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Synthesis of benzimidazolyl-1,3,4-
oxadiazol-2ylthio-N-phenyl
(benzothiazolyl) acetamides as
antibacterial, antif...
Dr Dhanji P Rajani

European Journal of Medicinal Chemistry

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 European Journal of Medicinal Chemistry xxx (2012) 1e11

Contents lists available at SciVerse ScienceDirect

European Journal of Medicinal Chemistry

journal homepage: http://www.elsevier.com/locate/ejmech

Original article

Synthesis of benzimidazolyl-1,3,4-oxadiazol-2ylthio-N-phenyl (benzothiazolyl)

acetamides as antibacterial, antifungal and antituberculosis agents
Rahul V. Patel a, *, Paresh K. Patel a, Premlata Kumari a, Dhanji P. Rajani b, Kishor H. Chikhalia c
a
Department of Applied Chemistry, S. V. National Institute of Technology, Surat 395 007, India
b
Microcare Laboratory, Surat 395 001, India
c
Department of Chemistry, School of Science, Gujarat University, Ahmedabad 380 009, India

a r t i c l e i n f o a b s t r a c t

Article history: To affiliate multiple bioactivities in a compact heteronuclei, two series of benzimidazole based 1,3,4-
Received 20 September 2011 oxadiazoles were synthesized and assessed in vitro for their efficacy as antimicrobial agents against
Received in revised form eight bacteria (Staphylococcus aureus, Bacillus cereus, Escherichia coli, Pseudomonas aeruginosa, Klebsiella
16 March 2012
pneumoniae, Salmonella typhi, Proteus vulgaris, Shigella flexneri), four fungi (Aspergillus niger, Aspergillus
Accepted 16 March 2012
Available online xxx
fumigatus, Aspergillus clavatus, Candida albicans) and Mycobacterium tuberculosis H37Rv and best results
were observed amongst the Nebenzothiazolyl aetamide series. The lipophilicity (LogP) influence on the
biological profile (MICs) of the prepared products was also discussed. Upon biological screening, it was
Keywords:
Benzimidazole
observed that the majority of the compounds were found to possess a significant broad spectrum
Benzothiazole antimicrobial (3.12e25 mg/mL of MIC) and antitubercular (6.25e25 mg/mL of MIC) potential. The struc-
1,3,4eOxadiazole tural assignments of the new products were done on the basis of IR, 1H NMR, 13C NMR spectroscopy and
Biological activity elemental analysis.
Ó 2012 Elsevier Masson SAS. All rights reserved.

1. Introduction unique antibacterial agents to be implemented as a best way to

At the present time, the frightening threat of pathogens with
multidrug resistance acquirement to the well established antimi-
crobial arsenal constitutes a serious public health threat. These
organisms possessed the ability to withstand attack by antimicro-
bial drugs currently available, and the uncontrolled rise in resistant
pathogens threatens lives. Such infections most commonly affect
patients with decreased immunity, neoplastic disorders and
undergoing organ transplantation [1]. On the other hand; Myco-
bacteria are ubiquitous organisms that are responsible to cause
mycobacterium tuberculosis, the most common infectious diseases
known by the mankind admitting high mortality rate worldwide.
Due to the quiescent form of mycobacterium tuberculosis strains,
many of the current frontline therapeutics have become ineffective
by the imminent exigency of multidrugeresistant [2e4]. The 2010
statistics from World Health Organization (WHO) indicated that, 1.3
million MDReTB cases will need to be treated in the 27 high
MDReTB burden countries between 2010 and 2015 [5]. Thus the
above mentioned factors reveal the necessity for newer, potent and
* Corresponding author. Tel.: þ91 9712755525.
E-mail address: rahul.svnit11@gmail.com (R.V. Patel).
develop effective therapy.
The exploration of new heterocycles that can accommodate
potency to multiple biological targets remains an intriguing scientific
endeavour. In continuation to extend our research [6] it was sought of
interest to design and synthesize 1,3,4-oxadiazole derivatives hoping
to go a step forward in the field of antimicrobial agents and thus, we
undertook design, synthesis and examination of pharmacological
activities of novel benzimidazolyle1,3,4eoxadiazoles as antimicro-
bial precursors. Benzimidazole nucleus is a fertile source of bioac-
tivity in the area of drug discovery because of its varied biological
activities viz. antimicrobial [7e11], antituberculosis [12,13] and
anticancer [14e16]. Moreover, It has long been known that
compounds bearing 1,3,4eoxadiazole ring occupy a prominent place
in medicinal chemistry due to its significant biological properties
such as antimicrobial [17e22], antituberculosis [23e25] and anti-
cancer [26]. Recently Ansari et al. discovered that the
benzimidazoleeoxadiazole system plays an essential role to furnish
promising antimicrobial activities [27,28]. Fascinated by multifarious
bioactivity of these heterocycles, we planned to synthesize a compact
system encompassing benzimidazole and oxadiazole entities
conjugated through an acetamide linkage with a hope to develop
compounds possessing noteworthy pharmacological properties. It is
well documented that the benzothiazole template is regarded as

0223-5234/$ e see front matter Ó 2012 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2012.03.033

Please cite this article in press as: R.V. Patel, et al., Synthesis of benzimidazolyl-1,3,4-oxadiazol-2ylthio-N-phenyl (benzothiazolyl) acetamides as
antibacterial, antifungal and antituberculosis agents, European Journal of Medicinal Chemistry (2012), doi:10.1016/j.ejmech.2012.03.033
2 R.V. Patel et al. / European Journal of Medicinal Chemistry xxx (2012) 1e11

a valuable lead to design bioactive heterocycles able to exhibit
promising antimicrobial activities [29e31]. Taking the above points
in consideration, we studied the antimicrobial and antituberculosis
action of the resultant molecules against wide range of different
human pathogenic microorganisms in order to obtain comprehen-
sive SAR indications. Furthermore, according to the thumb rule for
physicochemical parameter logP as calculated hydrophobicity, to
a drug like molecule it must be lower than “5” to by-pass the cell
barrier. To describe the uptake, distribution, biotransformation, and
excretion of organic chemicals in biological systems, partition or
distribution coefficient is critical elements [32] and hence, in this
context, the newer molecules with appreciable lipophilic character
are presented here in order to produce remarkable bioactivities.
2. Chemistry
To achieve the synthesis of the target compounds 6ae7k, the
steps outlined in Scheme 1 were adopted. Starting material,
1Hebenzimidazole 2 was prepared according to a reported proce-
dure [33]. Nucleophilic substitution of compound 2 in the presence
of ethyl chloroacetate in methanol yielded ethyl
1Hebenzimidazole1eylacetate 3. An ester intermediate was
hydrazinolyzed with 99% hydrazine hydrate to afford hydrazide 4,
which reacted with carbon disulfide and potassium hydroxide in
ethanol followed by acidification furnished the corresponding
1,3,4eoxadiazolee2ethiol (5). 2eChloroeNephenyl acetamides
were synthesized according to the reported literature [34]. The
2eaminoe6eSubstituted benzothiazoles (3aek) were synthesized
by reacting aryl amines with potassium thiocyanates in a satisfactory
yield by a known preparation method [35,36]. The prepared
2eaminoe6esubstituted benzothiazoles were converted to
the respective Ne(benzo[d]thiazole2eyl)e2echloroacetamides
(4aek) using chloroacetyl chloride in benzene solvent as described
in literature [37,38]. Above mentioned acetamide derivatives (2aek
and 4aek) were then condensed to the 5e((1Hebenzo[d]
imidazole1eyl)methyl)e1,3,4eoxadiazolee2ethiol (5) in acetone

Scheme 1. Schematic diagram for the synthesis of 6aek and 7aek derivatives. Reagents and Conditions: (a1) ClCH2COCl, Anhyd. K2CO3, Acetone, Reflux (a2) ClCH2COCl, Anhyd.
K2CO3, Benzene, Reflux; (b) KSCN, Br2, AcOH, R.T.; (c) 90% HCOOH, 100  C, 2h; (d) ClCH2COOC2H5, Anhyd. K2CO3, MeOH, Reflux; (e) NH2NH2.H2O, 4–5 h, EtOH, Reflux; (f) CS2/KOH,
EtOH, Reflux; (g) acetone, reflux.

Please cite this article in press as: R.V. Patel, et al., Synthesis of benzimidazolyl-1,3,4-oxadiazol-2ylthio-N-phenyl (benzothiazolyl) acetamides as
antibacterial, antifungal and antituberculosis agents, European Journal of Medicinal Chemistry (2012), doi:10.1016/j.ejmech.2012.03.033
 R.V. Patel et al. / European Journal of Medicinal Chemistry xxx (2012) 1e11 3

solvent at reflux temperature yielded 6aek and 7aek. All the IR, 1H
NMR, 13C NMR spectral data of compounds 6aek and 7aek were in
accordance with assumed structures. The purity of the synthesized
compounds was monitored by TLC and ascertained by elemental
analysis.
3. Results and discussion
3.1. Pharmacology
3.1.1. Antimicrobial activity
The antimicrobial activity assessed (Table 1) for analogues
6ae7k against several strains demonstrated that some of the
compounds revealed a good deal of activity against all the
mentioned bacteria. From the bioassay it can be stated that the final
analogues with the substitutions of benzothiazole ring were, in
most of the cases, active against all the pathogenic strains studied
than those with phenyl acetamides. In addition, all the final ben-
zothiazole bssed derivatives with electron withdrawing halogen
substitution were found more active then the remaining final
analogues against both the Gram positive strains. Compound 7c
with bromine and 7d with fluorine on benzothiazole ring appeared
with potential inhibitory efficacy against Staphylococcus aureus at
3.12 mg/mL of MIC. Among the active compounds against S. aureus,
it can be clearly seen that the compound (7c, LogP ¼ 4.52) with
higher lipophilicity displayed higher activity. In addition, the above
mentioned two derivatives (7c and 7d) were also found to
contribute highest inhibition of Salmonella typhi at 25 mg/mL of
MIC. Among the second line active compounds, 6c and 7g indicated
MIC of 6.25 mg/mL, in which more lipophilic compound (7g)
showed better results. Final analogue 7d with electron with-
drawing fluorine substituent indicated diminished activity at
6.25 mg/mL of MIC against Bacillus cereus. It can be noted that
among the halogenated analogues with benzothiazole series,
compound 7d with the lowest lipophilicity (LogP ¼ 3.85) showed
highest activity. Another analogue 7b within the same series
endowed with chlorine atom exerted similar MIC as that of 7d
(LogP ¼ 4.25). Final derivatives 7j (LogP ¼ 3.90) with ethoxyl
functional group and 7g (LogP ¼ 3.72) with cyano group to the
benzothiazole nucleus were found to contribute excellent potency
towards Escherichia coli at 25 mg/mL of MIC, while 6j (LogP ¼ 2.71)
with ethoxy functionality to the phenyl acetamide ring indicated
similar MICs as that of 7j and 7g. It can be said that, the final
benzothiazolyl derivatives with electron donating methoxy or
cyano functional group(s) were more active against E. coli, in which
the more liphophilic derivative showed higher potency. Final
phenyl acetamide based derivatives 6be6d with halo substituents
displayed strong Pseudomonas aeruginosa inhibitory effects at
12.5 mg/mL of MIC. Likewise, among the potent derivatives against
P. aeruginosa, the most potent compounds possessed highest
liphophilicity (6c, LogP ¼ 3.32). Final derivatives with Nephenyl
acetamides were more potent against P. aeruginosa than the those
envolving substitution of Nebenzothiazolyl acetamides. Newly
synthesized analogues with benzonitrile functionality either to
Nephenyl acetamide (6g, LogP ¼ 2.53) or Nebenzothiazolyl acet-
amide (7g, LogP ¼ 3.72) moiety displayed good activity (MIC, 25 mg/
mL) against Klebsiella pneumoniae. Final analogues with electron
donating alkoxy (6j: LogP ¼ 2.71, 7i: LogP ¼ 3.56 and 7j:
LogP ¼ 3.90), acetamido (7k, LogP ¼ 2.60) and electron with-
drawing iodoesubstitution (7e, LogP ¼ 5.05) were appeared with
remarkable activity against Proteus vulgaris at 12.5 mg/mL of MIC.
Moreover, it can be stated that in case on inhibiting P. vulgaris, more
lipophilic derivatives showed higher inhibitory effects than the
same with lower lipophilicity. In case of the inhibition of Shigella
flexneri, final benzothiazolyl derivatives with chloro (7b,
LogP ¼ 4.25), fluoro (7d, LogP ¼ 3.85) and methoxy (7i, LogP ¼ 3.56)
substituent were found potentially active with excellent 6.25 mg/mL
of MIC and it can be stated that among the potent derivatives
against S. flexneri, higher the lipophilicity, higher the activity.
The bioassay results summarized in Table 2 revealed that, the
synthesized compounds showed good potency against the
mentioned fungi. Final compounds 7f (23 mm of inhibition zone)
with electron withdrawing nitro functional group (LogP ¼ 3.64)
and compound 7k (24 mm of inhibition zone) with acetamide

