Synthesis, antibacterial and antifungal activities of electron-rich olefins derived benzimidazole compounds

Article abstract of DOI:10.1016/S0014-827X(03)00068-5

New benzimidazole derivatives were synthesised by electron-rich olefines (7, 8 and 9) with appropriate reagents. The compounds synthesised were identified by ¹H NMR, ¹³C NMR, FT-IR spectroscopic techniques and elemental analysis. All compounds studied in this work were screened for their in vitro antimicrobial activities against the standard strains: Enterococcus faecalis (ATCC 29212), Staphylococcus aureus (ATCC 29213), Escherichia coli (ATCC 25922), Pseudomonas aeruginosa (ATCC 27853) and the yeasts Candida albicans and Candida tropicalis. Eleven of the compounds inhibited the growth of gram-positive bacteria (E. faecalis and S. aureus) at MIC values between 50 and 400 μg/ml. None of the compounds exhibit antimicrobial activity against Gram-negative bacteria (E. coli and P. Aeruginosa) at the concentrations studied (6.25-800 μg/ml). Nine of the tested compounds showed an antifungal activity with a range of the MICs between 50 and 400 μg/ml.

Full text of DOI:10.1016/S0014-827X(03)00068-5

Il Farmaco 58 (2003) 431ꢀ437
/
www.elsevier.com/locate/farmac
Synthesis, antibacterial and antifungal activities of electron-rich
olefins derived benzimidazole compounds
Hasan Kucukbay a,*, Riza Durmaz b, Ersin Orhan a, Selami Gunal b
¸
¨ ¨
¨
a Department of Chemistry, Faculty of Arts and Sciences, Inonu University, 44069 Malatya, Turkey
¨ ¨
b Department of Microbiology, Faculty of Medicine, Inonu University, 44069 Malatya, Turkey
¨ ¨
Received 24 August 2002; accepted 11 February 2003
Abstract
New benzimidazole derivatives were synthesised by electron-rich olefines (7, 8 and 9) with appropriate reagents. The compounds
synthesised were identified by 1H NMR, 13C NMR, FT-IR spectroscopic techniques and elemental analysis. All compounds studied
in this work were screened for their in vitro antimicrobial activities against the standard strains: Enterococcus faecalis (ATCC
29212), Staphylococcus aureus (ATCC 29213), Escherichia coli (ATCC 25922), Pseudomonas aeruginosa (ATCC 27853) and the
yeasts Candida albicans and Candida tropicalis. Eleven of the compounds inhibited the growth of gram-positive bacteria (E. faecalis
and S. aureus) at MIC values between 50 and 400 mg/ml. None of the compounds exhibit antimicrobial activity against Gram-
negative bacteria (E. coli and P. Aeruginosa) at the concentrations studied (6.25ꢀ800 mg/ml). Nine of the tested compounds showed
/
an antifungal activity with a range of the MICs between 50 and 400 mg/ml.
´
# 2003 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved.
Keywords: Benzimidazole derivatives; Antibacterial activities; Antifungal activities; In vitro studies; Electron-rich olefins
1. Introduction
been known, but there is limited information about ero
contain benzimidazolidine (III) [4,5,14ꢀ16] moiety.
In previous studies, we have synthesised eros such as
III (R, R?ꢁMe, Et or CH2Ph) and used them as a
/
Electron-rich olefins (ero) are very versatile reagents
and highly reactive. Eros have been used as powerful
/
reducing agents [1ꢀ
metal complexes [4,5], catalyst for acyloin type Cꢀ
coupling reactions [6,7]. They have an extensive organic
chemistry, particularly ero that contain imidazolidine (I)
/
3], sources of carbene transition
starting compounds to obtain versatile benzimidazole
derivatives and some rhodium [4] and ruthenium [5]
complexes (Scheme 1).
On the other hand, benzimidazole derivatives consti-
tute an important class of heterocyclic compounds
/C
[8ꢀ
/
11] or benzothiazolidine (II) [12,13] moiety have long
e
for their versatile pharmacological activities such as
antibacterial, antifungal, antihelmintic, antiallergic,
antineoplastic, local analgesic, antihistaminic, vasodila-
* Corresponding author.
E-mail address: hkucukbay@inonu.edu.tr (H. Kucukbay).
¸
¨ ¨
´
0014-827X/03/$ - see front matter # 2003 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved.
doi:10.1016/S0014-827X(03)00068-5

432
H. Kucukbay et al. / Il Farmaco 58 (2003) 431ꢀ437
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¨¸¨
Scheme 1. Synthesis pathways of the new electron-rich olefins and their benzimidazole derivatives.
tive, hypotensive, and spasmolytic activities [17,18].
