Synthesis and antimicrobial activity of N-alkyl substituted p-methyl (E)-3- and 4-azachalconium bromides

Article abstract of DOI:10.3906/kim-0904-41

Twenty new N-alkyl substituted p-methyl (E) -3- and 4-azachalcones (1a-j, 2a-j) {3-[(1E)-3-(4-methylphenyl)- 3-oxoprop-1-en-1-yl]-1-alkyl (C _{5-12 , 14-15)} pyridinium bromides (1a-j) and 4-[(1E)-3-(4- methylphenyl)- 3-oxoprop-1-en-1-yl]-1-alkyl (C_{5-12 , 14-15)} pyridinium bromides (2a-j)} were synthesized and tested for antimicrobial activities against Staphylococcus aureus, Staphylococcus epidermidis, Bacillus subtilis, Enterococcus faecalis, Proteus vulgaris, and Escherichia coli. They showed good antimicrobial activity especially against the gram-positive bacteria tested with minimal inhibitory concentration (MIC) values less than 4.7 μg/mL in most cases. The optimum length of the alkyl chain for better and broader activity is situated in the range of 8-12 carbon atoms in the series of compounds 1a-j, 2a-j. The non-alkylated compounds 1-2 were not effective as were the ones alkylated with 14 or 15 C alkyl groups (1i, 1j, 2i, 2j). N-Alkyl derivatives of p-methyl (E) -3-azachalcone (1a-h) showed better activity in comparison to those of p-methyl (E)-4- azachalcone (2a-h). The antimicrobial activity increased as the length of the alkyl substitution increased from 5 to 12 carbons. TUeBITAK.

Full text of DOI:10.3906/kim-0904-41

Turk J Chem
34 (2010) , 219 – 228.
¨
˙
c
ꢀ TUBITAK
doi:10.3906/kim-0904-41
Synthesis and antimicrobial activity of N-alkyl
substituted p-methyl (E)-3- and 4-azachalconium
bromides
Nurettin YAYLI1,∗, Gu¨lbin MISIR1, Nuran YAYLI1, Ahmet YAS¸AR1,
2
2
˙
˙
˘
Emine DEMIR , Zihni DEMIRBAG
1Department of Chemistry, Faculty of Arts and Sciences, Karadeniz Technical University,
61080, Trabzon-TURKEY
e-mail: yayli@ktu.edu.tr
2Department of Biology, Faculty of Arts and Sciences, Karadeniz Technical University,
61080, Trabzon-TURKEY
Received 28.04.2009
Twenty new N-alkyl substituted p-methyl (E)-3- and 4-azachalcones (1a-j, 2a-j) {3-[(1E)-3-(4-methylp-
henyl)-3-oxoprop-1-en-1-yl]-1-alkyl (C5−12
henyl)-3-oxoprop-1-en-1-yl]-1-alkyl (C5−12
,14−15) pyridinium bromides (1a-j) and 4-[(1E)-3-(4-methylp-
,
14−15) pyridinium bromides (2a-j)} were synthesized and tested
for antimicrobial activities against Staphylococcus aureus, Staphylococcus epidermidis, Bacillus subtilis, Ente-
rococcus faecalis, Proteus vulgaris, and Escherichia coli. They showed good antimicrobial activity especially
against the gram-positive bacteria tested with minimal inhibitory concentration (MIC) values less than 4.7
μg/mL in most cases. The optimum length of the alkyl chain for better and broader activity is situated in
the range of 8-12 carbon atoms in the series of compounds 1a-j, 2a-j. The non-alkylated compounds 1-2
were not effective as were the ones alkylated with 14 or 15 C alkyl groups (1i, 1j, 2i, 2j). N-Alkyl derivatives
of p-methyl (E)-3-azachalcone (1a-h) showed better activity in comparison to those of p-methyl (E)-4-
azachalcone (2a-h). The antimicrobial activity increased as the length of the alkyl substitution increased
from 5 to 12 carbons.
Key Words: N-Alkyl p-Methyl-(E)-3-, 4-azachalconium bromides; antimicrobial activity.
Introduction
Chalcones are a group of natural compounds possessing a broad spectrum of biological activity.1,2 Chalcones are
reported to display antimicrobial, anticancer, antichinovirus, antipicornavirus, insecticidal, and bacteriostatic
∗Corresponding author
219

