Synthesis and antibacterial activity of novel ethyl 2-alkoxyimino-2-benzimidazol-2-yl acetates bearing a morpholine group

Article abstract of DOI:10.1007/s11164-013-1437-0

In the search for new benzimidazole derivatives with high antibacterial activity and for which bacterial resistance is low, novel ethyl 2-(alkoxyimino)-2-[1-(4-morpholinocarbonylmethyl)-1H-benzimidazol-2-yl]acetates have been synthesized by multi-step rea

Full text of DOI:10.1007/s11164-013-1437-0

Res Chem Intermed
DOI 10.1007/s11164-013-1437-0
Synthesis and antibacterial activity of novel ethyl
2-alkoxyimino-2-benzimidazol-2-yl acetates bearing
a morpholine group
•
•
•
•
Peizhi Zhang Fuxian Wan Ying Li Chengkun Li
Lin Jiang
Received: 11 August 2013 / Accepted: 3 October 2013
Ó Springer Science+Business Media Dordrecht 2013
Abstract In the search for new benzimidazole derivatives with high antibacterial
activity and for which bacterial resistance is low, novel ethyl 2-(alkoxyimino)-2-
[1-(4-morpholinocarbonylmethyl)-1H-benzimidazol-2-yl]acetates have been syn-
1
thesized by multi-step reactions and characterized by H NMR, IR, and ESI–MS
analysis. The compounds were evaluated for in-vitro antibacterial activity against
Escherichia coli and Staphylococcus aureus. The results revealed that four of the
compounds had excellent bioactivity against S. aureus, with IC50 values of
12.72–26.58 lg/mL, even better than that of the control agent (levofloxacin
hydrochloride).
Keywords Benzimidazole ꢀ N-Alkoxyimine ꢀ Morpholine ꢀ Synthesis ꢀ
Antibacterial activity
Introduction
Antibacterial drugs are widely used clinically and are important in disease control
and treatment. In recent years, however, increasing and unreasonable use of
antibacterial drugs have resulted in the development of resistant pathogens [1–3],
and overcoming drug resistance has become a crucial issue in antibacterial medicine
research. The development of new antibacterial agents with novel structures is an
important strategy for solving the problem of bacterial resistance.
Benzimidazole derivatives have attracted much interest because of their broad
biological activity, for example antibacterial [4], antifungal [5], antitumor [6],
anticancer [7], and anti-inflammatory [8] activity. As antimicrobial agents,
P. Zhang ꢀ F. Wan ꢀ Y. Li ꢀ C. Li ꢀ L. Jiang (&)
College of Chemistry and Material Science, Shandong Agricultural University,
Tai’an 271018, China
e-mail: jiangl@sdau.edu.cn
123

P. Zhang et al.
especially, these derivatives have been extensively studied [9]. For example,
dibenzyl ether bearing a benzimidazole group has high antibacterial activity which
can effectively inhibit Staphylococcus aureus, methicillin-resistant S. aureus
(MRSA), and Escherichia coli, with MIC values of 3.12–6.25 lg/mL [10].
4-Benzimidazol-2-yl benzoyl hydrazone has good inhibitory activity against
E. coli, Bacillus proteus, Klebsiella pneumoniae, and Pseudomonas aeruginosa,
with MIC values of 6.25–50 lg/mL [5]. N-Alkoxyimines have also attracted much
attention, because of their remarkable biological activity, for example antibacterial
[11], antifungal [12], insecticidal [13], and herbicidal [14] activity. Moreover, many
N-alkoxyimine derivatives have the advantages of high efficiency and low toxicity,
and are environmentally friendly. Many benzimidazole derivatives bearing a
morpholine group have antimicrobial activity, e.g. antibacterial and antifungal
activity [15–17]. Motivated by these findings, and in continuation of our interest in
the synthesis and bioactivity of benzimidazole derivatives [18, 19], we have
attached an N-alkoxyimine group to a benzimidazole ring. Also, to improve
penetration of pathogen cells, we linked an ester moiety to the molecule. Thus, we
designed and synthesized ten novel ethyl 2-(alkoxyimino)-2-[1-(4-morpholinocar-
bonylmethyl)-1H-benzimidazol-2-yl]acetates, and evaluated their antibacterial
activity against two types of bacteria. The synthetic pathway is shown in Scheme 1.
Experimental
Chemicals and instruments
Commercial reagents were purchased from Aladdin Chemistry (Shanghai, China)
and BASF Chemical (Tianjin, China). Melting points were determined on an X-5
microscope melting point apparatus and are uncorrected. IR spectra were recorded
on a Shimadzu IR-440 infrared spectrophotometer, as KBr discs or as films of
solutions in CHCl3. 1H NMR spectra were acquired on a Bruker AM-400
spectrometer with CDCl3 as solvent and TMS as internal standard. ESI mass spectra
were acquired on an Agilent 6410 triple-quadrupole mass spectrometer. Microwave-
assisted synthesis was performed in an XH-100B microwave reactor.
1H-Benzimidazol-2-yl acetonitrile (1) was synthesized in accordance with a
procedure reported elsewhere [20]. The key intermediate ethyl 2-(1H-benzimidazol-
2-yl)acetate (2) was prepared in accordance with Ref. [21].
Synthesis of ethyl 2-(1H-benzimidazol-2-yl)-2-hydroxyimino acetate 3
A solution of 4.08 g (20 mmol) compound 2 in glacial acetic acid (30 mL) was
added dropwise to 45 % aqueous sodium nitrite solution (10 mL, 65 mmol) at
0–5 8C under a nitrogen atmosphere. The reaction mixture was stirred at 20 8C for
2 h then poured into ice–water and neutralized with saturated sodium carbonate
solution. The precipitate was isolated by filtration, washed with water, and vacuum
dried. The solid obtained was recrystallized from methanol–diethyl ether (2:1 v/v) to
give compound 3 (3.34 g; yield 72 %) as pale yellow crystals, m.p. 152.3–153.9 8C.
123