We also observed that many benzimidazole derivatives
and related heterocyclic compounds have shown con-
siderable antimicrobial activities against standard
strains; Enterococcus faecalis (ATCC 29212), Staphylo-
coccus aureus (ATCC 29213), Escherichia coli (ATCC
25922), Pseudomonas aeruginosa (ATCC 27853)
and yeasts Candida albicans and Candida tropicalis
2. Experimental
2.1. Chemistry
All experiments were performed under argon using
1
freshly distilled dry solvents. H NMR and 13C NMR
spectra were recorded using a Varian ML 60 (Varian
Associates Inc., Sunnyvale, CA) and Bruker DPX-400
high performance digital FT NMR (Bruker WM360,
Bruker Instruments, Inc., Billercia, USA) spectrometers,
respectively. Infrared spectra were recorded as KBr
[19ꢀ24].
/
The aim of this study was to synthesise electron rich
olefin derived benzimidazole compounds and to study
their antibacterial and antifungal activities.
pellets in the range 4000ꢀ
400 cmꢂ1 on an ATI Unicam,
/

H. Kucukbay et al. / Il Farmaco 58 (2003) 431ꢀ
/
437
433
¨¸¨
Mattson 1000 (Unicam Ltd. Cambridge, UK) spectro-
photometer. Elemental analysis was performed by the
elemental analysis laboratory of Tubitak (The Scientific
¨
113.46, 127.33, 127.44, 129.09, 129.17, 131.26, 131.90,
136.56. n(amine salt): 2950 cmꢂ1
.
and Technical Research Consul of Turkey) at Ankara
(Turkey). Melting points were recorded using an elec-
trothermal melting point apparatus, Electrothermal
9200 (Electrothermal Engineering Ltd., Essex, UK)
and are uncorrected.
2.1.4. 1,3-Di(2-phenylethyl)benzimidazolium bromide
(4)
1
Yield: 68%, m.p.: 100ꢀ
/
101 8C. H NMR (TFA): d
2.7(t, CH2CH2Ph, 2H), 4.2 (t, CH2CH2Ph, 2H), 6.5ꢀ
/
7.1
H, 9H), 7.7 (s, CH, 1H). 13C NMR (CDCl3): d
(m, Arꢀ
/
35.16, 49.08, 113.37, 127.39, 129.13, 129.25, 131.23,
136.36, 142.00. n(amine salt): 2750 cmꢂ1. Anal. Calc. for
C23H23N2Br: C, 67.81; H, 5.65; N, 6.88. Found: C,
68.45; H, 5.78; N, 7.06%.
2.1.1. Preparation of 1-(2-phenylethyl)benzimidazole
(1)
Benzimidazole (2 g, 16.95 mmol) and 2-bromoethyl-
benzene (2.5 ml, 18.30 mmol) were added to a solution
of KOH (1.43 g, 25.54 mmol) in 20 ml of ethanol and
the mixture was refluxed 3 h. The mixture was then
cooled, after which potassium bromide was filtered,
washed with a little ethanol, and the solvent was
removed from the filtrate in vacuo. The residue was
treated with chloroform (10 ml), and the chloroform
extract was washed with NaOH solution, then with
water, and dried over anhydrous sodium sulphate over-
night. The sodium sulphate was then filtered off and the
oily residue was crystallised from toluene/n-hexane (2:1)
after removal of the all volatiles in vacuo. Yield: 2.89 g,
2.1.5. 1-(2-Methoxyethyl)-3-(2-
phenylethyl)benzimidazolium bromide (5)
Yield: 79%, m.p.: 94ꢀ
/
95 8C. 1H NMR (TFA): d 3.2(s,
CH3, 3H), 3.8 (m, CH2CH2Ph, 2H), 4.0 (t, CH2CH2O,
2H), 4.7 (m, NCH2CH2ꢀ
/
, 4H), 6.7ꢀ
/
7.6 (m, ArꢀH, 9H),
/
9.3 (s, CH, 1H). n(amine salt): 2790 cmꢂ1
.
2.1.6. 1-(2-Etoxyethyl)-5-methyl-3-(2-
phenylethyl)benzimidazolium bromide (6)
Yield: 97%, m.p.: 152ꢀ
153 8C. 1H NMR (TFA): d 1.2
(t, CH3, 3H), 2.6 (s, CH3, 3H), 3.3 (m, CH2CH2Ph, 2H),
/
3.8 (q, CH2CH3, 2H), 4.1 (t, CH2CH2O, 2H), 4.8 (m,
77%; m.p.: 77ꢀ
1H NMR (TFA): d 2.2 (t, CH2CH2Ph, 2H), 3.9 (t,
H, 9H), 7.3 (s, CH,
/
78 8C.
NCH2CH2ꢀ
/
, 4H), 6.9ꢀ
/
7.8 (m, ArꢀH, 8H), 8.8 (s, CH,
/
1H). n(amine salt): 2950 cmꢂ1
.
CH2CH2Ph, 2H), 6.0ꢀ
/
6.9 (m, Arꢀ
/
1H). 13C NMR (CDCl3): d 36.59, 47.05, 110.06, 120.76,
122.58, 123.36, 129.05, 129.25, 133.94, 137.94, 143.42.
