Synthesis and antimicrobial activity of methoxy azachalcones and N-Alkyl substituted methoxy azachalconium bromides

Article abstract of DOI:10.3906/kim-1007-790

In this study, 18 new N-octyl, N-decyl, and N-dodecyl substituted o-, m-, and p-methoxy (E)-3-and 4-azachalcones, {4-or 3-[(1E)-3-(4-, 3-, or 2-methoxyphenyl)-3-oxoprop-1-en-1-yl]-1-alkyl (C_8,10,12) pyridinium bromides} (1a-6a, 1b-1b, and 1c-6c), and 4 new o-, and m-methoxy (E)-3-and 4-azachalcones (2, 3, 5, and 6) were synthesized and tested for antimicrobial activities against Escherichia coli, Yersinia pseudotuberculosis, Enterobacter aerogenes, Pseudomonas aeruginosa, Staphylococcus aureus, Enterococcus faecalis, Bacillus cereus, and Candida albicans. N-Alkyl substituted azachalconium bromides showed good antimicrobial activity against all tested microorganisms with minimal inhibitory concentration (MIC) values in the range of 0.42-58.7 μg/mL in most cases. Nonalkylated compounds 1-9 were not as effective as the alkylated compounds. They showed only antimicrobial activity against gram-positive bacteria and yeast in the range of 1.77-123.7 μg/mL. The optimum length of the alkyl chain for better activity is situated with 12 carbon atoms in the series of compounds 1a-c, 2a-c, 3a-c, 4a-c, 5a-c, and 6a-c. N-Alkyl derivatives of m-methoxy (E)-3-azachalcone (4a-c, 5a-c, and 6a-c) showed better activity in comparison to those of oand p-methoxy (E)-4-azachalcones (1a-c, 2a-c, and 3a-c). TUeBITAK.

Full text of DOI:10.3906/kim-1007-790

Turk J Chem
35 (2011) , 441 – 454.
¨
˙
c
ꢀ TUBITAK
doi:10.3906/kim-1007-790
Synthesis and antimicrobial activity of methoxy
azachalcones and N-alkyl substituted methoxy
azachalconium bromides
1
1
1
˙
˙
1,∗
Canan ALBAY , Nuran KAHRIMAN , Nagihan YILMAZ ISKENDER ,
2
˘
S¸engu¨l ALPAY KARAOGLU , Nurettin YAYLI
1Department of Chemistry, Faculty of Sciences, Karadeniz Technical University,
61080, Trabzon-TURKEY
e-mail: yayli@ktu.edu.tr
2Department of Biology, Faculty of Arts and Sciences, Rize University, 53100, Rize-TURKEY
Received: 12.07.2010
In this study, 18 new N-octyl, N-decyl, and N-dodecyl substituted o-, m-, and p-methoxy (E)-3-
and 4-azachalcones, {4- or 3-[(1E)-3-(4-, 3-, or 2-methoxyphenyl)-3-oxoprop-1-en-1-yl]-1-alkyl (C8,10,12
)
pyridinium bromides} (1a-6a, 1b-1b, and 1c-6c), and 4 new o-, and m-methoxy (E)-3- and 4-azachalcones
(2, 3, 5, and 6) were synthesized and tested for antimicrobial activities against Escherichia coli, Yersinia
pseudotuberculosis, Enterobacter aerogenes, Pseudomonas aeruginosa, Staphylococcus aureus, Enterococcus
faecalis, Bacillus cereus, and Candida albicans. N-Alkyl substituted azachalconium bromides showed good
antimicrobial activity against all tested microorganisms with minimal inhibitory concentration (MIC) values
in the range of 0.42-58.7 μg/mL in most cases. Nonalkylated compounds 1-9 were not as effective as the
alkylated compounds. They showed only antimicrobial activity against gram-positive bacteria and yeast in
the range of 1.77-123.7 μg/mL. The optimum length of the alkyl chain for better activity is situated with
12 carbon atoms in the series of compounds 1a-c, 2a-c, 3a-c, 4a-c, 5a-c, and 6a-c. N-Alkyl derivatives of
m-methoxy (E)-3-azachalcone (4a-c, 5a-c, and 6a-c) showed better activity in comparison to those of o-
and p-methoxy (E)-4-azachalcones (1a-c, 2a-c, and 3a-c).
Key Words: N-Alkyl p-methyl-(E)-3- and 4-azachalconium bromides, antimicrobial activity
Introduction
A range of synthetic chalcones and azachalcones were prepared and the structure-activity relationships were
explored.1−4 Chalcones (1,3-diphenyl-2-propen-1-ones) are key precursors in the synthesis of a large array of
∗Corresponding author
441

