Synthesis and antimicrobial activities of new polyhalogenated benzimidazoles

Article abstract of DOI:10.1002/jhet.936

A series of new polyhalogenated benzimidazoles has been synthesized and their antibacterial and antiprotozoal activity was evaluated. Several of new substituted halogenobenzimidazoles and their 2'-deoxynucleosides showed noteworthy antiprotozoal toxicity particularly against Giardia lamblia. The most potent agents against bacteria and fungi were 4,5,6,7-tetrachlorobenzimidazoles with polyfluoroalkyl chain at position 2 of the heterocyclus.

Full text of DOI:10.1002/jhet.936

September 2012
Synthesis and Antimicrobial Activities of
New Polyhalogenated Benzimidazoles
1059
Agnieszka E. Laudy,a Rosa Moo‐Puc,b Roberto Cedillo‐Rivera,b
Zygmunt Kazimierczuk,c and Andrzej Orzeszkoc,d
*
aDepartment of Pharmaceutical Microbiology, Medical University of Warsaw,
Warsaw 00‐007, Poland
bUnidad de Investigación Médica Yucatán, Unidad Médica de Alta Especialidad,
Instituto Mexicano del Seguro Social, Mérida, Yuc., México
cInstitute of Chemistry, Warsaw University of Life Sciences, Warsaw 02‐787, Poland
dMilitary University of Technology, Warsaw 00‐908, Poland
*
E-mail: Andrzej_Orzeszko@sggw.pl
Received February 5, 2011
DOI 10.1002/jhet.936
Published online 26 October 2012 in Wiley Online Library (wileyonlinelibrary.com).
A series of new polyhalogenated benzimidazoles has been synthesized and their antibacterial and antiprotozoal
activity was evaluated. Several of new substituted halogenobenzimidazoles and their 2′‐deoxynucleosides showed
noteworthy antiprotozoal toxicity particularly against Giardia lamblia. The most potent agents against bacteria
and fungi were 4,5,6,7‐tetrachlorobenzimidazoles with polyfluoroalkyl chain at position 2 of the heterocyclus.
J. Heterocyclic Chem., 49, 1059 (2012).
INTRODUCTION
Their antibacterial, antifungal, and antiprotozoal activity
has been reported [11–13].
Halogenated benzimidazoles and their derivatives have
raised special interest because of their diversified biologi-
cal activity. For example, tetrabromobenzimidazoles and
tetraiodobenzimidazoles are known as very strong inhi-
bitors of antiapoptotic protein kinase CK2 [1–3]. Among
antiviral agents, benzimidazole nucleosides and acyclo-
nucleosides have also received much attention. The 5,6‐
dichloro‐1‐(β‐D‐ribofuranosyl)‐benzimidazole (DRB) and
its derivatives (TCRB and BDCRB) were found to show
activity against RNA and DNA viruses [4, 5]. Also some
benzimidazole L‐ribonucleosides, particularly 5,6‐dichloro‐
2‐isopropylamino‐1‐(β‐L‐ribofuranosyl)‐benzimidazole (mar-
ibavir) inhibit replication of human cytomegalovirus and
have favorable safety profiles in animal species [6].
Benzimidazole system is present in numerous antipara-
sitic, fungicidal, anthelmintic, and anti‐inflammatory
drugs [7–9]. Substituted 2‐trifluorobenzimidazoles are
potent decouplers of oxidative phosphorylation in mito-
chondria. These compounds also inhibit photosynthesis
and therefore exhibit appreciable herbicidal activity [10].
These findings have inspired us to widen the list of halo-
geno‐substituted benzimidazoles and to test the new deri-
vatives against selected Gram‐positive and Gram‐negative
bacteria and protozoa. In addition to previously reported
compounds, we have synthesized several new halogen-
obenzimidazole derivatives as well as two 2′‐deoxyribonu-
cleosides. Despite
a
pilot‐study character of our
investigation, we were able to indicate the direction which
can provide new effective antimicrobial agents of wide ac-
tivity spectrum. The emergence of resistance to the major
classes of antibacterial agents is recognized as a serious
health concern. The search for antimicrobial agents with
new mode of action will always remain an important task.