Table 1
Inevitro antibacterial activity.

Entry (100 mg/disc) R LogP MIC in mg/mL (zone of inhibition in mm)

S.a B.c E.c P.a K.p S.t P.v S.f

6a H 2.49 10 0 (12) 100 (<10) 100 (13) 50 (21) 100 (13) 100 (<10) 100 (13) 100 (13)
6b Cl 3.05 50 (15) 50 (11) 100 (15) 12.5 (26) 50 (21) 100 (17) 50 (20) 12.5 (22)
6c Br 3.32 6.25 (23) 12.5 (26) 50 (19) 12.5 (26) 50 (22) 50 (22) 100 (17) 25 (22)
6d F 2.65 25 (18) 50 (16) 50 (18) 12.5 (24) 50 (22) 50 (21) 50 (14) 12.5 (23)
6e I 3.85 50 (17) 100 (15) 100 (12) 25 (22) 50 (23) 100 (16) 25 (22) 50 (20)
6f NO2 2.45 12.5 (20) 100 (13) 100 (12) 50 (20) 100 (20) 100 (13) 100 (14) 100 (19)
6g CN 2.53 25 (18) 50 (19) 50 (19) 50 (21) 25 (24) 50 (20) 50 (19) 100 (17)
6h CH3 2.98 100 (11) 100 (13) 100 (14) 100 (14) 100 (<10) 100 (17) 100 (14) 100 (<10)
6i OCH3 2.37 100 (13) 50 (18) 50 (20) 50 (21) 100 (11) 50 (20) 25 (21) 50 (19)
6j OC2H5 2.71 50 (14) 50 (18) 25 (23) 100 (16) 100 (<10) 50 (21) 12.5 (25) 25 (22)
6k NHCOCH3 1.40 100 (<10) 100 (11) 50 (20) 100 (19) 100 (13) 100 (<10) 25 (20) 100 (16)
7a H 3.69 50 (15) 100 (14) 100 (15) 100 (12) 100 (<10) 100 (<10) 100 (17) 100 (13)
7b Cl 4.25 12.5 (22) 6.25 (27) 50 (20) 25 (23) 50 (20) 50 (22) 50 (20) 6.25 (25)
7c Br 4.52 3.12 (26) 25 (24) 50 (19) 25 (23) 100 (14) 25 (24) 50 (20) 12.5 (23)
7d F 3.85 3.12 (25) 6.25 (29) 50 (17) 50 (20) 50 (19) 25 (24) 25 (22) 6.25 (24)
7e I 5.05 12.5 (22) 25 (23) 50 (15) 100 (14) 100 (14) 100 (16) 12.5 (26) 25 (22)
7f NO2 3.64 12.5 (21) 12.5 (25) 50 (18) 100 (16) 100 (16) 50 (19) 100 (15) 50 (20)
7g CN 3.72 6.25 (24) 50 (22) 25 (24) 50 (15) 25 (25) 100 (17) 50 (19) 50 (21)
7h CH3 4.18 50 (15) 50 (19) 100 (12) 100 (15) 100 (18) 100 (11) 50 (20) 100 (14)
7i OCH3 3.56 25 (19) 50 (20) 50 (18) 100 (12) 50 (21) 50 (20) 12.5 (26) 6.25 (24)
7j OC2H5 3.90 12.5 (22) 50 (21) 25 (24) 50 (18) 50 (21) 50 (19) 12.5 (26) 50 (19)
7k NHCOCH3 2.60 50 (19) 100 (16) 50 (20) 100 (<10) 50 (20) 100 (16) 12.5 (24) 100 (16)
Cip. 1.56 (30) 0.39 (31) 1.56 (32) 0.78 (33) 0.78 (33) 0.39 (30) 0.39 (31) 1.56 (32)
DMSO e e e e e e e e

Cip e Ciprofloxacin S.a e Staphylococcus aureus, B.c e Bacillus cereus, E.c e Escherichia coli, P.a e Pseudomonas aeruginosa, K.p e Klebsiella pneumoniae, S.t e Salmonella typhi, P.v
e Proteus vulgaris, S.f e Shigella flexneri.

Please cite this article in press as: R.V. Patel, et al., Synthesis of benzimidazolyl-1,3,4-oxadiazol-2ylthio-N-phenyl (benzothiazolyl) acetamides as
antibacterial, antifungal and antituberculosis agents, European Journal of Medicinal Chemistry (2012), doi:10.1016/j.ejmech.2012.03.033
4 R.V. Patel et al. / European Journal of Medicinal Chemistry xxx (2012) 1e11

Table 2 Table 3
Inevitro antifungal activity. Inevitro antituberculosis activity.

Entry R LogP MIC in mg/mL (zone of inhibition in mm) Entry R LogP BACTEC MGIT L. J. MIC Methoda
(100 mg/disc) methoda
A.n A.f A.c C.a
6a H 2.49 100 (<10) 100 (13) 100 (<10) 100 (<10) MIC % inhibition MIC % inhibition
6b Cl 3.05 100 (<10) 100 (16) 100 (14) 100 (14) (mg/mL) (mg/mL)
6c Br 3.32 100 (16) 25 (24) 50 (23) 100 (16) 6a H 2.49 >6.25 e 500 95
6d F 2.65 50 (19) 50 (23) 100 (17) 100 (16) 6b Cl 3.05 >6.25 e 25 98
6e I 3.85 100 (<10) 100 (17) 100 (13) 100 (12) 6c Br 3.32 >6.25 e 12.5 99
6f NO2 2.45 50 (18) 100 (18) 50 (24) 100 (15) 6d F 2.65 >6.25 e 50 97
6g CN 2.53 100 (<10) 100 (14) 100 (13) 100 (11) 6e I 3.85 >6.25 e 250 95
6h CH3 2.98 100 (<10) 100 (<10) 100 (12) 100 (14) 6f NO2 2.45 >6.25 e 100 94
6i OCH3 2.37 100 (16) 100 (10) 100 (<10) 50 (22) 6g CN 2.53 >6.25 e 62.5 96
6j OC2H5 2.71 50 (17) 100 (11) 100 (16) 25 (24) 6h CH3 2.98 >6.25 e 100 95
6k NHCOCH3 1.40 25 (22) 100 (15) 100 (18) 100 (18) 6i OCH3 2.37 6.25 99 6.25 99
7a H 3.69 100 (<10) 100 (<10) 100 (<10) 100 (13) 6j OC2H5 2.71 >6.25 e 50 98
7b Cl 4.25 100 (16) 100 (13) 100 (15) 100 (14) 6k NHCOCH3 1.40 >6.25 e 100 95
7c Br 4.52 50 (19) 50 (21) 50 (20) 100 (17) 7a H 3.69 >6.25 e 500 94
7d F 3.85 25 (21) 25 (23) 50 (21) 50 (23) 7b Cl 4.25 >6.25 e 62.5 97
7e I 5.05 100 (14) 100 (<10) 100 (14) 100 (19) 7c Br 4.52 >6.25 e 25 99
7f NO2 3.64 12.5 (23) 50 (22) 25 (27) 100 (15) 7d F 3.85 >6.25 e 12.5 99
7g CN 3.72 50 (18) 50 (22) 100 (18) 100 (13) 7e I 5.05 >6.25 e 200 96
7h CH3 4.18 100 (12) 100 (<10) 100 (12) 100 (15) 7f NO2 3.64 >6.25 e 50 98
7i OCH3 3.56 50 (17) 100 (<10) 50 (22) 25 (25) 7g CN 3.72 >6.25 e 100 95
7j OC2H5 3.90 25 (20) 100 (13) 100 (17) 25 (26) 7h CH3 4.18 >6.25 e 200 97
7k NHCOCH3 2.60 12.5 (24) 100 (<10) 50 (23) 50 (23) 7i OCH3 3.56 >6.25 e 12.5 99
Kit. 1.56 (30) 0.78 (29) 0.78 (31) 1.56 (33) 7j OC2H5 3.90 >6.25 e 50 99
DMSO e e e e 7k NHCOCH3 2.60 >6.25 e 50 98
Isoniazid 0.20 99%
Kit e Ketoconazole A.n e Aspergillus niger, A.f e Aspergillus fumigatus, A.c e Asper-
Refampicin 0.25 99%
gillus clavatus, C.a e Candida albicans.
Ethambutol 3.12 99%
Pyrazinamide 6.25 99%
a
linkage (LogP ¼ 2.60) to the benzothiazole ring showed promising Each value is the mean of three independent experiments.
activity against Aspergillus niger at 12.5 mg/mL of MIC. The later
compound 7f was also appeared with potential inhibitory effects
towards Aspergillus clavatus at 25 mg/mL of MIC. NePhenyl acet- activity at MIC ranging from 25 to 500 mg/mL. From the antutu-
amide derivatives with halogen substituent like bromine (6c, berculosis activity results it can be stated that analogues of both the
LogP ¼ 3.32) and fluorine (7d, LogP ¼ 3.85) exhibited excellent series were mixdly active as well as no specific relationship was
growth inhibitory activity against Aspergillus fumigatus at 25 mg/mL observed in case of lipophilicity verses antituberculosis activity
of MIC. It can be noted that similar to potentially active compounds profiles.
against A. niger and A. clavatus, in case of A. fumigatus, the
compounds exhibiting lower lipophilicity showed higher activity
and in case of second line active analogues against the mentioned 4. Conclusion
fungi, activity decreased with the increase in lipophiliciy (LogP). In
case of inhibition of Candida albicans, analogues 7i (LogP ¼ 3.56), 7j This work focused on the development of new potentially
(LogP ¼ 3.90) and 6j (LogP ¼ 2.71) with alkoxy substituent were active antibacterial and antifungal agents based on benzimi-
found to demonstrate excellent activity at 25 mg/mL of MIC. In dazoleeoxadiazole compact system. In general, the results of the
addition, an opposite trend of activity versus lipophilic character in vitro pharmacological activities are encouraging, as out of two
was observed in case of active analogues towards C. albicans series tested, compounds with Nebenzothiazolyl acetamide
compared to active analogues against the remaining three fungal moiety emerged as the class of compounds exhibiting the highest
strains as the compound with higher lipophilicity showed higher antimicrobial activity, while in case of antituberculosis activity
activity. a compound (6i) with Nephenyl acetamide moiety was found
superior. Based on the results described above, such compounds
3.1.2. Antituberculosis activity with Nebenzothiazolyl acetamide ring can be highlighted as new
In vitro antituberculosis activity of compounds 6aek and 7aek active leads that provide a powerful incentive for further research
was assessed against Mycobacterium tuberculosis H37Rv. The in this area. Overall, The MIC values of these novel compounds
results (Table 3) observed from BACTEC MGIT indicated that final evidenced that the presence of halogen atom(s), alkoxy and cyano
derivatives 6i with methoxy group to the Nephenyl acetamide substituent gave rise to a better pharmacological potency. In
moiety exhibited highest inhibition (99%) at a constant concen- addition, the relationship between activity profiles and lip-
tration level (6.25 mg/mL) against M. tuberculosis H37Rv. This ophilicity of the newer analogues was also discussed in which, in
compound was considered as a most potent analogue against some cases higher lipophilic compounds showed higher bioac-
mycobacteria and was found to indicate similar antituberculosis tivities, whereas, in some cases the opposite trend was observed.
potency as that of standard drug pyrazinamide. Results of In case of antituberculosis activity results there was no specific
secondary biological screening using LowensteineJensen MIC relationship observed between MIC profiles versus lipophilicity.
method revealed that two compounds 7d with chlorine and 7i with Consequently, the degree of activity, encouraging physicochemical
methoxy substituent to the benzothiazole ring as well as parameters, displayed by a novel innovative structural combina-
compound 6c with bromo-substituted phenyl acetamide ring tion system of benzimidazole, oxadiazole and benzothiazole rings
showed 12.5 mg/mL of MIC against mycobacterial strain. All the makes such compounds a privileged structure to achieve more
remaining derivatives were found to exhibit moderate to poor active derivatives in ongoing studies.

