Synthesis and evaluation of novel benzimidazole derivatives as antimicrobial agents

Article abstract of DOI:10.1007/s00044-013-0732-z

Benzimidazole analogs bearing electron-withdrawing as well as electron-donating substituent were synthesized to achieve bioactive molecules with significant antimicrobial property. The desired compounds were prepared by multi-step synthesis process. The formation of intermediates and their corresponding derivatives (III _1-13 ) was confirmed by spectral characterization such as ¹H NMR, ¹³C NMR, mass spectra, IR, and elemental analysis. The compounds were screened for their antimicrobial properties against a broad panel of Gram-positive and Gram-negative bacteria as well as fungi. From the SAR study data, it was observed that the derivatives with electron-withdrawing functional groups were more bioactive than that with electron-donating functional groups.

Full text of DOI:10.1007/s00044-013-0732-z

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2014) 23:1290–1299
DOI 10.1007/s00044-013-0732-z
ORIGINAL RESEARCH
Synthesis and evaluation of novel benzimidazole derivatives
as antimicrobial agents
•
Deepkumar Joshi Kalpesh Parikh
Received: 16 April 2013 / Accepted: 16 August 2013 / Published online: 30 August 2013
Ó Springer Science+Business Media New York 2013
Abstract Benzimidazole analogs bearing electron-with-
drawing as well as electron-donating substituent were
synthesized to achieve bioactive molecules with significant
antimicrobial property. The desired compounds were pre-
pared by multi-step synthesis process. The formation of
Benzimidazoles are the class of heterocyclic scaffolds
exhibiting antiparasitic (Castilloa et al., 2002), analgesic
(Dixit et al., 2013), anticancer (Reffat, 2011), antiprotozoal
´
(Navarette-Vazquez et al., 2001; Kazimierczuk et al.,
2002), and chemotherapeutic properties (Youssef et al.,
2013). Some of the benzimidazole derivatives are utilized
as inhibitors of MDA-MB-231 human breast cell prolifer-
ation (Rangappa et al., 2008). Several benzimidazole
derivatives are observed to exhibit anti-inflammatory
(Tsukamoto et al., 1980), antihypertensive (Jat et al.,
2006), antidiabetic, as well as anti-asthametic properties
(Ramanatham et al., 2008).
intermediates and their corresponding derivatives (III1–13
)
was confirmed by spectral characterization such as 1H
NMR, 13C NMR, mass spectra, IR, and elemental analysis.
The compounds were screened for their antimicrobial
properties against a broad panel of Gram-positive and
Gram-negative bacteria as well as fungi. From the SAR
study data, it was observed that the derivatives with elec-
tron-withdrawing functional groups were more bioactive
than that with electron-donating functional groups.
Presence of benzimidazole nucleus in several categories of
therapeutic molecules such as antimicrobial (Patel et al.,
2013), proton pump inhibitor (Iwahi et al., 1991), antihyper-
tensive (Shah et al., 2008), anticoagulant, anti-inflammatory,
antioxidants (Narasimhan et al., 2012) has made it an
important part in development of novel therapeutic agents.
Benzimidazole nucleus serves as an important core in several
antiulcer (Patil et al., 2008) and antihelmintic drugs (Dubey
et al., 1985). Majority of the drugs available in the market viz.
omeprazole, lansoprazole, pantoprazole as proton pump have
benzimidazole as its center nuclei (Iwahi et al., 1991). Other
drugs available in market such as albendazole comprising of
benzimidazole nucleus is used for the treatment of various
parasitic worm infestations. Also mebendazole and benda-
mustine used as antihelmintic and in treatment of chronic
lymphocytic leukemia (Kath et al., 2001) are found to contain
benzimidazole as their core (Fig. 1).
Keywords Benzimidazole Á Antifungal Á Antibacterial Á
MIC Á SAR study
Introduction
The versatility of benzimidazole and its property of
exhibiting high potency against several microbial strains
(Tuncbilek et al., 2009) and cancer cell lines (O’Sullivan
and Wallis, 1963) has drawn attention of many researchers
to concentrate their work around it. Different derivatives of
benzimidazole are found to possess antibacterial, anti-
fungal, and molluscicidal activities (Nofal et al., 2002).
Substituted 2-mercapto benzimidazole (Saxena et al.,
1982; Scherhag et al., 1974) is used as a precursor for the
synthesis of desired compounds III1–13. It is also found that
benzimidazole derivatives are capable of possessing anti-
oxidant properties (Ayhan-Kilcigil et al., 2004). Keeping in
light all the above findings and in accordance with our
Deepkumar Joshi: DST-JRF (INSPIRE Fellow).
D. Joshi Á K. Parikh (&)
Chemistry Research Laboratory, Chemistry Division, Sheth M.
N. Science College, Patan 384265, India
e-mail: deepjoshi359@yahoo.co.in
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Med Chem Res (2014) 23:1290–1299
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previous research (Parikh and Joshi, 2013); we have reported
Table 1 Results of antibacterial and antifungal screening for com-
pounds III1-13
the synthesis2-(5-methoxy-1H-benzo[d]imidazol-2-ylthio)-
N-arylacetamides derivatives III1–13
5-methoxy-1H-benzo[d]imidazole-2-thiol used was synthe-
.
The precursor
-R
(derivatives)
MIC in lg/ml
Gram-positive Gram-negative
bacteria
Fungi
sized by using the reported procedure (Wang and Liu, 2007).
bacteria
S.
aureus faecalis
E.
E. coli P.
C.
aeruginosa albicans niger
A.
Result and discussion
-3-NO2
-4-NO2
-3-Cl
250
125
125
125
125
125
250
250
125
125
125
250
125
125
125
62.5
62.5
62.5
62.5
125
125
62.5
62.5
62.5
62.5
–
62.5
62.5
62.5
62.5
125
125
125
250
62.5
125
125
125
125
–
250
125
125
125
125
125
250
250
250
250
125
250
250
125
–
250
250
250
250
125
125
125
250
250
250
125
250
125
62.5
–
Chemistry
The formation of the titled compounds III1–13 was achieved
in three steps. Initially synthesis of 5-methoxy-1H-
benzo[d]imidazole-2-thiol I was undertaken by reacting
4-methoxybenzene-1,2-diamine in presence of carbondi-
sulphide and KOH using ethanol as solvent (Wang and Liu,
2007). Simultaneously different derivatives of 2-chloro-N-
(aryl)acetamide II1–13 were prepared by reacting substituted
anilines with chloroacetylchloride, where triethylamine was
used as a catalyst. The obtained intermediates 5-methoxy-
1H-benzo[d]imidazole-2-thiol I and 2-chloro-N-(aryl)acet-
amide II1–13 were reacted in presence of K2CO3 using ace-
tone as a suitable solvent, which resulted in the formation of
titled compounds III1–13 in good yield as indicated in
Scheme 1. The minimum inhibitory concentration (MIC)
value for each final product against the wide panel of
microorganisms was studied and is demonstrated in Table 1.