Synthesis and antimicrobial activity of N-alkyl substituted..., N. YAYLI, et al.,
activities,3−9 and also act as an antibiotic.10 The analogues of chalcones with an annular nitrogen atom in
the A or B phenyl rings are called azachalcones.3,4,11−18 Over the last 25 years, azachalcones and their N-
alkyl derivatives have been synthetically prepared by several investigators3,4,7−9 and shown to possess a wide
variety of biological activities, such as antituberculostatic, antimicrobial, anti-inflammatory, and antibacterial
potentials.3,4,13−15,19−24
In our previous work, nitro substituted (E)-3-, and 4-azachalcones, and their N-alkyl derivatives were
synthesized and showed very good antimicrobial activities especially against gram-positive bacteria.13−16 In view
of the continuing interest in new antimicrobial agents, we synthesized other N-alkyl(C5−12,14,15) substituted
p-methyl-(E)-3- and 4-azachalconium bromides in this respect. We aimed to determine the influence of the
length of the carbon chain in the N-alkyl substituent and position of N in the pyridyl ring. The attempts to
N-alkylate the p-methyl (E)-2-azachalcone was unsuccessful probably because of the steric effects.
The present work deals with the synthesis, spectral characterization, and antimicrobial activity of 20 new
N-alkyl substituted p-methyl (E)-3- and 4-azachalcones (1a-j, 2a-j) (Scheme).
Experimental
General
NMR spectra were recorded on a Varian Mercury NMR at 200 MHz in CDCl3 . The mass spectral analyses were
carried out on a Micromass Quattro LC-MS/MS spectrometer. The elemental analyses were performed on a
Leco CHNS 932 instrument. Infrared spectra were obtained with a Perkin-Elmer 1600 FT-IR (4000-400 cm−1
)
spectrophotometer. Melting points were determined using a Thermo-var apparatus fitted with a microscope
and are uncorrected. UV-Vis spectral analyses were carried out on a Unicam UV2-100 spectrophotometer at
25 ◦ C. Thin-layer chromatography (TLC) was carried out on Merck precoated 60 Kieselgel F254 analytical
aluminum plates. Column chromatography studies were carried out on silica gel.
Materials and methods
p-Methylacetophenone and 3-/4-pyridine carboxaldehydes were purchased from Aldrich/Merck and used with-
out further purification. The solvents used (chloroform, n-hexane, ethanol, methanol, acetonitrile, and diethyl
ether) were either of analytical grade or bulk solvents distilled before use. The known compounds 1-2 were
prepared according to the literature.3,4,13−16
General procedure for synthesis of compounds 1a-j, 2a-j
p-Methyl (E)-3- or 4-azachalcones (0.02 mol each) and n-bromoalkanes (1-bromopentane, 1-bromohexane,
1-bromoheptane, 1-bromooctane, 1-bromononane, 1-bromodecane, 1-bromoundecane, 1-bromododecane, 1-
bromotetradecane, and 1-bromopentadecane (0.05 mol each) in acetonitrile (30 mL) were refluxed separately
for 6-16 h.4,16,17 The reactions were followed and monitored by TLC. After the reactions were completed, the
acetonitrile was removed using a rotary evaporator and the residues were separated by column chromatography
on silica gel (30 × 2 cm, ∼25 g each, Merck, 230-400 mesh) first with ethyl acetate (30 mL) and then with ethyl
220