Please cite this article in press as: R.V. Patel, et al., Synthesis of benzimidazolyl-1,3,4-oxadiazol-2ylthio-N-phenyl (benzothiazolyl) acetamides as
antibacterial, antifungal and antituberculosis agents, European Journal of Medicinal Chemistry (2012), doi:10.1016/j.ejmech.2012.03.033
 R.V. Patel et al. / European Journal of Medicinal Chemistry xxx (2012) 1e11
5. Materials and methods
5.1. Chemistry
Melting points were determined in open capillaries on a Veego
electronic apparatus VMPeD (Veego Instrument Corporation,
Mumbai, India) and are uncorrected. IR spectra (4000e400 cm 1)
of synthesized compounds were recorded on a Shimadzu 8400eS
FTeIR spectrophotometer (Shimadzu India Pvt. Ltd., Mumbai,
India) using KBr pellets. Thin Layer Chromatography was per-
formed on object glass slides (2  7.5 cm) coated with silica geleG
and spots were visualized under UV irradiation. 1H NMR and 13C
NMR spectra were recorded on a Varian 400 MHz model spec-
trometer (Varian India Pvt. Ltd., Mumbai, India) using DMSO as
a solvent and TMS as internal standard with 1H resonant frequency
of 400 MHz and 13C resonant frequency of 100 MHz. The 1H NMR
and 13C NMR chemical shifts were reported as parts per million
(ppm) downfield from TMS (Me4Si) and were performed at Centre
for Excellence, Vapi, India. The splitting patterns are designated as
follows; s, singlet; br s, broad singlet; d, doublet; m, multiplet.
Elemental analyses (C, H, N) were performed using a Heraeus Carlo
Erba 1180 CHN analyzer (Hanau, Germany).
5.1.1. General synthetic procedure for 2echloroeNe(substituted)
phenyl acetamides (2ae2k)
Chloroacetyl chloride (0.06 mol) was added dropwise to
a mixture of the appropriate amine (0.05 mol) and K2CO3
(0.06 mol) in acetone (50 mL) at room temperature. The reaction
mixture was refluxed for 4e8 h, then, after cooling to room
temperature, it was slowly poured into 100 mL of ice water. A solid
was formed thereafter. The precipitate was separated by filtration
and washed successively with water. The product was dried under
vacuum to obtain 2aek. The progress of the reaction was moni-
tored by Thin Layer Chromatography using toluene: acetone (8:2)
solvent system.
5.1.1.1. 2eChloroeNephenyl acetamide (2a). While Solid, Yield:
78%, mp.: 135e138  C. IR (KBr, cm 1): 3281 (NH), 1680 (C]O). 1H
NMR (400 MHz, DMSOed6): d 8.56 (br s, 1H, eNH), 7.66 (m, 2H),
7.40 (m, 2H), 7.14 (m, 1H), 4.22 (s, 2H, eCH2eCl).
5.1.1.2. 2eChloroeNe(4echlorophenyl)acetamide (2b). Pale Yellow
Solid, Yield: 83%, mp.: 168e170  C. IR (KBr, cm 1): 3292 (NH), 1672
(C]O). 1H NMR (400 MHz, DMSOed6): d 8.35 (br s, 1H, eNH), 7.63
(m, 2H), 7.45 (m, 2H), 7.19 (m, 1H), 4.21 (s, 2H, eCH2eCl).
5.1.1.3. Ne(4eBromophenyl)e2echloroacetamide (2c). Grey Solid,
Yield: 67%, mp.: 180e184  C. IR (KBr, cm 1): 3307 (NH), 1668 (C]
O). 1H NMR (400 MHz, DMSOed6): d 8.32 (br s, 1H, eNH), 7.54e7.47
(m, 3H), 7.22 (m, 1H), 4.25 (s, 2H, eCH2eCl).
5.1.1.4. 2eChloroeNe(4efluorophenyl)acetamide (2d). While Solid,
Yield: 62%, mp.: 131e132  C. IR (KBr, cm 1): 3299 (NH), 1670 (C]
O). 1H NMR (400 MHz, DMSOed6): d 8.21 (br s, 1H, eNH), 7.51 (dd,
J ¼ 7.1, 4.4 Hz, 2H), 7.27 (t, J ¼ 8.2 Hz, 2H), 4.12 (s, 2H, eCH2eCl).
5.1.1.5. 2eChloroeNe(4eiodophenyl)acetamide (2e). While Solid,
Yield: 85%, mp.: 192e196  C. IR (KBr, cm 1): 3314 (NH), 1678 (C]
O). 1H NMR (400 MHz, DMSOed6): d 8.44 (br s, 1H, eNH), 7.64 (d,
J ¼ 7.1 Hz, 2H), 7.42 (d, J ¼ 7.4 Hz, 2H), 4.20 (s, 2H, eCH2eCl).
5.1.1.6. 2eChloroeNe(4enitrophenyl)acetamide (2f). Yellow Solid,
Yield: 75%, mp 185e186  C. IR (KBr, cm 1): 3283 (NH), 1669 (C]O).
1
H NMR (400 MHz, DMSOed6): d 8.41 (br s, 1H, eNH), 7.53e7.41 (m,
4H), 4.18 (s, 2H, eCH2eCl).
Please cite this article in press as: R.V. Patel, et al., Synthesis of benzimidazolyl-1,3,4-oxadiazol-2ylthio-N-phenyl (benzothiazolyl) acetamides as
antibacterial, antifungal and antituberculosis agents, European Journal of Medicinal Chemistry (2012), doi:10.1016/j.ejmech.2012.03.033
5
5.1.1.7. 2eChloroeNe(4ecyanophenyl)acetamide (2g). While Solid,
Yield: 88%, mp 182e184  C. IR (KBr, cm 1): 3270 (NH), 1669 (C]O).
1
H NMR (400 MHz, DMSOed6): d 8.32 (br s, 1H, eNH), 7.67 (d,
J ¼ 7.3 Hz, 2H), 7.58 (d, J ¼ 7.4 Hz, 2H), 4.14 (s, 2H, eCH2eCl).
5.1.1.8. 2eChloroeNepetolylacetamide (2h). While Solid, Yield:
80%, mp 164e166  C. IR (KBr, cm 1): 3295 (NH), 1671 (C]O). 1H
NMR (400 MHz, DMSOed6): d 8.30 (br s, 1H, eNH), 7.52e7.49 (m,
2H), 7.34e7.36 (m, 2H), 4.21 (s, 2H, eCH2eCl), 2.19 (s, 3H, eCH3).
5.1.1.9. 2eChloroeNe(4emethoxyphenyl)acetamide (2i). While Solid,
Yield: 76%, mp.: 121e122  C. IR (KBr, cm 1): 3311 (NH), 1668 (C]O).
1
H NMR (400 MHz, DMSOed6): d 8.27 (br s, 1H, eNH), 7.60 (d,
J ¼ 7.5 Hz, 2H), 7.44 (d, J ¼ 7.1 Hz, 2H), 4.24 (s, 2H, eCH2eCl), 3.77 (s,
3H, eOCH3).
5.1.1.10. 2eChloroeNe(4eethoxyphenyl)acetamide (2j). While Solid,
Yield: 68%, mp.: 189e193  C. IR (KBr, cm 1): 3319 (NH), 1664 (C]O).
1
H NMR (400 MHz, DMSOed6): d 8.39 (br s, 1H, eNH), 7.55 (d,
J ¼ 7.3 Hz, 2H), 7.38 (d, J ¼ 7.4 Hz, 2H), 4.22 (s, 2H, eCH2eCl), 3.97 (q,
J ¼ 5.9 Hz, 2H, eOeCH2e), 1.49 (t, 3H, eCH3).
5.1.1.11. Ne(4eAcetamidophenyl)e2echloroacetamide (2k). Pale
Yellow solid, Yield: 72%, mp.: 240e243  C. IR (KBr, cm 1): 3290
(NH), 1671 (C]O). 1H NMR (400 MHz, DMSOed6): d 8.21 (br s, 1H,
eNH), 8.33 (s, 1H, eNH), 7.63e7.56 (m, 2H), 7.39e7.35 (m, 2H),
4.20 (s, 2H, eCH2eCl), 1.91 (s, 3H, eCH3).
5.1.2. General synthetic procedure for 2eaminoe6eSubstituted
benzothiazoles (3aek)
A mixture of 0.1 mol of 4esubstituted aniline and 0.1 mol of
Potassium thiocyanate (KCNS) in 100 ml glacial acetic acid (AcOH)
was cooled in an ice bath and stirred for 10e20 min, and then
0.1 mol bromine in glacial acetic acid was added dropwise at such
a rate to keep the temperature below 10  C throughout the addition.
The reaction mixture was stirred at room temperature for 2e4 h, the
hydrobromide (HBr) salt thus separated out was filtered, washed
with acetic acid, dried, dissolved in hot water and basified to pH 11.0
with ammonia solution (NH4OH) and the resulting precipitate was
filtered, washed with water and dried to get the desired product
3aek. The progress of the reaction was monitored by Thin Layer
Chromatography using toluene: acetone (8:2) solvent system.
5.1.2.1. Benzo[d]thiazole2eamine (3a). Light brown solid, Yield:
78%, mp.: 128e130  C. IR (KBr, cm 1): 3371 (NH), 1578 (C]N). 1H
NMR (400 MHz, DMSOed6): d 7.28 (s, 2H, NH2, D2O exchangeable),
7.24e7.51 (m, 4H, AreH).