-3-F-4-Cl
-H
-4-F
-2-OCH3
-3-CH3
-3-OCH3
-2-NO2
-2-CH3
-4-CH3
-3-CF3
Fluconazole
31.25 125
250
62.5
62.5
125
250
250
–
250
125
125
125
250
250
–
Ciprofloxacin 62.5
125
125
125
MIC minimum inhibitory concentration, Std. Standard drug fluco-
nazole for antifungal and ciprofloxacin for antibacterial tests
its formation. A singlet at d = 3.75 helped to prove the
presence of three protons of the methoxy group. The pres-
ence of the protons of the methylene group was indicated by
d = 4.11 showing a sharp singlet peak. The aromatic protons
present in the phenyl ring were confirmed by the multiplet
peak obtained in the range of d = 6.74–8.03. In the structure
there are two –NH (secondary amine) present; the two pro-
tons of each secondary amine can be easily differentiated
from the shift observed in the peaks of the corresponding
amines. The proton of –NH in the vicinity of –C=O group
was confirmed by the value d = 11.21 whereas the proton of
secondary amine in the ring confirmed its presence by
showing a singlet at downfield shift of d = 12.33.
Characterization
IR data
IR data obtained for the final compounds III1–13 help us to
a great extent to confirm their formation. If we observe the
data for 2-(5-methoxy-1H-benzo[d]imidazol-2-ylthio)-N-
(3-(trifluoromethyl)phenyl)acetamide III13; an absorption
peak obtained at 3,393 cm-1 has helped in confirming the
presence of –NH in vicinity to the carbonyl group. The
presence of aromatic C–H linkage is confirmed by the peak
obtained at 3,095 cm-1. A sharp peak at 2,921 cm-1
helped to assign the presence of –C–H bond in –OCH3
group. A stretching band at 2,853 cm-1 concluded the
presence of methylene group in the final motif. The pres-
ence of carbonyl (–C=O) in the structure is proved due to
the presence of a sharp peak at 1,698 cm-1. The presence
of –C=N in the benzimidazole nucleus was also confirmed
13C NMR data
The d values obtained between 39.4 and 167.3 helped to
confirm the formation of the final products III1–13. The
formation of the linkage between the two derivatives
resulting in the formation of final compounds in the form of
Methylene group (–CH2) was proved by the peak obtained at
d = 39.4. With respect to the other carbon of phenyl group,
the one possessing the –OCH3 substitution showed more
downfield shift exhibiting the d value to 157.2. The carbonyl
carbon (C-7) also exhibited a downfield shift d = 166.1 due
by the presence of a sharp absorption band at 1,580 cm-1
.
1H NMR
Compound III13 when observed under 1H NMR, the differ-
ent peaks obtained at desirable d values (in ppm) confirmed
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Med Chem Res (2014) 23:1290–1299
Fig. 1 Drugs with benzimidazole nucleus
to the presence of electronegative environment. A drastic
shift in the d value was observed when the protons of the
phenyl ring were replaced by the different substituents.
When –NO2 was introduced as a substituent at para position
in the phenyl ring, the shift was observed to d = 136.8 (III2).
Similarly when –OCH3 was used in compound III7 and III9;
the shifts were observed for that particular carbon at d value
149.6 and 159.1, respectively. When electronegative func-
tional groups like fluorine and chlorine were introduced at
meta position in the phenyl ring, the d values were observed
at 135.0 (III3) and 163.0 (III4), respectively. The carbon
enumeration is given in Fig. 2.
antibacterial and antifungal details for each compound (III1–
13) are discussed below.
Antibacterial activity and antifungal activity
Gram-positive bacteria S. aureus (ATCC No. 25923) and
E. faecalis (ATCC No. 27853) were introduced for testing
the antibacterial potential of the synthesized molecules
III1–13. When tested against S. aureus, it was found that
from the complete series synthesized; compounds III9 (p-
OCH3) and III10 (o-NO2) exhibited activity equivalent to
that of the standard ciprofloxacin (62.5 lg/ml). Other
derivatives from the series exhibited higher MIC value than
the standard resulting in poor results against Gram-positive
bacteria S. aureus. Similarly the synthesized compounds
were tested against another Gram-positive bacterial strain
E. faecalis, where it was observed that the derivatives III3
(m-Cl), III4 (3-F-4-Cl), III5 (H), III9 (p-OCH3), III10 (o-
NO2), and III11 (o-CH3) exhibited equivalent (125 lg/ml)
activity as compared to the standard. Overall half of the
derivatives showed equivalent activity against Gram-posi-
tive bacteria S. aureus and E. faecalis. The final derivatives
III1–13 were also tested against two Gram-negative bacteria
E. coli (ATCC No. 25922) and P. aeruginosa (27853) and
compared with the same standard ciprofloxacin. The results
of most of the compounds as antibacterial were excellent
against both the Gram-negative bacterial strains. The
compounds III4 (3-F-4-Cl), III5 (H), III6 (p-F), III10 (o-
NO2), III11 (o-CH3), III12 (p-CH3), and III13 (m-CF3)
showed MIC value (62.5 lg/ml) even better than that of the
standard drug ciprofloxacin proving excellent potency as
antibacterial. The remaining derivatives from the same
series which included III1 (m-NO2), III2 (p-NO2), III3 (m-
Cl), III8 (m-CH3), III9 (p-OCH3) exhibited activity
equivalent to the standard (125 lg/ml). These derivatives
Antimicrobial activity
A broad panel of bacterial and fungal strains was used for
testing the antimicrobial properties of the synthesized mol-
ecules III1–13. The results obtained were depicted in the form
of MIC values for the synthesized derivatives III1–13. The
samples were tested by standard protocols like Micro dilu-
tion/Broth titer method. The screening for antimicrobial
activity was carried out by diluting the solution and pre-
paring the sets consecutively from 1000, 500, 250, 125, 62.5,
31.25, 15.62 up to 7.8 lg/ml. Ciprofloxacin was used as a
standard drug for antibacterial activity and fluconazole was
used as a standard for antifungal activity tests. The MIC
values for standards fluconazole against Candida albicans
and Aspergillus niger were recorded as 125 and 62.5 lg/ml,
respectively. On the other hand, the MIC values obtained for
the standard ciprofloxacin against Gram-positive bacteria
Staphylococcus aureus and Enterococcus faecalis were 62.5
and 125 lg/ml, respectively; similarly the MIC value was
recorded 125 lg/ml when tested against both the Gram-
negative bacteria Escherichia coli and Pseudomonas aeru-
ginosa for the same standard drug ciprofloxacin. The
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Med Chem Res (2014) 23:1290–1299
1293
when tested against P. aeruginosa also resulted in very
good antibacterial activity, where compounds III1 (m-
NO2), III2 (p-NO2), III3 (m-Cl), III4 (3-F-4-Cl), and III9
(p-OCH3) were showing excellent activity (62.5 lg/ml).
There were other compounds exhibiting equivalent activity
(125 lg/ml) as compared to the standard drug, viz. III5
(H), III6 (p-F), III10 (o-NO2), III11 (o-CH3), III12 (p-CH3),
and III13 (m-CF3). Thus from the series of synthesized
derivatives III1–13 more than half of the compounds
showed equivalent activity against Gram-positive bacteria
and all the compounds were excellent or equivalent when
tested against Gram-negative bacteria when compared to
ciprofloxacin.
activity (125 lg/ml) to that of the standard drug when
tested against fungal strain C. albicans. The rest of the
compounds exhibited poor activity as compared to the
standard drug result. A. niger when introduced for anti-
fungal activity test, none of the compounds exhibit even
equivalent activity to that of the standard drug. All the
compounds were seen to exhibit poor activity. Very few
compounds among the synthesized derivatives III1–13 were
capable of exhibiting antifungal property.