Anal. Calc. for C15H14N2: C, 81.08; H, 6.31; N, 12.61.
Found: C, 80.91; H, 6.31; N, 12.87%.
2.1.7. Preparation of bis[1,3-di-(2-
phenylethyl)benzimidazolidine-2-ylidene] (9)
A mixture of 1,3-bis(2-phenylethyl)benzimidazolium
bromide (5 g, 12.28 mmol) and NaH (0.34 g, 14.16
mmol) in tetrahydrofuran (50 ml) was stirred for 3 h at
r.t. and then for further 1 h at 50 8C. The solvent was
extracted with hot toluene (30 ml) and the extract
filtered when hot. The yellow filtrate was concentrated
(to ca. 15 ml), n-hexane (15 ml) was added and the
2.1.2. Preparation of 1-ethyl-3-(2-
phenylethyl)benzimidazolium bromide (2)
A mixture of 1-ethylbenzimidazole (4 ml, 34.24 mmol)
and 2- bromoethylbenzene (5.00 ml, 36.61 mmol) was
heated on water bath at 90ꢀ95 8C for 2 h. The solution
/
solution was cooled to ꢂ
yellow compound 9. Yield: 3.20 g, 80%; m.p.: 156ꢀ
157 8C.
1H NMR (CDCl3): d 2.3 (t, CH2CH2Ph, 4H), 3.0 (t,
CH2CH2Ph, 4H), 6.1ꢀ
6.7 (m, Ph, 28H). 13C NMR
/
20 8C to yield the crystalline
was cooled to room temperature (r.t.) and Et2O (5 ml)
was added. The precipitate was then crystallised from
/
EtOH/Et2O (2:1). Yield: 11.1 g, 98%; m.p.: 108ꢀ
/
109 8C.
Similarly compounds 3ꢀ6 were synthesised from appro-
/
/
priate benzimidazole derivatives and alkyl halides.
1H NMR (TFA): d 1.5(t, CH2CH3, 3H), 3.2 (t,
CH2CH2Ph, 2H), 4.4(t, CH2CH2Ph, 2H), 4.5 (q,
(CDCl3): d 34.05, 44.79, 105.64, 117.25, 120.66, 126.94,
129.11, 129.17, 130.26, 139.23. n(CÄC): 1710 cmꢂ1.Anal.
Calc. for C46H44N4: C, 84.66; H, 6.75; N, 8.59. Found:
C, 84.76; H, 6.76; N, 9.01%.
Similar to compound 9, compounds 7 and 8 were
synthesised from appropriate benzimidazolium salts and
NaH. Although the crystallisation of the compound 7
and 8 were not achieved, but some of their derivatives
were synthesised successively.
CH2CH3, 2H), 6.9ꢀ
/
7.8 (m, ArꢀH, 9H), 8.4 (s, CH,
/
1H). 13C NMR (CDCl3): d 15.14, 35.78, 42.16, 48.95,
113.52, 113.55, 127.38, 127.42, 127.45, 129.10, 129.14,
131.02, 131.43, 136.47, 141.82. n(amine salt): 2720 cmꢂ1
.
2.1.3. 1-Methyl-3-(2-phenylethyl)benzimidazolium
iodide (3)
Yield: 84%, m.p.: 104ꢀ
(t, CH2CH2Ph, 2H), 2.9 (s, NCH3, 3H), 3.7 (t,
CH2CH2Ph, 2H), 6.0ꢀ6.6 (m, ArꢀH, 9H), 7.4 (s, CH,
1H). 13C NMR (CDCl3): d 34.35, 35.88, 49.00, 113.30,
/
105 8C. 1H NMR (TFA): d 2.2
2.1.8. Preparation of 1-ethyl-3-(2-
phenylethyl)benzimidazole-2-selenone (12)
A mixture of 8 (1.0 g, 2.11 mmol) and selenium (0.33
g, 4.24 mmol) in toluene (10 ml) was heated under reflux
/
/

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H. Kucukbay et al. / Il Farmaco 58 (2003) 431ꢀ
/
437
¨¸¨
for 2 h. Then the mixture was filtered to remove
unreacted selenium and all volatiles were removed in
vacuo (0.02 mmHg). The crude product was crystallised
2.1.13. Preparation of mercapto-N-phenylformimidoyl-1-
ethyl-3-(2-phenylethyl)-benzimidazolinium inner salt
(15)
from alcohol upon cooling to ꢂ
/
30 8C. Yield: 1.16 g,
To a solution of 7 (0.5 g, 1.00 mmol) in toluene (15
ml) PhNCS (0.3 ml, 2.49 mmol) was added. When the
mixture was stirred at r.t., an exothermic reaction took
place shortly. All volatiles were then removed in vacuo
87%, m.p.: 103ꢀ104 8C.