Synthesis and antimicrobial activity of methoxy azachalcones and..., C. ALBAY, et al.
biologically important heterocycles (azachalcones).5,6 Thus, the synthesis of azachalcones has generated vast
interest among organic and medicinal chemists. Chalcones and their heterocyclic analogs (azachalcones) display
a wide range of biological activities, such as anticancer,7 antimitotic,8 antiinflammatory,9 antituberculosis,10
antimalarial,11,12 antileishmanial,13,14 nitric oxide regulation modulatory,15 cardiovascular,16 cell differentiation-
inducing17 and antihyperglycemic,18 activities.
N-alkyl derivatives of azachalcones have also been synthesized by several researchers5,6,19−25 and were
shown to possess a wide variety of biological activities, such as antiinflammatory, antimicrobial, antitubercu-
lostatic, and antibacterial potentials.19−33 In our previous works, nitro- and methyl-substituted (E)-3- and
4-azachalcones and their N-alkyl derivatives were synthesized and showed very good antimicrobial activities,
especially against gram-positive bacteria.25−28 Many of the more active chalcone and azachalcone compounds
are substituted with methoxy and/or hydroxyl groups.1,2 In view of the continuing interest in new antimicro-
bial agents, we prepared other N-alkyl(C8,10,12) substituted m- and p-methoxy-(E)-3- and 4-azachalconium
bromides in this respect. We aimed to determine the influence of the methoxy substitution, the length of the
carbon chain in the N-alkyl substituent, and the position of N in the pyridyl ring on antimicrobial activity. The
attempts to synthesize N-alkylated o-, m-, and p-methoxy (E)-2-azachalcones were unsuccessful. The present
work deals with the synthesis, spectral characterization, and antimicrobial activity of 18 new N-alkyl substi-
tuted m- and p-methoxy (E)-3- and 4-azachalcones (1a-6a, 1b-6b, and 1c-6c) and 4 new o- and m-methoxy
(E)-3- and 4-azachalcones (2, 3, 5, and 6) (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 PerkinElmer 1600 FT-IR (4000-400 cm−1
)
spectrophotometer. Melting points were determined by using a Thermovar 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
o−,m−, andp-Methoxy acetophenone and 2-, 3-, and 4-pyridine carboxaldehydes were purchased from Sigma-
Aldrich and Merck and were used without further purification. The analytical grade or bulk solvents used
(chloroform, n-hexane, ethanol, methanol, acetonitrile, and diethyl ether) were distilled before use.
Synthesis of compounds 1-9
Compounds 1-9 were prepared according to the literature.5,18−36 See the physicochemical and 1 H- and 13 C-
NMR data of compounds 1-9 in Tables 1-3.
442

Synthesis and antimicrobial activity of methoxy azachalcones and..., C. ALBAY, et al.
443

Synthesis and antimicrobial activity of methoxy azachalcones and..., C. ALBAY, et al.
444