SAR study
It was observed that the use of electron-withdrawing and
electron-donating groups to confer different electronic
environments on the molecules showed a great impact on
their biological properties. It is very clear from the data
showed in Table 1 that the derivatives possessing electron-
withdrawing substituent like –NO2, –F, and –Cl exhibit
much better activity than the other derivatives, sometimes
The antifungal tests were carried against two fungal
strains C. albicans and A. niger, where fluconazole was
used as a standard drug for comparison and evaluation of
the antifungal activity of the synthesized molecules III1–13
The derivatives III2 (p-NO2), III3 (m-Cl), III4 (3-F-4-Cl),
III5 (H), III6 (p-F), and III11 (o-CH3) showed equivalent
.
Scheme 1 Scheme for
synthesis of benzimidazole
derivatives
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Med Chem Res (2014) 23:1290–1299
Solid light brown; Yield: 72 %; m.p.: 258 °C; IR (ATR,
cm-1): 1580 (–C=N str. benzimidazole nucleus), 2923
(–CH str. methoxy group), 3090 (–CH str. aromatic ring),
3390 (–NH str. sec. amine); 1H NMR (400 MHz, DMSO-
d6, d, ppm): 3.75 (1H, s, –OCH3), 6.74–7.79 (3H, m, Ar–
H), 12.33 (1H, s, benzimidazole-NH); 13C NMR
(100 MHz, DMSO-d6, d, ppm): 103.2 (C14), 112.2 (C12),
117.1 (C11), 147.8 (C9), 157.2 (C13); MS (m/z): 181; For
C8H8N2OS C, 53.3; H, 4.47; N, 15.54; S, 17.79 % Found:
C, 53.35; H, 4.50; N, 15.58; s, 17.83 %.
Fig. 2 Carbon enumeration of synthesized compounds III1–13
even better than the standard drugs ciprofloxacin and
fluconazole. Compounds III3 (m-Cl), III4 (3-F-4-Cl), and
III10 (o-NO2) possessing electron-withdrawing functional
groups exhibited excellent activity against Gram-positive
bacterial strains S. aureus and E. faecalis. One more
electron-withdrawing functional group fluorine was added
to the list, as the compound III6 (p-F) and III13 (m-CF3)
also exhibited excellent activity along with the other
derivatives possessing electro-withdrawing groups when
tested against the Gram-negative bacteria E. coli and P.
aeruginosa. It was found that only the derivatives with
electron-withdrawing groups were present among the few
exhibiting equivalent antifungal activity as that of the
standard drug fluconazole. SAR study helped to lead to a
conclusion that modifications if undertaken by introducing
electron-withdrawing functional group can help to enhance
the antimicrobial properties of the synthesized compounds.
General procedure for the synthesis of 2-chloro-N-
(aryl)acetamide derivatives II1–13
Various substituted amines (0.01 mol) were added to a
solution of DMF (35 ml) containing TEA (3–4 drops). The
mixture was stirred for 10 min at room temperature.
Chloroacetylchloride (0.015 mol, 113 g/mol, 1.19 ml) was
added to the above mixture, maintaining the temperature
between 0 and 5 °C. The obtained solution was then stirred
at room temperature for 4–6 h. The completion of reaction
was monitored with TLC using toluene:acetone (8:2) as
mobile phase. The solution was then added onto crushed
ice and the separated precipitates were filtered and dried.
The product was crystallized from methanol.
2-Chloro-N-(3-nitrophenyl)acetamide II1 Solid buff;
yield: 71 %; m.p.: 130 °C; IR (ATR, cm-1): 1692 (–C=O
str.), 2854 (–CH2 str. methylene), 3092 (–CH str. aromatic
Experimental
Methods, materials, and physical measurements
1
ring), 3396 (–NH str. sec. amine); H NMR (400 MHz,
DMSO-d6, d, ppm): 4.16 (2H, s, –CH2), 6.69–8.19 (4H, m,
Ar–H), 11.29 (1H, s, –NH); 13C NMR (100 MHz, DMSO-
d6, d, ppm): 43.4 (C8), 114.5 (C1), 119.8 (C3), 127.8 (C5),
129.9 (C4), 141.7 (C6), 148.2 (C2), 166.1 (C7); MS (m/z):
215; For C8H7ClN2O3: C, 44.77; H, 3.29; N, 13.05 %.
Found: C, 44.81; H, 3.34; N, 13.09 %.
All the chemicals required for the synthesis were purchased
from Merck ltd., HIMEDIA, LOBA Chemie, and sdfine
chemicals. Melting points of the final compounds as well as
derivatives were determined by open end capillary method
and were uncorrected. The monitoring of the completion of
reaction was determined by using TLC plates purchased from
Merck (TLC Silica gel 60 F254). Bruker spectrophotometer-
2-Chloro-N-(4-nitrophenyl)acetamide II2 Solid light
yellow; yield: 84 %; m.p.: 195 °C; IR (ATR, cm-1): 1699
(–C=O str.), 2859 (–CH2 str. methylene), 3087 (–CH str.
aromatic ring), 3385 (–NH str. sec. amine); 1H NMR
(400 MHz, DMSO-d6, d, ppm): 4.12 (2H, s, –CH2),
6.74–8.09 (7H, m, Ar–H), 11.32 (1H, s, –NH); 13C NMR
(100 MHz, DMSO-d6, d, ppm): 43.4 (C8), 121.7 (C1),
143.8 (C3), 121.7 (C5), 124.2 (C4), 141.7 (C6), 124.2 (C2),
166.1 (C7); MS (m/z): 215; For C8H7ClN2O3 C, 44.77; H,
3.29; N, 13.05 %. Found: C, 44.80; H, 3.35; N, 13.10 %.
1
400 MHz and -100 MHz were used to determine the H
NMR and 13C NMR, respectively, for the designed com-
pounds III1–13 using DMSO-d6 as solvent and TMS as ref-
erence. The IR spectral data were recorded using Bruker FT-
IR alpha-t (ATR). The mass spectral analysis was conducted
on Shimadzu mass spectrophotometer. The elemental anal-
ysis was carried out on Perkin-Elmer 2400 CHN Analyzer.
Synthesis and physical data
Synthesis of 5-methoxy-1H-benzo[d]imidazole-2-thiol I
2-Chloro-N-(3-chlorophenyl)acetamide II3 Solid light
yellow; yield: 84 %; m.p.: 110 °C; IR (ATR, cm-1): 1692
(–C=O str.), 2843 (–CH2 str. methylene), 3099 (–CH str.
aromatic ring), 3383 (–NH str. sec. amine); 1H NMR
The titled compound I was obtained by the literature pro-
cedure (Castilloa et al., 2002).