/
1H NMR (TFA): d 0.4(t, CH3, 3H), 2.0 (t,
CH2CH2Ph, 2H), 3.4 (q, CH2CH3, 2H), 3.7 (t,
CH2CH2Ph, 2H), 5.8ꢀ
/
6.2 (m, Arꢀ
/
H, 4H), 6.7 (s, Arꢀ
/
and the yellow crude product 0.5 g; 76%, m.p.: 114ꢀ
115 8C.
1H NMR (CDCl3): d 1.7 (t, CH2CH3, 3H), 3.4 (t,
CH2CH2Ph, 2H), 4.8 (t, CH2CH2Ph, 2H), 4.9 (q,
CH2CH3, 2H), 7.2ꢀ7.7 (m, Arꢀ
H, 14H). 13C NMR
(CDCl3): d 15.03, 35.95, 41.68, 47.82, 112.80, 112.90,
122.86, 124.25, 126.55, 127.56, 129.13, 129.28, 129.39,
130.05, 130.81, 137.48, 150.00, 151.17, 166.33. Anal.
Calc. for C24H23N3S: C, 74.81; H, 5.97; N, 10.91.
Found: C, 74.61; H, 6.08; N, 10.84%.
/
H, 5H). 13C NMR (CDCl3): d 13.72, 34.70, 41.96, 43.05,
109.90, 110.00, 123.62, 123.63, 127.20, 129.10, 129.42,
132.80, 133.46, 138.39, 165.31. n(CÄSe): 1487 cmꢂ1. Anal.
Calc. for C16H16N2Se: C, 60.95; H, 5.08; N, 8.85.
Found: C, 60.76; H, 5.08; N, 9.03%.
/
/
Similarly compounds 10, 11, 13 and 14 were synthe-
sised from appropriate benzimidazole derivatives and
Group 16 elements.
Similarly, compound 16 was synthesised from bis[1-
methyl-3-(2-phenylethyl)-benzimidazolidine-2-ylidene],
2.1.9. 1-Ethyl-3-(2-phenylethyl)benzimidazole-2-one
(10)
8 and PhNCS. Yield: 89%, m.p.: 133ꢀ134 8C.
/
Yield: 71%, m.p.: 94ꢀ
CH2CH3, 3H), 2.6 (t, CH2CH2Ph, 2H), 4.0
(t,CH2CH2Ph, 2H), 4.1 (q, CH2CH3, 2H), 6.5ꢀ6.9 (m,
Arꢀ
H, 9H). n(CÄO): 1690 cmꢂ1
/
95 8C. 1H NMR (TFA): d 0.9(t,
2.1.14. Mercapto-N-phenylformimidoyl-1-methyl-3-(2-
phenylethyl)benzimidazol-inium inner salt (16)
/
1
/
.
Yield: 89%, m.p.: 133ꢀ
/
134 8C. H NMR (CDCl3): d
3.5 (t, CH2CH2Ph, 2H), 4.1 (s, CH3, 3H), 4.8 (t,
H, 14H). 13C NMR
CH2CH2Ph, 2H), 7.2ꢀ7.7 (m, Arꢀ
/
/
2.1.10. 1-Ethyl-3-(2-phenylethyl)benzimidazole-2-thione
(11)
(CDCl3): d 32.24, 36.03, 47.99, 112.67, 112.76, 122.87,
124.38, 126.63, 126.69, 127.60, 129.17, 129.31, 129.41,
130.54, 137.43, 150.11, 151.01, 166.47. Anal. Calc. for
C23H21N3S: C, 74.39; H, 5.66; N, 11.32. Found: C,
74.77; H, 5.88; N, 10.88%.
Yield: 65%, m.p.: 88ꢀ
CH2CH3, 3H), 2.9 (t, CH2CH2Ph, 2H), 4.2 (q, CH2CH3,
2H), 4.5 (t, CH2CH2Ph, 2H), 6.4ꢀ7.1 (m, ArꢀH, 4H),
7.3 (s, Arꢀ
H, 5H). n(CÄS): 1456 cmꢂ1
/
89 8C. 1H NMR (TFA): d 1.0 (t,
/
/
/
.
2.1.15. Preparation of 2,4-dioxy-1,3-diphenyl-7,8-benzo-
6-ethyl-9-(2-phenylethyl)-1,3,6,9-
tetrazaspiro[4.4]nonane (17)
To a solution of 7 (0.5 g, 1.00 mmol) in toluene (15
ml) PhNCO (0.5 ml, 4.60 mmol) was added and the
resulting mixture was refluxed for 1 h. All volatiles were
then removed in vacuo and residue was crystallised from
2.1.11. 1-Ethyl-3-(2-phenylethyl)benzimidazole-2-
tellurone (13)
Yield: 78%, m.p.: 127ꢀ
(t, CH2CH3, 3H), 2.8 (t, CH2CH2Ph, 2H), 4.1 (q,
CH2CH3, 2H), 4.3 (t, CH2CH2Ph, 2H), 6.4ꢀ6.9 (m,
Arꢀ
H, 9H). 13C NMR (CDCl3): d 14.22, 35.22, 45.42,
/
128 8C. 1H NMR (TFA): d 1.0
/
/
CHCl3ꢀ/Et2O mixture (3:1). Yield: 0.67 g, 69%, m.p.:
51.59, 110.73, 110.78, 124.10, 124.12, 127.31, 129.14,
129.47, 133.84, 134.57, 138.12, 143.47. n(CÄTe): 1468
cmꢂ1. Anal. Calc. for C17H18N2Te: C, 54.02; H, 4.77;
N, 7.42. Found: C, 54.09; H, 4.56; N, 7.54%.