5.1.2.2. 6eChlorobenzo[d]thiazole2eamine (3b). White solid, Yield:
72%, mp.: 202e203  C. IR (KBr, cm 1): 3391 (NH), 1546 (C]N). 1H
NMR (400 MHz, DMSOed6): d 7.52 (d, J ¼ 1.7 Hz, 1H, H-7), 7.35 (d,
J ¼ 7.3 Hz, 1H, H-4), 7.21 (dd, J ¼ 7.9, 2.1 Hz, 1H, H-5), 6.72 (s, 2H, NH2,
D2O exchangeable).
5.1.2.3. 6eBromobenzo[d]thiazole2eamine (3c). Light yellow solid,
Yield: 76%, mp.: 216e219  C. IR (KBr, cm 1): 3410 (NH), 1589 (C]
N). 1H NMR (400 MHz, DMSOed6): d 7.72 (d, J ¼ 1.5 Hz, 1H, H-7),
7.39e7.46 (m, 2H, H-4 and H-5), 6.72 (s, 2H, NH2, D2O
exchangeable).
5.1.2.4. 6eFluorobenzo[d]thiazole2eamine (3d). Off while solid,
Yield: 80%, mp.: 181e184  C. IR (KBr, cm 1): 3368 (NH), 1584 (C]
N). 1H NMR (400 MHz, DMSOed6): d 7.59 (dd, J ¼ 2.4, 8.3 Hz, 1H, H-
7), 7.34 (dd, J ¼ 4.8, 8.6 Hz, 1H, H-4), 7.16 (dt, J ¼ 2.2, 8.8 Hz, 1H, H-5),
7.09 (s, 2H, NH2, D2O exchangeable).
6 R.V. Patel et al. / European Journal of Medicinal Chemistry xxx (2012) 1e11
5.1.2.5. 6eIodobenzo[d]thiazole2eamine (3e). Off while solid,
Yield: 70%, mp.: 206e208  C. IR (KBr, cm 1): 3290 (NH), 1573 (C]
N). 1H NMR (400 MHz, DMSOed6): d 7.79 (d, J ¼ 1.9 Hz, 1H, H-7),
7.51 (d, J ¼ 7.1 Hz, 1H, H-4), 7.16 (dd, J ¼ 8.1, 2.2 Hz, 1H, H-5), 6.92
(s, 2H, NH2, D2O exchangeable).
5.1.2.6. 6eNitrobenzo[d]thiazole2eamine (3f). Yellow solid, Yield:
74%, mp.: 248e251  C. IR (KBr, cm 1): 3402 (NH), 1569 (C]N). 1H
NMR (400 MHz, DMSOed6): d 7.62 (d, J ¼ 1.9 Hz, 1H, H-7), 7.29e7.37
(m, 2H, H-4 and H-5), 6.22 (s, 2H, NH2, D2O exchangeable).
5.1.2.7. 2eAminobenzo[d]thiazolee6ecarbonitrile (3g). A mixture
of 0.1 mol of 4eaminobenzonitrile and 0.2 mol of potassium thio-
cyanate (KSCN) in 100 ml glacial acetic acid was cooled in an ice
bath and stirred for 10e20 min, and then 0.1 mol of bromine in
glacial acetic acid was added drop wise at such a rate to keep the
temperature below 10  C throughout the addition. The reaction
mixture was stirred at room temperature for 2e4 h, the hydro-
bromide (HBr) salt thus separated out. In the reaction mixture
150 ml water was added. The solid 4ecyanoe2ethiocyanatoaniline
thus obtained was filtered, dried and recrystallized from ethanol.
Then in 0.05 mol of this intermediate, 10 mL of concentrated HCl
and 20 mL of water was added and the mixture was refluxed for 2 h.
The progress of the reaction was monitored by Thin Layer Chro-
matography using toluene: acetone (9:1) solvent system. After the
completion of the reaction, the solution was cooled and the product
was filtered, washed with water, and recrystallized from ethanol to
give 3g [39]. Light yellow solid, Yield: 61%, mp.: 206e207  C. IR
(KBr, cm 1): 3376 (NH), 1576 (C]N). 1H NMR (400 MHz,
DMSOed6): d 7.70 (d, J ¼ 1.8 Hz, 1H, H-7), 7.55 (d, J ¼ 7.4 Hz, 1H, H-
4), 7.26 (dd, J ¼ 8.4, 2.0 Hz, 1H, H-5), 7.18 (s, 2H, NH2, D2O
exchangeable).
5.1.2.8. 6eMethylbenzo[d]thiazole2eamine (3h). Light yellow solid,
Yield: 77%, mp.: 144e145  C. IR (KBr, cm 1): 3393 (NH), 1570 (C]N).
1 5.1.3.6. 2eChloroeNe(6enitrobenzo[d]thiazole2eyl)acetamide
H NMR (400 MHz, DMSOed6): d 7.53e7.39 (m, 3H, H-4, H-5, H-7),
5.89 (s, 2H, NH2, D2O exchangeable), 1.96 (s, 3H, CH3).
5.1.2.9. 6eMethoxybenzo[d]thiazole2eamine (3i). Off white solid,
Yield: 71%, mp.: 169e170  C. IR (KBr, cm 1): 3278 (NH), 1571 (C]
N). 1H NMR (400 MHz, DMSOed6): d 7.62e7.53 (m, 2H, H-4, H-7),
7.20 (dd, J ¼ 8.2, 1.9 Hz, 1H, H-5), 5.42 (s, 2H, NH2, D2O exchange-
able), 3.80 (s, 3H, OCH3).
5.1.2.10. 6eEthoxybenzo[d]thiazole2eamine (3j). Off white solid,
Yield: 74%, mp.: 162e165  C. IR (KBr, cm 1): 3390 (NH), 1585 (C]
N). 1H NMR (400 MHz, DMSOed6): d 7.53e7.37 (m, 2H, H-4, H-7),
7.27 (dd, J ¼ 8.6, 1.6 Hz, 1H, H-5), 5.53 (s, 2H, NH2, D2O exchange-
able), 4.08 (q, J ¼ 6.2 Hz, 2H, OCH2CH3), 2.21 (t, J ¼ 6.4 Hz, 3H,
CH2CH3).
5.1.2.11. Ne(2eAminobenzo[d]thiazole6eyl)acetamide (3k). While
solid, Yield: 61%, mp.: 141e143  C. IR (KBr, cm 1): 3401 (NH), 1573
(C]N). 1H NMR (400 MHz, DMSOed6): d 8.13 (s, 1H, eNH),
7.67e7.54 (m, 2H, H-4, H-7), 7.30 (dd, J ¼ 8.6, 1.6 Hz, 1H, H-5),
7.15 (s, 2H, NH2, D2O exchangeable), 2.04 (s, 3H, CH3).
5.1.3. General synthetic procedure for Ne(benzo[d]thiazole2eyl)e
2echloroacetamides (4aek)
Chloroacetyl chloride (0.06 mol) was added dropwise to
a mixture of the appropriate 2eaminoe6eSubstituted benzothia-
zole, 3aek (0.05 mol) and K2CO3 (0.06 mol) in benzene (50 mL) at
room temperature. The reaction mixture was refluxed for 6e12 h,
then, after cooling to room temperature, it was slowly poured
into 100 mL of ice water. A solid was formed thereafter. The
Please cite this article in press as: R.V. Patel, et al., Synthesis of benzimidazolyl-1,3,4-oxadiazol-2ylthio-N-phenyl (benzothiazolyl) acetamides as
antibacterial, antifungal and antituberculosis agents, European Journal of Medicinal Chemistry (2012), doi:10.1016/j.ejmech.2012.03.033
precipitate was separated by filtration and washed successively
with water. The product was dried under vacuum to obtain 4aek.
The progress of the reaction was monitored by Thin Layer Chro-
matography using toluene: acetone (8:2) solvent system.
5.1.3.1. Ne(Benzo[d]thiazole2eyl)e2echloroacetamide (4a). Light
brown solid, Yield: 73%, mp.: 135e138  C. IR (KBr, cm 1): 3283
(NH), 1679 (CO). 1H NMR (400 MHz, DMSOed6): d 8.43 (s, 1H, eNH),
7.19e7.38 (m, 4H, AreH), 4.23 (s, 2H, CH2eCl).
5.1.3.2. 2eChloroeNe(6echlorobenzo[d]thiazole2eyl)acetamide
(4b). While solid, Yield: 88%, mp.: 207e210  C. IR (KBr, cm 1):
3290 (NH), 1689 (CO). 1H NMR (400 MHz, DMSOed6): d 8.56 (s, 1H,
eNH), 7.64 (d, J ¼ 1.6 Hz, 1H, H-7), 7.45 (d, J ¼ 7.6 Hz, 1H, H-4), 7.27
(dd, J ¼ 8.1, 1.8 Hz, 1H, H-5), 4.17 (s, 2H, eCH2eCl).
5.1.3.3. Ne(6eBromobenzo[d]thiazole2eyl)e2echloroacetamide
(4c). Light yellow solid, Yield: 72%, mp.: 195e197  C. IR (KBr,
cm 1): 3310 (NH), 1671 (CO). 1H NMR (400 MHz, DMSOed6): d 8.43
(s, 1H, eNH), 7.60 (d, J ¼ 1.7 Hz, 1H, H-7), 7.35e7.43 (m, 2H, H-4 and
H-5), 4.06 (s, 2H, eCH2eCl).
5.1.3.4. 2eChloroeNe(6efluorobenzo[d]thiazole2eyl)acetamide
(4d). Off while solid, Yield: 60%, mp.: 177e179  C. IR (KBr, cm 1):
3277 (NH), 1665 (CO). 1H NMR (400 MHz, DMSOed6): d 8.39 (s, 1H,
eNH), 7.70 (dd, J ¼ 2.3, 8.5 Hz, 1H, H-7), 7.38 (dd, J ¼ 4.5, 8.2 Hz, 1H,
H-4), 7.23 (dt, J ¼ 2.4, 8.9 Hz, 1H, H-5), 4.25 (s, 2H, eCH2eCl).
5.1.3.5. 2eChloroeNe(6eiodobenzo[d]thiazole2eyl)acetamide
(4e). Off while solid, Yield: 79%, mp.: 197e200  C. IR (KBr, cm 1):
3256 (NH), 1680 (CO). 1H NMR (400 MHz, DMSOed6): d 8.46 (s, 1H,