Novel ethyl 2-alkoxyimino-2-benzimidazol-2-yl acetates
H
O
N
O
N
N
N
a
b
H
H
3
O
C
O
C
3
N
H
N
H
N
H
CN
O
1
2
3
R
N
H
O
O
O
N
O
N
N
N
O
H
C
H
C
c
3
d
3
N
O
O
O
N
N
O
O
4
a-
5
5
j
Scheme 1 Synthetic route to compounds 5a–j. Reagents and conditions: a 95 % EtOH, H2SO4, reflux,
6 h; b NaNO2, AcOH, 0–5 8C, 2 h, c 4-(chloroacetyl)morpholine, K2CO3, MeCN, microwave, 6 min;
d RX or ArCH2X, K2CO3, TABI, acetone, r.t., overnight
1H NMR (400 MHz, CDCl3) d: 1.44–1.49 (t, J = 7.2 Hz, 3H, CH3), 4.47–4.53 (q,
J = 7.2 Hz, 2H, CH2), 7.26–7.69 (m, 4H, ArH), 11.06 (s, 1H, OH). IR (KBr) m
(cm-1): 3416 (N–H), 3258 (O–H), 3070 (Ar–H), 1714 (C=O), 1622 (C=N), 1279,
1043 (C(O)–O–C). ESI–MS m/z: calcd for C11H11N3O3 [M ? Na]? 256.2, obsd
[M ? H]? 256.4.
Synthesis of ethyl 2-(hydroxyimino)-2-[1-(4-morpholinocarbonylmethyl)-1H-
benzimidazol-2-yl]acetate 4
Method A A mixture of compound 3 (3.3 g, 14 mmol), anhydrous potassium
carbonate (2.4 g, 14 mmol), and 4-(chloroacetyl)morpholine (2.5 g, 15 mmol) in
acetone (70 mL) was heated under reflux for 2 h. After cooling to room
temperature, the precipitate was isolated by filtration and the solvent was removed
from the filtrate by rotary evaporation, leaving an oily residue which was purified by
silica gel chromatography with acetone–petroleum ether (1:5 v/v) to furnish
compound 4 (1.48 g; yield 30 %) as a white solid.
Method B A well-ground mixture of compound 3 (0.47 g, 2 mmol), anhydrous
potassium carbonate (0.28 g, 2 mmol), and dibenzo-18-crown-6 (0.10 g) was added
to a solution of 4-(chloroacetyl)morpholine (0.33 g, 2 mmol) in acetonitrile
(10 mL). The reaction mixture was placed in a microwave reactor and subjected
to microwave irradiation (500 W) for 6 min. After cooling to room temperature, the
mixture was filtered and the solvent was removed from the filtrate by rotary
evaporation to afford a pale yellow solid. The solid was washed with an appropriate
amount of water–acetonitrile (3:1 v/v) to give compound 4 (0.37 g; yield 51 %) as a
white solid.
123

P. Zhang et al.
M.p. 176.8–178.3 8C (from acetone–H2O). 1H NMR (400 MHz, CDCl3) d: 1.38–
1.42 (t, 3H, J = 7.2 Hz, CH3), 3.40–3.77 (m, 8H, morpholine-H), 4.45–4.51 (q, 2H,
J = 7.2 Hz, COOCH2), 5.12 (s, 2H, NCH2), 7.26–7.89 (m, 4H, ArH), 12.36 (s, 1H,
OH). IR (KBr) m (cm-1): 3249 (O–H), 3078 (Ar–H), 1748 (C=O), 1672 (C=O),
1272, 1,064 (C(O)–O–C). ESI–MS m/z: calcd for C17H20N4O5 [M ? Na]? 383.4,
obsd 383.6.
General procedure for synthesis of ethyl 2-(alkoxyimino)-2-[1-(4-
morpholinocarbonylmethyl)-1H-benzimidazol-2-yl]acetates 5a–5j
A mixture of compound 4 (1.5 mmol), anhydrous potassium carbonate (2.8 g,
20 mmol), the corresponding halohydrocarbon (1.5 mmol), and tetrabutylammo-
nium iodide (TBAI, 0.1 g) in anhydrous acetone (20 mL) was stirred at room
temperature overnight. The solvent was removed by rotary evaporation, furnishing
an oily residue which was purified by silica gel chromatography with dichloro-
methane–methanol (20:1 v/v) to give compounds 5a–5j.
Ethyl 2-(methoxyimino)-2-[1-(4-morpholinocarbonylmethyl)-1H-benzimidazol-2-
yl]acetate 5a
1
White solid, yield 66 % (0.37 g), m.p. 142.2–144.8 8C (from ethanol–H2O). H
NMR (400 MHz, CDCl3) d: 1.33 (t, 3H, J = 7.2 Hz, COOCH2CH3), 3.32–3.67 (m,
8H, morpholine-H), 3.89 (s, 3H, NOCH3), 4.37 (q, 2H, J = 7.2 Hz, COOCH2), 4.95
(s, 2H, NCH2), 7.26–7.83 (m, 4H, ArH). IR (KBr) m (cm-1): 3053 (Ar–H), 1734
(C=O), 1660 (C=O), 1614 (C=N), 1239, 1029 (C(O)–O–C). ESI–MS m/z:
[M ? Na]? 397.2, [M ? H]? 375.3, [M – 101 – OR]? 242.5, herein 101 means
the weight of (methyl ? morpholinyl). HRMS m/z: [M ? Na]? calcd for
C18H22N4O5 397.3808, obsd 397.3802.
Ethyl 2-(ethoxyimino)-2-[1-(4-morpholinocarbonylmethyl)-1H-benzimidazol-2-
yl]acetate 5b
1
White solid, yield 49 % (0.29 g), m.p. 117.1–118.7 8C (from ethanol–H2O). H
NMR (400 MHz, CDCl3) d: 1.31 (t, 3H, J = 7.2 Hz, COOCH2CH3), 1.45 (t, 3H,
J = 7.2 Hz, NOCH2CH3), 3.31–3.67 (m, 8H, morpholine-H), 4.32–4.39 (m, 4H,
COOCH2- and NOCH2), 4.94 (s, 2H, NCH2), 7.27–7.83 (m, 4H, ArH). IR (KBr) m
(cm-1): 3062 (Ar–H), 1735 (C=O), 1,655 (C=O), 1618 (C=N), 1238, 1027 (C(O)–
O–C). ESI–MS m/z: [M ? Na]? 411.4, [M ? H]? 389.4, [M – 101 – OR]? 242.7.
HRMS m/z: [M ? Na]? calcd for C19H24N4O5 411.4074, obsd. 411.4069.
Ethyl 2-(n-propoxyimino)-2-[1-(4-morpholinocarbonylmethyl)-1H-benzimidazol-2-
yl]acetate 5c
1
White solid, yield 50 % (0.30 g), m.p. 153.5–154.8 8C (from ethanol–H2O). H
NMR (400 MHz, CDCl3) d: 0.94 (t, 3H, J = 7.6 Hz, NO(CH2)2CH3), 1.41 (t, 3H,
J = 7.2 Hz, COOCH2CH3), 1.82–1.88 (m, 2H, NOCH2CH2), 3.32–3.69 (m, 8H,
123

Novel ethyl 2-alkoxyimino-2-benzimidazol-2-yl acetates
morpholine-H), 4.39 (q, 2H, J = 7.2 Hz, COOCH2), 4.51 (t, 2H, J = 7.2 Hz,
NOCH2), 4.94 (s, 2H, NCH2), 7.27–7.79 (m, 4H, ArH). IR (KBr) m (cm-1): 3051
(Ar–H), 1740 (C=O), 1664 (C=O), 1617 (C=N), 1237, 1027 (C(O)–O–C). ESI–MS
m/z: [M ? Na]? 425.4, [M ? H]? 403.5, [M – 101 – OR]? 242.8. HRMS m/z:
[M ? Na]? calcd for C20H26N4O5 425.4339, obsd.425.4336.
Ethyl 2-(n-butoxyimino)-2-[1-(4-morpholinocarbonylmethyl)-1H-benzimidazol-2-
yl]acetate 5d
1
White solid, yield 46 % (0.29 g), m.p. 167.3–168.6 8C (from ethanol–H2O). H
NMR (400 MHz, CDCl3) d: 0.92 (t, 3H, J = 7.6 Hz, NO (CH2)3CH3), 1.31 (t, 3H,
J = 7.2 Hz, COOCH2CH3), 1.35 (m, 2H, NO(CH2)2CH2), 1.71 (m, 2H,
NOCH2CH2), 3.31–3.66 (m, 8H, morpholine-H), 4.29 (t, 2H, J = 7.6 Hz, NOCH2),
4.36 (q, 2H, J = 7.2 Hz, COOCH2), 4.93 (s, 2H, NCH2), 7.27–7.82 (m, 4H, ArH).
IR (KBr) m (cm-1): 3059 (Ar–H), 1727 (C=O), 1662 (C=O), 1610 (C=N), 1239,
1016 (C(O)–O–C). ESI–MS m/z: [M ? Na]? 439.4, [M ? H]? 417.4, [M – 101 –
OR]? 242.6. HRMS m/z: [M ? Na]? calcd for C21H28N4O5 439.4605, obsd.
439.4609.
Ethyl 2-(benzyloxyimino)-2-[1-(4-morpholinocarbonylmethyl)-1H-benzimidazol-2-
yl]acetate 5e
1
Pale yellow solid, yield 60 % (0.41 g), m.p. 66.7–69.8 8C (from ethanol–H2O). H
NMR (400 MHz, CDCl3) d: 1.40 (t, 3H, J = 7.2 Hz, COOCH2CH3), 3.31–3.72 (m,
8H, morpholine-H), 4.51 (q, 2H, J = 7.2 Hz, COOCH2), 4.78 (s, 2H, NCH2), 5.74
(s, 2H, OCH2-Ar), 7.07–7.88 (m, 9H, ArH). IR (KBr) m (cm-1): 3058 (Ar–H), 1735
(C=O), 1666 (C=O), 1607 (C=N), 1243, 1028 (C(O)–O–C). ESI–MS m/z:
[M ? Na]? 473.5, [M ? H]? 451.4, [M – 101 – OR]? 242.6. HRMS m/z:
[M ? Na]? calcd for C24H26N4O5 473.4767, obsd. 473.4771.
Ethyl 2-(4-fluorobenzyloxyimino)-2-[1-(4-morpholinocarbonylmethyl)-1H-
benzimidazol-2-yl]acetate 5f
Yellow oil, yield 57 % (0.40 g). 1H NMR (400 MHz, CDCl3) d: 1.16 (t, 3H,
J = 7.2 Hz, COOCH2CH3), 3.32–3.69 (m, 8H, morpholine-H), 4.18 (q, 2H,
J = 7.2 Hz, COOCH2), 4.93 (s, 2H, NCH2), 5.57 (s, 2H, OCH2-Ar), 6.95–7.40 (m,
8H, ArH). IR (CHCl3) m (cm-1): 3064 (Ar–H), 1735 (C=O), 1664 (C=O), 1605
(C=N), 1224, 1029 (C(O)–O–C). ESI–MS m/z: [M ? Na]? 491.5, [M ? H]? 469.4,
[M – 101 – OR]? 242.5. HRMS m/z: [M ? Na]? calcd for C24H25FN4O5
491.4672, obsd. 491.4668.
Ethyl 2-(4-nitrobenzyloxyimino)-2-[1-(4-morpholinocarbonylmethyl)-1H-
benzimidazol-2-yl]acetate 5g
Yellow oil, yield 58 % (0.43 g). 1H NMR (400 MHz, CDCl3) d: 1.41 (t, 3H,
J = 7.2 Hz, COOCH2CH3), 3.41–3.76 (m, 8H, morpholine-H), 4.48 (q, 2H,
123

P. Zhang et al.
J = 7.2 Hz, COOCH2), 5.13 (s, 2H, NCH2), 5.77 (s, 2H, OCH2-Ar), 7.21–8.17 (m,
8H, ArH). IR (CHCl3) m (cm-1): 3064 (Ar–H), 1740 (C=O), 1661 (C=O), 1601
(C=N), 1239, 1032 (C(O)–O–C). ESI–MS m/z: [M ? Na]? 518.5, [M ? H]? 496.3,
[M – 101 – OR]? 242.6. HRMS m/z: [M ? Na]? calcd for C24H25N5O7 518.4743,
obsd. 518.4749.
Ethyl 2-(4-cyanobenzyloxyimino)-2-[1-(4-morpholinocarbonylmethyl)-1H-
benzimidazol-2-yl]acetate 5h
1
Pale yellow solid, yield 45 % (0.32 g), m.p. 75.3–77.4 8C (from ethanol–H2O). H
NMR (400 MHz, CDCl3) d: 1.18 (t, 3H, J = 7.2 Hz, COOCH2CH3), 3.32–3.71 (m,
8H, morpholine-H), 4.20 (q, 2H, J = 7.2 Hz, COOCH2), 4.93 (s, 2H, NCH2), 5.72
(s, 2H, OCH2-Ar), 7.18–7.88 (m, 8H, ArH). IR (KBr) m (cm-1): 3051 (Ar–H), 2228
(C:N), 1739 (C=O), 1664 (C=O), 1609 (C=N), 1238, 1029 (C(O)–O–C). ESI–MS
m/z: [M ? Na]? 498.6, [M ? H]? 476.7, [M – 101 – OR]? 242.4. HRMS m/z:
[M ? Na]? calcd for C25H25N5O5 498.4862, obsd 498.4866.
Ethyl 2-(4-methoxylbenzyloxyimino)-2-[1-(4-morpholinocarbonylmethyl)-1H-
benzimidazol-2-yl]acetate 5i
Yellow oil, yield 53 % (0.38 g). 1H NMR (400 MHz, CDCl3) d: 1.15 (t, 3H,
J = 7.2 Hz, COOCH2CH3), 3.30–3.68 (m, 8H, morpholine-H), 3.75 (s, 3H, OCH3),
4.17 (q, 2H, J = 7.2 Hz, COOCH2), 4.93 (s, 2H, NCH2), 5.50 (s, 2H, OCH2-Ar),
6.78–7.84 (m, 8H, ArH). IR (CHCl3) m (cm-1): 3061 (Ar–H), 1728 (C=O), 1667
(C=O), 1612 (C=N), 1241, 1029 (C(O)–O–C). ESI–MS m/z: [M ? Na]? 503.7,
[M ? H]? 481.6, [M – 101 – OR]? 242.7. HRMS m/z: [M ? Na]? calcd for
C25H28N4O6 503.5027, obsd 503.5031.
Ethyl 2-((2,4-dichlorobenzyl)oxyimino)-2-[1-(4-morpholinocarbonylmethyl)-1H-
benzimidazol-2-yl]acetate 5j
1
Pale yellow solid, yield 54 % (0.42 g), m.p. 77.7–80.2 8C (from ethanol–H2O). H
NMR (400 MHz, CDCl3) d: 1.23 (t, 3H, J = 7.2 Hz, COOCH2CH3), 3.29–3.77 (m,
8H, morpholine-H), 4.24 (q, 2H, J = 7.2 Hz, COOCH2), 4.87 (s, 2H, NCH2), 5.62
(s, 2H, CH2-Ar), 6.92–7.86 (m, 7H, ArH). IR (KBr) m (cm-1): 3058 (Ar–H), 1740
(C=O), 1664 (C=O), 1590 (C=N), 1237, 1030 (C(O)–O–C). ESI–MS m/z:
[M ? Na?H]? 543.3, [M ? H]? 520.5, [M – 101 – OR]? 242.8. HRMS m/z:
[M ? Na]? calcd for C24H24Cl2N4O5 542.3669, obsd 542.3674.
Antibacterial activity assays
The antibacterial activity of compounds 5a–5j against E. coli (ATCC 29522) and S.
aureus (ATCC 29213) (obtained from the College of Animal Science and
Technology, Shandong Agricultural University, Taian, China) was evaluated by
use of the plate count method [22]. The culture medium was obtained by mixing a
123

Novel ethyl 2-alkoxyimino-2-benzimidazol-2-yl acetates
solution of 5 with nutrient agar medium on which bacteria suspensions were coated
uniformly.
Culture was performed at 37 1 °C for 16 h. Levofloxacin hydrochloride, a
commercial pharmaceutical, was used as positive control, and sterile water was used
as blank. Three replicates were performed in antibacterial activity assays. Inhibition
was expressed as the mean of values obtained from three independent experiments.
Last, the concentration that inhibited growth by 50 % (IC50) was calculated
(Table 1). Percentage inhibition was calculated by use of the formula:
N0 ꢁ N1
Inhibition rate ¼
ꢂ 100ð%Þ
N0
where N0 is the number of bacterial colonies in the blank test and N1 is the number
of bacterial colonies in the presence of the tested compounds.
Results and discussion
Chemistry
Compounds 5a–5j were prepared by use of the reaction sequence shown in
Scheme 1. The starting material 1H-benzimidazol-2-yl acetonitrile (1) was treated
with 95 % alcohol and concentrated sulfuric acid to give ethyl 2-benzimidazol-2-yl
acetate (2), which was reacted with sodium nitrite in glacial acetic acid to produce
ethyl 2-(1H-benzimidazol-2-yl)-2-hydroxyimino acetate (3). Compound 3 was
reacted with 4-(chloroacetyl)morpholine in acetone to yield intermediate 4,
followed by etherification to obtain compounds 5a–5j.
To improve the yield and reduce reaction time we used a microwave-assisted
synthetic method. For preparation of compound 4 the reaction was performed with a
yield of 51 % in 6 min whereas the yield was low (30 %) under conventional reflux
conditions for 2 h. However, compound 5 could not be obtained by use of the
microwave-assisted method because the N-alkoxyimine readily decomposes at high
temperature.
1
The identities of all the newly synthesized compounds were confirmed by H
NMR, IR, and MS analysis; results were in good agreement with the proposed
structures.
Antibacterial activity
The antibacterial activity of the compounds against E. coli (ATCC 29522) and S.
aureus (ATCC 29213) is presented in Table 1. All the compounds had weak
antibacterial activity against E. coli; IC50 values were larger than that of the
positive control, levofloxacin hydrochloride (IC50 = 28.38 lg/mL). However,
most of the compounds, especially 5a, 5f, 5h, and 5i, had significant antibacterial
activity against S. aureus; IC50 values of 5a, 5f, 5h, and 5i were 19.34, 12.72,
20.34, and 26.58 lg/mL, respectively, much higher than that of the control
(IC50 = 48.51 lg/mL).
123

P. Zhang et al.
Table 1 The in vitro
antibacterial activities of
compounds 5a–5j
Compound
R
IC50 (lg/mL)
E. coli
S. aureus
5a
5b
5c
5d
5e
5f
CH3
85.17
103.04
111.15
114.86
88.84
19.34
30.71
43.54
67.56
50.54
12.72
47.24
20.34
26.58
48.51
41.37
CH2CH3
n-C3H7
n-C4H9
C6H5CH2
4-FC6H4CH2
4-O2NC6H4CH2
4-NCC6H4CH2
4-CH3OC6H4CH2
2,4-Cl2C6H3CH2
116.28
106.99
83.29
5g
5h
5i
56.35
5j
84.80
Levofloxacin
hydrochloride
28.38
Conclusion
In summary, ten novel ethyl 2-(alkoxyimino)-2-[1-(4-morpholinocarbonylmethyl)-
1H-benzimidazol-2-yl] acetates were synthesized by multi-step reactions, and their
in-vitro antibacterial activity against E. coli and S. aureus was evaluated. The result
revealed that four of the compounds had excellent bioactivity against S. aureus, with
IC50 values of 12.72–26.58 lg/mL, even better than that of levofloxacin
hydrochloride. This study is a useful reference in the search for novel benzimidazole
antibacterial agents.
Acknowledgments This project was supported by Shandong Province Natural Science Foundation (no.
ZR2009BM044).
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