167ꢀ168 8C.
/
1H NMR(CDCl3): d 1.1 (t, CH2CH3, 3H), 2.7 (t,
CH2CH2Ph, 2H), 3.2 (t, CH2CH2Ph, 2H), 3.3 (q,
CH2CH3, 2H), 6.1ꢀ
/
7.4 (m, Arꢀ
H, 19H). 13C NMR
/
(CDCl3): d 13.65, 38.30, 42.33, 45.93, 104.41, 104.47,
119.09, 119.33, 124.62, 126.74, 129.13, 129.17, 129.26,
129.63, 129.83, 152.57, 167.24. n(CÄO): 1720 cmꢂ1. Anal.
Calc. for C31H28N4O2: C, 78.09; H, 6.23; N, 11.38.
Found: C, 78.02; H, 6.23; N, 11.47%.
2.1.12. 1-Methyl-3-(2-phenylethyl)benzimidazole-2-
selenone (14)
Yield: 81%, m.p.: 103ꢀ
(t, CH2CH2Ph, 2H), 4.0 (s, CH3, 3H), 4.6 (t,
CH2CH2Ph, 2H), 7.1ꢀ7.4 (m, Arꢀ
H, 9H). 13C NMR
/
104 8C. 1H NMR (TFA): d 3.2
/
/
(CDCl3): d 33.59, 34.70, 48.60, 109.87, 109.91, 123.67,
123.71, 127.21, 129.10, 129.41, 133.21, 133.80, 138.37,
166.38. Anal. Calc. for C16H16N2Se: C, 60.95; H, 5.08;
N, 8.85. Found: C, 61.46; H, 4.72; N, 9.01. n(CÄS): 1485
2.1.16. Preparation of 1,3-di(2-
phenylethyl)benzimidazole-2-dithiote (19)
To a solution of 9 (0.5 g 0.77 mmol) in toluene (15 ml)
was added CS2 (0.1 ml, 1.65 mmol). A red precipitate
was formed instantly. The red compound was washed
cmꢂ1
.

H. Kucukbay et al. / Il Farmaco 58 (2003) 431ꢀ
/
437
435
¨¸¨
Table 1
The MICs (mg/ml) of the tested compounds
Comp. no. Enterococcus faecalis (ATCC
29212)
Staphylococcus aureus (ATCC
29213)
Escherichia coli (ATCC
25922)
Pseudomonas aeruginosa (ATCC
27853)
Ampicillin
0.78
400
0.39
400
3.12
800
ꢀ75
/
1
2
800
800
800
800
800
800
800
800
800
50
800
800
400
800
800
800
200
50
400
ꢀ
ꢀ
ꢀ
ꢀ
/
800
800
800
800
800
800
800
800
50
ꢀ
/
3
ꢀ
/
ꢀ
/
800
200
800
800
800
200
50
/
ꢀ
/
4
/
ꢀ
/
5
ꢀ
/
/
ꢀ
/
6
ꢀ/
ꢀ
/
10
11
12
13
14
15
16
17
18
19
20
ꢀ
/
ꢀ/
200
50
200
100
400
800
200
800
400
50
800
800
800
800
800
800
800
800
800
800
800
800
800
800
400
800
200
800
400
200
ꢀ
ꢀ
ꢀ
ꢀ
/
ꢀ
/
/
ꢀ
/
/
ꢀ
/
/
ꢀ/
twice with Et2O and dried in vacuo. Yield: 0.45 g, 73%,
m.p.: 191ꢀ192 8C.
1H NMR (CDCl3): d 2.9 (t, CH2CH2Ph, 4H), 4.2 (t,
CH2CH2Ph, 4H), 6.7-7.2 (m, Arꢀ
H, 14H). 13C NMR
(CDCl3): d 35.83, 47.73, 112.70, 126.42, 127.65, 129.29,
129.40, 130.29, 137.29, 152.78, 224.60. Anal. Calc. for
C24H22N2S2: C, 71.64; H, 5.47; N, 6.96. Found: C,
71.48; H, 5.43; N, 6.89%.