eNH), 7.58 (d, J ¼ 2.2 Hz, 1H, H-7), 7.45 (d, J ¼ 7.4 Hz, 1H, H-4), 7.29
(dd, J ¼ 8.5, 1.9 Hz, 1H, H-5), 4.16 (s, 2H, eCH2eCl).
(4f). Yellow solid, Yield: 78%, mp.: 218e220  C. IR (KBr, cm 1):
3278 (NH), 1671 (CO). 1H NMR (400 MHz, DMSOed6): d 8.55 (s, 1H,
eNH), 7.60 (d, J ¼ 1.8 Hz, 1H, H-7), 7.35e7.46 (m, 2H, H-4 and H-5),
4.28 (s, 2H, eCH2eCl).
5.1.3.7. 2eChloroeNe(6ecyanobenzo[d]thiazole2eyl)acetamide
(4g). Light yellow solid, Yield: 69%, mp.: 225e227  C. IR (KBr, cm 1):
3298 (NH), 1685 (CO). 1H NMR (400 MHz, DMSOed6): d 8.37 (s, 1H,
NH), 7.55 (d, J ¼ 1.6 Hz, 1H, H-7), 7.43 (d, J ¼ 7.7 Hz, 1H, H-4), 7.18 (dd,
J ¼ 8.6, 2.1 Hz, 1H, H-5), 4.20 (s, 2H, eCH2eCl).
5.1.3.8. 2eChloroeNe(6emethylbenzo[d]thiazole2eyl)acetamide
(4h). Light yellow solid, Yield: 53%, mp.: 175e177  C. IR (KBr,
cm 1): 3311 (NH), 1673 (CO). 1H NMR (400 MHz, DMSOed6):
d 8.45 (s, 1H, NH), 7.63e7.46 (m, 3H, H-4, H-5, H-7), 4.20 (s, 2H,
eCH2eCl), 1.81 (s, 3H, CH3).
5.1.3.9. 2eChloroeNe(6emethoxybenzo[d]thiazole2eyl)acetamide
(4i). Off white solid, Yield: 75%, mp.: 169e172  C. IR (KBr, cm 1):
3291 (NH), 1667 (CO). 1H NMR (400 MHz, DMSOed6): d 8.55 (s, 1H,
NH), 7.71e7.64 (m, 2H, H-4, H-7), 7.33 (dd, J ¼ 8.3, 2.0 Hz, 1H, H-5),
4.24 (s, 2H, eCH2eCl), 3.80 (s, 3H, OCH3)
5.1.3.10. 2eChloroeNe(6eethoxybenzo[d]thiazole2eyl)acetamide
(4j). Off white solid, Yield: 84%, mp.: 179e181  C. IR (KBr, cm 1):
3287 (NH), 1679 (CO). 1H NMR (400 MHz, DMSOed6): d 8.40 (s,
1H, NH), 7.60e7.47 (m, 2H, H-4, H-7), 7.34 (dd, J ¼ 8.5, 1.8 Hz, 1H,
H-5), 4.26 (s, 2H, eCH2eCl), 4.18 (q, J ¼ 5.8 Hz, 2H, OCH2CH3), 2.19
(t, J ¼ 6.7 Hz, 3H, CH2CH3).
 R.V. Patel et al. / European Journal of Medicinal Chemistry xxx (2012) 1e11
5.1.3.11. Ne(6eAcetamidobenzo[d]thiazole2eyl)e2echloroacetamide
(4k). White solid, Yield: 52%, mp.: 227e229  C. IR (KBr, cm 1): 3277
(NH), 1670 (CO). 1H NMR (400 MHz, DMSOed6): d 8.57 (s, 1H, NH),
8.33 (s, 1H, eNH), 7.62e7.51 (m, 2H, H-4, H-7), 7.27 (dd, J ¼ 8.4, 1.9 Hz,
1H, H-5), 4.21 (s, 2H, eCH2eCl), 2.04 (s, 3H, CH3).
5.1.4. Synthesis of 1Hebenzimidazole (2)
To 0.50 mol of oephenylenediamine, 1.00 mol of 90% formic
acid was added. Then the mixture was heated on water bath at
100  C for 2 h. After cooling the mixture at room temperature, 10%
NaOH solution was added slowly with constant stirring until the
mixture is just alkaline to litmus. The crude benzimidazole thus
obtained was filtered out at the vacuum pump, washed with ice
cold water and dried to get 2. The progress of the reaction was
monitored by Thin Layer Chromatography using toluene: acetone
(8:2) solvent system. White solid, Yield 82%, mp.: 173e175  C. IR
(KBr, cm 1): 1621 (C]N), 1155 (CeN). 1H NMR (400 MHz,
DMSOed6): d 7.68 (s, 1H, eN ¼ CH), 7.56e7.25 (m, 4H, AreH), (s,
1H, eNH).
5.1.5. Synthesis of ethyl 1Hebenzimidazole1eylacetate (3)
A mixture of equimolar alkaline solution (0.5 mL, 4 N NaOH) of
1Hebenzimidazole 2 (0.25 mol) in methanol (50 mL) and ethyl
chloroacetate (0.25 mol) in methanol (30 mL) was heated gently on
boiling water bath for 0.5 h. The solid thus obtained on cooling was
recrystallized from chloroform to give 3. The progress of the reac-
tion was monitored by Thin Layer Chromatography using toluene:
acetone (8:2) solvent system. White solid, Yield 72%, mp.:
181e182  C. IR (KBr, cm 1): 1621 (C]N), 1163 (CeN), 1729 (C]O,
ester), 1466 (NeCH2). 1H NMR (400 MHz, DMSOed6): d 8.39 (s, 1H,
eN ¼ CH), 7.83e7.67 (m, 4H, AreH), 4.21 (q, J ¼ 5.8 Hz, 2H,
eCOOCH2e), 3.77 (s, 2H, eNeCH2), 1.32 (t, J ¼ 6.1 Hz, 3H,
eCOOCH2CH3).
5.1.6. Synthesis of 2e(1Hebenzo[d]imidazole1eyl)acetohydrazide (4)
Compound 3 (0.10 mol) was dissolved in ethanol (50 mL) and
99% hydrazine hydrate (0.10 mol) was added and the mixture was
refluxed for 4e5 h. The reaction mixture was cooled and the solid
obtained was filtered, washed with small quantity of cold methanol
to give 4 [27]. The progress of the reaction was monitored by Thin
Layer Chromatography using toluene: acetone (8:2) solvent system.
White solid, Yield 73%, mp 202e204  C. IR (KBr, cm 1): 1644 (C]
N), 1133 (CeN), 1689 (C]O, amide), 1463 (eNeCH2). 1H NMR
(400 MHz, DMSOed6): d 8.40 (s, 1H, eN ¼ CH), 8.10 (m, 1H,
CONHNH2), 7.91e7.59 (m, 4H, AreH), 4.82 (s, 2H, NH2, D2O
exchangeable), 3.69 (s, 2H, eNeCH2).
5.1.7. Synthesis of 5e((1Hebenzo[d]imidazole1eyl)methyl)e1,3,4e
oxadiazolee2ethiol (5)
To a solution of the 2e(1Hebenzo[d]imidazole1eyl)
acetohydrazide, 4 (0.05 mol) in ethanol (50 ml) at 0  C, carbon
disulphide (0.05 mol) and potassium hydroxide (0.05 mol) were
added and the reaction mixture was refluxed until the evolution
of H2S gas ceased. Excess solvents were evaporated under
reduced pressure and the residue was dissolved in water and
then acidified with dilute hydrochloric acid (10%) to pH 6. The
precipitate was filtered off, dried, and crystallized from ethanol
to give 5 [19]. The completion of reaction was monitored by Thin
Layer Chromatography in nehexane: ethyl acetate (8:2) solvent
system. Dark yellow solid, Yield 71%, mp.: 227e229  C. IR (KBr,
cm 1): 2588 (SH), 1652 (C]N, benzimidazole), 1626, 1530 (2C]
N, oxadiazole), 1471 (eNeCH2), 1138 (CeN, benzimidazole), 1043
(CeOeC, oxadiazole). 1H NMR (400 MHz, DMSOed6): d 14.55 (br
s, 1H, SH), 8.52 (s, 1H, eN ¼ CH), 7.81e7.48 (m, 4H, AreH), 3.61 (s,
2H, eNeCH2).
Please cite this article in press as: R.V. Patel, et al., Synthesis of benzimidazolyl-1,3,4-oxadiazol-2ylthio-N-phenyl (benzothiazolyl) acetamides as
antibacterial, antifungal and antituberculosis agents, European Journal of Medicinal Chemistry (2012), doi:10.1016/j.ejmech.2012.03.033
7
5.1.8. General synthetic procedure for benzimidazolyle1,3,4eoxadia-
zole2ylthioeNephenyleacetamides (6aek)
To a 0.05 mol of 5e((1Hebenzo[d]imidazole1eyl)methyl)e
1,3,4eoxadiazolee2ethiol (5) in 25 mL of acetone, 0.05 mol of
2echloroeNe(substituted)phenyl acetamide (2aek) in acetone
and 0.05 mol of K2CO3 was added and the reaction mixture was
refluxed for 6e12 h, then, after cooling to room temperature, it was
slowly poured into 100 mL of ice water and the resulting solid was
separated by filtration and washed successively with water. The
product was dried under vacuum to obtain 6aek [40]. The progress
of the reaction was monitored by Thin Layer Chromatography using
n-hexane: ethyl acetate (8:2) solvent system.
5.1.8.1. 2e(5e((1Hebenzo[d]imidazole1eyl)methyl)e1,3,4eoxadia-
zole2eylthio)eNephenylacetamide (6a). Light yellow solid, Yield