Synthesis and antimicrobial activity of N-alkyl substituted..., N. YAYLI, et al.,
acetate-methanol (3:1, 20 mL and 3:2, 20 mL), methanol (30 mL), and finally methanol-water (4:1, 30 mL).
Fractions (5-10 mL each) were collected and monitored by analytical TLC. The desired dark red amorphous
solids (1a-j, 2a-j) were obtained from fractions 10-18 (yields are in Table 1).
3-[(1E)-3-(4-methylphenyl)-3-oxoprop-1-en-1-yl]-1-alkyl(C5−12
,
14−15 )pyridinium bromides,
1a-j
See the physico-chemical, and 1 H- and 13 C-NMR data of compounds 1a-j in Tables 1-3.
O
O
H
+
Y
X
Na2CO3
Y
X
O
1 X=N, Y=CH
2 X=CH, Y=N
RX, CH3CN, Reflux
Br
N
R1
Br
N
3
1''
R1
1''''
1
2
'
1
O
O
-R1
-R1
1a
:
:
:
:
:
:
:
:
:
:
C5H11
C6H13
C7H15
C8H17
C9H19
C10H21
C11H23
C12H25
C14H29
C15H31
2a
2b
2c
2d
2e
2f
:
C5H11
C6H13
C7H15
C8H17
C9H19
C10H21
C11H23
C12H25
C14H29
C15H31
1b
1c
1d
1e
1f
1g
1h
1i
2g
2h
2i
1j
2j
Scheme
221

Synthesis and antimicrobial activity of N-alkyl substituted..., N. YAYLI, et al.,
222

Synthesis and antimicrobial activity of N-alkyl substituted..., N. YAYLI, et al.,
223

Synthesis and antimicrobial activity of N-alkyl substituted..., N. YAYLI, et al.,
4-[(1E)-3-(4-methylphenyl)-3-oxoprop-1-en-1-yl]-1-alkyl(C5−12
,
14−15 )pyridinium bromides,
2a-j
See the physico-chemical, and 1 H- and 13 C-NMR data of compounds 2a-j in Tables 1, 2, and 4.
Antimicrobial activity and microbial strains
The compounds were tested individually against 6 microbial species, 4 gram-positive, and 2 gram-negative
bacteria. The bacterial strains, obtained from the American Type Culture Collection (ATCC), were Staphy-
lococcus aureus (ATCC 25923), Staphylococcus epidermidis (ATCC 12228), Bacillus subtilis (ATCC 6633),
Enterococcus faecalis (ATCC 29212), Proteus vulgaris (ATCC 13315), and Escherichia coli (ATCC 25922). All
the synthesized compounds were weighed and dissolved in methanol to prepare sample stock solutions of 300
μg/mL.
Table 3. 13 C-NMR (δC ppm) data of compounds 1a-j in CDCl3 .
CNo.
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1
2
187.88 188.40 188.04 188.24 188.0 188.07 188.22 188.18 187.96 187.90
135.74 136.15 135.87 136.16 135.81 136.04 136.13 136.08 135.91 135.87
133.78 134.89 134.42 134.41 134.39 134.32 134.43 134.36 133.90 133.86
132.90 134.23 134.78 134.10 133.86 133.98 134.10 134.03 132.44 133.01
129.12 129.57 129.32 129.43 129.40 129.58 129.45 129.47 129.77 129.27
129.54 129.75 129.69 129.67 129.60 129.96 129.69 129.63 132.44 129.61
145.50 145.01 144.70 144.91 144.66 144.84 144.93 144.87 145.33 145.50
132.93 130.14 130.27 130.10 130.09 130.38 130.05 130.05 129.38 130.08
150.82 144.32 144.53 144.33 144.45 144.58 144.32 144.53 145.33 145.11
145.50 143.92 144.17 144.06 144.07 144.00 144.80 143.97 144.50 144.18
126.60 128.74 128.30 128.35 128.31 128.25 128.37 128.28 127.24 126.71
145.50 143.79 143.86 143.88 143.85 143.75 143.88 143.80 145.33 143.97
3
1ꢀ
2ꢀ / 6ꢀ
3ꢀ / 5ꢀ
4ꢀ
1ꢀꢀ
2ꢀꢀ
4ꢀꢀ
5ꢀꢀ
6ꢀꢀ
1ꢀꢀꢀ
2ꢀꢀꢀ
(CH2)ꢀnꢀꢀ
61.37
31.41
28.49
21.61
61.98
32.18
22.50
31.27
31.27
61.95
31.91
22.29
25.81
28.54
31.29
61.95
32.02
22.43
28.93
28.93
31.54
61.97
31.91
22.37
25.87
28.89
29.11
31.53
61.98
32.75
22.57
26.03
29.04
29.15
29.39
61.99
32.13
22.66
26.11
29.13
29.29
29.38
29.54
31.86
14.13
21.80
61.97
32.06
22.62
26.06
29.08
29.27
29.54
31.83
61.79
31.90
22.68
26.12
29.09
29.36
29.67
61.51
31.75
22.53
25.99
28.98
29.20
29.50
-CHꢀ3ꢀꢀ
13.83
22.08
14.11
21.93
13.82
21.60
14.07
21.83
13.87
21.57
14.03
21.72
14.08
21.75
14.13
21.83
13.99
21.67
Ph-CH3
aAssignment based on APT and comparison with ACD NMR program.
224