2.2. Microbiology
/
Antimicrobial activities of the compounds were
determined by using agar dilution procedure outlined
by the National Committee for Clinical Laboratory
standards [25,26]. Minimal inhibitory concentrations for
each compound were investigated against standard
bacterial strains; E. faecalis (ATCC 29212), S. aureus
(ATCC 29213), E. coli (ATCC 25922), P. aeruginosa
(ATCC 27853) and yeast-like fungi; C. albicans and C.
tropicalis obtained from the Department of Microbiol-
ogy, Faculty of Medicine, Ege University, Turkey. The
stock solutions were prepared in dimethyl sulfoxide
(DMSO) and DMSO had no effect on the microorgan-
isms in the concentrations studied. All of the dilutions
were done with distillated water. The concentrations of
tested compounds were 800, 400, 200, 100, 50, 25, 12.5
and 6.25 mg/ml. Ampicilin and flucanazole from FAKO
(Istanbul, Turkey) were used as a reference compound
for the experimental conditions. A loopfull (0.01 ml) of
the standardised inoculum of the bacteria and fungi (106
CFUs/ml) was spreaded over the surface of agar plates.
All the inoculated plates were incubated at 35 8C and
/
Similarly, compound 18 was synthesised from 7 and
CS2.
1
Yield: 82%, m.p.: 201ꢀ
/
202 8C. H NMR (CDCl3): d
1.1 (t, CH2CH3, 3H), 2.9 (t, CH2CH2Ph, 2H), 4.1 (t,
CH2CH2Ph, 2H), 4.2 (q, CH2CH3, 2H), 6.9ꢀ7.2 (m,
Arꢀ
H, 9H). 13C NMR (CDCl3): d 14.81, 35.84, 41.44,
/
/
47.66, 112.69, 112.86, 126.51, 127.61, 129.81, 129.34,
129.91, 130.68, 137.29, 152.88, 224.56. Anal. Calc. for
C18H18N2S2: C, 66.26; H, 6.75; N, 8.59. Found: C,
66.43; H, 6.80; N, 8.06%.
2.1.17. Preparation of 2-cyanomethyl-1-ethyl-3-(2-
phenylethyl)benzimidazolidine (20)
To a solution of bis[1-ethyl-3-(2-phenylethyl)benzimi-
dazolidine-2-ylidene] (7) (0.75 g, 1.50 mmol) in toluene
(10 ml) was added acetonitrile (0.2 ml, 3.75 mmol) and
heated at reflux for 2 h. All volatiles were then driven off
in vacuo, the crude product was crystallised from
results were evaluated after 16ꢀ20 h for bacteria and 48
/
h for fungi. The lowest concentration of the compounds
that prevented visible growth was considered to be
minimal inhibitor concentrations (MICs).
toluene/n ꢀ
/
hexane mixture (2:1). Yield: 0.48 g; 83%,
1
m.p.: 82ꢀ83 8C. H NMR (CDCl3): d 1.1 (t, CH2CH3,
/
3H), 2.6 (d, CH2CN, 2H), 3.0 (t, CH2CH2Ph, 2H), 3.2
(t, CH2CH2Ph, 2H), 3.3 (q, CH2CH3, 2H), 5.0 (t, CH,
3. Results and discussion
1H), 6.4ꢀ
/
6.8 (m, Arꢀ
/
H, 4H), 7.2 (s, Arꢀ
/
H, 5H). n(CN)
:
The structure of all compounds synthesised were
identified by 1H NMR, 13C NMR, FT-IR (Fourier
transformation-infrared) and elemental analysis. 1H
2210 cmꢂ1. Anal. Calc. for C19H21N3: C, 78.35; H, 7.22;
N, 14.43. Found: C, 78.32; H, 7.22; N, 14.44%.

436
H. Kucukbay et al. / Il Farmaco 58 (2003) 431ꢀ
/
437
¨¸¨
Table 2
The MICs (mg/ml) of the tested compounds
Consideration of the structural formula of the com-
pounds that exhibited some antibacterial activity, the
selenium moiety in compounds 12 and 14 may play a
role for the activity, and even selenium itself has some
biological properties [27]. The compounds tested here
generally do not show antimicrobial activity against
gram-negative bacteria. The antimicrobial activity
against gram-positive bacteria may depend on the
difference between cell structures of gram-positive and
gram-negative bacteria.
Comp. no.
Tested organisms
Candida albicans
Candida tropicalis
Fluconazole
1.25
400
1.25
400
1
2
ꢀ
ꢀ
/
800
800
400
400
800
800
800
400
800
400
800
50
ꢀ
ꢀ/
/
800
800
400
400
800
800
800
400
800
400
800
50
3
/
4
5
10
11
12
13
14
15
16
17
18
19
20
ꢀ
ꢀ
/
ꢀ
/
/
ꢀ/
Acknowledgements
We wish to thank Inonu University (grant no. 2000/
¨ ¨
05) for financial support for this study.