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Med Chem Res (2014) 23:1290–1299
1295
(400 MHz, DMSO-d6, d, ppm): 4.15 (2H, s, –CH2),
6.79–8.12 (4H, m, Ar–H), 11.30 (1H, s, –NH); 13C NMR
(100 MHz, DMSO-d6, d, ppm): 43.4 (C8), 121.7 (C1),
128.2 (C3), 120.1 (C5), 130.3 (C4), 141.7 (C6), 135.0 (C2),
166.1 (C7); MS (m/z): 205; For C8H7Cl2NO C, 47.09; H,
3.46; N, 6.86 %. Found: C, 47.13; H, 3.50; N, 6.90 %.
str. methylene), 3092 (–CH str. aromatic ring), 3396 (–NH
1
str. sec. amine); H NMR (400 MHz, DMSO-d6, d, ppm):
4.22 (2H, s, –CH2), 6.66–8.02 (4H, m, Ar–H), 11.21 (1H,
s, –NH); 13C NMR (100 MHz, DMSO-d6, d, ppm): 43.4
(C8), 121.7 (C1), 124.5 (C3), 119.2 (C5), 128.5 (C4), 141.7
(C6), 136.6 (C2), 166.1 (C7); MS (m/z): 184; For C9H10ClNO
C, 58.86; H, 5.49; N, 7.63 %. Found: C, 58.90; H, 5.54; N,
7.68 %.
2-Chloro-N-(4-chloro-3-fluorophenyl)acetamide II4 Solid
white; yield: 74 %; m.p.: 122 °C; IR (ATR, cm-1): 1688
(–C=O str.), 2852 (–CH2 str. methylene), 3090 (–CH str.
aromatic ring), 3395 (–NH str. sec. amine); 1H NMR
(400 MHz, DMSO-d6, d, ppm): 4.31 (2H, s, –CH2),
6.74–8.05 (3H, m, Ar–H), 11.21 (1H, s, –NH); 13C NMR
(100 MHz, DMSO-d6, d, ppm): 43.4 (C8), 112.0 (C1), 116.8
(C3), 120.1 (C5), 128.2 (C4), 137.7 (C6), 163.0 (C2), 166.1
(C7); MS (m/z): 205; For C8H6Cl2NOF C, 43.27; H, 2.72; N,
6.31 %. Found: C, 43.31; H, 2.76; N, 6.35 %.
2-Chloro-N-(4-methoxyphenyl)acetamide II9 Solid gray;
yield: 67 %; m.p.: 138 °C; IR (ATR, cm-1): 1698 (–C=O
str.), 2846 (–CH2 str. methylene), 3086 (–CH str. aromatic
1
ring), 3391 (–NH str. sec. amine); H NMR (400 MHz,
DMSO-d6, d, ppm): 4.16 (2H, s, –CH2), 6.74–8.10 (4H, m,
Ar–H), 11.28 (1H, s, –NH); 13C NMR (100 MHz, DMSO-
d6, d, ppm): 43.4 (C8), 121.7 (C1), 159.1 (C3), 121.7 (C5),
115.2 (C4), 141.7 (C6), 115.2 (C2), 166.1 (C7); MS (m/z):
201; For C9H10ClNO2 C, 54.15; H, 5.05; N, 7.02 %.
Found: C, 54.19; H, 5.09; N, 7.05 %.
2-Chloro-N-phenylacetamide II5 Solid white; yield: 66 %;
m.p.: 150 °C; IR (ATR, cm-1):1690(–C=O str.), 2858(–CH2
str. methylene), 3088 (–CH str. aromatic ring), 3387 (–NH str.
2-Chloro-N-(2-nitrophenyl)acetamide II10 Chrome yel-
low; yield: 84 %; m.p.: 100 °C; IR (ATR, cm-1): 1693
(–C=O str.), 2848 (–CH2 str. methylene), 3098 (–CH str.
aromatic ring), 3388 (–NH str. sec. amine); 1H NMR
(400 MHz, DMSO-d6, d, ppm): 4.18 (2H, s, –CH2),
6.70–8.19 (4H, m, Ar–H), 11.15 (1H, s, –NH); 13C NMR
(100 MHz, DMSO-d6, d, ppm): 43.4 (C8), 131.9 (C1),
118.0 (C3), 115.0 (C5), 135.8 (C4), 145.2 (C6), 126.0 (C2),
166.1 (C7); MS (m/z): 215; For C8H7ClN2O3 C, 44.77; H,
3.29; N, 13.05 %. Found: C, 44.80; H, 3.34; N, 13.10 %.
1
sec. amine); H NMR (400 MHz, DMSO-d6, d, ppm): 4.19
(2H, s, –CH2), 6.66–8.12 (5H, m, Ar–H), 11.14 (1H, s, –NH);
13C NMR (100 MHz, DMSO-d6, d, ppm): 43.4 (C8), 121.7
(C1), 128.2 (C3), 121.7 (C5), 128.2 (C4), 141.7 (C6), 129.0
(C2), 166.1 (C7); MS (m/z): 170; For C8H8ClNO C, 56.65; H,
4.75; N, 8.26 %. Found: C, 56.69; H, 4.79; N, 8.30 %.
2-Chloro-N-(4-fluorophenyl)acetamide II6 Solid off-
white; yield: 76 %; m.p.: 145 °C; IR (ATR, cm-1): 1688
(–C=O str.), 2856 (–CH2 str. methylene), 3099 (–CH str.
aromatic ring), 3391 (–NH str. sec. amine); 1H NMR
(400 MHz, DMSO-d6, d, ppm): 4.22 (2H, s, –CH2),
6.56–8.02 (4H, m, Ar–H), 11.23 (1H, s, –NH); 13C NMR
(100 MHz, DMSO-d6, d, ppm): 43.4 (C8), 121.7 (C1),
163.2 (C3), 121.7 (C5), 115.2 (C4), 141.7 (C6), 115.2 (C2),
166.1 (C7); MS (m/z): 188; For C8H8ClFNO C, 51.22; H,
3.76; N, 7.47 %. Found: C, 51.25; H, 3.80; N, 7.50 %.
2-Chloro-N-o-tolylacetamide II11 Solid white; yield:
44 %; m.p.: 125 °C; IR (ATR, cm-1): 1687 (–C=O str.),
2856 (–CH2 str. methylene), 3091 (–CH str. aromatic ring),
1
3397 (–NH str. sec. amine); H NMR (400 MHz, DMSO-
d6, d, ppm): 4.14 (2H, s, –CH2), 6.80–8.21 (4H, m, Ar–H),
11.27 (1H, s, –NH); 13C NMR (100 MHz, DMSO-d6, d,
ppm): 43.4 (C8), 132.0 (C1), 129.5 (C3), 125.2 (C5), 126.0
(C4), 137.7 (C6), 130.8 (C2), 166.1 (C7); MS (m/z): 184;
For C9H10ClNO C, 58.86; H, 5.49; N, 7.63 %. Found: C,
58.90; H, 5.55; N, 7.68 %.
2-Chloro-N-(2-methoxyphenyl)acetamide
II7 Solid
brown; yield: 61 %; m.p.: 159 °C; IR (ATR, cm-1): 1690
(–C=O str.), 2859 (–CH2 str. methylene), 3087 (–CH str.
aromatic ring), 3402 (–NH str. sec. amine); 1H NMR
(400 MHz, DMSO-d6, d, ppm): 4.17 (2H, s, –CH2),
6.71–8.06 (4H, m, Ar–H), 11.14 (1H, s, –NH); 13C NMR
(100 MHz, DMSO-d6, d, ppm): 43.4 (C8), 149.6 (C1),
128.5 (C3), 120.5 (C5), 124.5 (C4), 126.9 (C6), 113.0 (C2),
166.1 (C7); MS (m/z): 201; For C9H10ClNO2 C, 54.15; H,
5.05; N, 7.02 %. Found: C, 54.19; H, 5.09; N, 7.05 %.