RESULTS AND DISCUSSION
The synthesis of several newly modified benzimidazoles
carrying chloro‐ and bromo‐substituents on the benzene
part of heterocyclus as well as other substituents on C‐2
and N‐1 position constituted the chemical part of this
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Scheme 1. Reagents and conditions: (i) HCl/HNO3 (aqua regia).
regia” [15] or in the case of 2‐trifluorobenzimidazole by
action of chlorine at elevated temperature [16]. We have
applied successfully the first procedure for chlorination
of 2‐perfluoroalkylbenzimidazoles 1a–d with good or
moderate yields to obtain respective products 2a–d
(Scheme 1). Additionally, the two previously obtained
4,5,6,7‐tetraiodo‐2‐perfluoroalkyl benzimidazoles 2e and
2f were subjected to antimicrobial testing [3]. 4,5,6,7‐Tet-
rachlorobenzimidazole 3a was substituted in position N‐1
with ethyl bromoacetate to give the respective ester 4a.
This ester was transformed to acid 5 by alkaline hydroly-
sis. The hydrazide 6 and amides derived from piperidine,
morpholine, and methylpiperazine 7a–c were obtained by
reaction of 4a with hydrazine or prolonged heating with
piperidine, morpholine, or N‐methylpiperazine, respec-
tively. A similar procedure was adapted for a tetrabro-
moester 4b in the synthesis of its metylpiperazinyl
amide 7d (Scheme 2). Because of the moderate biological
activity of 7d, we gave up the synthesis of other similarly
modified tetrabromobenzimidazoles. Compounds 3b and
4b used here as starting materials for further synthesis
and biological investigations have been described previ-
ously [3, 17]. Additionally, the synthesis of two 2′‐deox-
yribonucleosides 10a and 10b by condensation of sodium
salts of 4,5,6,7‐tetrachlorobenzimidazole 3a and 5,6‐
study. Additionally, two 2′‐deoxyribo‐nucleosides of
4,5,6,7‐tetrachloro‐ and 5,6‐dichloro‐4,7‐diiodobenzimida-
zoles (10a,b) were obtained according to “sodium salt pro-
cedure” [14] (Schemes 1–3).
Benzimidazole ring system endures even hard reaction
conditions. The full chlorination of benzimidazole in the
benzene part of molecule was achieved by action of “aqua
Scheme 2. Reagents and conditions: (i) BrCH2COOEt, K2CO3, acetone, reflux; (ii) NaOH/ETOH; (iii) hydrazine/EtOH; (vi) NH(CH2)4X, reflux.
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Synthesis and Antimicrobial Activities of New Polyhalogenated Benzimidazoles
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Scheme 3. Reagents and conditions: (i) 2‐deoxy‐3,5‐bis‐O‐(4‐methylbenzoyl)‐β‐D‐erythro‐pentafuranosyl chloride, NaH, CH3CN, stirring; (ii) MeONa/
MeOH.
dichloro‐4,7‐diiodobenzimidazole 8 with 3,5‐di‐O‐(p‐
toluoyl)‐α‐D‐ribofuranosyl chloride was carried out. This
stereoselective reaction provides almost exclusively β‐
anomers. Removal of p‐toluoyl groups from 9a and 9b
was realized by treating of blocked nucleosides with
methanolic sodium methoxylate (Scheme 3).
The halogenated benzimidazoles were screened for their
antiprotozoal activity against Enthamoeba histolytica,
Trichomonas vaginalis, and Giardia lamblia (Table 1).
The results revealed that some of tested compounds are
endowed with an appreciable antiprotozoal activity. The
most potent agents against E. histolytica were 2a, 7a, and
7c. Tetrachlorobenzimidazoles with longer polyfluoroalkyl
chain 2b–d showed the best toxicity toward T. vaginalis,
whereas its 2‐trifluoromethyl analogue (2a) has distinctly
lower IC50 value. Four compounds: amides 7a and 7b
and deoxynucleosides 10a and 10b exhibited very potent
antigiardial activity, comparable but higher than control
compounds: albendazole and metronidazole. In all tests,
tetraiodinated (2e and 2f) or tetrabrominated benzimid-
azole derivatives (7d) were less toxic than their tetrachloro
congeners (see also results in [13]).
The majority of the halogenobenzimidazoles investigated
here were active against Gram‐positive bacteria (Table 2).
Table 1
In vitro susceptibility of Enthamoeba histolytica, Trichomonas vaginalis, and Giardia lamblia to novel polyhalogenobenzimidazoles.
