Synthesis and?QSAR studies of?novel 1-substituted-2-aminobenzimidazoles derivatives

Article abstract of DOI:10.1016/j.ejmech.2006.01.002

A series of novel 1-substituted-2-aminobenzimidazole derivatives were synthesized. The structures of the synthesized compounds were confirmed by ¹H-NMR spectra and by elemental analysis. Acute toxicities of these compounds were detected on mice via toxicity (logLD₅₀). QSAR analysis of these chemicals was studied on the relationship between acute toxicity and the octanol/water partition coefficient (LogP). The products were identified by the results of elemental analysis and ¹H-NMR spectra. The toxicity (logLD₅₀) of 2-aminobenzimidazole 1-substituents were correlated well with the partition coefficient LogP, r = 0.9243. The bioactivity (toxicity) of 2-aminobenzimidazoles can be predicted by the molecular structural parameter such as LogP.

Full text of DOI:10.1016/j.ejmech.2006.01.002

European Journal of Medicinal Chemistry 41 (2006) 1080–1083
http://france.elsevier.com/direct/ejmech
Short communication
Synthesis and QSAR studies of novel
1-substituted-2-aminobenzimidazoles derivatives
Xuan Guida *, Han Jianhua, Li Xiaomin
Zhejiang University of City College, Hangzhou 310015, China
Received 15 July 2005; received in revised form 27 December 2005; accepted 3 January 2006
Available online 07 July 2006
Abstract
A series of novel 1-substituted-2-aminobenzimidazole derivatives were synthesized. The structures of the synthesized compounds were con-
firmed by 1H-NMR spectra and by elemental analysis. Acute toxicities of these compounds were detected on mice via toxicity (logLD50). QSAR
analysis of these chemicals was studied on the relationship between acute toxicity and the octanol/water partition coefficient (LogP). The pro-
1
ducts were identified by the results of elemental analysis and H-NMR spectra. The toxicity (logLD50) of 2-aminobenzimidazole 1-substituents
were correlated well with the partition coefficient LogP, r = 0.9243. The bioactivity (toxicity) of 2-aminobenzimidazoles can be predicted by the
molecular structural parameter such as LogP.
© 2006 Published by Elsevier SAS.
Keywords: 2-aminobenzimidazole derivatives; Synthesis; Acute toxicity; QSAR
1. Introduction
and acute toxicities as well as QSAR analysis. At present, there
are four primary QSAR methods in common use: octanol/water
partition coefficient (LogP); linear solvation energy relation-
ship (LSER); molecular connectivity index, and molecular
group contribution. Our choice was to estimate the acute toxi-
city by QSAR analysis using measured LogP values derived
via the protocol described by Ruilan et al. [12], because it is
simple and feasible.
Heterocyclic compounds containing nitrogen occurred
widely in roast food and drugs and possess different pharma-
cological properties due to the oxidation of nitrogen in mole-
cule [1]. The studies recently carried out in many laboratories
dealt mainly with the synthesis of 2-aminobenzimidazole deri-
vatives exhibiting antilipidemic or platelet antiaggregatory ac-
tivity [2], antimicrobial [3], antiinflammatory and analgesic
properties [4], anti-HIV and antitumor activity [5], antiallergic
[6], immunosuppressive, and antiviral activity [7]. Many of
these compounds display affinity at the benzodiazepine recep-
tor [8]; some of them are selective inhibitors of nitric oxide [9]
and the neuronal calcium channel blockers [10]. The 1-substi-
tuted-2-aminobenzimidazoles were not only a sort of vermi-
fuge, but also an intermediate for synthesis of many drugs.
Their biological activities were susceptible to the substituted
groups attaching to the nitrogen atom on the ring [11]. The
goal of the present investigations was to synthesize a series
of novel 1-substituted-2-aminobenzimidazole derivatives and
elucidate their preliminary relationships between structures
2. Chemistry
Eight compounds were synthesized as below: The potas-
sium salt of 2-aminobenzimidazole was first prepared by reac-
tion with powdered potassium hydroxide in acetone at room
temperature, and then submitted to the reaction with a slight
excess of the alkyl halides to give the desired monoalkylated
products (Scheme 1).
3. Results and discussion
3.1. Chemistry
The most common method for the synthesis of 1-substi-
* Corresponding author.
E-mail address: xuangd@zucc.edu.cn (X. Guida).
tuted-2-aminobenzimidazoles derivatives was the N-alkylation
0223-5234/$ - see front matter © 2006 Published by Elsevier SAS.
doi:10.1016/j.ejmech.2006.01.002

X. Guida et al. / European Journal of Medicinal Chemistry 41 (2006) 1080–1083
1081
Scheme 1. The new synthesized compounds were characterized by elemental analyses and 1H-NMR spectra.
in the presence of alkaline reagents using benzimidazole as
3.2. Assessment of acute toxicities
starting material and then amination at 2-position with soda-
mide (prepared in liquid ammonia [13]). This method, how-
ever, was scarcely used at present because of its difficult opera-
tion. Herein we reported a new facile method for the N-
alkylation at 1-position of 2-aminobenzimidazole. The potas-
sium salt was well formed when the powdered potassium hy-
droxide used, which was favorable to the alkylation. The use of
excess of alkyl halides and longer reaction time leaded to the
alkylation on the amino group and to an increase in side pro-
ducts. Melting points and spectral data of the compounds were
collected in Table 1.
The LD50 values for acute toxicities of the selected 1-sub-
stituted-2-aminobenzimidazole derivatives in mice after admin-
istration were summarized in Table 2. Neurotoxicities were the
principal acute toxic effects observed in mice after receiving
the 1-substituted-2-aminobenzimidazole derivatives via intra-
peritoneal (i.p.) route. All the tested compounds resulted in
acute toxic manifestation including tremor, jerky breath,
twitch, jumping. Death occurred mostly within 30 min. For
survived animals, it could return to normal gradually. Autopsy
of the animals that died in the course of experiment and the
Table 1
Some characteristics and spectral data of the compounds
Com-
pound
1
R
m.p. (°C) [lit.]a
Analysesb
H
1H-NMR DMSO δ
C
N
H
182~184
63.32
63.14
65.08
65.29
66.97
67.06
68.73
68.54
69.67
69.81
68.95
69.34
75.02
75.31
69.68
69.70
5.17
5.30
6.07
6.16
6.71
6.88
7.56
7.48
7.86
7.99
6.54
6.40
6.02
5.87
4.93
5.01
31.51
31.56
28.85
28.55
26.32
26.07
23.70
23.98
22.47
22.20
24.51
24.26
18.96
18.83
17.65
17.42
9.72(s,1H,NH) 6.37(s,2H,NH2) 6.86~7.11(m,4H,ArH)
3.48 (s,3H,CH3) 6.36(s,2H,NH2) 6.87~7.12(m,4H,ArH)
2
3
4
5
6
7
8
a
CH3
201~203
(202~203) [14]
158~159
(158) [15]
130
(132~133) [16]
127~128
CH3CH2
CH3CH2CH2
CH3(CH2)2CH2
CH2=CH–CH2
C6H5CH2
FC6H4CH2
1.18~1.21(t,3H,CH3) 3.98~4.03(m,2H,CH2) 6.37(s,2H,NH2)
6.85~7.13(m,4H,ArH)
0.96~1.01(t,3H,CH3) 1.79~1.87(m,2H,CH2) 3.89~3.92(t,2H,CH2)
6.37(s,2H,NH2) 6.88~7.14(m,4H,ArH)
0.93~0.97(t,3H,CH3) 1.35~1.45(m,2H,CH2) 1.73~1.80(m,2H,CH2)
2.89~3.93(t,2H,CH2) 6.38(s,2H,NH2) 6.85~7.10(m,4H,ArH)
4.58~4.59(d,2H,–CH2–) 5.14~5.31(m,2H,=CH2) 5.93~6.00(m,H,
CH) 6.39(s,2H,NH2) 6.89~7.15(m,4H,ArH)
(127~128) [16]
129~130
195~196
(194~195) [17]
192
5.16(s,2H,CH2) 6.39(s,2H,NH2) 6.88~7.12(m,9H,ArH)
5.17(s,2H,CH2) 6.39(s,2H,NH2) 6.74~7.18(m,8H,ArH)
Upper values: found; lower ones: data from reference.
Upper values: found; lower ones: calculated.
b
Table 2
Acute toxicity and overall LogP value in the QSAR studies
Compound
R
LogP
LD50 (mg·kg–1
)
logLD50
Calculateda
Observed
2.833
2.167
1.875
1.567
1.944
1.967
3.033
2.833
1
2
3
4
5
6
7
8
a
H
681
147
75
3.049
2.141
1.557
1.592
2.236
2.287
2.729
2.776
1.047
1.396
1.836
2.270
2.704
2.727
2.951
2.969
CH3
CH3CH2
CH3CH2CH2
CH3(CH2)2CH
CH2=CH–CH2
C6H5CH2
FC6H4CH2
36.9
88
92.6
1080
681
Values calculated according to Eq. (1).

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X. Guida et al. / European Journal of Medicinal Chemistry 41 (2006) 1080–1083
necropsy finding in surviving animals at the end of experimen-
tal period (7 days) revealed no apparent changes in any organs.
These compounds perhaps had acute toxicity towards central
nervous system (CNS). Table 2 summarized the results of the
acute toxicity and QSAR study.
Analysis of the experimental data on the acute toxicity
(LD50) after i.p. application shows that compound 4 is more
toxic than any other compounds. Compounds 1, 8 and 7 show
low toxicity. Others are mid toxic. Substituent at position N1
of 2-aminobenzimidazole plays a crucial role in determining
their effect on acute toxicity. From this table, we can find that
the ranking of toxicity was: 4 > 3 > 5 > 6 > 2 > 1,8 > 7.
Electron-withdrawing group (e.g.–F) and large group (e.g.
benzyl) in the molecule seem to be related to the low toxicity.
According to the equation, we can predict the toxicity of 2-
aminobenzimidazole derivatives and more compounds with
different substituents at other positions can be designed on
the basis of QSAR studies.
4. Experimental
4.1. Chemistry
Melting points of the compounds were determined using
microscopy melting point apparatus and were reported uncor-
1
3.3. QSAR studies
rected. The H-NMR spectra were recorded in DMSO-d6 by
the Avance 400 MHz spectrometer using tetramethylsilane
(TMS) as an internal standard. Elemental analyses were per-
formed by 240C Analyzer and results for C,H,N were within
0.4% of calculated values. All the chemicals and solvents
used in this study were of analytical grade.
QSAR studies were carried out by the existence of correla-
tion between logLD50 and logP as below:
2
(1)
logLD50¼ 7:380 ꢀ 5:719logPþ1:404ðlogPÞ
N = 8, r = 0.9243, s = 0.2458, F = 14.67, R2 = 0.8543.
4.2. Pharmacology
In the above equation, R2 is the square of correlation coeffi-
cient; S is standard error; F is mean square radio; N is the
number of compounds; r is correlation coefficient. According
to the equation, plots of logLD50 against LogP are shown in
Fig. 1.
4.2.1. Acute toxicities
Acute toxicity experiments were carried out using ICR mice
of both sexes weighing 18–30 g. The food and water were
provided according to institutional guidelines. All animals
were provided by Zhejiang Laboratory animal center of Chi-
nese Academy of science. Prior to each experiment, mice were
fastened overnight and allowed free access to water. Various
doses of the 1-substituted-2-aminobenzimidazole derivatives
dissolved in 0.5% carboxymethyl cellulose sodium (CMC–
Na) salt solution were given via intraperitoneal (i.p.) to differ-
ent groups of healthy ICR mice, and each group contained 10
mice (five males and five females). After the administration of
the compounds, mice were observed continuously for any
gross behavioral changes and deaths, and intermittently for
1 week. All animals were sacrificed at seventh day after drug
administration and checked macroscopically for possible da-
mage to the heart, liver, spleen, lung, kidneys and stomach.
Mice of immediate death following drug administration were
also examined for any possible organ damage. LD50 values
were calculated graphically. To ensure that the solvent had no
acute toxicities on ICR mice, a control test was performed with
test medium supplemented with CMC–Na at the same dilutions
as used in the experiment.
The Eq. (1) enable us to conclude that the acute toxicity of
the 2-aminobenzimidazole was related to partition coefficient
LogP, r = 0.9243. If LogP < 2.037, logLD50 is inversely pro-
portional to logP and if LogP > 2.037, it (logLD50) is directly
proportional to LogP. As value of logLD50 is least at
LogP = 2.037 point. If we dropped two values of N (com-
pounds 7 and 8), we can get another Eq. (2):
2
(2)
logLD50¼ 0:929ðlogPÞ ꢀ 4:0279logPþ6:026
r = 0.9856, N = 6.
When we decrease values of N (compounds), the corre-
sponding values of r approaches 1.
Compounds 8 and 7 have different chemical structures,
compound 7 containing benzyl substituent and compound 8
containing –F at position 4 of the benzyl ring substituent.
4.2.2. QSAR studies
Quantitative structure-activity relationship (QSAR) could
provide correlations between toxicological properties and phy-
sico-chemical descriptors of a chemical. We could estimate the
toxicities of chemicals with the QSAR models based on their
easily measured or calculated characteristics. And the applica-
tion of QSAR models could provide scientific basis for the risk
assessments of chemicals.
Octanol/water partition coefficient (LogP) was one of the
most important physico-chemical descriptors in the toxicology
Fig. 1. Plot of logLD50 versus logP values.

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1083
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