2-chloro-N-p-tolylacetamide II12 Solid white; yield: 66 %;
m.p.: 170 °C; IR (ATR, cm-1): 1692 (–C=O str.), 2848 (–CH2
str. methylene), 3088 (–CH str. aromatic ring), 3387 (–NH str.
1
sec. amine); H NMR (400 MHz, DMSO-d6, d, ppm): 4.20
(2H, s, –CH2), 6.96–8.12 (4H, m, Ar–H), 11.17 (1H, s, –NH);
13C NMR (100 MHz, DMSO-d6, d, ppm): 43.4 (C8), 121.7
(C1), 136.8 (C3), 123.5 (C5), 129.4(C4), 141.7 (C6), 129.4 (C2),
166.1 (C7); MS (m/z): 184; For C9H10ClNO C, 58.86; H, 5.49;
N, 7.63 %. Found: C, 58.91; H, 5.54; N, 7.68 %.
2-chloro-N-m-tolylacetamide II8 Solid white; yield: 63 %;
m.p.: 95 °C; IR (ATR, cm-1): 1691 (–C=O str.), 2852 (–CH2
123

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Med Chem Res (2014) 23:1290–1299
(m/z): 359 (M?). For C16H14N4O4S: C, 53.62; H, 3.94; N, 15.63;
2-Chloro-N-(3-(trifluoromethyl)phenyl)acetamide II13
Solid light brown; yield: 68 %; m.p.: 102 °C; IR (ATR,
S, 8.95 %. Found: C, 53.66; H, 3.99; N, 15.66; S, 8.99 %.
cm-1): 1698 (–C=O str.), 2853 (–CH2 str. methylene), 3095
1
(–CH str. aromatic ring), 3393 (–NH str. sec. amine); H
N-(3-Chlorophenyl)-2-(5-methoxy-1H-benzo[d]imidazol-2-
ylthio)acetamide III3 Solid off-white; yield: 63 %; m.p.:
121 °C; IR (ATR, cm-1): 1587 (–C=N str. benzimidazole
nucleus), 1692 (–C=O str.), 2843 (–CH2 str. methylene), 2935 (–
CH str. methoxy group), 3099 (–CH str. aromatic ring), 3383 (–
NH str. sec. amine); 1H NMR (400 MHz, DMSO-d6, d, ppm):
3.71 (3H, s, –OCH3), 4.15 (2H, s, –CH2), 6.79–8.12 (7H, m,
Ar–H), 11.30 (1H, s, –NH), 12.29 (1H, s, benzimidazole-NH);
13C NMR (100 MHz, DMSO-d6, d, ppm): 39.4 (C8), 103.2
(C14), 112.2 (C12), 117.1 (C11), 120.1 (C5), 121.7 (C1), 128.2
(C3), 130.3 (C4), 139.0 (C15), 141.7 (C6), 147.8 (C9), 157.2 (C13),
163.0 (C2), 167.3 (C7); MS (m/z): 348 (M?). For
C16H14N3O2SCl: C, 55.25; H, 4.06; N, 12.08; S, 9.22 %. Found:
C, 55.29; H, 4.10; N, 12.11; S, 9.25 %.
NMR (400 MHz, DMSO-d6, d, ppm): 4.11 (2H, s, –CH2),
6.74–8.03 (4H, m, Ar–H), 11.21 (1H, s, –NH); 13C NMR
(100 MHz, DMSO-d6, d, ppm): 43.4 (C8), 123.4 (C1), 120.9
(C3), 123.5 (C5), 129.4 (C4), 141.7 (C6), 131.6 (C2), 166.1
(C7); MS (m/z): 238; For C9H7ClF3NO: C, 45.49; H, 2.97;
N, 5.89 %. Found: C, 45.53; H, 3.01; N, 5.93 %.
General method for the synthesis of final derivatives III1–13
5-Methoxy-1H-benzo[d]imidazole-2-thiol
I
(0.01 mol,
180 g/mol, 1.8 g) was made soluble in acetone. To this well-
stirred solution different acetamide derivatives II1–13
(0.01 mol) were added. K2CO3 (0.02 mol, 138 g/mol,
2.76 g) was added to the above mixture and was allowed to
stir for 4 h at room temperature. The completion of reaction
was monitored using TLC plate with mobile phase ethyl
acetate:n-hexane (6:4). The final products thus obtained
were poured into ice cold water and stirred for 30 min. The
precipitates were filtered and washed occasionally. The final
products III1–13 obtained were crystallized from alcohol.
N-(4-Chloro-3-fluorophenyl)-2-(5-methoxy-1H-
benzo[d]imidazol-2-ylthio)acetamide III4 Solid white;
59 %; m.p.: 202 °C; IR (ATR, cm-1): 1592 (–C=N str.
benzimidazole nucleus), 1688 (–C=O str.), 2852 (–CH2 str.
methylene), 2930 (–CH str. methoxy group), 3090 (–CH
1
str. aromatic ring), 3395 (–NH str. sec. amine); H NMR
(400 MHz, DMSO-d6, d, ppm): 3.72 (3H, s, –OCH3), 4.31
(2H, s, –CH2), 6.74–8.05 (6H, m, Ar–H), 11.21 (1H, s,
–NH), 12.35 (1H, s, benzimidazole-NH); 13C NMR
(100 MHz, DMSO-d6, d, ppm): 39.4 (C8), 103.2 (C14),
112.0 (C1), 112.2 (C12), 116.8 (C3), 117.1 (C11), 121.8
(C5), 130.6 (C4), 139.0 (C15), 137.7 (C6), 147.8 (C9), 157.2
(C13), 163.0 (C2), 167.3 (C7); MS (m/z): 366 (M?). For
C16H13N3O2SClF: C, 52.53; H, 3.58; N, 11.49; S, 8.77 %.
Found: C, 53.56; H, 3.62; N, 11.53; S, 8.80 %.
2-(5-Methoxy-1H-benzo[d]imidazol-2-ylthio)-N-(3-nitro-
phenyl)acetamide III1 Solid dark yellow; yield: 50 %;
m.p.: 118 °C; IR (ATR, cm-1): 1587 (–C=N str. benz-
imidazole nucleus), 1692 (–C=O str.), 2854 (–CH2 str.
methylene), 2926 (–CH str. methoxy group), 3092 (–CH
1
str. aromatic ring), 3396 (–NH str. sec. amine); H NMR
(400 MHz, DMSO-d6, d, ppm): 3.72 (3H, s, –OCH3), 4.16
(2H, s, –CH2), 6.69–8.19 (7H, m, Ar–H), 11.29 (1H, s,
–NH), 12.31 (1H, s, benzimidazole-NH); 13C NMR
(100 MHz, DMSO-d6, d, ppm): 39.4 (C8), 103.2 (C14),
112.2 (C12), 114.5 (C1), 117.1 (C11), 119.8 (C3), 127.8
(C5), 129.9 (C4), 139.0 (C15), 141.7 (C6), 147.8 (C9), 148.2
(C2), 157.2 (C13), 167.3 (C7); MS (m/z): 359 (M?). For
C16H14N4O4S: C, 53.62; H, 3.94; N, 15.63; S, 8.95 %.
Found: C, 53.67; H, 3.98; N, 15.67; S, 8.98 %.
