6766
L. Yurttaßs et al. / Bioorg. Med. Chem. Lett. 23 (2013) 6764–6768
Table 1
Table 2
List of the synthesized compounds (1–40) and reaction conditions
Antimicrobial activity of the compounds 1–40 (
l
g/mL)
Compound
R1
R2
Time (h)
yield (%)
Comp
A
B
C
D
E
F
G
H
I
J
K
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
3–4
3–4
3–4
3–4
3–4
3–4
3–4
3–4
3–4
3–4
3–4
3–4
3–4
3–4
3–4
3–4
3–4
3–4
3–4
3–4
3–4
3–4
3–4
3–4
3–4
3–4
3–4
3–4
3–4
3–4
3–4
3–4
3-4
82
69
73
77
62
71
72
75
68
77
73
75
78
80
52
67
68
71
64
60
62
65
70
75
74
72
69
64
77
78
77
79
67
71
70
68
66
78
69
73
1
2
3
4
5
6
7
8
800 800 200 800 800 800 800 800 400 800 400
400 800 400 400 800 800 800 800 400 400 400
400 800 200 800 400 800 800 800 400 800 800
800 200 400 400 400 800 200 400 200 800 50
800 400 400 400 400 400 400 400 400 400 200
800 400 400 400 400 400 800 400 400 400 200
3-OCH3
4-OCH3
3,4-Di-OCH3
3-F
4-F
3,4-Di-F
3-Cl
4-Cl
3,4-Di-Cl
H
3-OCH3
4-OCH3
3,4-Di-OCH3
3-F
4-F
3,4-Di-F
3-Cl
4-Cl
3,4-Di-Cl
H
3-OCH3
4-OCH3
3,4-Di-OCH3
3-F
4-F
3,4-Di-F
3-Cl
4-Cl
3,4-Di-Cl
H
3-OCH3
4-OCH3
3,4-Di-OCH3
3-F
4-F
3,4-Di-F
3-Cl
4-Cl
3,4-Di-Cl
400 400 400 400 25
400 100 50
400 400 200
400 400 400 800 400 400 400 400 800 400 200
800 400 400 800 200 400 800 400 200 400 200
800 800 400 800 200 800 800 400 400 200 200
800 200 800 400 400 800 800 800 800 400 400
800 200 800 800 800 400 800 400 400 400 200
9
H
H
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
Cl
100 400 400 400 25
400 400 50
25
100 25
200 200 400 400 100 400 400 50
100 100 50
800 800 400 400 200 400 800 400 800 800 400
1600 1600 1600 1600 1600 1600 1600 1600 1600 1600 1600
800 800 800 800 400 200 800 800 200 400 100
800 800 800 800 800 800 800 800 800 800 800
400 800 800 800 400 400 800 800 400 400 200
400 800 800 800 400 400 800 800 800 800 800
800 800 800 800 800 100 800 800 800 800 800
800 800 800 800 800 200 800 800 800 800 800
800 800 800 800 800 800 800 800 400 800 400
800 800 800 800 800 1600 800 800 200 400 200
800 800 400 800 400 800 400 400 400 400 400
800 800 800 800 1600 800 800 400 400 400 400
800 800 800 800 1600 800 800 800 400 800 400
800 800 800 800 800 800 800 800 800 800 400
400 800 800 400 400 800 400 400 400 400 400
400 800 400 800 400 800 800 800 800 800 800
800 800 400 800 200 800 800 400 800 800 800
800 800 800 400 200 400 800 1600 800 800 200
800 800 800 400 200 400 400 1600 800 800 200
400 800 400 800 100 800 800 100 400 400 400
400 800 400 800 100 800 800 200 400 400 400
1600 1600 1600 800 1600 800 800 3200 800 1600 800
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
3-4
3–4
3–4
3–4
3–4
3–4
3–4
400 800 400 400 50
400 400 50
50
100 100
800 800 400 800 400 800 800 800 800 400 800
800 800 400 800 800 800 800 800 800 800 400
Cl
800 200 400 800 50
800 800 200 800 400 400
Ref. 1 50
Ref. 2
25
—
50
—
50
—
12.5 100 50
50
—
—
—
—
—
—
—
—
100 100 50
was manifested especially in the activities of the methyl deriva-
tives (R2 = CH3) against the Candida species. Thus, compounds 7,
13, 14, 33, 34, and 37 were the most active. In addition, we ob-
served that 4-methoxy, 3,4- dimethoxy, and 3,4-difluoro substitu-
tion (R1 = 4-OMe; 3,4-di-OMe; 3,4-di-F) all had a beneficial effect
on the observed antimicrobial activities. Interestingly, the 4-fluoro
substituted compounds 6, 16, 26 and 36 (R1 = 4-F) were not active,
while the 3,4-difluoro analogues (R1 = 3,4-di-F) were active. A com-
plex interplay of electronic and other effects may be responsible
for these observed differences.
Cytotoxicity in brine shrimp lethality test was studied in order
to reveal new antimicrobial and anticancer compounds. This assay
is regarded as a useful method for preliminary evaluation of toxic-
ity which is also used for antitumor, pesticidal and antitrypanoso-
mal activity evaluation.22 Toxicity test was analysed with the LC50
computer program (Trimmed Spearman–Karber Method, Version
1.5) so as to calculate LC50 values and 95% confidence intervals.23
LC50 values of the compounds 7, 13 and 37 (465.05, 152.74 and
Ref. 1: Chloramphenicol, Ref. 2: Ketoconazole.
A: E. coli (ATCC 25922), B: E. coli (ATCC 35218), C: P. aeruginosa (ATCC 27853), D: K.
pneumonia (ATCC 13883), E: E. faecalis (ATCC 29212), F: E. faecalis (ATCC 51299), G:
S. aureus (ATCC 25923), H: L. monocytogenes (ATCC 19115), I: C. albicans (ATCC
90028), J: C. glabrata (ATCC 90030),K: C. krusei (ATCC 6258).
compounds (Table 4). The expected potential anticancer activity
could not be observed from the compounds. Among three tested
compounds compound 3 was assigned as the most active one
and among the sixty tumor cell line UO-31 which is derived from
renal cancer was found to be the most sensitive cell line against
three tested compounds (compounds 1, 3 and 9) with the growth
percentages 68.60%, 69.91% and 66.15%, respectively.
In summary, the objective of the present study was the
synthesis of 2-[(4,5-dimethyl-1-(substituted phenylamino)-1H-
imidazol-2-yl)thio]-1-(substituted phenyl)ethanone derivatives
(1–40) and evaluation of their antibacterial, antifungal and anti-
cancer activities. Compounds 13, 14 and 37 displayed significant
antifungal activity warranting further attention. Antibacterial
activity of the compounds was higher against Gram-positive bac-
teria than Gram-negative bacteria and a Gram-positive bacte-
rium L. monocytogenes (ATCC 19115) was found to be the most
susceptible bacterium. According to toxicity test results, our
compounds were found to be non-toxic or have little toxicity
in the brine shrimp test. From the comparison of cytotoxicity
and antimicrobial activity test results, it might be claimed that
359.21
and categorized as having moderate cytotoxicity.24 LC50 values
greater than 1000 g/ml were considered to be non toxic. Accord-
lg/mL) were found between 100 lg/mL and 500 lg/mL
l
ingly, compounds 1 and 14 were appreciated as non-toxic. Toxicity
test results were presented in Table 3.
Compound 1 (NSC 772200), 3 (NSC 772201) and 9 (NSC 722202)
were selected by NCI for 60 human tumor cell lines’ anticancer
screening test at single dose assay. Results were given as percent-
age growth of tumor cells which were treated with selected three