-
chia coli PZH 026 B6, Klebsiella pneumoniae 231, Pseudomo-
nas aeruginosa SR1), yeasts (Candida albicans PCM 1409
PZH) dermatophytes (Microsporum Gypseum K1), moulds (As-
pergillus fumigatus C1) (Scheme 3).
–
–
–
50.0 50.0
B
–
–
0.5
10.0 1.0
*
SA: Staphylococcus aureus 209P FDA; CA: Candida albicans PCM 1409
PZH; SF: Streptococcus faecalis ATCC 8040; MG: Microsporum gypseum K1;
BS: Bacillus subtilis ATCC 1633; AF: Aspergillus fumigatus C1; EC: Escher-
ichia coli PZH 026 B6; A: chloroamphenicole; KP: Klebsiella pneumoniae
231; B: amphoterricin B; PA- Pseudomonas aeruginosa SP1; – Not tested be-
cause MIC value is higher than 100 μg/cm3.
4. Results
Table 6 lists the antimicrobial susceptibility results against
Gram-positive cocci, aerobic bacilli, Gram-negative rods, yeast,
dermatophytes and moulds. (E)-4-[piperidino-N-ethoxy-]stil-
bene 3a, (E)-4-[piperidino-N-propioxy-]stilbene 3b, (E)-4-[pi-
peridino-N-butoxy-]stilbene 3c, (E)-4-[piperidino-N-butoxy-]
4`-nitrostilbene 3f, (E)-4-[piperidino-N-pentoxy-]4`-nitrostil-
bene 3g, (E)-4-[4`-methylpiperidino-N-ethoxy-]stilbene 3h,
(E)-4-[4`-methylpiperidino-N-pentoxy-]stilbene 3k, (E)-4-[4`-
methylpiperidino-N-propioxy-]4`-nitrostilbene 3l, (E)-4-[4`-
methylpiperidino-N-butoxy-]4`-nitrostilbene 3m and (E)-4-[4`-
methylpiperidino-N-pentoxy-]4`-nitrostilbene 3n tested in this
study exhibited considerable antimicrobial activity against
Gram-positive cocci Staphylococcus aureus. (E)-4-[4`-methylpi-
peridino-N-ethoxy-]stilbene 3h, (E)-4-[4`-methylpiperidino-N-
pentoxy-]4`-nitrostilbene 3n exhibited also a high activity
against Streptococcus feacalis and aerobic bacilli- Bacillus sub-
tilis. (E)-4-[4`-methylpiperidino-N-pentoxy-]stilbene 3k and
dowed only with medium antimicrobial activity against Gram-
positive cocci- Staphylococcus aureus and moulds- Aspergillus
fumigatus. All the compounds tested in this study displayed not
significant effect against the Gram-negative rods Klebsiella
pneumoniae and Pseudomonas aeruginosa, in general, MIC >
100g/cm3.
The newly synthesised compounds (E)-[4`-metylpiperidino-
N-pentoxy-]stilbene 3k and (E)-4-[4`-methylpiperidino-N-bu-
toxy-]stilbene 3m showed good antimicrobial properties
against moulds- Aspergillus fumigatus. The compounds 3a,
3b, 3c, 3d, 3g, 3h, 3i, 3j, 3l and 3n as well as 5a-5g showed
a medium activity against Aspergillus fumigatus. Additionally,
a medium activity against yeast- Candida albicans was exhib-
ited by compounds 3a, 3 h, 3i, 3j, 3k and 3m. It is noteworthy
that 3a displayed a wide spectrum of antimicrobial activity
against 6 strains (SA, SF, BS, EC, CA, CF – Table 6) as well
as 3h, 3k, and 3m against 5 strains (SA, SF, BS, EC, AF-
Table 6).
(E)-4-[4`-methylpiperidino-N-butoxy-]4`-nitrostilbene
3m
showed considerable antibacterial activity agaist Bacilus subti-
lis. Compounds 3d, 3e, were endowed with a medium activity
against cocci Staphylococcus aureous, Streptococcus faecalis as
well as Bacillus subtilis. A medium activity against, Streptococ-
cus faecalis and Bacillus subtilis was exhibited also by 3a, 3e,
3f, 3g and 3l. Coumpound 3a was also endowed with a medium
activity against Gram-negative rods- Escherichia coli. (E)-4-
[morpholino-N-butoxy-]stilbene 5c, (E)-4-[morpholino-N-pen-
toxy-]stilbene 5d, (E)-4-[morpholino-N-propioxy-]4`-nitrostil-
bene 5e, (E)-4-[morpholino-N-butoxy-]4`-nitrostilbene 5f and
(E)-4-[morpholino-N-pentoxy-]4`-nitrostilbene 5g were en-
5. Discussion
This work presents a novel class of potent, wide-spectrum
antimicrobial compounds. The results are worth noting because
in recent years increasing rates of antimicrobial resistance
among community and nosocomial pathogenes has severely
limited the therapeutic options for treating infections caused
by such organisms. From among the compounds tested 3h,
3k and 3m proved to be the most effective.

524
E. Wyrzykiewicz et al. / European Journal of Medicinal Chemistry 41 (2006) 519–525
As regards the structure-activity relationship of the substi-
cording to literature. Piperidine, 4-methylpiperidine and mor-
pholine were purchased from Aldrich.
General procedure for the synthesis of compounds 3a-3n
and 5a-5g.