Enthamoeba histolytica
Trichomonas vaginalis
Giardia lamblia
Compound
tested
IC50 95% Confidence
IC50 95% Confidence
IC50
[μg/ml]
95% Confidence
[μg/ml]
limits
[μg/ml]
limits
limits
2a
2b
2c
2d
2e
2f
0.29
2.43
5.05
1.90
2.60
0.289–0.292
2.42–2.44
5.03–5.08
1.89–1.91
2.58–2.61
5.35
0.37
0.40
0.22
17
5.33–5.38
0.375–0.378
0.402–0.405
0.218–0.225
16.7–17.4
8.6
n.a
11.5
21.3
8.25
4.92
8.62–8.77
11.4–11.7
20.4–22.3
8.20–8.31
151
149–152
149
143–156
4.89–4.95
3a
5
6
7a
7b
7c
7d
1.655
2.279
3.07
1.208
1.449
0.18
0.48
1.124
1.643
1.648–1.662
2.265–2.292
3.05–3.09
1.203–1.214
1.441–1.457
0.178–0.180
0.478–0.483
1.119–1.129
1.633–1.653
10.0–20.0
0.75
117.8
5.33
19.62
134.8
1.72
0.745–0.754
114.7–121.3
5.28–5.39
19.34–19.91
130.4–139.5
170–173
0.027
0.188
13.06
0.007
0.002
9.16
0.026–0.028
0.189–0.186
12.94–13.18
0.0069–0.0071
0.0018–0.0021
9.06–9.27
20.8
20.5–20.8
46.5
45.7–47.4
10a
10b
Albendazole
Metronidazole
0.993
0.678
0.422
0.037
0.989–0.997
0.674–0.0.682
0.419–0.425
0.037–0.037
0.004
0.029
0.010
0.210
0.0039–0.0041
0.029–0.030
0.008–0.012
0.150–0.270
15.0
0.060
0.029–0.103
n.a, no activity.
IC50, the concentration required to inhibit growth by 50%.
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Particularly, tetrachlorobenzimidazoles 2a–d exhibited big
diameters of growth inhibition areas and low MIC values
against Staphylococcus and Bacillus species. The moderate
activity toward Gram‐negative bacteria and fungi were ob-
served only for aforementioned compounds 2a–d (Table 3).
The other of compounds described here showed no detectable
antifungal and antibacterial activity toward Gram‐negative
rods.
In conclusion, our results suggest that new deriva-
tives of polyhalogenated benzimidazoles are promising
group of antimicrobial and antiprotozoal agents. How-
ever, further synthetic and biological investigations
are needed to establish their structure‐activity relation-
ship (SAR).
EXPERIMENTAL
Melting points were determined on a Gallenkamp Melting
Point Apparatus, Mod. MFB 595030G, in open capillary tubes.
1
The H‐NMR spectra were recorded on a Bruker AMX instru-
ment (400 MHz 1H frequency) at 25°C. Chemical shifts are
reported in ppm from internal tetramethylsilane standard are
given in δ‐units. The solvent used for NMR spectra was
DMSO‐d6. The UV spectra were determined on Techcomp
UV8500 spectrophotometer. Elemental analyses were performed
at the Faculty of Chemistry, Warsaw Technical University.
4,5,6,7‐Tetrachloro‐2‐trifluoromethyl‐1H‐benzimidazole (2a).
Adopting the procedure described in [15], a mixture of
hydrochloric acid (120 mL) and nitric acid (50 mL) containing
2‐trifluoromethylbenzimidazole (1a) (650 mg, 3.5 mmol) was
stirred and heated for 8 h at 60°C. Next, the reaction mixture was
refluxed for additional 20 h. The precipitate formed after cooling
was collected and crystallized from ethanol to give white needles
(720 mg, 63%) of mp 274–276°C; lit. mp 273°C [16].
4,5,6,7‐Tetrachloro‐2‐pentafluoroethyl‐1H‐benzimidazole
(2b). Analogously as described above from 2‐pentafluoroethyl‐
1H‐benzimidazole (1b). Yield: 865 mg, (66%), mp. 242–245°
C; 1H‐NMR (DMSO‐d6): δ 15.3 (bs, 1H); uv (MeOH): λ (ε)
227 (21,800), 276 (9400), 293 (5900), 305 (4900) nm. Anal.
Calcd. for C9HCl4F5N2 (373.93): C, 28.91; H, 0.27; N, 7.49.
Found: C, 29.02; H, 0.35; N, 7.36.
4,5,6,7‐Tetrachloro‐2‐heptafluoropropyl‐1H‐benzimidazole (2c).
As described for 2a from 2‐heptafluoropropyl‐1H‐benzimidazole.