Synthesis and antimicrobial activity of N-alkyl substituted..., N. YAYLI, et al.,
Table 4. 13 C-NMR (δC ppm) data of compounds 2a-j in CDCl3 .
C No.
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
1
187.99 187.80 187.84 187.81 187.79 187.88 187.74 187.81 188.10 187.88
135.91 135.96 135.78 137.76 135.57 135.79 135.71 135.76 136.08 135.86
133.10 132.93 132.99 132.90 133.22 133.24 132.82 132.91 133.19 133.00
133.94 133.74 133.79 133.73 133.74 133.95 133.67 133.76 134.05 133.84
129.32 129.31 129.18 129.19 129.31 129.36 129.08 129.18 129.45 129.24
129.70 129.66 129.54 129.49 129.66 129.80 129.42 129.52 129.78 129.58
145.23 145.01 145.03 145.01 145.01 145.40 144.91 145.03 145.27 145.08
150.97 150.76 150.83 150.75 150.76 151.11 150.67 150.78 151.04 150.83
2
3
1ꢀ
2ꢀ / 6ꢀ
3ꢀ / 5ꢀ
4ꢀ
1ꢀꢀ
2ꢀꢀ / 6ꢀꢀ 126.72 126.70 126.64 126.61 126.74 126.59 126.59 126.62 126.93 126.69
3ꢀꢀ / 5ꢀꢀ 145.23 144.87 144.89 144.96 144.84 145.16 144.87 144.93 145.09 144.77
1ꢀꢀꢀ
2ꢀꢀꢀ
(CH2)ꢀnꢀꢀ
61.54
31.46
22.07
28.01
61.30
31.56
22.08
25.47
30.85
61.40
31.67
22.27
25.83
28.49
31.26
61.37
31.63
22.31
25.86
28.77
31.40
61.36
31.64
22.33
25.86
28.89
29.05
31.48
31.54
61.79
31.88
22.65
26.12
29.06
29.21
29.33
29.42
31.80
14.12
21.85
61.74
31.53
22.32
25.81
28.80
28.95
29.06
29.20
61.40
31.64
22.43
25.91
28.88
29.09
29.15
29.29
29.34
13.90
21.59
61.67
31.93
22.69
26.17
29.17
29.37
29.66
29.66
61.50
31.73
22.51
25.98
28.97
29.18
29.48
29.48
-CHꢀ3ꢀꢀ
13.76
21.76
13.68
21.55
13.80
21.61
13.82
21.58
13.84
21.57
13.81
21.50
14.16
21.85
13.96
21.65
Ph-CH3
aAssignment based on APT and comparison with ACD NMR program.
Determination of the in vitro antimicrobial activity by the microwell dilution assay
The minimum inhibitory concentration (MIC) of all the test compounds was determined by microwell dilution
assay. The inocula of the bacterial strains were prepared from 12-h broth cultures, and suspensions were adjusted
to 0.5 McFarland standard turbidity. The compounds dissolved in methanol were first diluted to the highest
concentration (300 μg/mL) to be tested, and then serial 2-fold dilutions were made to obtain a concentration
range from 2.3 to 300 μg/mL in 1-mL sterile test tubes containing Mueller-Hinton broth (MHB). The MIC
values of the synthetic compounds against bacterial strains were determined on the basis of a microwell dilution
method.25−27 The 96-well plates were prepared by dispensing 100 μL of MHB containing the inoculum into
each well. One hundred microliters from the stock solutions of synthetic compounds prepared at the 300 μg/mL
concentration was added to the first wells. Then 100 μL from the serial dilutions was transferred into the 7
consecutive wells. The last well, containing 200 μL of MHB without the test compound and with the inoculum
on each strip, was used as a negative control. The final volume in each well was 200 μL. Ampicillin at a
concentration range of 300-0.12 μg/mL was prepared in MHB and used as a standard drug for positive control.
225