To a solution of the corresponding (E)-4-bromoalkoxystil-
bene 1a-1g (1 mmol) in DMF (70 ml) triethylamine (8 mmol)
and piperidine (4`-methylpiperidine, or morpholine) (1 mmol)
were added on constant stirring. After stirring for 10-25 h (i.e.
3a, 3b, 5a, 5b – 25 h; 3c,3f – 24 h; 3g, 5e, 5f, 5g – 21 h, 3d,
3i, 3e, 5c, 5d – 18 h; 3h, 3k – 15 h; 3m, 3j – 11 h; 3h, 3l –
10 h) at room temperature, distilled water (60 ml) was added to
the reaction mixture. The precipitated solids of 3a-3n and 5a-
5g were then filtered off, dried and recrystallized from DMF:
H2O (3:2).
tuted derivatives of (E)-stilbenol-4 and (E)-4`-nitrostilbenol-4,
the introduction of 4-alkoxy-N-piperidine group and 4-alkoxy-
N-4`-methylpiperidine group as substitutent in the para posi-
tion of the (E)-stilbene [(E)-4`-nitrostilbene] moiety noticeably
enhanced the antibacterial activity displayed by the unsubsti-
tuted stilbenols [15]. The introduction of 4-alkoxy-N-morpho-
line group as substituent in the para position of the (E)-stilbene
[(E)-4`-nitrostilbene] moiety did not noticeably enhance the
antimicrobial activity displayed by the unsubstituted stilbenols
[15]. (E)-4-(piperidino-N-propioxy-]stilbene 3b and (E)-[piper-
idino-N-butoxy-]stilbene 3c displayed the antibacterial activity
against Staphylococcus aureus comparative to that of the refer-
ence drug chloramphenicol (Table 6). (E)-4-[4`-methylpiperidi-
no-N-pentoxy-]stilbene 3k and (E)-4-[4`-methylpiperidino-N-
ethoxy-]stilbene 3h displayed the same antibacterial activity
against Bacillus subtilis similar to that of the reference drug
chloramphenicol (Table 6).
6.2. Microbiology
6.2.2. Determination of minimum inhibitory concentration
(MIC)
In conclusion, taking into account that 3a, 3h, 3k and 3m
are wide spectrum antimicrobial substances, it can be con-
cluded that they are promising new agents for treatment of mi-
crobial infections.
The microorganisms used were supplied by – National In-
stitute of Hygiene in Warsaw (Staphylococcus aureus 209P
FDA, Escherichia coli PZH 026 B6, Candida albicans PCM
1409 PZH), American type Culture Collection (Streptococcus
faecalis ATCC 8040, Bacillus subtilis ATCC 1633), Depart-
ment of Microbiology, Poznań University of Medical Sciences
(Klebsiella pneumoniae 231, Pseudomonas aeruginosa SP1),
Department of Medical Mycology, Poznań University of Med-
ical Sciences (Aspergillus fumigatus C1, Microsporum gyp-
seum K1).
6. Experimental
6.1. Chemistry
The purity of all described compounds was checked by m.
p.’s TLC and elemental analysis. Melting points (uncorrected)
were determined on Böetius microscope hot stage. Rf values
refer to TLC silica gel F254 TLC plates (Merck) developed with
CHCl3 : MeOH (5:1) and observed under UV light (λ=254 and
366 nm). UV/VIS spectra were recorded with a Specord UV/
VIS spectrophotometer in CHCl3. IR spectra were recorded
with a FTIR Bruker IFS-113 V spectrophotometer in KBr pel-
lets. The 1H NMR (300 MHz) and 13C NMR (75 MHz) spectra
were recorded on a Varian Mercury Spectrometer operating at
300.07 MHz (proton) or 75.46 mHz (carbon). The data were
obtained from CDCl3 solutions. The chemical shifts were re-
ferenced to tetramethylsilane. Chemical shifts are given in the
δ scale (ppm) and coupling constants in Hz. 1H NMR (300.07)
spectra were recorded with spectral width 9 KHz, acquisition
time 2.0 s, pulse width 6 μs and double precision acquisition
time. 13C NMR (75.460 MHz) spectra were recorded with
spectral width 18.76 KHz, acquisition time 1.0 s, recycle delay
The compounds were dissolved using DMSO (Serva); to
form solutions of the concentration 1000 μg/cm3. A series of
dilutions with concentrations ranging form 10 to 1000 μg/cm3
were prepared for each compound.
The MIC values of the compounds were determined, with
reference to standard microorganisms, by introducing 1 cm3 of
the corresponding solutions at various concentrations into a
series of tubes (each 12×100 mm), 0.1 cm3 of a standarized
1:1000 diluted suspension of a microorganism was added.
The MIC values were determined after 18 hours of incubation
at 37°C. Penassay Broth (Difco) was used as the test medium
for bacteria; in all assays both bacterial culture sterility and
standard bacterial growth were checked. Sabouraud dextrise
broth (Difco) was used as a test medium for fungi; MIC values
were determined after 3-7 days of incubation at 25°C. In all
assay both fungi culture sterility and standard fungi growth
were checked. The MIC values determined were compared
with those of the standards, chloramphenicol (the reference
bactericidal drug) and amphotericine B (the reference antifun-
gal drug). The results are listed in Table 6.
1
1.0 s and pulse width 15 μs. Heteronuclear 2D13C NMR – H
NMR chemical shift correlation experiments were carried out
using HETCOR spectra. The spectra were acquired with 2K
data points, 256 increments and spectral width 19.63 KHz for
1
13C and 4.97 KHz for H. Elemental analyses were performed
with a Vector Euro EA 3000 Analyzer.
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