70%, mp.: 267e269  C. IR (KBr, cm 1): 3302 (NH), 1682 (C]O), 1661
(C]N, benzimidazole), 1636, 1542 (2C]N, oxadiazole), 1482
(eNeCH2), 1147 (CeN, benzimidazole), 1062 (CeOeC, oxadiazole).
1
H NMR (400 MHz, DMSOed6): d 8.52 (s, 1H, eN ¼ CH), 8.42 (s,eNH),
7.62e7.24 (m, 9H, AreH), 4.32 (s, 2H, SeCH2), 3.56 (s, 2H, eNeCH2).
13
C NMR (100 MHz, DMSOe d6): d 170.24 (1C, C-2, oxadiazole),
167.82 (1C, CO), 162.99 (1C, C-5, oxadiazole), 153.11 (1C, C-2, benz-
imidazole), 141.17, 139.32, 135.52, 133.20, 129.87, 126.78, 125.01,
122.35, 114.89 (12C, AreC), 46.90 (1C, NeCH2), 35.13 (1C, SeCH2).
Anal Calcd. for C18H15N5O2S: C, 59.16; H, 4.14; N, 19.17; Found: C,
58.98; H, 4.27; N, 19.33.
5.1.8.2. 2e(5e((1Hebenzo[d]imidazole1eyl)methyl)e1,3,4eoxadia-
zole2eylthio)eNe(4echlorophenyl)acetamide (6b). Light yellow
solid, Yield 68%, mp.: 256e257  C. IR (KBr, cm 1): 3297 (NH), 1689
(C]O), 1650 (C]N, benzimidazole), 1630, 1536 (2C]N, oxadia-
zole), 1477 (eNeCH2), 1141 (CeN, benzimidazole), 1071 (CeOeC,
oxadiazole). 1H NMR (400 MHz, DMSOed6): d 8.45 (s, 1H, eN
¼ CH), 8.31 (s, 1H, eNH), 7.51e7.26 (m, 8H, AreH), 4.19 (s, 2H,
SeCH2), 3.63 (s, 2H, eNeCH2). 13C NMR (100 MHz, DMSOe d6):
d 168.91 (1C, C-2, oxadiazole), 167.03 (1C, CO), 164.10 (1C, C-5,
oxadiazole), 150.29 (1C, C-2, benzimidazole), 139.22, 138.97,
135.67, 132.88, 130.12, 127.75, 126.10, 124.99, 122.27, 121.52, 119.30,
117.03 (12C, AreC), 42.31 (1C, NeCH2), 34.58 (1C, SeCH2). Anal
Calcd. for C18H14ClN5O2S: C, 54.07; H, 3.53; N, 17.51; Found: C,
54.23; H, 3.68; N, 17.27.
5.1.8.3. 2e(5e((1Hebenzo[d]imidazole1eyl)methyl)e1,3,4eoxadia-
zole2eylthio)eNe(4ebromophenyl)acetamide (6c). Yellow solid,
Yield 77%, mp.: 260e262  C. IR (KBr, cm 1): 3287 (NH), 1678 (C]O),
1654 (C]N, benzimidazole), 1626, 1548 (2C]N, oxadiazole), 1480
(eNeCH2),1134 (CeN, benzimidazole),1052 (CeOeC, oxadiazole). 1H
NMR (400 MHz, DMSOed6): d 8.56 (s,1H, eN ¼ CH), 8.29 (s,1H, eNH),
7.52e7.31 (m, 8H, AreH), 4.26 (s, 2H, SeCH2), 3.74 (s, 2H, eNeCH2).
13
C NMR (100 MHz, DMSOe d6): d 169.01 (1C, C-2, oxadiazole),
165.44 (1C, CO), 165.12 (1C, C-5, oxadiazole), 155.81 (1C, C-2, benz-
imidazole), 146.68, 144.81, 142.10, 138.09, 134.98, 132.17, 129.02,
126.78, 123.56, 120.76, 117.90, 115.97 (12C, AreC), 45.16 (1C, NeCH2),
35.27 (1C, SeCH2). Anal Calcd. for C18H14BrN5O2S: C, 48.66; H, 3.18; N,
15.76; Found: C, 48.50; H, 2.99; N, 15.89.
5.1.8.4. 2e(5e((1Hebenzo[d]imidazole1eyl)methyl)e1,3,4eoxadia-
zole2eylthio)eNe(4e fluorophenyl)acetamide (6d). Light yellow
solid, Yield 71%, mp.: 278e280  C. IR (KBr, cm 1): 3279 (NH), 1681
(C]O), 1656 (C]N, benzimidazole), 1628, 1533 (2C]N, oxadiazole),
1471 (eNeCH2), 1142 (CeN, benzimidazole), 1074 (CeOeC, oxadia-
zole). 1H NMR (400 MHz, DMSOed6): d 8.63 (s, 1H, eN ¼ CH), 8.36 (s,
1H, eNH), 7.66e7.41 (m, 4H, AreH), 7.26e7.16 (m, 4H, AreH), 4.20 (s,
2H, SeCH2), 3.62 (s, 2H, eNeCH2). 13C NMR (100 MHz, DMSOe d6):
d 170.14 (1C, C-2, oxadiazole), 166.22 (1C, CO), 163.99 (1C, C-5,
8 R.V. Patel et al. / European Journal of Medicinal Chemistry xxx (2012) 1e11
oxadiazole), 151.51 (1C, C-2, benzimidazole), 144.19, 142.15, 139.02,
136.89, 133.12, 129.80, 127.89, 125.65, 122.14, 120.19, 118.97, 116.33
(12C, AreC), 44.82 (1C, NeCH2), 36.02 (1C, SeCH2). Anal Calcd. for
C18H14FN5O2S: C, 56.39; H, 3.68; N, 18.27; Found: C, 56.53; H, 3.81; N,
18.21.
5.1.8.5. 2e(5e((1Hebenzo[d]imidazole1eyl)methyl)e1,3,4eoxadia-
zole2eylthio)eNe(4eiodophenyl)acetamide (6e). Light yellow
solid, Yield 69%, mp.: 272e274  C. IR (KBr, cm 1): 3290 (NH), 1678
(C]O), 1657 (C]N, benzimidazole), 1631, 1547 (2C]N, oxadia-
zole), 1489 (eNeCH2), 1142 (CeN, benzimidazole), 1067 (CeOeC,
oxadiazole). 1H NMR (400 MHz, DMSOed6): d 8.52 (s, 1H,
eN ¼ CH), 8.29 (s, 1H, eNH), 7.69e7.41 (m, 6H, AreH), 7.32 (d,
J ¼ 7.7 Hz, 2H), 4.27 (s, 2H, SeCH2), 3.72 (s, 2H, eNeCH2). 13C NMR
(100 MHz, DMSOe d6): d 169.88 (1C, C-2, oxadiazole), 166.69 (1C,
CO), 165.72 (1C, C-5, oxadiazole), 153.10 (1C, C-2, benzimidazole),
140.48, 139.02, 136.77, 134.87, 132.90, 128.99, 126.72, 125.06,
122.23, 119.99, 116.36, 113.92 (12C, AreC), 41.91 (1C, NeCH2), 35.11
(1C, SeCH2). Anal Calcd. for C18H14IN5O2S: C, 44.00; H, 2.87; N,
14.25; Found: C, 44.28; H, 3.04; N, 14.38.
5.1.8.6. 2e(5e((1Hebenzo[d]imidazole1eyl)methyl)e1,3,4eoxadia-
zole2eylthio)eNe(4enitrophenyl)acetamide (6f). Yellow solid,
Yield 74%, mp.: 289e290  C. IR (KBr, cm 1): 3320 (NH), 1685 (C]
O), 1667 (C]N, benzimidazole), 1631, 1549 (2C]N, oxadiazole),
1486 (eNeCH2), 1151 (CeN, benzimidazole), 1081 (CeOeC, oxa-
diazole). 1H NMR (400 MHz, DMSOed6): d 8.58 (s, 1H, eN ¼ CH),
8.35 (s, 1H, eNH), 7.82 (d, J ¼ 7.3 Hz, 2H), 7.55e7.23 (m, 6H,
AreH), 4.31 (s, 2H, SeCH2), 3.61 (s, 2H, eNeCH2). 13C NMR
(100 MHz, DMSOe d6): d 167.82 (1C, C-2, oxadiazole), 165.91 (1C,
CO), 164.15 (1C, C-5, oxadiazole), 152.55 (1C, C-2, benzimidazole),
145.02, 144.13, 142.90, 140.11, 137.91, 134.68, 131.92, 128.99, 126.10,
124.37, 120.69, 118.46 (12C, AreC), 45.65 (1C, NeCH2), 35.30 (1C,
SeCH2). Anal Calcd. for C18H14N6O4S: C, 52.68; H, 3.44; N, 20.48;
Found: C, 52.52; H, 3.59; N, 20.31.
5.1.8.7. 2e(5e((1Hebenzo[d]imidazole1eyl)methyl)e1,3,4eoxadia-
zole2eylthio)eNe(4ecyanophenyl)acetamide (6g). Off white solid,
Yield 69%, mp.: 259e260  C. IR (KBr, cm 1): 3282 (NH), 1674 (C]
O), 1652 (C]N, benzimidazole), 1633, 1532 (2C]N, oxadiazole),
1470 (eNeCH2), 1145 (CeN, benzimidazole), 1071 (CeOeC, oxa-
diazole). 1H NMR (400 MHz, DMSOed6): d 8.50 (s, 1H, C-2,
benzimidazole), 8.43 (s, 1H, eNH), 7.71 (d, J ¼ 7.6 Hz, 2H), 7.61
(d, J ¼ 7.1 Hz, 2H), 7.51e7.29 (m, 4H, AreH), 4.22 (s, 2H, SeCH2),
3.65 (s, 2H, eNeCH2). 13C NMR (100 MHz, DMSOe d6): d 170.17
(1C, C-2, oxadiazole), 167.33 (1C, CO), 165.09 (1C, C-5, oxadiazole),
154.78 (1C, C-2, benzimidazole), 147.19, 144.86, 142.18, 139.81,
137.66, 135.10, 132.29, 130.99, 127.97, 123.42, 117.21 (11C, AreC),
106.02 (1C, C^N), 99.14 (1C, eCeChN), 43.13 (1C, NeCH2),
33.96 (1C, SeCH2). Anal Calcd. for C19H14N6O2S: C, 58.45; H,
3.61; N, 21.53; Found: C, 58.61; H, 3.49; N, 21.44.
5.1.8.8. 2e(5e((1Hebenzo[d]imidazole1eyl)methyl)e1,3,4eoxadia-
zole2eylthio)eNepetolylacetamide (6h). Light yellow solid, Yield
71%, mp.: 252e254  C. IR (KBr, cm 1): 3281 (NH), 1678 (C]O), 1660
(C]N, benzimidazole),1631,1540 (2C]N, oxadiazole),1473 (eNeCH2),
1136 (CeN, benzimidazole), 1058 (CeOeC, oxadiazole). 1H NMR
(400 MHz, DMSOed6): d 8.56 (s, 1H, eN ¼ CH), 8.30 (s, 1H, eNH),
7.72e7.35 (m, 8H, AreH), 4.16 (s, 2H, SeCH2), 3.70 (s, 2H, eNeCH2),