Synthesis and antimicrobial activity of N-alkyl substituted..., N. YAYLI, et al.,
The plate was covered with a sterile plate sealer. The contents of each well were incubated at 37 ◦ C for 24
h. Microbial growth in each medium was determined by reading the respective absorbance (Abs) at 600 nm
using the spectrophotometer (Molecular Devices, SpectraMax M2) and confirmed by plating 10-μL samples
from each well on Mueller-Hinton agar (MHA) medium. The compounds tested in this study were screened
twice against each organism. The results are shown in Table 5.
Results and discussion
The Scheme illustrates the synthetic approach chosen for the preparation of p-methyl (E)-3- and 4-azachalcones
(1a-j, 2a-j) [5-6, 12-23] by Claisen-Schmidt condensation13−16 of an appropriate p-methylacetophenone and
Table 5. Minimum inhibitory concentrations (MIC, μg/mL) of the compounds 1a-j, 2a-j based on dilution assay.
Comp. Stock conc.
Minimum inhibitory concentrations (MIC, μg/mL)
No.
1
(μg/mL)
300
300
300
300
300
300
300
300
300
300
300
300
300
300
300
300
300
300
300
300
300
300
300
Sa (G+) Se (G+) Bs (G+) Ef (G+) Pv (G-) Ec (G-)
-
-
-
-
-
-
-
-
-
2
-
-
-
1a
1b
1c
1d
1e
1f
9.4
< 2.3
< 4.7
< 4.7
< 4.7
9.4
-
-
-
-
9.4
37.5
9.4
9.4
75
-
< 4.7
< 4.7
9.4
< 4.7
< 4.7
9.4
37.5
37.5
37.5
9.4
9.4
-
37.5
< 4.7
9.4
37.5
37.5
< 4.7
< 4.7
< 4.7
-
< 4.7
< 4.7
< 4.7
-
< 4.7
< 4.7
< 4.7
-
< 4.7
< 4.7
-
18.75
1g
1h
1i
-
-
-
-
-
1j
-
-
-
-
-
-
2a
2b
2c
2d
2e
2f
75
75
300
37.5
37.5
9.4
150
37.5
18.75
< 4.7
< 4.7
9.4
75
-
18.75
18.75
< 4.7
< 4.7
< 4.7
< 4.7
-
37.5
18.75
< 4.7
< 4.7
< 4.7
< 4.7
< 4.7
-
18.75
18.75
9.4
< 4.7
9.4
< 4.7
-
-
-
18.75
< 4.7
9.4
9.4
18.75
2g
2h
2i
< 4.7
< 4.7
-
< 4.7
< 4.7
-
-
-
-
-
-
2j
-
-
-
-
-
-
Amp.
0.12
0.5
0.5
0.5
0.5
2.0
Sa: Staphylococcus aureus, Se: Staphylococcus epidermidis, Bs: Bacillus subtilis, Ef: Enterococcus faecalis, Pv: Proteus
vulgaris, Ec: Escherichia coli, Amp.: Ampicillin, (-): no activity.
226