Yield: 1.05 g, (71%), mp 262–264°C; 1H‐NMR (DMSO‐d6): δ
15.05 (bs, 1H); uv (MeOH): λ (ε) 225 (23,400), 277 (9700), 293
(7000), 304 (5100) nm. Anal. Calcd. for C10HCl4F7N2 (423.93):
C, 28.33; H, 0.24; N, 6.61. Found: C, 28.22; H, 0.34; N, 6.48.
4,5,6,7‐Tetrachloro‐2‐nonafluorobutyl‐1H‐benzimidazole (2d).
As described for 2a from 2‐nonafluorobutyl‐1H‐benzimidazole.
Yield: 1.16 g, (70%), mp 226–228°C; 1H‐NMR (DMSO‐d6): δ
14.8 (bs, 1H), uv (MeOH): λ (ε) 227 (25,200), 277 (9800), 293
(7100), 304 (5300) nm. Anal. Calcd. for C11HCl4F9N2 (473.94):
C, 27.88; H, 0.21; H, 5.91. Found: C, 27.76; H, 0.30; N, 5.78.
(4,5,6,7‐Tetrachlorobenzimidazol‐1‐yl)acetic acid ethyl ester
(4a). To the mixture of 4,5,6,7‐tetrachlorobenzimidazole (3) (3.84
g, 15 mmol) and finely powdered K2CO3 (5.8 g, 42 mmol) in
acetone (100 mL), bromoacetic acid ethyl ester (4.0 g, 24 mmol)
was added. The mixture was stirred and refluxed for 2 h. The
solid was filtered off and the filter cake was washed twice with
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acetone (2 × 40 mL). The filtrate was evaporated to dryness,
1‐(4‐Methylpiperazin‐1‐yl)‐2‐(4,5,6,7‐tetrabromobenzimidazol‐
1‐yl)‐etanone (7d). As described above for 7c from 4b [2] and N‐
methylpiperazine. Yield: 315 mg (50%), mp 219–221°C; 1H‐NMR
(DMSO‐d6): δ 2.18 (s, 3H), 2.41 (t, J = 5.1 Hz, 4H), 2.93 (t, J = 5.2
Hz, 4H), 4.90 (s, 2H), 8.35 (s, 1H). uv (MeOH): λ (ε) 230 (35,000),
750 (sh, 9400) 275 (9600), 302.5 (3600). Anal. Calcd. for
C14H14Br4N4O (573.91): C, 29.30; H, 2.46; N, 9.76. Found: C,
29.36, H, 2.54, N, 9.64.
and the residue crystallized from ethanol to give white needles.
1
Yield: 4.2 g, (81%), mp 167–168°C; H‐NMR (DMSO‐d6): δ 1.21
(t, J = 7.1 Hz, 3H), 4.20 (q, J = 7.1 Hz, 2H), 5.46 (s, 2H), 8.47
(s, 1H). Anal. Calcd. for C11H8Cl4N2O2 (342.01): C, 38.63; H 2.36;
N, 8.19. Found: C, 38.51; H, 2.39; N, 8.08.
(4,5,6,7‐Tetrachlorobenzimidazol‐1‐yl)acetic acid (5). The
mixture containing 4a (680 mg, 2 mmol), ethanol (15mL),
water (10 mL) and NaOH (240 mg, 6 mmol) was stirred at
room temp. for 3 h. The suspension became clear after this
time. Next, the mixture was brought to reflux for 10 min. The
solution was acidified to pH 2–3 with diluted aqueous HCl and
left to crystallization. The amorphous white powder was
obtained. Yield: 610 mg (97 %), mp 303–306°C (from ethanol‐
1‐[2‐Deoxy‐3,5‐di‐O‐(4‐methylbenzoyl)‐β‐D‐erythro‐
pentafuranosyl]‐4,5,6,7‐tetrachloro‐benzimidazole (9a).
To the suspension of 3a (1.02 g, 4 mmol) in dry acetonitrile (70 mL),
sodium hydride (200 mg, 5 mmol, 60% in oil) was added
portionwise. The mixture was stirred and refluxed for 10 min.
After cooling 2‐deoxy‐3,5‐bis‐O‐(4‐methylbenzoyl)‐β‐D‐erythro‐
pentafuranosyl chloride [18] (1.55 g, 4 mmol) was added in
portions. The mixture was stirred for 20 min at r.t. Next,
methylene chloride (70 mL) was added and the mixture
filtered through Cellite. The solvents were evaporated and
the residue was chromatographed on silica gel column
(2.5 × 12 cm) with toluene‐acetone (95:5, v/v) as eluent.