400
200
400
400
200
400
References
NMR, 13C NMR, IR, colour, yields, melting points (or
boiling points) and analytical data of the newly synthe-
sised compounds are given in experimental section. The
antimicrobial and antifungal activity results (MIC
values) are given in Tables 1 and 2, respectively. Tables
1 and 2 also contain ampicilin and flucanozole reference
compounds results, respectively, for all microorganisms
used in this work to compare and the reliability of the
method used.
[1] M.F. Lappert, The coordination chemistry of electron-rich
alkenes (enetetramines), J. Organomet. Chem. 358 (1988) 185ꢀ
/
214.
[2] H. Bock, H. Borrmann, Z. Havlas, H. Oberhammer, K. Ruppert,
A. Simon, Structures of sterically overcrowded and charge-
perturbed molecules. 12. tetrakis(dimethylamino) ethene an
extremely electron-rich molecule with unusual structure both in
the crystal and in the gas-phase, Angew. Chem., Int. Ed. Engl. 30
(1991) 1678ꢀ1681.
/
[3] B. C¸ etinkaya, G.H. King, S.S. Krishnamuthy, M.F. Lappert, J.B.
Pedley, Photoelectron spectra of electron-rich olefins and an
isostructural boron compound olefins of exceptionally low first
ionisation potential, J. Chem. Soc., Chem. Commun. (1971)
In this study, seventeen new benzimidazole derivatives
were tested against standard strains of gram-positive
and gram-negative bacteria. As it can be seen in Table 1,
the compounds 1, 2, 4, 11, 12, 13, 14, 15, 17, 19 and 20
inhibited the growth of gram-positive bacteria with
MICs between 50 and 400 mg/ml. None of the com-
pounds studied here except contain tellurium showed
antimicrobial activity against gram negative bacteria.
But the antibacterial activity of the compound 13
particularly against gram negative bacteria, E. coli and
P. aeruginosa may not be related to their molecular
structure since the compound 13 slightly air sensitive in
the solid state and unstable in solution, depositing
tellurium. Therefore the antimicrobial activity probably
originates from metallic tellurium. Similar observations
were also observed in our previously study [23]. As
shown in Table 2, the compounds 1, 4, 5, 13, 15, 17, 18,
19 and 20 also showed activity against C. albicanis and
C. tropicalis with a range of MICs between 50 and 400
mg/ml. Among the tested compounds, 17 was the most
effective compound with MIC 50 mg/ml against C.
albicanis and C. tropicalis. The antifungal activity of
the compound 17 may relate spiro structure and
hydantoin moiety of the compound.
1370ꢀ/1.
[4] E. .Cetinkaya, P.B. Hitchcock, H. Kucukbay, M.F. Lappert, S.
¸
¸
¨ ¨
Al-Juaid, XXIV, Preparation and characterization of two enete-
tramine-derived carbenerhodium(I) chloride complexes
RhCl(LR)3 and [RhCl(COD)LR] {LRꢁ
N(Me)C(CH4CNMe-o}
and the preparation and X-ray structures of the enetetramine L22
and its salt [L22][BF4]2, J. Organomet. Chem. 481 (1994) 89ꢀ
95.
[5] H. Kucukbay, B. .Cetinkaya, S. Guesmi, P.H. Dixneuf, New
/
/
¸
¸
¨ ¨
(carbene) rutheniumꢀ
catalytic synthesis of furans, Organometallics 15 (1996) 2434ꢀ
/
arene complexes: preparation and uses in
/
2439.
[6] M.F. Lappert, R.K. Maskell, A new class of benzoin condensa-
tion catalyst, the bi-(1,3-dialkylimidazolidin-2-ylidenes), J. Chem.
Soc., Chem. Commun. (1982) 580ꢀ
/
1.
[7] E. .Cetinkaya, H. Kucukbay, Effective acyloin condensations
¸
¸
¨ ¨
catalyzed by electron-rich olefins, Turk. J. Chem. 19 (1995) 24ꢀ
/
30.
[8] H.W. Wanzlick, E. Schikora, Ein nucleophiles carben, Chem. Ber.
94 (1961) 2389ꢀ2393.
/
[9] J. Hocker, R. Merten, Reactions of electron-rich olefins with
proton-active compounds, Angew. Chem., Int. Ed. Engl. 11
(1972) 964ꢀ
[10] R.W. Hoffmann, Reactions of electron-rich olefins, Angew.
Chem., Int. Ed. Engl. 7 (1968) 754ꢀ765.
/
973.
/
[11] J. Hocker, R. Merten, Reaktionen von ethylentetraminen mit
sulfonamiden und phosphororganischen verbindungen, Leibigs
Ann. Chem. 719 (1978) 16ꢀ28.
/

H. Kucukbay et al. / Il Farmaco 58 (2003) 431ꢀ
/
437
437
¨¸¨
[12] H.W. Wanzlick, H.J. Kleiner, I. Lasch, H.U. Fuldner, H.