Synthesis and antimicrobial activity of N-alkyl substituted..., N. YAYLI, et al.,
3- or 4-pyridinecarboxaldehydes with 2 equivalents of Na2 CO3 solution (EtOH, 95%), which yields the trans-
isomer of the corresponding α,β-unsaturated (J =15.5/15.6 Hz, respectively) compounds (1-2).3,4,11−18
N-Alkyl derivatives of p-methyl (E)-3- or 4-azachalcones were synthesized from the corresponding
azachalcones with n-bromoalkanes (1-bromopentane, 1-bromohexane, 1-bromoheptane, 1-bromooctane, 1-bro-
mononane, 1-bromodecane, 1-bromoundecane, 1-bromododecane, 1-bromotetradecane, and 1-bromopentadecane)
in acetonitrile solution by reflux.3,4,13−15 In the 1 H-NMR spectra of 1a-j, 2a-j, the characteristic -CH2 - signal
of N-alkyl groups was exhibited at δ 4.9-5.1 ppm (2H, t, J =6.2-7.4 Hz) (Table 2) due to pyridinium salt.4
N-Alkyl derivatives of azachalcones attract widespread interest because many of them have exhibited a
wide variety of biological activities.3,4,13−15,20−24 All the synthesized compounds (1a-j, 2a-j) were characterized
on the basis of spectral data analyses (1 H, 13 C, APT, 1 H-1 H COSY NMR, ACD-NMR, FT-IR, UV, LC-
MS/MS, and elemental analysis), whose results were in agreement with the proposed structures (Tables 1-4).
The LC mass spectra of 1a-j, 2a-j exhibited molecular ion peaks for [M(79 Br)]+ and [M(81 Br)]+ (Table 1)
and the base ion peaks were [M(79 Br)-79]+ and [M(81 Br)-81]+ with other fragment ions such as [M(79 Br)-R]+
and [M(81 Br)-R]+ . Based upon the above observations, the complete chemical shift assignments for 1a-j, 2a-j
were deduced to be 3-[(1E)-3-(4-methylphenyl)-3-oxoprop-1-en-1-yl]-1-alkyl (C5−12,14,15) pyridinium bromides
(1a-j) and 4-[(1E)-3-(4-methylphenyl)-3-oxoprop-1-en-1-yl]-1-alkyl (C5−12,14,15) pyridinium bromides (2a-j).
The antimicrobial activity of compounds 1, 2, 1a-j, 2a-j was determined against S. aureus, S. epider-
midis, B. subtilis, E. faecalis, P. vulgaris, and E. coli (Table 5). The activities of the synthesized compounds
were investigated by the dilution method.25−27 Some compounds showed slight to pronounced antimicrobial
activity against gram-positive and gram-negative bacteria. The non-alkylated compounds 1-2 were not effec-
tive as were the ones alkylated with 14 or 15 C alkyl groups (1i, 1j, 2i, 2 j). The derivatives with 8-12 alkyl
groups were active against the bacteria, and their activity was more pronounced against the gram-positive
bacteria compared to the gram-negative ones. Nowakowska et al. have previously shown a similar trend in
activity with respect to the bacterial type with 3ꢀ -hydroxy-substituted and unsubstituted N-alkyl derivatives of
4-azachalcones.4 N-Alkyl derivatives of 3-azachalcone (1a-h) showed better activity in comparison to those of 4-
azachalcone (2a-h). Compound 1h, C12 alkylated 3-azachalcone, was interestingly inactive against E. faecalis,
while its 4-azachalcone analogue (2h) showed inhibitory activity at the lowest test concentration. Similarly,
compound 2h was inactive against S. aureus, while its 3-azachalcone analogue (1h) showed inhibitory activity
at the lowest test concentration. The solvent control methanol showed no inhibition effect on all test microor-
ganisms. The antimicrobial activity increased as the length of the alkyl substitution increased from 5 to 10, and
similar findings have been observed by Nowakowska et al. for N-bromoalkyl derivatives of 4-azachalcones.3,4
Acknowledgements
This study was supported by grants from Karadeniz Technical University and the Scientific and Technological
¨
˙
Research Council of Turkey (TUBITAK).
227

Synthesis and antimicrobial activity of N-alkyl substituted..., N. YAYLI, et al.,
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