Synthesis and antimicrobial activity of methoxy azachalcones and..., C. ALBAY, et al.
Table 3. 13 C-NMR (δ ppm) data of compounds 1-9 in CDCl3 .
Compounds∗
H No.
1
2
3
4
5
6
7
8
9
1
2
187.8 189.2 191.7 187.7 189.3 192.9 188.5 190.1 193.0
125.7 125.8 130.5 123.6 123.6 128.6 125.4 125.4 124.5
140.5 141.3 139.0 139.8 140.7 138.7 141.9 142.7 141.4
130.2 138.6 128.2 130.6 138.9 128. 5 130.7 139.1 128.8
130.9 112.7 158.3 130.7 112.7 158.1 131.0 112.6 158.1
113.9 159.8 111.5 113.8 159.7 111.5 113.8 159.8 111.4
163.7 121.0 133.6 163.5 119.5 134.5 163.6 119.8 133.1
113.9 129.6 120.7 113.8 129.5 120.7 113.8 129.6 120.5
130.9 121.9 130.7 130.7 123.7 130.4 131.0 124.4 130.2
142.1 141.8 142.3 130.4 130.4 130.8 153.2 153.0 153.4
3
1’
2’
3’
4’
5’
6’
1”
2”
3”
4”
5”
6”
-OCH3
121.9 119.6 121.9 149.7 149.9 149.7
150.4 150.4 150.3
-
-
-
-
-
-
150.0 150.1 150.0
-
-
-
150.7 150.9 150.6 125.3 121.4 124.0
150.4 150.4 150.3 123.4 120.9 123.6 136.9 136.9 136.6
121.9 119.6 121.9 134.4 134.4 133.3 124.3 119.8 124.0
55.4
55.3
55.6
55.4
55.3
55.6
55.4
55.4
55.6
∗Assignment based on APT and comparison with ACD-NMR program.
Synthesis of compounds 1a-6a, 1b-6b, and 1c-6c
Compounds 1a-6a, 1b-6b, and 1c-6c were prepared according to the general procedure given below. See the
physicochemical and 1 H- and 13 C-NMR data of compounds 1a-6a in Tables 4-8.
General procedure for synthesis of compounds 1a-6a, 1b-6b, and 1c-6c
m−andp-Methoxy (E)-3- or 4-azachalcones (0.02 mol each) and n-bromoalkanes (1-bromooctane, 1-bromodecane,
and 1-bromododecane (0.05 mol each)) in acetonitrile (30 mL) were refluxed separately for 12-24 h.25 The re-
actions were followed and monitored by TLC. After the reactions were complete, the acetonitrile was removed
using a rotary evaporator and the residues were separated by column chromatography on silica gel (30 × 2 cm,
approximately 25 g each, Merck, 230-400 mesh), first with ethyl acetate (30 mL) and then with ethyl acetate-
methanol (3:1, 20 mL; 3:2, 20 mL), methanol (30 mL), and finally methanol-water (4:1, 30 mL). Fractions (6-12
mL each) were collected and monitored by analytical TLC. The desired dark red amorphous solids (1a-6a,
1b-6b, and 1c-6c) were obtained from fractions 6-13 (yields are shown in Table 1).
445

Synthesis and antimicrobial activity of methoxy azachalcones and..., C. ALBAY, et al.
446