1.87 (s, 3H, eCH3). 13C NMR (100 MHz, DMSOe d6): d 168.54 (1C, C-2,
oxadiazole), 167.15 (1C, CO), 164.91 (1C, C-5, oxadiazole), 151.55 (1C, C-
2, benzimidazole), 142.03, 138.90, 136.78, 134.91, 132.66, 131.23,
128.95, 124.81, 122.50, 119.66, 117.80, 115.31 (12C, AreC), 45.17 (1C,
NeCH2), 36.56 (1C, SeCH2),17.91 (1C, CH3). Anal Calcd. for C19H17N5O2S:
C, 60.14; H, 4.52; N, 18.46; Found: C, 59.95; H, 4.36; N, 18.59.
Please cite this article in press as: R.V. Patel, et al., Synthesis of benzimidazolyl-1,3,4-oxadiazol-2ylthio-N-phenyl (benzothiazolyl) acetamides as
antibacterial, antifungal and antituberculosis agents, European Journal of Medicinal Chemistry (2012), doi:10.1016/j.ejmech.2012.03.033
5.1.8.9. 2e(5e((1Hebenzo[d]imidazole1eyl)methyl)e1,3,4eoxadia-
zole2eylthio)eNe(4emethoxyphenyl)acetamide (6i). Light yellow
solid, Yield 76%, mp.: 247e248  C. IR (KBr, cm 1): 3295 (NH), 1680
(C]O), 1666 (C]N, benzimidazole), 1624, 1550 (2C]N, oxadia-
zole), 1471 (eNeCH2), 1141 (CeN, benzimidazole), 1063 (CeOeC,
oxadiazole). 1H NMR (400 MHz, DMSOed6): d 8.46 (s, 1H,
eN ¼ CH), 8.19 (s, 1H, eNH), 7.55e7.27 (m, 6H, AreH), 6.89 (d,
J ¼ 7.1 Hz, 2H), 4.25 (s, 2H, SeCH2), 3.80 (s, 3H, eOCH3), 3.72 (s, 2H,
eNeCH2). 13C NMR (100 MHz, DMSOe d6): d 170.23 (1C, C-2,
oxadiazole), 167.78 (1C, CO), 163.90 (1C, C-5, oxadiazole), 152.13
(1C, C-2, benzimidazole), 145.26, 143.12, 141.97, 137.66, 134.90,
131.27, 127.92, 126.53, 125.82, 122.60, 119.36, 116.29 (12C, AreC),
56.16 (1C, OCH3), 45.11 (1C, NeCH2), 33.89 (1C, SeCH2). Anal
Calcd. for C19H17N5O3S: C, 57.71; H, 4.33; N, 17.71; Found: C, 57.53;
H, 4.51; N, 17.83.
5.1.8.10. 2e(5e((1Hebenzo[d]imidazole1eyl)methyl)e1,3,4eoxadi-
azole2eylthio)eNe(4eethoxyphenyl)acetamide (6j). Light yellow
solid, Yield 72%, mp.: 243e246  C. IR (KBr, cm 1): 3319 (NH), 1684
(C]O), 1648 (C]N, benzimidazole), 1639, 1548 (2C]N, oxadia-
zole), 1480 (eNeCH2), 1154 (CeN, benzimidazole), 1066 (CeOeC,
oxadiazole). 1H NMR (400 MHz, DMSOed6): d 8.52 (s, 1H,
eN ¼ CH), 8.31 (s, 1H, eNH), 7.62e7.29 (m, 6H, AreH), 6.79 (d,
J ¼ 7.6 Hz, 2H), 4.17 (s, 2H, SeCH2), 3.91 (q, J ¼ 6.6 Hz, 2H, e
OeCH2e), 3.66 (s, 2H, eNeCH2), 1.41 (t, 3H, eCH3). 13C NMR
(100 MHz, DMSOe d6): d 168.90 (1C, C-2, oxadiazole), 166.68 (1C,
CO), 164.13 (1C, C-5, oxadiazole), 150.99 (1C, C-2, benzimidazole),
141.76, 140.12, 138.97, 135.80, 134.42, 132.17, 129.84, 127.62, 125.89,
121.54, 118.73, 117.39, (12C, AreC), 66.14 (1C, OCH2CH3), 44.19 (1C,
NeCH2), 35.29 (1C, SeCH2), 21.19 (1C, OCH2CH3). Anal Calcd. for
C20H19N5O3S: C, 58.67; H, 4.68; N, 17.10; Found: C, 58.51; H, 4.51; N,
16.98.
5.1.8.11. 2e(5e((1Hebenzo[d]imidazole1eyl)methyl)e1,3,4eoxadi-
azole2eylthio)eNe(4eacetamidophenyl)acetamide (6k). Yellow
solid, Yield 78%, mp.: 250e253  C. IR (KBr, cm 1): 3277 (NH), 1682
(C]O), 1649 (C]N, benzimidazole), 1627, 1532 (2C]N, oxadiazole),
1467 (eNeCH2), 1132 (CeN, benzimidazole), 1081 (CeOeC, oxa-
diazole). 1H NMR (400 MHz, DMSOed6): d 8.59 (s, 1H, eN ¼ CH),
8.34 (s, 1H, eNH), 8.11 (s, 1H, eNH), 7.64e7.23 (m, 8H, AreH), 4.20
(s, 2H, SeCH2), 3.71 (s, 2H, eNeCH2), 1.87 (s, 3H, eCH3). 13C NMR
(100 MHz, DMSOe d6): d 170.16 (1C, C-2, oxadiazole), 168.68, 168.90
(2C, CO), 165.22 (1C, C-5, oxadiazole), 153.27 (1C, C-2, benzimid-
azole), 142.19, 141.24, 138.77, 136.91, 133.88, 132.00, 129.83, 126.85,
123.77, 122.23, 119.99, 119.18 (12C, AreC), 43.28 (1C, NeCH2), 34.33
(1C, SeCH2), 19.98 (1C, CH3). Anal Calcd. for C20H18N6O3S: C, 56.86;
H, 4.29; N, 19.89; Found: C, 57.01; H, 4.44; N, 19.73.
5.1.9. General synthetic procedure for benzimidazolyle1,3,4eoxadi-
azole2ylthioeNephenyl benzothiazolyl acetamides (7aek)
To a 0.05 mol of 5e((1Hebenzo[d]imidazole1eyl)methyl)e
1,3,4eoxadiazolee2ethiol (5) in 25 mL of acetone, 0.05 mol of
Ne(benzo[d]thiazole2eyl)e2echloroacetamides (4aek) in acetone
and 0.05 mol of K2CO3 was added and the reaction mixture was
refluxed for 8e15 h, then, after cooling to room temperature, it was
slowly poured into 100 mL of ice water and the resulting solid was
separated by filtration and washed successively with water. The
product was dried under vacuum to obtain 7aek [41]. The progress
of the reaction was monitored by Thin Layer Chromatography using
n-hexane: ethyl acetate (8:2) solvent system.
5.1.9.1. 2e(5e((1Hebenzo[d]imidazole1eyl)methyl)e1,3,4eoxadia-
zole2eylthio)eNe(benzo[d]thiazole2eyl)acetamide (7a). Yellow
solid, Yield 70%, mp 256e257  C. IR (KBr, cm 1): 3324 (NH), 1675 (C]
O), 1659 (C]N, benzimidazole), 1652 (C]N, benzothiazole), 1631,
 R.V. Patel et al. / European Journal of Medicinal Chemistry xxx (2012) 1e11
1534 (2C]N, oxadiazole), 1479 (eNeCH2), 1141 (CeN, benzimid-
azole), 1058 (CeOeC, oxadiazole). 1H NMR (400 MHz, DMSOed6):
d 8.66 (s, 1H, eN ¼ CH), 8.37 (s, 1H, eNH), 7.61e7.17 (m, 12H, AreH),
4.28 (s, 2H, SeCH2), 3.80 (s, 2H, eNeCH2). 13C NMR (100 MHz,
DMSOe d6): d 169.90 (1C, C-2, oxadiazole),166.89 (1C, CO),165.66 (1C,
C-5, oxadiazole), 155.98 (1C, C-2, benzothiazole), 153.11 (1C, C-2,
benzimidazole), 144.90, 142.17, 139.80, 136.78, 134.77, 133.43, 130.15,
126.89, 125.05, 123.55, 121.90, 117.13 (12C, AreC), 44.68 (1C, NeCH2),
34.88 (1C, SeCH2). Anal Calcd. for C19H14N6O2S2: C, 54.01; H, 3.34; N,
19.89; Found: C, 53.92; H, 3.48; N, 20.02.
5.1.9.2. 2e(5e((1Hebenzo[d]imidazole1eyl)methyl)e1,3,4eoxadia-
zole2eylthio)eNe(6echlorobenzo[d]thiazole2eyl)acetamide
(7b). Yellow solid, Yield 75%, mp.: 267e268  C. IR (KBr, cm 1):
3299 (NH), 1681 (C]O), 1655 (C]N, benzimidazole), 1650 (C]N,
benzothiazole), 1622, 1554 (2C]N, oxadiazole), 1488 (eNeCH2),
1134 (CeN, benzimidazole), 1087 (CeOeC, oxadiazole). 1H NMR
(400 MHz, DMSOed6): d 8.59 (s, 1H, eN ¼ CH), 8.28 (s, 1H, eNH),
7.75 (d, J ¼ 1.6 Hz, 1H), 7.48 (d, J ¼ 7.5 Hz, 1H), 7.37 (dd, J ¼ 7.7,
1.8 Hz, 1H), 7.29e7.14 (m, 4H, AreH), 4.35 (s, 2H, SeCH2), 3.66 (s,
2H, eNeCH2). 13C NMR (100 MHz, DMSOe d6): d 171.13 (1C, C-2,
oxadiazole), 168.19 (1C, CO), 164.38 (1C, C-5, oxadiazole), 157.09
(1C, C-2, benzothiazole), 151.92 (1C, C-2, benzimidazole), 146.35,
143.78, 141.12, 136.89, 133.90, 131.11, 128.08, 126.82, 124.56, 121.86,
119.84, 117.10, 115.72 (12C, AreC), 41.90 (1C, NeCH2), 35.09 (1C,
SeCH2). Anal Calcd. for C19H13ClN6O2S2: C, 49.94; H, 2.87; N, 18.39;
Found: C, 50.11; H, 2.76; N, 18.21.
5.1.9.3. 2e(5e((1Hebenzo[d]imidazole1eyl)methyl)e1,3,4eoxadia-
zole2eylthio)eNe(6ebromobenzo[d]thiazole2eyl)acetamide
(7c). Light brown solid, Yield 78%, mp.: 258e259  C. IR (KBr,
cm 1): 3307 (NH), 1672 (C]O), 1664 (C]N, benzimidazole), 1656