2-(5-Methoxy-1H-benzo[d]imidazol-2-ylthio)-N-phen-
ylacetamide III5 Solid white; yield: 55 %; m.p.: 118 °C;
IR (ATR, cm-1): 1586 (–C=N str. benzimidazole nucleus),
1690 (–C=O str.), 2858 (–CH2 str. methylene), 2928 (–CH
str. methoxy group), 3088 (–CH str. aromatic ring), 3387
1
(–NH str. sec. amine); H NMR (400 MHz, DMSO-d6, d,
ppm): 3.71 (3H, s, –OCH3), 4.19 (2H, s, –CH2), 6.66–8.12
(8H, m, Ar–H), 11.14 (1H, s, –NH), 12.32 (1H, s, benz-
imidazole-NH); 13C NMR (100 MHz, DMSO-d6, d, ppm):
39.4 (C8), 103.2 (C14), 112.2 (C12), 117.1 (C11), 121.7 (C5),
121.7 (C1), 128.2 (C3), 129.0 (C4), 129.0 (C2), 139.0 (C15),
141.7 (C6), 147.8 (C9), 157.2 (C13), 167.3 (C7); MS (m/z):
314 (M?). For C16H15N3O2S: C, 61.32; H, 4.82; N, 13.41;
S, 10.23 %. Found: C, 61.35; H, 4.85; N, 13.45; S, 10.26 %.
2-(5-Methoxy-1H-benzo[d]imidazol-2-ylthio)-N-(4-nitro-
phenyl)acetamide III2 Solid yellow; yield: 59 %; m.p.:
125 °C; IR (ATR, cm-1): 1584 (–C=N str. benzimidazole
nucleus), 1699 (–C=O str.), 2859 (–CH2 str. methylene),
2915 (–CH str. methoxy group), 3087 (–CH str. aromatic
1
ring), 3385 (–NH str. sec. amine); H NMR (400 MHz,
DMSO-d6, d, ppm): 3.75 (3H, s, –OCH3), 4.12 (2H, s, –CH2),
6.74–8.09 (7H, m, Ar–H), 11.32 (1H, s, –NH), 12.36 (1H, s,
benzimidazole-NH); 13C NMR (100 MHz, DMSO-d6, d,
ppm): 39.4 (C8), 103.2 (C14), 112.2 (C12), 117.1 (C11), 121.7
(C5), 121.7 (C1), 124.2 (C2), 124.2 (C4), 139.0 (C15), 141.7
(C6), 143.8 (C3), 147.8 (C9), 157.2 (C13), 167.3 (C7); MS
N-(4-Fluorophenyl)-2-(5-methoxy-1H-benzo[d]imidazol-2-
ylthio)acetamide III6 Solid off-white; yield: 58 %; m.p.:
158 °C; IR (ATR, cm-1): 1592 (–C=N str. benzimidazole
123

Med Chem Res (2014) 23:1290–1299
1297
nucleus), 1688 (–C=O str.), 2856 (–CH2 str. methylene),
2926 (–CH str. methoxy group), 3099 (–CH str. aromatic
DMSO-d6, d, ppm): 39.4 (C8), 103.2 (C14), 112.2 (C12),
115.2 (C2), 115.2 (C4), 117.1 (C11), 121.7 (C5), 121.7 (C1),
139.0 (C15), 141.7 (C6), 147.8 (C9), 157.2 (C13), 159.1
(C3), 167.3 (C7); MS (m/z): 344 (M?). For C17H17N3O3S:
C, 59.46; H, 4.99; N, 12.24; S, 9.34 %. Found: C, 59.50; H,
5.04; N, 12.27; S, 9.38 %.
1
ring), 3391 (–NH str. sec. amine); H NMR (400 MHz,
DMSO-d6, d, ppm): 3.69 (3H, s, –OCH3), 4.22 (2H, s,
–CH2), 6.56–8.03 (7H, m, Ar–H), 11.23 (1H, s, –NH),
12.37 (1H, s, benzimidazole-NH); 13C NMR (100 MHz,
DMSO-d6, d, ppm): 39.4 (C8), 103.2 (C14), 112.2 (C12),
115.2 (C4), 115.2 (C2), 117.1 (C11), 121.7 (C5), 121.7 (C1),
139.0 (C15), 141.7 (C6), 147.8 (C9), 157.2 (C13), 163.2(C3),
167.3 (C7); MS (m/z): 332 (M?). For C16H14N3O2FS: C,
57.99; H, 4.26; N, 12.68; S, 9.68 %. Found: C, 58.02; H,
4.30; N, 12.72; S, 9.71 %.
2-(5-Methoxy-1H-benzo[d]imidazol-2-ylthio)-N-(2-nitro-
phenyl)acetamide III10 Solid yellow; yield: 60 %; m.p.:
105 °C; IR (ATR, cm-1): 1582 (–C=N str. benzimidazole
nucleus), 1693 (–C=O str.), 2848 (–CH2 str. methylene),
2925 (–CH str. methoxy group), 3098 (–CH str. aromatic
1
ring), 3388 (–NH str. sec. amine); H NMR (400 MHz,
2-(5-Methoxy-1H-benzo[d]imidazol-2-ylthio)-N-(2-methoxy-
phenyl)acetamide III7 Solid cream; yield: 44 %; m.p.:
156 °C; IR (ATR, cm-1): 1586 (–C=N str. benzimidazole
nucleus), 1690 (–C=O str.), 2859 (–CH2 str. methylene),
2920 (–CH str. methoxy group), 3087 (–CH str. aromatic
DMSO-d6, d, ppm): 3.75 (3H, s, –OCH3), 4.18 (2H, s,
–CH2), 6.70–8.19 (7H, m, Ar–H), 11.15 (1H, s, –NH),
12.27 (1H, s, benzimidazole-NH); 13C NMR (100 MHz,
DMSO-d6, d, ppm): 39.4 (C8), 103.2 (C14), 112.2 (C12),
117.1 (C11), 115.0 (C5), 118.0 (C3), 126.0 (C2), 131.9 (C1),
135.8 (C4), 139.0 (C15), 145.2 (C6), 147.8 (C9), 157.2
(C13), 167.3 (C7); MS (m/z): 359 (M?). For C16H16N4O4S:
C, 53.62; H, 3.94; N, 15.63; S, 8.95 %. Found: C, 53.66; H,
3.95; N, 15.66; S, 8.99 %.
1
ring), 3402 (–NH str. sec. amine); H NMR (400 MHz,
DMSO-d6, d, ppm): 3.72 (3H, s, –OCH3), 4.17 (2H, s,
–CH2), 6.71–8.06 (7H, m, Ar–H), 11.14 (1H, s, –NH),
12.37 (1H, s, benzimidazole-NH); 13C NMR (100 MHz,
DMSO-d6, d, ppm): 39.4 (C8), 103.2 (C14), 112.2 (C12),
117.1 (C11), 120.5 (C5), 149.6 (C1), 128.5(C3), 124.5 (C4),
113.0 (C2), 139.0 (C15), 126.9 (C6), 147.8 (C9), 157.2
(C13), 167.3 (C7); MS (m/z): 344 (M?). For C17H17N3O3S:
C, 59.46; H, 4.99; N, 12.24; S, 9.34 %. Found: C, 59.51; H,
5.04; N, 12.28; S, 9.39 %.
2-(5-Methoxy-1H-benzo[d]imidazol-2-ylthio)-N-o-tolylac-
etamide III11 Solid light brown; yield: 53 %; m.p.:
156 °C; IR (ATR, cm-1): 1576 (–C=N str. benzimidazole
nucleus), 1687 (–C=O str.), 2856 (–CH2 str. methylene),
2918 (–CH str. methoxy group), 3091 (–CH str. aromatic
1
ring), 3397 (–NH str. sec. amine); H NMR (400 MHz,
2-(5-Methoxy-1H-benzo[d]imidazol-2-ylthio)-N-m-tolylac-
etamide III8 Solid white; yield: 54 %; m.p.: 105 °C; IR
(ATR, cm-1): 1576 (–C=N str. benzimidazole nucleus),
1691 (–C=O str.), 2852 (–CH2 str. methylene), 2944 (–CH
str. methoxy group), 3092 (–CH str. aromatic ring), 3396
DMSO-d6, d, ppm): 2.53 (3H, s, –CH3); 3.76 (3H, s,
–OCH3), 4.14 (2H, s, –CH2), 6.80–8.21 (7H, m, Ar–H),
11.27 (1H, s, –NH), 12.33 (1H, s, benzimidazole-NH); 13
C
NMR (100 MHz, DMSO-d6, d, ppm): 39.4 (C8), 103.2
(C14), 112.2 (C12), 117.1 (C11), 125.2 (C5), 126.0 (C4),
129.5(C3), 130.8 (C2), 132.0 (C1), 137.7 (C6), 139.0 (C15),
147.8 (C9), 157.2 (C13), 167.3 (C7); MS (m/z): 328 (M?).
For C17H17N3O2S: C, 62.36; H, 5.23; N, 12.83; S, 7.79 %.
Found: C, 62.41; H, 5.26; N, 12.87; S, 7.74 %.
1
(–NH str. sec. amine); H NMR (400 MHz, DMSO-d6, d,
ppm): 3.69 (3H, s, –OCH3), 4.22 (2H, s, –CH2), 6.66–8.02
(7H, m, Ar–H), 11.21 (1H, s, –NH), 12.32 (1H, s, benz-
imidazole-NH); 13C NMR (100 MHz, DMSO-d6, d, ppm):
39.4 (C8), 103.2 (C14), 112.2 (C12), 117.1 (C11), 119.2 (C5),
121.7 (C1), 124.5(C3), 128.8 (C4), 136.6 (C2), 139.0 (C15),
141.7 (C6), 147.8 (C9), 157.2 (C13), 167.3 (C7); MS (m/z):
328 (M?). For C17H17N3O2S: C, 62.36; H, 5.23; N, 12.83;
S, 9.79 %. Found: C, 62.41; H, 5.28; N, 12.87; S, 9.84 %.
2-(5-Methoxy-1H-benzo[d]imidazol-2-ylthio)-N-p-tolylac-
etamide III12 Solid light brown; yield: 76 %; m.p.:
175 °C; IR (ATR, cm-1): 1584 (–C=N str. benzimidazole
nucleus), 1692 (–C=O str.), 2848 (–CH2 str. methylene),
2926 (–CH str. methoxy group), 3088 (–CH str. aromatic
2-(5-Methoxy-1H-benzo[d]imidazol-2-ylthio)-N-(4-methoxy-
phenyl)acetamide III9 Solid off-white; yield: 62 %; m.p.:
195 °C; IR (ATR, cm-1): 1587 (–C=N str. benzimidazole
nucleus), 1698 (–C=O str.), 2846 (–CH2 str. methylene),
2936 (–CH str. methoxy group), 3086 (–CH str. aromatic
1
ring), 3387 (–NH str. sec. amine); H NMR (400 MHz,
DMSO-d6, d, ppm): 2.49 (3H, s, –CH3); 3.79 (3H, s,
–OCH3), 4.20 (2H, s, –CH2), 6.96–8.12 (7H, m, Ar–H),
11.17 (1H, s, –NH), 12.30 (1H, s, benzimidazole-NH); 13
C
1
NMR (100 MHz, DMSO-d6, d, ppm): 39.4 (C8), 103.2
(C14), 112.2 (C12), 117.1 (C11), 121.7 (C1), 123.5 (C5),
129.4 (C2), 129.4 (C4), 136.8(C3), 139.0 (C15), 141.7 (C6),
147.8 (C9), 157.2 (C13), 167.3 (C7); MS (m/z): 328 (M?).
ring), 3391 (–NH str. sec. amine); H NMR (400 MHz,
DMSO-d6, d, ppm): 3.80 (3H, s, –OCH3), 4.16 (2H, s,
–CH2), 6.74–8.10 (7H, m, Ar–H), 11.28 (1H, s, –NH),
12.29 (1H, s, benzimidazole-NH); 13C NMR (100 MHz,
123

1298
Med Chem Res (2014) 23:1290–1299
Dubey R, Abuzar S, Sharma S, Chatterjee RK, Katiyar JC (1985)
Aynthesis and antihelmintic activity of 5(6)-[(benzimidazole-2-
yl) carboxamido]- and {4-substituted piperazine-1-yl) benzimi-
dazoles. J Med Chem 28:1748–1750. doi:10.1021/jm00149a036
Iwahi T, Satoh H, Nakao M, Iwasaki T, Yamazaki T, Kubo K,
Tamura T, Imada A (1991) Lansoprazole, a novel benzimidazole
proton pump inhibitor, and its related compounds have selective
activity against Helicobacter pylori. Antimicrob Agents Che-
mother 35:490–496. doi:10.1128/AAC.35.3.490
For C17H17N3O2S: C, 62.36; H, 5.23; N, 12.83; S, 7.79 %.
Found: C, 62.41; H, 5.28; N, 12.87; S, 7.73 %.
2-(5-Methoxy-1H-benzo[d]imidazol-2-ylthio)-N-(3-(trifluo-
romethyl)phenyl)acetamide III13 Solid light cream; yield:
66 %; m.p.: 109 °C; IR (ATR, cm-1): 1161 (–C–F str.
–CF3), 1580 (–C=N str. benzimidazole nucleus), 1698
(–C=O str.), 2853 (–CH2 str. methylene), 2921 (–CH str.
methoxy group), 3095 (–CH str. aromatic ring), 3393 (–NH
Jat RK, Jat JL, Pathak DP (2006) Synthesis of benzimidazole
derivatives: as anti-hypertensive agents. E-J Chem 3:278–285
1
¨
Kath R, Blumenstengel K, Fricke HJ, Hoffken K (2001) Bendamus-
str. sec. amine); H NMR (400 MHz, DMSO-d6, d, ppm):
tine monotherapy in an advanced and refractory chronic
lymphocytic leukemia. J Cancer Res Clin Oncol 127:48–54.
doi:10.1007/s004320000180
3.75 (3H, s, –OCH3), 4.11 (2H, s, –CH2), 6.74–8.03 (7H, m,
Ar–H), 11.21 (1H, s, –NH), 12.33 (1H, s, benzimidazole-
NH); 13C NMR (100 MHz, DMSO-d6, d, ppm): 39.4 (C8),
103.2 (C14), 112.2 (C12), 117.1 (C11), 120.9 (C3), 123.4 (C1),
123.5 (C5), 129.4 (C4), 131.6 (C2), 139.0 (C15), 141.7 (C6),
147.8 (C9), 157.2 (C13), 167.3 (C7); MS (m/z): 382 (M?). For
C17H14F3N3O2S: C, 53.54; H, 3.70; N, 11.02; S, 8.41 %.