The product containing fractions were evaporated and the
residue crystallized from methanol to give white needles.
Yield: 1.09 g, (45%), mp 191–192°C; 1H‐NMR (DMSO‐d6):
δ 2.37 (s, 3H), 2.40 (s, 3H), 2.96 (m, 1H), 3.07 (m, 1H),
4.52 (m, 2H), 4.58 (m, 1H), 5.72 (m, 1H), 7.01 (t, J = 6.4
Hz, 1H), 7.30–8.0 (4d, arom. H, 8H), 8.82 (s, 1H). Anal.
Calcd. for C28H22Cl4N2O5 (608.31): C, 55.29; H, 3.65; N,
4.61. Found: C, 55.25; H, 3.60; N, 4.52.
1‐[2‐Deoxy‐3,5‐di‐O‐(4‐methylbenzoyl)‐β‐D‐erythro‐
pentafuranosyl]‐5,6‐dichloro‐4,7‐diiodobenzimidazole (9b).
As described for 9a from 8 [3] instead of 3a. Yield: 1.64 mg
(52%), mp 194–196°C; 1H‐NMR (DMSO‐d6): δ 2.37 (s, 3H), 2.40
(s, 3H), 2.96 (m, 1H), 3.09(m, 1H), 4.56 (m, 2H), 4.60 (m, 1H),
5.70 (m, 1H), 7.37 (t, J = 7.9 Hz, 1H), 7.30–8.0 (4d, arom.H, 8H),
8.81 (s, 1H). Anal. Calcd. for C28H22Cl4I2N2O5 (791.21): C, 42.51;
H, 2.80; N, 3.54. Found: C, 42,43; H, 2.86; N, 3.45.
1‐(2‐Deoxy‐β‐D‐erythro‐pentafuranosyl)‐4,5,6,7‐tetrachloro-
benzimidazole (10a). The mixture of 9a (1.6 g, 2.63 mmol) and
methanolic sodium methanolate (50 mL, 0.1M) was stirred and
refluxed for 15 min. Methanol was evaporated and the residue
purified by flash chromatography on silica gel (2.5 × 10 cm) using
chloroform as eluent. The product containing fractions were
evaporated and the residue crystallized from methanol water to give
colorless needles. Yield: 685 mg, (70%), mp 141–144°C; 1H‐NMR
(DMSO‐d6): δ 2.46 (m, 1H), 2.58 (m, 1H), 3.65 (2m, 2H), 3.89
(q, J = 3.9 Hz, 1H), 4.47 (m, 1H), 5.04 (t, J = 5.2 Hz, 1H), 5.36
(d, J = 4.5 Hz, 1H), 6.85 (t, J = 5.9 Hz, 1H), 8.88 (s, 1H). uv
(MeOH): λ (ε) 225 (22,400). 270 (9200), 298 (3100). Anal. Calcd.
for C12H10Cl4N2O3 (372.04): C, 38.74; H, 2.71; N, 7.53. Found: C,
38.66; H, 2.77; N, 7.47.
1
water); H‐NMR (DMSO‐d6): δ 5.35 (s, 1H), 8.47 (s, 1H), 13.5
(s, 1H). uv (MeOH): λ (ε) nm. Anal. Calcd. for C9H4Cl4N2O2
(313.96): C, 34.43; H 1.28; N, 8.92. Found: C, 34.50; H, 1.37;
N, 8.81.
(4,5,6,7‐Tetrachlorobenzimidazol‐1‐yl)acetic acid hydrazide
(6). To the solution of 4a (1.02 g, 3 mmol) in ethanol (30 mL)
hydrazine monohydrate (98%, 1.2 g, 24 mmol) was added. The
mixture was stirred and refluxed for 3h. Next, the water (15 mL)
was added and the mixture was left to crystallization. The white
precipitate was formed. Yield: 870 mg, (88%), mp > 300°C
(with decomp.). For analysis, a small amount of (6) was
1
crystallized from ethanol. H‐NMR (DMSO‐d6): δ 4.35 (bs, 2H),
5.18 (s, 2H), 8.45 (s, 1H), 9.42 (s, 1H). uv (MeOH): λ (ε) 230
(16,600), 264 (8900), 271 (9900), 290 (sh, 3300), 300 (3100)
nm. Anal. Calcd. for C9H6Cl4N4O (327.99): C, 32.96; H, 1.84;
N, 17.08. Found: C, 32.85; H, 1.84; N, 17.08.