Synthesis and antimicrobial activity of methoxy azachalcones and..., C. ALBAY, et al.
Table 5. 1 H-NMR (δ ppm, J Hz) data of compounds 1a-6a in CDCl3 .
Compounds∗
H No.
1a
2a
3a
4a
5a
6a
2
7.7, d, 15.8
8.3, d, 15.8
8.2, d, 9.0
7.0, d, 9.0
-
7.7, d, 15.6
8.3, d, 15.6
7.6, s
7.6, d, 15.8
7.9, d, 15.8
-
7.7, d, 15.8
8.6, d, 15.8
8.4, d, 8.8
7.0, d, 8.8
-
7.7, d, 15.8
8.5, d, 15.8
7.7, s
7.7, d, 15.8
7.9, d, 15.8
-
3
2’
3’
-
7.0, d, 9.0
7.6, t, 8.4
7.1, t, 8.4
7.5, t, 8.4
8.2, d, 6.4
9.5, d, 6.4
-
-
7.0, d, 8.4
7.5, t, 8.4
7.0, t, 8.4
7.7, d, 8.2
10.0, s
4’
7.8, d, 7.8
7.4, t, 8.0
7.2, t, 8.0
8.5, d, 6.8
9.3, d, 6.8
-
7.1, t, 8.0
7.4, t, 8.0
7.9, d, 7.8
10.5, s
5’
6’
7.0, d, 9.0
8.2, d,9.0
8.5, d, 6.4
9.4, d, 6.4
-
7.0, d, 8.8
8.4, d, 8.8
10.5, s
2”
3”
-
-
-
4”
9.1, d, 6.0
8.1, t, 7.0
8.7, d, 6.8
5.1, t, 7.4
2.1, m, 2H
9.2, d, 5.6
8.2, t, 6.4
8.7, d, 8.0
5.0, t, 7.4
2.1, m, 2H
9.4, d, 5.8
8.3, t, 6.4
8.7, d, 7.6
5.1, t, 7.4
2.1, m, 2H,
5”
9.4, d, 6.4
8.5, d, 6.4
4.9, t, 7.0
2.0, m, 2H
9.3, d, 6.8
8.5, d, 6.8
4.9, t, 7.4
2.0, m, 2H
9.5, d, 6.4
8.2, d, 6.4
5.0, t, 7.4
2.0, m, 2H
6”
NCH2-
-(CH2)6-
1.3, m, 10H 1.3, m, 10H 1.3, m, 10H 1.3, m, 10H 1.3, m, 10H 1.3, m, 10H
-CH3
0.8, t, 6.6
0.9, t, 7.0
0.9, t, 6.2
0.8, t, 6.8
0.8, t, 7.2
0.8, t, 6.8
4.0, s
-OCH3
3.9, s
3.9, s
4.0, s
3.9, s
3.9, s
∗Assignment based on 1H, 1H-1H COSY, and comparison with ACD-NMR program.
Table 6. 1 H-NMR (δ ppm, J Hz) data of compounds 1b-6b in CDCl3 .
Compounds∗
H No.
1b
2b
3b
4b
5b
6b
2
7.7, d, 15.4
8.4, d, 15.4
8.2, d, 8.8
7.0, d, 8.8
-
7.7, d, 15.4
8.3, d, 15.4
7.6, s
7.6, d, 15.8
7.9, d, 15.8
-
7.7, d, 15.8
8.7, d, 15.8
8.4, d, 9.0
7.0, d, 9.0
-
7.7, d, 15.8
8.5, d, 15.8
7.7, s
7.7, d, 15.8
7.9, d, 15.8
-
3
2’
3’
-
7.0, d, 8.2
7.6, t, 8.2
7.1, t, 8.0
7.8, d, 8.0
8.2, d, 6.8
9.5, d, 6.8
-
-
7.0, d, 8.0
7.5, t, 8.0
7.0, t, 8.0
7.7, d, 7.8
9.9, s
4’
7.2, d, 8.2
7.4, t, 8.0
7.8, d, 7.8
8.5, d, 6.4
9.4, d, 6.4
-
7.1, d, 8.0
7.4, t, 8.0
8.0, d, 7.8
10.4, s
5’
6’
7.0, d, 8.8
8.2, d, 8.8
8.5, d, 6.8
9.4, d, 6.8
-
7.0, d, 9.0
8.4, d, 9.0
10.6, s
2”
3”
-
-
-
4”
9.1, d, 5.8
8.1, t, 6.2
8.7, d, 8.4
5.1, t, 7.4
2.2, m, 2H
9.2, d, 6.2
8.1, t, 6.4
8.7, d, 8.0
5.1, t, 7.4
2.1, m, 2H
9.4, d, 5.6
8.3, t, 6.4
8.7, d, 8.2
5.1, t, 7.4
2.1, m, 2H
5”
9.4, d, 6.8
8.5, d, 6.8
4.9, t, 7.0
2.0, m, 2H
9.4, d, 6.4
8.5, d, 6.4
4.9, t, 7.8
2.1, m, 2H
9.5, d, 6.8
8.2, d, 6.8
5.0, t, 7.4
2.0, m, 2H
6”
NCH2-
-(CH2)8-
1.3, m, 14H 1.3, m, 14H 1.3, m, 14H 1.2, m, 14H 1.3, m, 14H 1.3, m, 14H
-CH3
0.9, t, 6.6
0.9, t, 6.4
0.9, t, 6.8
0.9, t, 6.8
0.9, t, 7.0
0.9, t, 6.8
4.0, s
-OCH3
3.9, s
3.9, s
4.0, s
3.9, s
3.9, s
∗Assignment based on 1H, 1H-1H COSY, and comparison with ACD-NMR program.
447

Synthesis and antimicrobial activity of methoxy azachalcones and..., C. ALBAY, et al.
Table 7. 1 H-NMR (δ ppm, J Hz) data of compounds 1c-6c in CDCl3 .
Compounds∗
3c 4c
H No.
1c
2c
5c
6c
2
3
7.7, d, 15.8 7.7, d, 15.4 7.6, d, 15.8 7.6, d, 15.8 7.7, d, 15.8 7.6, d, 16.2
8.3, d, 15.8 8.2, d, 15.4 7.9, d, 15.8 8.7, d, 15.8 8.5, d, 15.8 7.9, d, 16.2
2’
8.2, d, 8.8
7.0, d, 8.8
-
7.6, s
-
-
8.4, d, 8.0
7.0, d, 8.0
-
7.7, s
-
-
3’
7.0, d, 8.8
7.6, t, 8.4
7.1, t, 8.6
7.8, d, 8.4
8.2, d, 6.4
9.5, d, 6.4
-
7.0, d, 7.8
7.5, t, 8.4
7.0, t, 7.8
7.7, d, 7.8
9.9, s
4’
7.8, d, 7.8
7.4, t, 8.0
7.2, t, 8.0
8.5, d, 6.8
9.3, d, 6.8
-
7.1, d, 8.4
7.4, t, 8.0
7.9, d, 7.8
10.5, s
5’
7.0, d, 8.8
8.2, d, 8.8
8.5, d, 6.8
9.3, d, 6.8
-
7.0, d, 8.0
8.4, d, 8.0
10.6, s
6’
2”
3”
4”
5”
6”
NCH2-
-
-
-
8.9, d, 5.8
8.0, t, 6.2
8.6, d, 8.8
5.1, t, 7.4
2.2, m, 2H
9.2, d, 6.0
8.1, t, 6.2
8.7, d, 8.0
5.1, t, 7.0
2.1, m, 2H
9.4, d, 6.0
8.3, d, 6.0
8.7, d, 8.0
5.1, t, 7.4
2.1, m, 2H
9.3, d, 6.8
8.5, d, 6.8
4.9, t, 7.2
9.3, d, 6.8
8.5, d, 6.8
4.9, t, 7.4
2.0, m, 2H
9.5, d, 6.4
8.2, d, 6.4
5.0, t, 7.4
2.0, m, 2H
-(CH2)10- 2.1, m, 2H
1.2, m, 18H 1.3, m, 18H 1.3, m, 18H 1.3, m, 18H 1.3, m, 18H 1.3, m, 18H
-CH3
0.9, t, J 6.6
0.9, t, 7.0
3.9, s
0.9, t, 6.8
4.0, s
0.9, t, 6.8
3.8, s
0.9, t, 7.2
3.9, s
0.9, t, 6.8
4.0, s
-OCH3
3.9, s
*Assignment based on 1H, 1H-1H COSY, and comparison with ACD-NMR program.
Antimicrobial activity assessment
All test microorganisms were obtained from the Refik Saydam National Public Health Agency (Ankara, Turkey)
and were as follows: Escherichia coli ATCC 25922, Yersinia pseudotuberculosis ATCC 911, Enterobacter aero-
genes ATCC 13048, Pseudomonas aeruginosa ATCC 27853, Staphylococcus aureus ATCC 25923, Enterococcus
faecalis ATCC 29212, Bacillus cereus 702 Roma, and Candida albicans ATCC 60193. All of the newly syn-
thesized compounds were weighed and dissolved in dimethylsulphoxide (DMSO) to prepare an extract stock
solution of milligrams per milliliter.
The antimicrobial effects of the substances were tested quantitatively by the microdilution technique in
Mueller Hinton broth. The minimal inhibition concentration (MIC) of the extracts was also determined using
a 2-fold dilution method.37 The antibacterial and antifungal assays were performed in Mueller-Hinton broth
(MH) (Difco, Detroit, MI) at pH 7.3 and a buffered yeast nitrogen base (Difco) at pH 7.0, respectively. The
MIC was defined as the lowest concentration that showed no growth. Ampicillin (1.2 mg/mL) and fluconazole (2
mg/mL) were used as standard antibacterial and antifungal drugs, respectively. Dimethylsulphoxide (DMSO)
was used as the solvent control. The results are shown in Table 9.
448

Synthesis and antimicrobial activity of methoxy azachalcones and..., C. ALBAY, et al.
449

Synthesis and antimicrobial activity of methoxy azachalcones and..., C. ALBAY, et al.
Table 9. Minimum inhibitory concentrations (MIC, μg/mL) of compounds 1-9, 1a-6a, 1b-6b, and 1c-6c.
Stock conc.
Minimal inhibition concentration values (μg/mL)
Comp.
(μg/100 μL) Ec (-) Yp (-) En (-) Pa (-) Sa (+) Ef (+) Bc (+)
Ca
15.5
1
2
9900
11,300
9900
10,400
12,100
9600
10,200
9100
9100
8600
8800
9300
9200
9600
9800
1040
8700
9800
9300
8800
9900
9500
9600
8700
9400
9400
9300
1200
2000
> 495 > 495 > 495 > 495
> 283 > 283 > 283 > 283
> 247 > 247 > 247 > 247
> 260 > 260 > 260 > 260
> 303 > 303 > 303 > 303
> 240 > 240 > 240 > 240
> 510 > 510 > 510 > 260
> 227 > 227 > 227 > 227
> 227 > 227 > 227 > 227
61.9
2.20
7.72
65.0
4.72
30.0
7.96
1.77
7.10
0.42
0.42
0.45
0.45
123.7
8.83
30.9
30.0
37.8
120
61.9
8.83
15.5
65.0
9.45
30.0
15.9
7.10
14.2
1.67
0.42
0.45
0.90
17.6
3
15.5
4
32.5
5
37.8
6
15.0
7
31.8
14.7
28.4
1.67
0.42
0.45
0.90
15.9
8
< 7.10
7.10
9
1a
1b
1c
2a
2b
2c
3a
3b
3c
4a
4b
4c
5a
5b
5c
6a
6b
6c
Amp.
Flu.
6.72
3.44
13.5
3.44
26.8
3.44
53.7
13.7
116.2
28.7
15.0
7.65
32.5
13.6
3.82
29.0
13.7
7.73
14.8
7.50
13.8
58.7
3.67
14.5
> 128
< 6.72
< 6.87
58.1
> 233 > 233 > 233
3.59
0.94
0.47
8.12
3.40
0.96
3.63
0.84
0.48
3.71
1.87
1.70
7.34
0.90
0.90
8
7.18
3.75
0.96
16.2
6.80
3.82
7.26
3.44
1.93
7.42
7.50
3.40
14.7
3.67
1.81
32
14.4
3.75
0.45
16.2
3.40
1.92
29.0
6.8
< 7.18
< 0.47 < 0.47 < 0.47 < 7.50
< 0.47 < 0.47 < 0.47 < 7.65
0.50
1.01
2.03
< 8.12
< 0.43 < 0.43 < 0.43 < 6.80
< 0.46 < 0.46 < 0.46 < 7.65
0.45
0.90
0.90
< 7.26
< 6.8
< 0.44 < 0.44 < 0.44
0.96
7.42
3.75
1.70
14.7
1.83
1.81
> 64
< 0.48 < 0.48 < 0.48 < 7.73
< 0.46 < 0.46 < 0.46 < 7.42
< 0.46 < 0.46 < 0.46 < 7.50
< 0.43 < 0.43 < 0.43 < 6.80
< 0.45 < 0.45 < 0.45 < 7.34
< 0.45 < 0.45 < 0.45 < 7.34
< 0.45 < 0.45 < 0.45 < 7.25
2
2
< 1
< 8
a: C8 , b: C10 , c: C12 ; Ec: Escherichia coli, Yp: Yersinia pseudotuberculosis, En: Enterobacter aerogenes, Pa:
Pseudomonas aeruginosa, Sa: Staphylococcus aureus, Ef : Enterococcus faecalis, Bc: Bacillus cereus 702 Roma, Ca:
Candida albicans, Amp: ampicillin, Flu: fluconazole.
450

Synthesis and antimicrobial activity of methoxy azachalcones and..., C. ALBAY, et al.
Results and discussion
The convenient approach for the synthesis of o-, m-, and p-methoxy (E)-2-, -3-, and 4-azachalcones (1-9) in-
volves the Claisen-Schmidt condensation of methoxy-substituted aryl methyl ketones with pyridine carboxalde-
hydes with 3 equivalents of Na2 CO3 solution (EtOH, 95%), which yields the trans isomer of the corresponding
α,β-unsaturated (J = 15.4/16.8 Hz, respectively) compounds (1-9) (Scheme, Tables 2-3).5,25−28
Z
+
CH3O
Y
H
X
O
O
oC
Na2CO3
60-70
1''
Z
Y
R1Br (R1= C8H17)
R2Br (R2= C10H21)
R3Br (R3= C12H25)
M
L
X
K
3
2
CH3O
CH3O
CH3CN
Reflux
1
'
1
O
O
1-9
1a-6a,1b-6b, and 1c-6c
+
1
2
3
4
5
6
7
8
9
X,Y= CH, Z= N, 4-OCH3
X,Y= CH, Z= N, 3-OCH3
X,Y= CH, Z= N, 2-OCH3
X, Z= CH, Y= N, 4-OCH3
X, Z= CH, Y= N, 3-OCH3
X, Z= CH, Y= N, 2-OCH3
Y, Z= CH, X= N, 4-OCH3
Y, Z= CH, X= N, 3-OCH3
Y, Z= CH, X= N, 2-OCH3
1a K, L= CH,
M= N R1 / Br -, 4-OCH3
+
2a K, L = CH, M= N R1 / Br -, 3-OCH3
+
3a K, L = CH , M= N R1 / Br -, 2-OCH3
4a K, M = CH, L= N+R1 / Br -,
4-OCH3
3-OCH3
2-OCH3
+
5a K, M= CH, L= N R1 / Br -,
6a K, M = CH, L= N+R1 / Br -,
+
1b K, L = CH, M= N R2 / Br -, 4-OCH3
+
2b K, L = CH, M= N R2 / Br -, 3-OCH3
+
3b K, L = CH, M= N R2 / Br -, 2-OCH3
4b K, M = CH, L= N+R2 / Br -,
5b K, M = CH, L= N+R2 / Br -,
4-OCH3
3-OCH3
2-OCH3
6b K, M = CH, L= N+R2 / Br -,
+
1c K, L = CH, M= N R3 / Br -, 4-OCH3
+
2c K, L = CH, M= N R3 / Br -, 3-OCH3
+
3c K, L = CH, M= N R3 / Br -, 2-OCH3
4c K, M = CH, L= N+R3 / Br -,
5c K, M = CH, L= N+R3 / Br -,
6c K, M = CH, L= N+R3 / Br -,
4-OCH3
3-OCH3
2-OCH3
Scheme
N-alkyl derivatives of m- and p-methoxy (E)-3- or 4-azachalcones were synthesized from the correspond-
ing azachalcones with n-bromoalkanes (1-bromooctane, 1-bromodecane, and 1-bromododecane) in acetonitrile
451

Synthesis and antimicrobial activity of methoxy azachalcones and..., C. ALBAY, et al.
solution by reflux.19,20,25−27 In the 1 H-NMR spectra of 1a-6a, 1b-6b, and 1c-6c, the characteristic -CH2 - sig-
nal of the N-alkyl groups was exhibited at δ 4.9-5.1 ppm (2H, t, J = 7.0-7.4 Hz) (Tables 5-7) due to pyridinium
salt.19,20,25
N-Alkyl derivatives of azachalcones attract widespread interest because many of them have exhibited a
wide variety of biological activities.25−33 All of the synthesized compounds (1-9, 1a-6a, 1b-6b, and 1c-6c) were
characterized on the basis of spectral data analyses (1 H-NMR, 13 C-NMR, 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 1-8). The LC mass spectra of 1a-6a, 1b-6b, and 1c-6c exhibited molecular ion peaks
for [M(79 Br)]+ and [M(81 Br)]+ , 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]+ (Table 4).
The antimicrobial activity of compounds 1-9, 1a-6a, 1b-6b, and 1c-6c was determined against E. coli,
Y. pseudotuberculosis, E. aerogenes, P. aeruginosa, S. aureus, E. faecalis, B. cereus, and C. albicans (Table
9). The activities of compounds 1-9, 1a-6a, 1b-6b, and 1c-6c were investigated by the dilution method.37
Some compounds showed from slight to pronounced antimicrobial activity against gram-positive and gram-
negative bacteria. Nonalkylated compounds 1-9 were not as effective as the alkylated compounds with 8, 10,
or 12 C alkyl groups (1a-6a, 1b-6b, and 1c-6c). The N-alkyl derivatives of compounds 1-9 were more active
against the gram-positive bacteria (S. aureus, E. faecalis, and B. cereus) in the range of 0.42-2.03 μg/mL
compared to the gram-negative bacteria (E. coli, Y. pseudotuberculosis, E. aerogenes, and P. aeruginosa) in the
range of 0.47-233 μg/mL. o-, m-, and p-Methoxy substituted 3-azachalcones displayed better activity against
gram-negative bacteria in the range of 0.48-58.7 μg/mL compared to o-, m-, and p-methoxy substituted 4-
azachalcones in the range of 0.47-233 μg/mL. m-Methoxy 4- and 3-azachalcones showed better activity against
E. coli, Y. pseudotuberculosis, E. aerogenes, and P. aeruginosa in the ranges of 0.47-28.7 and 1.70-14.8 μg/mL,
as opposed to p-methoxy 4- and 3-azachalcones (3.44-233 and 0.48-29.0 μg/mL) and o-methoxy 4- and 3-
azachalcones (0.96-32.5 and 0.90-58.7 μg/mL), respectively. Our previous works and research by Nowakowska
et al. have shown a similar trend in activity with respect to bacterial type with methyl-, nitro-, and hydroxy-
substituted and unsubstituted N-alkyl derivatives of azachalcones.20,26−31 The antimicrobial activity increased
as the length of the alkyl substitution increased from 8 to 12, and similar results have been observed in the
literature for N-bromoalkyl derivatives of azachalcones.20,26−31 The solvent control DMSO showed no inhibition
effect on any test microorganisms.
Acknowledgements
¨
This study was supported by grants from Karadeniz Technical University (KTU) and the Scientific and Tech-
¨
˙
nological Research Council of Turkey (TUBITAK).
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454

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