Found: C, 53.58; H, 3.74; N, 11.05; S, 8.45 %.
´
Kazimierczuk Z, Upcroft JA, Upcroft P, Gorska A, Starosciak B,
Laudy A (2002) Synthesis, antiprotozoal and antibacterial
activity of nitro-and halogeno-substituted benzimidazole deriv-
atives. Acta Biochimi Pol 49:185–196
Narasimhan B, Sharma D, Kumar Pradeep (2012) Benzimidazole: a
medicinally important heterocyclic moiety. Med Chem Res
21:269–283. doi:10.1007/s00044-010-9533-9
´
Navarrete-Vazquez G, Cedillo R, Hernandez-Campos A, Yepez L,
Hernandez-Luis F, Valdez J, Castillo R (2001) Synthesis and
´
´
´
antiparasitic activity of 2-(trifluoromethyl) benzimidazole deriv-
atives. Bioorg Med Chem Lett 11:187–190. doi:10.1016/S0960-
894X(00)00619-3
Conclusion
Nofal ZM, Fahmy HH, Mohamed HS (2002) Synthesis, antimicrobial
and molluscicidal activities of new benzimidazole derivatives.
Arch Pharm Res 25:28–38. doi:10.1007/BF02975257
O’Sullivan DG, Wallis AK (1963) New benzimidazole derivatives
with powerful protective action on tissue-culture cells infected
with types 1, 2 and 3 poliovirus. Nature 198:1270–1273. doi:10.
1038/1981270a0
Parikh KS, Joshi DS (2013) Antibacterial and antifungal screening of
newly synthesized benzimidazole-clubbed chalcone derivatives.
Med Chem Res 22:3688–3697. doi:10.1007/s00044-012-0369-3
Patel MP, Patel RG, Jardosh HH, Sangani CB (2013) Microwave-
assisted synthesis of pyrido[1,2-a]benzimidazole derivatives of
b-aryloxyquinoline and their antimicrobial and antituberculosis
activities. Med Chem Res 22:3035–3047. doi:10.1007/s00044-
012-0322-5
Patil A, Ganguly S, Surana S (2008) A systematic review of
benzimidazole derivatives as antiulcer agent. Rasayan J Chem
3:447–460
Ramanatham V, Vaidya SD, Sivakumar BV, Bhise UN, Bhirud SB,
Mashelkar UC (2008) Synthesis, anti-bacterial, anti-asthmatic
and anti-diabetic activities of novel N-substituted-2-(4-phenyl-
ethynyl-phenyl)-1H-benzimidazoles and N-substituted 2[4-(4,4-
dimethyl-thiochroman-6-yl-ethynyl)-phenyl)-1H-benzimidaz-
oles. Eur J Med Chem 43:986–995. doi:10.1016/j.ejmech.2007.
06.013
The bioactive molecules synthesized by the authors were
found to possess excellent antibacterial property. The SAR
study undertaken for the synthesized derivatives (III1–13
)
clearly lead to a conclusion that the use of electron-with-
drawing functional groups as substituent helped to enhance the
antimicrobial property. The molecules synthesized here can be
further optimized by introducing more electron-withdrawing
sites, which may help to develop few newer potent leads. On
the basis of above results, attempts are made to optimize the
lead structure to obtain more potent antimicrobial molecules.
The modifications undertaken for future study will help to
develop much better antimicrobial heterocyclic scaffolds.
Acknowledgments Authors DSJ and KSP are highly indebted and
thankful to the Department of Science and Technology (DST),
INDIA, for providing DSJ with INSPIRE fellowship. We appreciate
the support and laboratory facilities provided by the Sheth M.
N. Science College, Patan and North Gujarat Education Society,
Mumbai. We are thankful to SAIF Chandigarh for providing analyt-
ical and instrumentation facilities.
Rangappa KS, Thimmegowda NR, Swamy SN, Anandkumar CS,
Sunilkumar YC, Chandrappa S, Yip GW (2008) Synthesis,
characterization and evaluation of benzimidazole derivative and
its precursors as inhibitors of MDA-MB-231 human breast
cancer cell proliferation. Bioorg Med Chem Lett 18:432–435.
doi:10.1016/j.bmcl.2007.08.078
Reffat HM (2011) Synthesis of potential anticancer derivatives of
pyrido[1,2-a]benzimidazoles. Med Chem Res 21:1253–1260.
doi:10.1007/s00044-011-9636-y
References
Ayhan-Kilcigil G, Kus C, Eke BC (2004) Synthesis and antioxidant
properties of some novel benzimidazole derivatives on lipid
peroxidation in the rat liver. Arch Pharm Res 27:156–163.
doi:10.1007/BF02980099
Castilloa R et al (2002) Synthesis and antiparasitic activity of 1H-
benzimidazole derivatives. Bioorg Med ChemLett 12:2221–2224.
doi:10.1016/S0960-894X(02)00346-3
Saxena DB, Khajuria RK, Suri OP (1982) Synthesis and spectral
studies of 2-mercaptobenzimidazole derivatives. J Hetero Chem
19:681–683. doi:10.1002/jhet.5570190350
Dixit S, Sharma PK, Kaushik
N (2013) Synthesis of novel
Scherhag B, Kopplemann E, Wolz H (1974) Production of 2-mer-
captobenzimidazole by reacting o-phenylene diamine and
benzimidazole derivatives as potent analgesic agent. Med Chem
Res 22:900–904. doi:10.1007/s00044-012-0083-1
123

Med Chem Res (2014) 23:1290–1299
1299
carbondisulphide.
freepatentsonline.com/3842098.html
U.S.
Patent
3842098.
http://www.
derivatives having potent activity against MRSA. Eur J Med
Chem 44:1024–1033. doi:10.1016/j.ejmech.2008.06.026
Wang M-L, Liu B-L (2007) Synthesis of 2-mercaptobenzimidazole
from the reaction of o-phenylenediamine and carbon disulfide in
presence of potassium hydroxide. J Chin Inst Chem Eng
38:161–167. doi:10.1016/j.jcice.2007.01.003
Youssef AM, Masoud GN, Khalek A, Wahab AE, Labouta IM, Hazaa
AA (2013) Design, synthesis, and biological evaluation of new
4-thiazolidinone derivatives substituted with benzimidazole ring
as potential chemotherapeutic agents. Med Chem Res
22:707–725. doi:10.1007/s00044-012-0057-3
Shah DI, Sharma M, Bansal Y, Bansal G, Singh M (2008)
Angiotensin II–AT1 receptor antagonists: design, synthesis and
evaluation of substituted carboxamido benzimidazole deriva-
tives. Eur J Med Chem 43:1808–1812. doi:10.1016/j.ejmech.
2007.11.008
Tsukamoto G, Yoshino K, Toshihiko K, Hiroshi O, Kagaya H, Ito K
(1980) 2-substituted azole derivatives. 1. Synthesis and anti-
inflammatory activity of some 2-(substituted-pyridinyl)benzim-
idazoles. J Med Chem 23:734–738. doi:10.1021/jm00181a007
˘
Tuncbilek M, Tulug K, Altanlar N (2009) Synthesis and in vitro
antimicrobial activity of some novel substituted benzimidazole
123