1‐(Piperidyn‐1‐yl)‐2‐(4,5,6,7‐tetrachlorobenzimidazol‐1‐yl)‐
etanone (7a). The mixture of 4a (340 mg, 1 mmol) and piperidine
(510 mg, 6 mmol) was stirred and refluxed for 36 h. Next, the
mixture was evaporated to oil. The residue was crystallized twice
1
from toluene‐ethanol. Yield: 295 mg, (77%), mp 240–242°C; H‐
NMR (DMSO‐d6): δ 1.09 (t, J = 5.3 Hz, 4H) and 2.87 (q, J =
7.2 Hz, 4H), 4.94 (s, 2H), 8.38 (s, 1H). uv (MeOH): λ (ε) 227
(22,700), 273 (8900), 301 (3400) nm. Anal. Calcd. for
C14H13Cl4N3O (381.09): C, 44.12; H, 3.44; N, 11.03. Found: C,
44.21; H, 3.54; N, 10.91.
1‐(Morpholin‐4‐yl)‐2‐(4,5,6,7‐tetrachlorobenzimidazol‐1‐yl)‐
etanone (7b). Analogously as for 7a. Yield: 195 mg, (51%), mp
221–223°C; 1H‐NMR (DMSO‐d6): δ 2.95 (t, J = 4.8 Hz, 4H),
3.68 (t, J = 4.8 Hz, 4H), 4.93 (s, 2H), 8.40 (s, H C); uv (MeOH):
λ (ε) 226 (23,400), 272 (8800), 300 (3300) nm. Anal. Calcd. for
C13H11Cl4N3O2 (383.06): C, 40.76; H, 2.89; N, 10.97. Found: C,
40.67; H, 2.99; N, 10.85.
1‐(4‐Methylpiperazin‐1‐yl)‐2‐(4,5,6,7‐tetrachlorobenzimidazol‐
1‐yl)‐etanone (7c). The mixture of ester 4a (380 mg, 1.1 mmol) and
N‐methylpiperazine (1.2 g, 12 mmol) in methoxyethanol (20 mL)
was stirred and heated at 110°C (bath temp.) for 2 days. The
solvent was removed and the brown residue was chromatographed
on silica gel column (2.5 × 8 cm) with CHCl3 (100 mL), CHCl3‐
MeOH (8:2, v/v) (100 mL) and CHCl3‐MeOH‐Et3N (80:18:2, v/v/
v). The product containing fractions were evaporated and the
residue crystallized from toluene‐EtOH to give white cottonlike
powder. Yield: 230 mg, (53%), mp 229–232°C; 1H‐NMR
(DMSO‐d6): δ 2.18 (s, 3H), 2.42 (t, J = 5.8 Hz, 4H), 2.94 (t, J =
5.0 Hz, 4H), 4.89 (s, 2H), 8.37 (s, 1H). uv (MeOH): λ (ε) 228
(24,000), 272 (8900), 301 (3300). Anal. Calcd. for C14H14Cl4N4O
(396.11): C, 42.45; H, 3.56; N, 14.14. Found: C, 42.56, H, 3.63,
N, 14.06.
1‐(2‐Deoxy‐β‐D‐erythro‐pentafuranosyl)‐5,6‐dichloro‐4,7‐
diiodobenzimidazole (10b). As described for 10a from 9b.
Yield: 695 mg, (68%), mp 200°C; 1H‐NMR (DMSO‐d6): δ
2.46 (m, 1H), 2.55 (m, 1H), 3.60 (2m, 2H), 3.89 (q, J = 3.8
Hz, 1H), 4.37 (q, J = 4.7 Hz, 1H), 5.07 (bs, 1H), 5.37 (bs, 1H),
7.23 (t, J = 6.1 Hz, 1H), 8.87 (s, 1H). uv (MeOH): λ (ε) 230
(27,000), 279 (14,000), 305 (sh, 6100). Anal. Calcd. for
C12H10Cl2I2N2O3 (554.94): C, 25.97; H, 1.82; N, 5.05. Found: C,
25.85; H, 1.91; N, 4.95.
Experimental for antiprotozoal and antibacterial studies.
Experimental details concerning antiprotozoal and antimicrobial
studies were described in literature [13, 19].
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Synthesis and Antimicrobial Activities of New Polyhalogenated Benzimidazoles
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet