Synthesis and antitumour activity of trimethylsilylpropyl substituted benzimidazoles

Article abstract of DOI:10.1016/S0223-5234(01)01241-7

The quaternisation of N-substituted benzimidazoles by heating with various alkyl, allyl, propargyl and benzyl chlorides and bromides leads to the formation of benzimidazolinium salts. The interaction of N-monosubstituted benzimidazoles with various salts (CuCl₂, ZnCl₂, CoCl₂, PdCl₂ and AgNO₃) yielded stable solid complexes. Potential cytotoxic activity of synthesised benzimidazolinium salts and benzimidazole metal complexes was tested in vitro on four monolayer tumour cell lines: MG-22A (mouse hepatoma), HT-1080 (human fibrosarcoma), B16 (mouse melanoma), Neuro 2A (mouse neuroblastoma) and normal mouse fibroblast cells. A preliminary analysis of the structure-activity relationship for the benzimidazole derivatives clearly indicates that the character of substituents in the benzimidazole ring has strong influence on the cytotoxic activity. The insertion of the silicon atom into the N-alkyl chain increases the cytotoxic activity of benzimidazolinium salts significantly, which show a very significant potency in vitro against all studied tumour cell lines, being particularly active in experiments with B16 (mouse melanoma). TD₅₀ for the most active compounds are in the range 0.001-0.008 μg ml^-1. Cytotoxicity of benzimidazole metal complexes (L₂MX₂) strongly depends on the metal nature. 1-(3-Trimethylsilylpropyl)benzimidazole in dose 1 mg kg^-1 inhibits carcinoma S-180 tumour growth by 62% (on ICR mice).

Full text of DOI:10.1016/S0223-5234(01)01241-7

Eur. J. Med. Chem. 36 (2001) 507–515
´
© 2001 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved
PII: S0223-5234(01)01241-7/FLA
Original article
Synthesis and antitumour activity of trimethylsilylpropyl substituted
benzimidazoles
Edmunds Lukevics*, Pavel Arsenyan, Irina Shestakova, Ilona Domracheva, Alena Nesterova,
Olga Pudova
Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga LV-1006, Latvia
Received 29 January 2001; revised 10 May 2001; accepted 16 May 2001
Abstract – The quaternisation of N-substituted benzimidazoles by heating with various alkyl, allyl, propargyl and benzyl chlorides
and bromides leads to the formation of benzimidazolinium salts. The interaction of N-monosubstituted benzimidazoles with various
salts (CuCl2, ZnCl2, CoCl2, PdCl2 and AgNO3) yielded stable solid complexes. Potential cytotoxic activity of synthesised
benzimidazolinium salts and benzimidazole metal complexes was tested in vitro on four monolayer tumour cell lines: MG-22A
(mouse hepatoma), HT-1080 (human fibrosarcoma), B16 (mouse melanoma), Neuro 2A (mouse neuroblastoma) and normal mouse
fibroblast cells. A preliminary analysis of the structure–activity relationship for the benzimidazole derivatives clearly indicates that
the character of substituents in the benzimidazole ring has strong influence on the cytotoxic activity. The insertion of the silicon
atom into the N-alkyl chain increases the cytotoxic activity of benzimidazolinium salts significantly, which show a very significant
potency in vitro against all studied tumour cell lines, being particularly active in experiments with B16 (mouse melanoma). TD50 for
the most active compounds are in the range 0.001–0.008 mg ml−1. Cytotoxicity of benzimidazole metal complexes (L2MX2) strongly
depends on the metal nature. 1-(3-Trimethylsilylpropyl)benzimidazole in dose 1 mg kg−1 inhibits carcinoma S-180 tumour growth
´
by 62% (on ICR mice). © 2001 Editions scientifiques et me´dicales Elsevier SAS
benzimidazoles / benzimidazolinium salts / benzimidazole complexes / cytotoxic activity / antitumour activity
1. Introduction
functionalities) at either N(1) or N(1) and C(4) posi-
tions of aromatic heterocycle [4–6]. N-Substituted
benzimidazol-2-ones have low nanomolar affinity for
the human neuropeptide Y Y5 receptor and behave as
functional antagonists of the Y5 receptor [7]. To
discover new immunosuppressive compounds, a vari-
ety of 5-alkoxy substituted 2-(4-pyridylmethylsulfi-
nyl)benzimidazoles were synthesised and evaluated
for their ability to inhibit protein tyrosine phos-
phatase activities. Enzymatic analysis with several
The benzimidazole ring is an important pharma-
cophore in drug discovery [1]. Copper(II) and silver(I)
complexes of 2-pyridyl-1H-benzimidazoles possess
considerable activity against Staphylococcus aureus,
Staphylococcus epidermidis, Pseudomonas aeruginosa,
Salmonella typhi, Shigella flexneri and Candida albi-
cans [2]. Some N-(nitrophenylsulphonyl)benzimida-
zoles show good antiviral properties against RNA
(Coxsackie B5 and Mumps) viruses [3]. A series of
1,2,4-trisubstituted benzimidazoles was evaluated in
vitro as potent and selective neuropeptide Y Y1 re-
ceptor antagonists. Within this series the activity was
enhanced for compounds with two appropriately po-
sitioned aminoalkyl groups (e.g. 4-piperidinoalkyl
phosphatases
reveals
that
5-isopropoxy-2-[(4-
methylthiopyridyl-2)methylsulfinyl]benzimidazole
shows high specific inhibition against CD45 [8]. 1-
Methyl-2-phenylethynyl-3-(3-phenylpropyn-2-yl)-
benzimidazolinium tetrafluoroborate and trifluoro-
methanesulfonate salts cause extensive cleavage of
super-coiled DNA when incubated under mild condi-
tions. Frank single-strand DNA cleavage is observed
at concentrations as low as 1 mM [9]. Cytotoxicity of
* Correspondence and reprints
E-mail address: sinta@osi.lv (E. Lukevics).

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E. Lukevics et al. / European Journal of Medicinal Chemistry 36 (2001) 507–515
2-alkyl, 2-aryl, and 2-piperazinyl benzimidazole-4,7-
dione derivatives were tested against three cancer cell
lines (mouse lymphocytic leukaemia P388, and human
gastric carcinoma SNU-1 and SNU-16). These com-
pounds showed potent cytotoxicity against all three
cell lines tested and especially SNU-16 was sensitive
to them. 2-Aryl and 2-piperazinyl benzimidazole-4,7-
dione derivatives were more potent than mitomycin C
against P388 and SNU-16 [10]. Significant cytotoxic
activity against several human tumour cell lines was
displayed by 5,6-dichloro-2-(tetrahydropyran-2-yl)-
benzimidazole [11], 6-aziridinylbenzimidazoles [12],
zene–potassium hydroxide system in the presence of
18-crown-6 used as phase-transfer catalyst (the molar
ratio of benzimidazole:alkylating agent:18-crown-6 is
1:1:0.03) affords the corresponding N-alkyl substi-
tuted benzimidazoles 1–3 in high yields. The follow-
ing quaternisation of compounds 1 and 2 by heating
with various alkyl, allyl, propargyl and benzyl chlo-
rides and bromides leads to the formation of benzim-
idazolinium salts 4–25 (figure 1). In the case of
quaternisation by various (chloromethyl)silanes (e.g.
trimethyl(chloromethyl)silane, methyldi(2-furyl)-
(chloromethyl)silane, methyldi(2-thienyl)(chloro-
methyl)silane), the reaction with N-trimethylsilyl-
propylbenzimidazole (1) proceeds with desilylation of
trimethylsilyl group in the alkylating agent and for-
mation of N-trimethylsilylpropyl-N%-methylbenzimi-
dazolyl chloride (4) in good yield. The 1H-NMR
spectroscopic data obtained for compound 4 are simi-
lar to those of corresponding iodide 5 prepared by
heating of benzimidazole 1 with methyl iodide.
N-Monosubstituted benzimidazoles 1 and 3 were
used as ligands for synthesis of complexes 26–34 by
reaction with salts CuCl2, ZnCl2, CoCl2, PdCl2 and
AgNO3 (molar ratio of benzimidazole 1 or 3 with salt
2:1) in ethanol. All obtained complexes L2MXn are
stable solids, poorly soluble in common organic
solvents.
pyrido[1,2-a]benzimidazoles
[13],
3-substituted
pyrrolo[1,2-a]benzimidazoles [14] and 1-(2,6-difluoro-
phenyl)-1H,3H-thiazolo[3,4-a]benzimidazole [15].
Taking into account extensive DNA-cleaving abil-
ity of benzimidazolinium tetrafluoroborate and trifl-
uoromethanesulfonate salts [9], it may be concluded
that they have the potential to function as effective
antitumour agents. These results prompted us to syn-
thesise new silyl substituted benzimidazolinium salts
to investigate their in vitro cytotoxicity, in vivo anti-
tumour activity and the influence on cell morphology.
2. Chemistry
The general synthetic route chosen for preparation
of substituted benzimidazolinium salts included two
stages. Among the possible methods for synthesis of
3. Results and discussion
N-alkylsubstituted
imidazoles
phase-transfer
catalysed (PTC) N-alkylation is one of the simplest
and most convenient routes [16]. The alkylation of
benzimidazole by 1-trimethylsilylprop-3-yl iodide, al-
lyl bromide and heptyl bromide in a two-phase ben-
3.1. In vitro cytotoxic activity
Potential cytotoxic activity of synthesised benzimida-
zolinium salts 6–25 and benzimidazole complexes 26–34
was tested in vitro on four monolayer tumour cell lines:
MG-22A (mouse hepatoma), HT-1080 (human fibrosar-
coma), B16 (mouse melanoma), Neuro 2A (mouse neu-
roblastoma) and normal mouse fibroblast cells. The
experimental evaluations of cytotoxicity are presented in
tables I and II. A preliminary analysis of the structure–
activity relationship for the cytotoxic action clearly indi-
cates the strong influence of the substituents in the
benzimidazole heterocycle on toxic effects in vitro. Ini-
tial N-trimethylsilylpropylbenzimidazole (1) exhibits
high cytotoxic activity (TD50=0.55–2.13 mg ml−1
)
against all cell lines studied. The following quaternisa-
tion of this compound by various alkyl, allyl, propargyl
and benzyl halides as a rule increases cytotoxic effect,
which is especially expressed in the case of mouse
Fig. 1. Synthesis of benzimidazolinium salts 4–25 and benzim-
idazole metal complexes 26–34.

E. Lukevics et al. / European Journal of Medicinal Chemistry 36 (2001) 507–515
509
Table I. Cytotoxic activity of benzimidazolyl salts (TD50, mg ml−1).
melanoma B16. In the series of trimethylsilylpropylbenz-
imidazolinium salts 6–19 the TD50 values change from
0.25 mg ml−1 [R%=(C4H3S)2MeSi(CH2)3 (9) and
Me3SiCꢀCCH2) (13)] to 0.001 mg ml−1 [R%=Et (6) and
Me3Si(CH2)3 (8)] on B16 cell line. Methoxybenzyl
derivative 15 exhibits the highest cytotoxicity on B16
among benzylbenzimidazolinium salts (14–16). For
compounds with unsaturated substituent R% (salts 11–
13) the activity increases in the order: Me3SiCꢀCCH2<
HCꢀCCH2<CH2ꢁCHCH2 for all cell lines. The

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E. Lukevics et al. / European Journal of Medicinal Chemistry 36 (2001) 507–515
Table II. Cytotoxic activity of benzimidazole metal complexes 26–34 (TD50, mg ml−1).
No.
R
MX2
Colour HT-1080
MG-22A
B16
Neuro 2A
3T3
a
a
a
a
a
TD50 NO,
TD50 NO,
TD50 NO,
%CV b
TD50 NO,
TD50
%CV b
%CV b
%CV b
26
27
28
29
30
31
32
33
34
Me3Si(CH2)3 CuCl2 yellow
Me3Si(CH2)3 ZnCl2 white
Me3Si(CH2)3 CoCl2 blue
Me3Si(CH2)3 PdCl2 grey
Me3Si(CH2)3 AgNO3 white
5
400
4.4 450
0.75 250
0.75 450
0.8 500
3.6 250
2.5 300
1.2
0.4
0.5
200
300
200
2
250
3.6
4.1
1.2
4.1
2.2
–
–
–
–
0.6 250
0.5 450
2
2.9 250
1.5 450
35
4.2
4.9
3.9
5.4
300
200
200
250
500
0.45 200
1.5
1.8
–
–
–
350
333
–
–
–
C7H15
C7H15
C7H15
C7H15
CuCl2 yellow
ZnCl2 white
CoCl2 blue
PdCl2 grey
0.25 1000
300
221
400
21
300
300
158
–
–
–
–
–
–
23
52
15
33
a Concentration (mg ml−1) providing 50% cell killing effect [(CV+MTT)/2].
b NO concentration (%) (CV: coloration).
–, Not tested.
influence of quaternisation is less effective on mouse
hepatoma MG-22A (TD50=1–0.03 mg ml−1) and hu-
silylpropylbenzimidazole derivatives are medium NO-in-
ducers. In general, benzimidazolinium metal complexes
26–34 are more potent NO-inducers than the benzimi-
dazolinium salts 1–25, di(N-heptylbenzimidazole) cop-
per dichloride 31 being the most active (1000% in the
mouse neuroblastoma Neuro 2A).
man fibrosarcoma HT-1080 (TD50=0.55–0.07 mg ml−1
,
with the exception of derivative 13) being almost negligi-
ble on Neuro 2A cell line (TD50=4.5–0.5 mg ml−1).
N-Allylbenzimidazole 2 derivatives bearing methyl (17),
ethyl (18), butyl (19), allyl (21), propargyl (22),
trimethylsilylpropargyl (23), and benzyl (24) substituent
show a slight cytotoxic effect (table I). The substitution
of a short alkyl chain by a nonyl group (salt 20) leads to
a considerable increase of activity (0.4 mg ml−1 on
mouse hepatoma MG-22A and mouse melanoma B16
cell lines). Comparison of the tumour growth inhibition
for trimethylsilylpropyl 6–16 and allyl 17–25 benzimi-
dazolinium salts confirms a significant influence of the
long lipophilic trimethylsilylpropyl group or alkyl chain
on cytotoxic action.
3.2. Cell morphology
The influence of complexes 26–28 on tumour cell
morphology was examined. Figure 2 presents the mor-
phologic structure of human fibrosarcoma HT-1080 cells
at 30 °C (control). The copper complex of N-
trimethylsilylpropylbenziminazole 26 induces the full ne-
crosis of tumour cells (figure 3). In the case of zinc
dichloride complex 27, the cell size does not change after
Inspection of the results presented in table II for
di(N-trimethylsilylpropylbenziminazole) metal com-
plexes 27–30 and its silicon free analogues 32–34 shows
that the insertion of the silicon atom into the N-alkyl
chain defines high level of cytotoxic activity. The only
exception is di(N-trimethylsilylpropylbenzimidazole)
copper dichloride 26 which is a weaker tumour growth
inhibitor than the corresponding alkyl analogue 31.
It has been found that the metal nature in the L2MXn
complexes determine their in vitro activity. The inhibi-
tion ability of trimethylsilylpropyl substituted complexes
26–30 decreases in the following order: Zn>Co>Pd>
Ag>Cu.
Under our experimental conditions several benzimida-
zolinium salts (1, 11–13) exhibit remarkable NO-in-
hibitor properties, however, other active N-trimethyl-
Fig. 2. View of human fibrosarcoma HT-1080 cell fenotype
(30 °C, 24h).

E. Lukevics et al. / European Journal of Medicinal Chemistry 36 (2001) 507–515
511
4. Conclusions
N-Trimethylsilylpropylbenziminazole (1), and its
benzimidazolinium salts and complexes show a very
significant potency in vitro against different tumour
cell lines, being particularly active in experiments with
B16 (mouse melanoma) cell line (TD50 for the most
active compounds are in the range 0.001–0.008 mg
ml−1). In vivo evaluation of benzimidazole (1) also
confirms high antitumour activity against sarcoma
S-180.
5. Experimental
1H-NMR spectra were recorded on a Varian
Mercury 200 spectrometer at 200.06 MHz at 303 K.
The chemical shifts are given relative to TMS from
solvent (CDCl3) signal (lH =7.25). The melting points
Fig. 3. View of HT-1080 cell fenotype with CU complex 26
(30 °C, 24 h).
Fig. 4. View of HT-1080 cell fenotype with Zn complex 27
(30 °C, 24 h).
Fig. 5. View of HT-1080 cell fenotype with Co complex 28
(30 °C, 24 h).
apoptosis (figure 4). Action of complexes 26 and 28
results in HT-1080 cells culture necrosis with cell nucleus
fragmentation (figure 5).
3.3. In vivo antitumour activity
The antitumour activity of N-trimethylsilylpropylben-
zimidazole (1) was tested against sarcoma S-180 in male
ICR mice (18–20 g). In dose 1 mg kg−1 benzimidazole
(1) inhibits the tumour growth by 62%. The higher
concentration (3 mg kg−1) decreases the tumour growth
inhibition to 22% (figure 6).
Fig. 6. Antitumour activity of 1-(3-trimethylsilylpropyl)-
benzimidazole (1).

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E. Lukevics et al. / European Journal of Medicinal Chemistry 36 (2001) 507–515
were determined on a ‘Digital melting point analyser’
(Fisher), and the results are given without correction.
5.1.2.1. N-Methyl-N%-(3-trimethylsilylpropyl)-
benzimidazolyl chloride (4)
Yield 67%, m.p. 221 °C, TLC Rf=0.36 (2-propanol).
1H-NMR (CDCl3, TMS) l (ppm): 0.02 (s, 18H, Me3Si),
0.45–0.65 (m, 2H, CH2Si), 1.85–2.10 (m, 2H, CH2),
4.44 (s, 3H, CH3N), 4.67 (t, 6H, J=7.8 Hz, CH2N),
7.6–7.71 (4H, m, arom), 11.67 (s, 1H, CH). Anal.
(C22H39ClN2Si) C, H, N.
5.1. Chemistry
5.1.1. General method for synthesis of N-substituted
benzimidazoles 1–3
The mixture of benzimidazole (0.02 mol),
1-trimethylsilylprop-3-yl iodide (allyl bromide or heptyl
bromide) (0.02 mol), 18-crown-6 (0.6 mmol) and KOH
(0.06 mol) in benzene (200 ml) was stirred for 6 h at
reflux temperature (GLC control). After reaction
completion the mixture was filtered. Benzene was
evaporated and residue was dried in vacuum to give
products as solids or oils.
5.1.2.2. N-Methyl-N%-(3-trimethylsilylpropyl)-
benzimidazolyl iodide (5)
Yield 87%, m.p. 98–99 °C, TLC Rf=0.38 (2-
1
propanol). H-NMR (CDCl3, TMS) l (ppm): 0.07 (s,
18H, Me3Si), 0.60–0.69 (m, 2H, CH2Si), 2.07–2.12 (m,
2H, CH2), 4.39 (s, 3H, CH3N), 4.71 (t, 6H, J=7.8 Hz,
CH2N), 7.77–7.81 (m, 4H, arom), 11.20 (s, 1H, CH).
Anal (C14H23IN2Si) C, H, N.
5.1.1.1. N-(3-Trimethylsilylpropyl)benzimidazole (1)
Yield 83%, m.p. 63–64 °C. Impurities: <1% (HPLC
on Symmetry C183 3.9×150 mm. Mobile phase: 80%
5.1.2.3. N-(3-Trimethylsilylpropyl)-N%-(ethyl)-
benzimidazolyl bromide (6)
1
acetonitrile+20% H2O. Detector UV 254 nm). H-NMR
(CDCl3, TMS) l (ppm): 0.02 (s, 9H, Me3Si), 0.4–0.64
(m, 2H, CH2Si), 1.65–2.04 (m, 2H, CH2), 4.15 (t, 2H,
J=7.6 Hz, CH2N), 7.22–7.38 (m, 3H, arom), 7.33–7.89
(m, 2H, arom). Anal (C13H20N2Si) C, H, N.
Yield 85%, m.p. 207–208 °C, TLC Rf=0.70 (2-
propanol). H-NMR (CDCl3, TMS) l (ppm): 0.03 (s,
9H, Me3Si), 0.48–0.7 (m, 2H, CH2Si), 1.86–2.28 (m,
4H, CH3+CH2), 4.67 (t, 4H, J=7.6 Hz, CH2N+
CH2N), 7.67–7.76 (m, 4H, arom), 11.51 (s, 1H, CH).
Anal (C15H25BrN2Si) C, H, N.
1
5.1.1.2. N-Allylbenzimidazole (2)
Yield 80%. Impurities: <1% (HPLC on Symmetry
C18, 3.9×150 mm. Mobile phase: 80% acetonitrile+20%
H2O. Detector UV 254 nm). H-NMR (CDCl3, TMS) l
5.1.2.4. N-Nonyl-N%-(3-trimethylsilylpropyl)-
benzimidazolyl chloride (7)
1
(ppm): 4.73 (dt, 2H, J=5.4 Hz, J=1.4 Hz, CH2N),
5.09–5.26 (m, 2H, CH2), 5.88–6.04 (m, 1H, CH),
7.24–7.36 (m, 4H, arom), 7.87 (s, 1H, CH). Anal
(C10H10N2) C, H, N.
Yield 80%, m.p. 164–165 °C, TLC Rf=0.43 (2-
propanol). H-NMR (CDCl3, TMS) l (ppm): 0.02 (s,
18H, Me3Si); 0.42–0.66 (m, 2H, CH2Si); 0.90 (t, 3H,
J=6.3 Hz, CH3); 1.20 (m, 14H, (CH2)7); 1.90–2.10 (m,
2H, CH2); 4.67 (t, 6H, J=7.8 Hz, CH2N); 7.40 (m, 4H,
arom); 11.68 (s, 1H, CH). Anal (C22H39ClN2Si) C, H, N.
1
5.1.1.3. N-Heptylbenzimidazole (3)
Yield 80%. Impurities: <1% (HPLC on Symmetry
C18, 3.9×150 mm. Mobile phase: 80% acetonitrile+20%
H2O. Detector UV 254 nm). H-NMR (CDCl3, TMS) l
5.1.2.5. N,N%-Bis(3-trimethylsilylpropyl)benzimidazolyl
chloride (8)
1
(ppm): 0.85 (t, 3H, J=6.8 Hz Me), 1.27 (m, 8H,
(CH2)4), 1.85 (m, 2H, CH2), 4.12 (t, 2H, J=7.0 Hz,
CH2N), 7.24–7.29 (m, 3H, arom), 7.78–7.82 (m, 1H,
arom), 7.88 (s, 1H, CH). Anal (C14H20N2) C, H, N.
Yield 76%, m.p. >250 °C; TLC Rf=0.53 (2-
propanol). H-NMR (CDCl3, TMS) l (ppm): 0.02 (s,
18H, Me3Si), 0.4–0.64 (m, 4H, CH2Si), 1.84–2.04 (m,
4H, CH2), 4.62 (t, 4H, J=7.8 Hz, CH2N), 7.40 (m, 4H,
arom), 11.62 (s, 1H, CH). Anal (C19H35ClN2Si2) C, H,
N.
1
5.1.2. Preparation of benzimidazolinium salts
The mixture of N-substituted benzimidazole (0.02
mol) in toluene and alkylhalogenide (0.02 mol) was
refluxed with stirring for about 4 h. Then it was allowed
to stand at room temperature overnight to give a solid
product. The precipitate was filtered, washed with tolu-
ene and recrystallised from ethanol.
5.1.2.6. N-(3-Trimethylsilylpropyl)-N%-[3-tris(trimethyl-
siloxy)silylpropyl]benzimidazolyl chloride (9)
Yield 96%, m.p. 94–95 °C (from benzene). H-NMR
(CDCl3, TMS) l (ppm): 0.02 (s, 9H, Me3Si), 0.03 (s,
27H, Me3SiO), 0.51–0.61 (m, 4H, CH2Si), 1.93–2.01 (m,
1

E. Lukevics et al. / European Journal of Medicinal Chemistry 36 (2001) 507–515
513
4H, CH2), 4.10 (m, 4H, CH2N), 7.54–7.70 (m, 4H,
5.1.2.12. N-(3-Trimethylsilylpropyl)-N%-
arom), 11.61 (s, 1H, CH). Anal (C25H53ClN2O3Si5) C,
H, N.
(o-methoxybenzyl)benzimidazolyl bromide (15)
Yield 85%, m.p. 175–176 °C, TLC Rf=0.46 (2-
1
propanol). H-NMR (CDCl3, TMS) l (ppm): 0.04 (s,
5.1.2.7. N-(3-Trimethylsilylpropyl)-N%-[3-methyldi-
(2-thienyl)silylpropyl]benzimidazolyl chloride (10)
Yield 76%, m.p. 150–151 °C, TLC Rf=0.53 (2-
9H, Me3Si), 0.46–0.75 (m, 2H, CH2Si), 1.95–2.26 (m,
2H, CH2), 3.94 (s, 3H, MeO), 4.73 (t, 2H, J=7.6 Hz,
CH2N), 5.80 (s, 2H, CH2); 6.92–7.7 (m, 9H, arom);
11.42 (s, 1H, CH). Anal (C21H29BrN2OSi) C, H, N.
1
propanol). H-NMR (CDCl3, TMS) l (ppm): 0.02 (s,
12H, Me3Si, SiMe), 0.4–0.64 (m, 2H, CH2Si), 1.15–1.20
(m, 2H, CH2Si), 1.94–2.10 (m, 4H, CH2), 4.66 (m, 4H,
CH2N), 7.20–7.29 (m, 4H, arom), 7.47–7.67 (m, 6H,
arom), 11.67 (s, 1H, CH). Anal (C25H35ClN2S2Si2) C, H,
N.
5.1.2.13. N-(3-Trimethylsilylpropyl)-N%-
(p-bromobenzyl)benzimidazolyl bromide (16)
Yield 75%, m.p. 154–155 °C, TLC Rf=0.44 (2-
1
propanol). H-NMR (CDCl3, TMS) l (ppm): 0.02 (s,
9H, Me3Si), 0.44–0.71 (m, 2H, CH2Si), 1.90–2.28 (m,
2H, CH2), 4.62 (q, 2H, J=6.4 Hz, CH2N), 5.98 (s, 2H,
CH2), 7.51–7.86 (m, 8H, arom), 11.53 (s, 1H, CH). Anal
(C16H25Br2N2Si) C, H, N.
5.1.2.8. N-(3-Trimethylsilylpropyl)-N%-(allyl)-
benzimidazolyl bromide (11)
Yield 91%, m.p. 124–125 °C, TLC Rf=0.54
1
(2-propanol). H-NMR (CDCl3, TMS) l (ppm): 0.04 (s,
9H, Me3Si), 0.47–0.64 (m, 2H, CH2Si), 1.96–2.12 (m,
4H, CH2, CH2), 4.65 (dt, 2H, J=4, J=7.6Hz, CH2N),
5.3–5.56 (m, 2H, CH2N), 7.64–7.75 (m, 4H, arom),
11.47 (s, 1H, CH). Anal (Cl16H25BrN2Si) C, H, N.
5.1.2.14. N-Methyl-N%-allylbenzimidazolyl iodide (17)
Yield 91%, m.p. 144–145 °C, TLC Rf=0.19 (2-
propanol). H-NMR (CDCl3, TMS) l (ppm): 4.29 (s,
3H, CH3), 5.27–5.30 (m, 2H, CH2), 5.46–5.60 (m, 2H,
CH2), 6.10–6.19 (m, 1H, CH), 7.63–7.83 (m, 4H, arom),
10.75 (s, 1H, CH). Anal (C11H13N2I) C, H, N.
1
5.1.2.9. N-(3-Trimethylsilylpropyl)-N%-(propargyl)-
benzimidazolyl bromide (12)
Yield 90%, m.p. 164–168 °C; TLC Rf=0.57 (2-
propanol). H-NMR (CDCl3, TMS) l (ppm): 0.03 (s,
5.1.2.15. N-Ethyl-N%-allylbenzimidazolyl bromide (18)
Yield 85%, m.p. 174–175 °C, TLC Rf=0.21 (2-
propanol). H-NMR (CDCl3, TMS) l (ppm): 1.74 (t,
3H, J=7.4 Hz, CH3), 1.69 (t, 2H, J=7.4 Hz, CH2),
5.34–5.37 (m, 2H, CH2), 5.43–5.56 (m, 2H, CH2), 6.07–
6.21 (m, 1H, CH), 7.63–7.83 (m, 4H, arom), 11.19 (s,
1H, CH). Anal (C12H15N2Br) C, H, N.
1
1
9H, Me3Si), 0.46–0.72 (m, 2H, CH2Si), 1.88–2.15 (m,
2H, CH2), 2.64 (t, 2H, J=3 Hz, CH2), 4.61 (m, 2H,
CH2N); 5.71 (d, 1H, J=3 Hz, CH), 7.55–7.97 (m, 4H,
arom), 11.57 (s, 1H, CH). Anal (C16H23BrN2Si) C, H,
N.
5.1.2.10. N-(3-Trimethylsilylpropyl)-N%-
5.1.2.16. N-Butyl-N%-allylbenzimidazolyl chloride (19)
Yield 85%, m.p. 95–97 °C, TLC Rf=0.21 (2-
propanol). H-NMR (CDCl3, TMS) l (ppm): 0.98 (t,
3H, J=7.2 Hz, CH3), 1.40–1.47 (m, 2H, CH2), 1.97–
2.03 (m, 2H, CH2), 4.59–4.68 (m, 2H, CH2N), 5.33–
5.38 (m, 2H, CH2), 5.42–5.53 (m, 2H, CH2), 6.04–6.13
(m, 1H, CH), 7.65–7.76 (m, 4H, arom), 11.61 (s, 1H,
CH). Anal (C14H19N2Cl) C, H, N.
(trimethylsilylpropargyl)benzimidazolyl bromide (13)
Yield 90%, m.p. 90–191 °C, TLC Rf=0.34 (2-
1
1
propanol). H-NMR (CDCl3, TMS) l (ppm): 0.02 (s,
9H, Me3Si), 0.14 (s, 9H, Me3Si), 0.46–0.62 (m, 2H,
CH2Si), 1.88–2.15 (m, 2H, CH2), 4.56 (m, 2H, CH2N),
5.65 (s, 2H, CH2N), 7.67–7.72 (m, 4H, arom), 11.54 (s,
1H, CH). Anal (C19H31BrN2Si2) C, H, N.
5.1.2.11. N-(3-Trimethylsilylpropyl)-N%-
benzylbenzimidazolyl bromide (14)
5.1.2.17. N-Nonyl-N%-allylbenzimidazolyl chloride (20)
Yield 88%, m.p. 95–97 °C; TLC Rf=0.21 (2-
propanol). H-NMR (CDCl3, TMS) l (ppm): 0.98 (t,
3H, J=6.4 Hz, CH3), 1.23–1.36 (m, 10H, CH2), 2.05
(m, 2H, CH2), 2.59 (m, 2H, CH2), 4.58–4.64 (m, 2H,
CH2N), 5.36–5.39 (m, 2H, CH2); 5.42–5.51 (2H, m,
CH2); 6.10–6.13 (1H, m, CH); 7.66–7.71 (4H, m, arom);
11.57 (1H, s, CH). Anal (C19H29N2Cl) C, H, N.
1
Yield 85%, m.p. 128–130 °C, TLC Rf=0.38 (2-
1
propanol). H-NMR (CDCl3, TMS) l (ppm): 0.04 (s,
9H, Me3Si), 0.44–0.7 (m, 2H, CH2Si), 1.90–2.06 (m,
2H, CH2), 4.48 (t, 2H, J=7.6 Hz, CH2N), 5.93 (s, 2H,
CH2), 7.35–7.7 (m, 9H, arom), 11.71 (s, 1H, CH). Anal
(C20H27BrN2Si) C, H, N.

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E. Lukevics et al. / European Journal of Medicinal Chemistry 36 (2001) 507–515
5.1.2.18. N,N%-Bis(allyl)benzimidazolyl bromide (21)
Yield 78%, m.p. 95–97 °C, TLC Rf=0.21 (2-
propanol). H-NMR (CDCl3, TMS) l (ppm): 5.28–5.31
(m, 4H, CH2, CH2), 5.41–5.51 (m, 4H, CH2, CH2),
6.00–6.19 (m, 2H, CH, CH), 7.56–7.74 (m, 4H, arom),
11.31 (s, 1H, CH). Anal (C13H15N2Br) C, H, N.
5.1.3.1. Di[N-(3-trimethylsilylpropyl)benzimidazole]
copper dichloride (26)
1
Yield 81%, m.p. 243–245 °C; 1H-NMR (CDCl3,
TMS) l (ppm): −0.03 (s, 9H, Me3Si), 0.26–0.48 (m, 2H,
CH2Si), 1.91–2.16 (m, 2H, CH2), 4.43 (t, 2H, J=7.6
Hz, CH2N), 7.22–8.38 (m, 4H, arom), 9.78 (s, 1H,
arom). Anal (C26H40N4Cl2CuSi2) C, H, N.
5.1.2.19. N-Allyl-N%-propargylbenzimidazolyl bromide
(22)
5.1.3.2. Di[N-(3-trimethylsilylpropyl)benzimidazole] zinc
dichloride (27)
Yield 85%, m.p. 154–156 °C; 1H-NMR (CDCl3,
TMS) l (ppm): −0.04 (s, 9H, Me3Si), 0.31–0.48 (m, 2H,
CH2Si), 1.80–2.06 (m, 2H, CH2), 4.30 (t, 2H, J=7.2
Hz, CH2N), 7.27–8.11 (m, 4H, arom), 8.53 (s, 1H,
arom). Anal (C26H40N4Cl2Si2Zn) C, H, N.
Yield 83%, m.p. 177–178 °C, TLC Rf=0.31
1
(2-propanol). H-NMR (CDCl3, TMS) l (ppm): 1.94 (d,
1H, J=1.4 Hz, CH), 5.29–5.32 (m, 2H, CH2),
5.48–5.86 (m, 2H, CH2), 5.66–5.68 (m, 2H, CH2),
6.03–6.21 (m, 1H, CH), 7.64–7.97 (m, 4H, arom), 11.45
(s, 1H, CH). Anal (C13H13N2Br) C, H, N.
5.1.3.3. Di[N-(3-trimethylsilylpropyl)benzimidazole]
cobalt dichloride (28)
5.1.2.20. N-Allyl-N%-(3-trimethylsilylpropargyl)-
benzimidazolyl bromide (23)
Yield 78%, m.p. 140–143 °C; 1H-NMR (CDCl3,
TMS) l (ppm): −0.05 (9H, 5, Me3Si); 0.31–0.48 (2H, m,
CH2Si); 1.64–1.98 (2H, m, CH2); 5.62 (2H, t, J=7.2
Hz, CH2N); 7.27–8.04 (4H, m, arom); 7.76 (1H, s,
arom). Anal (C26H40N4Cl2CoSi2) C, H, N.
Yield 88%, m.p. 144–145 °C, TLC Rf=0.26 (2-
1
propanol). H-NMR (CDCl3, TMS) l (ppm): 0.14 (s,
9H, Me3Si), 5.29–5.32 (m, 2H, CH2), 5.47–5.49 (m, 2H,
CH2), 5.57–5.61 (m, 2H, CH2), 6.04–6.21 (m, 1H, CH),
7.64–7.95 (m, 4H, arom), 11.37 (s, 1H, CH). Anal
(C16H21N2BrSi) C, H, N.
5.1.3.4. Di[N-(3-trimethylsilylpropyl)benzimidazole]
palladium dichloride (29)
Yield 87%, m.p. 210–212 °C; 1H-NMR (CDCl3,
TMS) l (ppm): −0.03 (s, 9H, Me3Si), 0.43–0.50 (m, 2H,
CH2Si), 1.81 (m, 2H, CH2), 4.35 (t, 2H, J=7.2 Hz,
CH2N), 7.38–8.37 (m, 4H, arom), 8.80 (s, 1H, arom).
Anal (C26H40N4Cl2Si2Pd) C, H, N.
5.1.2.21. N-Allyl-N%-benzylbenzimidazolyl bromide (24)
Yield 82%, m.p. 200–201 °C, TLC Rf=0.23 (2-
1
propanol). H-NMR (CDCl3, TMS) l (ppm): 5.29–5.32
(m, 2H, CH2), 5.45–5.49 (m, 2H, CH2), 5.89 (s, 2H,
CH2), 6.04–6.20 (m, 1H, CH), 7.27–7.59 (m, 9H, arom),
11.66 (s, 1H, CH). Anal (C17H17N2Br) C, H, N.
5.1.3.5. Di[N-(3-trimethylsilylpropyl)benzimidazole]
silver nitrate (30)
Yield 89%, m.p. 160–162 °C; 1H-NMR (CDCl3,
TMS) l (ppm): −0.02 (s, 9H, Me3Si), 0.28–0.44 (m, 2H,
CH2Si), 1.90–2.12 (m, 2H, CH2), 4.40 (t, 2H, J=7.6
Hz, CH2N), 7.12–8.38 (m, 4H, arom), 9.55 (s, 1H,
arom). Anal (C26H40N5AgO3Si2) C, H, N.
5.1.2.22. N-Allyl-N%-(p-bromobenzyl)benzimidazolyl
bromide (25)
Yield 85%, m.p. 178–180 °C, TLC Rf=0.24 (2-
1
propanol). H-NMR (CDCl3, TMS) l (ppm): 5.26–5.29
(m, 2H, CH2), 5.45–5.54 (m, 2H, CH2), 5.94 (s, 2H,
CH2), 6.07–6.16 (m, 1H, CH), 7.47–7.72 (m, 8H, arom),
11.57 (s, 1H, CH). Anal (C17H16N2Br2) C, H, N.
5.1.3.6. Di[N-(heptyl)benzimidazole] copper dichloride
(31)
Yield 81%, m.p. 198–200 °C; 1H-NMR (CDCl3,
TMS) l (ppm): 0.91 (t, 3H, J=6 Hz, CH3), 1.23 (m,
8H, (CH2)4), 1.81 (m, 2H, CH2), 3.34 (m, 2H, CH2N),
7.30–7.87 (m, 4H, arom), 8.22 (s, 1H, CH). Anal
(C28H40N4Cl2Cu) C, H, N.
5.1.3. Preparation of metal complexes in ethanol–water
A 5 ml aqueous solution of metal salts (0.02 mol) and
0.04 mol ligand in 10 ml of ethanol in a reaction tube
was stirred vigorously. The mixture was refluxed by
stirring for about 4 h. The mixture was then allowed to
stand at room temperature overnight to give a solid
product. This was then filtered, washed with water and
ethanol, and dried in vacuo over anhydrous CaCl2.
5.1.3.7. Di[N-(heptyl)benzimidazole] zinc dichloride (32)
Yield 80%, m.p. 134–136 °C; 1H-NMR (CDCl3,
TMS) l (ppm): 0.82 (t, 3H, J=6 Hz, CH3), 1.20 (m,

E. Lukevics et al. / European Journal of Medicinal Chemistry 36 (2001) 507–515
515
8H, (CH2)4), 1.79 (m, 2H, CH2), 4.36 (t, 2H, J=7.1 Hz,
CH2N), 7.30–7.87 (m, 4H, arom), 8.64 (s, 1H, CH). Anal
(C28H40N4Cl2Zn) C, H, N.
mice used in each group was between six and ten. The
efficacy of the treatment was estimated by the ellipsoid
formula, and V of control group was taken in calcula-
tions for 100%.
5.1.3.8. Di[N-(heptyl)benzimidazole] cobalt dichloride
(33)
Acknowledgements
Yield 90%, m.p. 120–121 °C; 1H-NMR (CDCl3,
TMS) l (ppm): 0.89 (t, 3H, J=6 Hz, CH3), 1.31 (m, 8H,
(CH2)4), 2.53 (m, 2H, CH2), 3.57 (m, 2H, CH2N), 7.30–
7.87 (m, 4H, arom), 8.12 (s, 1H, CH). Anal
(C28H40N4Cl2Co) C, H, N.
The authors are grateful to the Latvian Taiho Foun-
dation for financial assistance. We wish to thank Dr.
Juris Popelis for NMR spectroscopic studies.
References
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