¨
Steinmaus, Untersuchungen an benzo- und naphto[2.1-d]thiazo-
[20] H. Kucukbay, E. .Cetinkaya, R. Durmaz, Synthesis and anti-
¸ ¸
¨ ¨
microbial activity of substituted benzimidazole, benzothiazole and
imidazole derivatives, Arzneim.-Forsch./Drug Res. 45 (1995)
lium-salzen, Liebigs Ann. Chem. 708 (1967) 155ꢀ169.
/
[13] J.E. Baldwin, S.E. Branz, J.A. Walker, Radical nature of
[1,3]sigmatropic rearrangements of electron-rich olefins, J. Org.
1331ꢀ1334.
/
[21] H. Kucukbay, B. Durmaz, Antifungal activity of organic and
¸
¨ ¨
organometallic derivatives of benzimidazole and benzothiazole,
Chem. 42 (1977) 4142ꢀ
/
4144.
[14] H. Kucukbay, E. .Cetinkaya, B. Cetinkaya, M.F. Lappert,
Arzneim.-Forsch./Drug Res. 47 (1995) 667ꢀ
/
670.
¸
¸
¸
¨ ¨
Reactions of electron-rich olefins with proton-active compounds,
Synth. Commun. 27 (1997) 4059ꢀ4066.
[15] B. .Cetinkaya, E. Cetinkaya, J.A. Chamizo, P.B. Hitchcock, H.A.
[22] B. .Cetinkaya, E. Cetinkaya, H. Kucukbay, R. Durmaz, Anti-
¸
¸
¸
¨ ¨
microbial activity of carbene complexes of rhodium(I) and
ruthenium(II), Arzneim.-Forsch./Drug Res. 46 (1996) 821ꢀ
823.
[23] B. .Cetinkaya, E. Cetinkaya, H. Kucukbay, R. Durmaz, Synthesis
/
/
¸
¸
Jasim, H. Kucukbay, M.F. Lappert, Synthesis and structures of
¸
¨ ¨
1,3,1?,3?-tetrabenzyl-2,2?-biimidazolidin ylidenes (electron-rich al-
kenes), their aminal intermediates and their degradation products,
¸
¸
¸
¨ ¨
and antimicrobial activity of electron rich olefin derived cyclic
ureas, Arzneim.-Forsch./Drug Res. 46 (1996) 1154ꢀ1158.
[24] R. Durmaz, M. Koroglu, H. Kucukbay, I. Temel, M.K. .Ozer, M.
J. Chem. Soc., Perkin Trans. 1 (1998) 2047ꢀ
/2054.
/
¨
[16] F.E. Hahn, L. Wittenbecher, M. Kuhn, T. Lugger, R. Frohlich, A
¨
¨
¨ ¨
¸
¨
¨
zwitterionic carbeneꢀ
zotetraazafulvalene by a stannylene, J. Organomet. Chem. 617ꢀ
618 (2001) 629ꢀ634.
/
stannylene adduct via cleavage of a diben-
Refiq, E. Cetinkaya, B. Cetinkaya, S. Yologlu, Investigation of
¸ ¸
serum minimal inhibitory concentrations of some benzimidazole,
/
/
imidazole and benzothiazole derivatives and their effects on liver
[17] J. Easmon, G. Puerstinger, T. Roth, H.H. Fiebig, M. Jenny, W.
Jaeger, G. Heinisch, J. Hofmann, 2-Benzoxazolyl and 2-benzimi-
dazolyl hydrazones derived from 2-acetylpyridine: a novel class of
and renal functions, Arzneim.-Forsch./Drug Res. 48 (1998) 1179ꢀ
1184.
/
[25] National Committee for Clinical Laboratory Standards
(NCCLS), Methods for diluation antimicrobial susceptibility tests
for bacteria that grow aerobically, Approved Standard M7-A2,
NCCLS Villanova, PA, 1997.
antitumor agents, Int. J. Cancer 94 (2001) 89ꢀ96.
/
[18] H.S. Gunes, G. Cosar, Synthesis of same hydroxamic acid
¨
derivatives of benzimidazole and their antibacterial and antifun-
gal activities, Arzneim.-Forsch./Drug Res. 42 (1992) 1045ꢀ
1048.
[19] H. Kucukbay, R. Durmaz, M. Guven, S. Gunal, Syntesis of some
/
[26] NCCLS, Reference method for broth diluation antifungal sus-
ceptibility testing of yeasts. Proposed Standard. Document M27-
P. NCCLS, Villanova, PA, 1992.
¸
¨ ¨
benzimidazole derivatives and their antibacterial and antifungal
activities, Arzneim.-Forsch./Drug Res. 51 (2001) 420ꢀ424.
¨
¨
[27] F.Z. Kuc¸ukbay, M. Demir, Selenium speciation in Karakaya dam
¨ ¨
/
lake’s water (TR-Turkey), Turk. J. Chem. 25 (2001) 341ꢀ347.
/