(C]N, benzothiazole), 1636, 1533 (2C]N, oxadiazole), 1472
(eNeCH2), 1134 (CeN, benzimidazole), 1060 (CeOeC, oxadiazole).
1
H NMR (400 MHz, DMSOed6): d 8.62 (s, 1H, eN ¼ CH), 8.38 (s, 1H,
eNH), 7.68 (d, J ¼ 1.4 Hz, 1H), 7.55e7.21 (m, 11H, AreH), 4.41 (s, 2H,
SeCH2), 3.77 (s, 2H, eNeCH2). 13C NMR (100 MHz, DMSOe d6):
d 168.79 (1C, C-2, oxadiazole), 166.18 (1C, CO), 165.52 (1C, C-5,
oxadiazole), 154.80 (1C, C-2, benzothiazole), 153.01 (1C, C-2,
benzimidazole), 141.38, 138.93, 136.70, 134.21, 132.10, 129.97,
125.79, 124.56, 122.47, 121.09, 119.29, 117.11 (12C, AreC), 44.20 (1C,
NeCH2), 33.93 (1C, SeCH2). Anal Calcd. for C19H13BrN6O2S2: C,
45.52; H, 2.61; N, 16.76; Found: C, 45.33; H, 2.74; N, 16.53.
5.1.9.4. 2e(5e((1Hebenzo[d]imidazole1eyl)methyl)e1,3,4eoxadia-
zole2eylthio)eNe(6efluorobenzo[d]thiazole2eyl)acetamide
(7d). Yellow solid, Yield 65%, mp.: 276e278  C. IR (KBr, cm 1): 3293
(NH), 1684 (C]O), 1660 (C]N, benzimidazole), 1653 (C]N, benzo-
thiazole), 1640,1528 (2C]N, oxadiazole), 1491 (eNeCH2), 1151 (CeN,
benzimidazole), 1066 (CeOeC, oxadiazole). 1H NMR (400 MHz,
DMSOed6): d 8.70 (s, 1H, eN ¼ CH), 8.31 (s, 1H, eNH), 7.81 (dd, J ¼ 8.1,
1.5 Hz, 1H), 7.68 (dd, J ¼ 2.2, 8.6 Hz, 1H), 7.40 (dd, J ¼ 5.1, 8.3 Hz, 1H),
7.29e7.14 (m, 4H, AreH), 4.35 (s, 2H, SeCH2), 3.61 (s, 2H, eNeCH2). 13C
NMR (100 MHz, DMSOe d6): d 169.05 (1C, C-2, oxadiazole),167.70 (1C,
CO), 166.17 (1C, C-5, oxadiazole), 156.72 (1C, C-2, benzothiazole),
151.91 (1C, C-2, benzimidazole), 144.19, 143.10, 140.92, 137.25, 134.79,
132.13,128.97,126.77,125.90,123.16,120.99,117.64, (12C, AreC), 46.01
(1C, NeCH2), 37.67 (1C, SeCH2). Anal Calcd. for C19H13FN6O2S2: C,
51.81; H, 2.97; N, 19.08; Found: C, 51.70; H, 3.14; N, 18.99.
5.1.9.5. 2e(5e((1Hebenzo[d]imidazole1eyl)methyl)e1,3,4eoxadia-
zole2eylthio)eNe(6eiodobenzo[d]thiazole2eyl)acetamide
(7e). Light Yellow solid, Yield 67%, mp.: 262e265  C. IR (KBr,
cm 1): 3301 (NH), 1672 (C]O), 1654 (C]N, benzimidazole), 1651
(C]N, benzothiazole), 1627, 1552 (2C]N, oxadiazole), 1461
Please cite this article in press as: R.V. Patel, et al., Synthesis of benzimidazolyl-1,3,4-oxadiazol-2ylthio-N-phenyl (benzothiazolyl) acetamides as
antibacterial, antifungal and antituberculosis agents, European Journal of Medicinal Chemistry (2012), doi:10.1016/j.ejmech.2012.03.033
9
(eNeCH2), 1133 (CeN, benzimidazole), 1070 (CeOeC, oxadiazole).
1
H NMR (400 MHz, DMSOed6): d 8.59 (s, 1H, eN ¼ CH), 8.26 (s, 1H,
eNH), 7.91 (d, J ¼ 2.2 Hz, 1H), 7.67 (d, J ¼ 7.6 Hz, 1H), 7.44 (dd,
J ¼ 8.4, 1.9 Hz, 1H), 7.33e7.17 (m, 4H, AreH), 4.30 (s, 2H, SeCH2),
3.68 (s, 2H, eNeCH2). 13C NMR (100 MHz, DMSOe d6): d 170.11
(1C, C-2, oxadiazole), 167.90 (1C, CO), 164.87 (1C, C-5, oxadiazole),
155.47 (1C, C-2, benzothiazole), 150.50 (1C, C-2, benzimidazole),
143.13, 141.19, 137.89, 134.12, 132.10, 129.80, 125.99, 124.67, 121.96,
119.20, 117.26, 116.53, 113.46 (12C, AreC), 45.07 (1C, NeCH2), 35.76
(1C, SeCH2). Anal Calcd. for C19H13IN6O2S2: C, 41.61; H, 2.39; N,
15.33; Found: C, 41.46; H, 2.56; N, 15.21.
5.1.9.6. 2e(5e((1Hebenzo[d]imidazole1eyl)methyl)e1,3,4eoxadia-
zole2eylthio)eNe(6enitrobenzo[d]thiazole2eyl)acetamide
(7f). Yellow solid, Yield 64%, mp.: 289e290  C. IR (KBr, cm 1):
3313 (NH), 1674 (C]O), 1667 (C]N, benzimidazole), 1656 (C]N,
benzothiazole), 1637, 1546 (2C]N, oxadiazole), 1487 (eNeCH2),
1140 (CeN, benzimidazole), 1054 (CeOeC, oxadiazole). 1H NMR
(400 MHz, DMSOed6): d 8.59 (s, 1H, eN ¼ CH), 8.26 (s, 1H, eNH),
8.02 (d, J ¼ 1.8 Hz, 1H), 7.77 (dd, J ¼ 7.3, 1.8 Hz, 1H), 7.60 (d,
J ¼ 7.1 Hz, 1H), 7.46 (dd, J ¼ 7.5, 1.7 Hz, 2H), 7.31e7.22 (m, 2H, AreH),
4.18 (s, 2H, SeCH2), 3.55 (s, 2H, eNeCH2). 13C NMR (100 MHz,
DMSOe d6): d 170.92 (1C, C-2, oxadiazole), 167.58 (1C, CO), 165.32
(1C, C-5, oxadiazole), 156.71 (1C, C-2, benzothiazole), 152.91 (1C, C-
2, benzimidazole), 147.10, 145.25, 143.19, 140.93, 138.76, 135.95,
132.19, 128.99, 127.11, 125.60, 122.38, 120.56 (12C, AreC), 45.19 (1C,
NeCH2), 36.72 (1C, SeCH2). Anal Calcd. for C19H13N7O4S2: C, 48.82;
H, 2.80; N, 20.97; Found: C, 48.93; H, 2.77; N, 21.11.
5.1.9.7. 2e(5e((1Hebenzo[d]imidazole1eyl)methyl)e1,3,4eoxadia-
zole2eylthio)eNe(6ecyanobenzo[d]thiazole2eyl)acetamide
(7g). Yellow solid, Yield 69%, mp.: 267e269  C. IR (KBr, cm 1):
3283 (NH), 1681 (C]O), 1653 (C]N, benzimidazole), 1649 (C]N,
benzothiazole), 1631, 1540 (2C]N, oxadiazole), 1479 (eNeCH2),
1142 (CeN, benzimidazole), 1081 (CeOeC, oxadiazole). 1H NMR
(400 MHz, DMSOed6): d 8.60 (s, 1H, eN ¼ CH), 8.24 (s, 1H, eNH),
7.96 (d, J ¼ 1.9 Hz, 1H), 7.71 (d, J ¼ 7.6 Hz, 1H), 7.49 (dd, J ¼ 8.6,
1.8 Hz, 1H), 7.39e7.26 (m, 4H, AreH), 4.29 (s, 2H, SeCH2), 3.67 (s,
2H, eNeCH2). 13C NMR (100 MHz, DMSOe d6): d 168.25 (1C, C-2,
oxadiazole), 167.11 (1C, CO), 164.69 (1C, C-5, oxadiazole), 155.14
(1C, C-2, benzothiazole), 150.96 (1C, C-2, benzimidazole), 141.19,
137.88, 134.90, 132.11, 130.09, 129.15, 126.79, 124.99, 123.10, 122.97,
118.60 (11C, AreC), 105.87 (1C, C^N), 96.91 (1C, eCeChN), 43.87
(1C, NeCH2), 35.10 (1C, SeCH2). Anal Calcd. for C20H13N7O2S2: C,
53.68; H, 2.93; N, 21.91; Found: C, 53.55; H, 2.76; N, 22.04.
5.1.9.8. 2e(5e((1Hebenzo[d]imidazole1eyl)methyl)e1,3,4eoxadia-
zole2eylthio)eNe(6emethylbenzo[d]thiazole2eyl)acetamide
(7h). Yellow solid, Yield 79%, mp.: 254e255  C. IR (KBr, cm 1): 3275
(NH), 1687 (C]O), 1657 (C]N, benzimidazole), 1651 (C]N, benzo-
thiazole), 1631, 1548 (2C]N, oxadiazole), 1485 (eNeCH2), 1147
(CeN, benzimidazole), 1059 (CeOeC, oxadiazole). 1H NMR
(400 MHz, DMSOed6): d 8.60 (s, 1H, eN ¼ CH), 8.21 (s, 1H, eNH), 7.83
(d, J ¼ 7.7 Hz, 1H), 7.60e7.17 (m, 6H, AreH), 4.37 (s, 2H, SeCH2), 3.58
(s, 2H, eNeCH2), 2.28 (s, 3H, CH3). 13C NMR (100 MHz, DMSOe d6):
d 168.16 (1C, C-2, oxadiazole), 166.71 (1C, CO), 165.13 (1C, C-5, oxa-
diazole), 158.60 (1C, C-2, benzothiazole), 151.36 (1C, C-2, benzimid-
azole), 148.00, 141.67, 137.89, 134.60, 133.21, 130.91, 127.89, 126.10,
123.57, 122.10, 119.90, 115.45 (12C, AreC), 42.92 (1C, NeCH2), 34.59
(1C, SeCH2), 17.90 (1C, CH3). Anal Calcd. for C20H16N6O2S2: C, 55.03;
H, 3.69; N, 19.25; Found: C, 54.91; H, 3.73; N, 19.05.
5.1.9.9. 2e(5e((1Hebenzo[d]imidazole1eyl)methyl)e1,3,4eoxadia-
zole2eylthio)eNe(6emethoxybenzo[d]thiazole2eyl)acetamide
(7i). Yellow solid, Yield 61%, mp.: 260e262  C. IR (KBr, cm 1): 3295
10 R.V. Patel et al. / European Journal of Medicinal Chemistry xxx (2012) 1e11

(NH), 1678 (C]O), 1661 (C]N, benzimidazole), 1658 (C]N, ben- L. J. (Lowenstein and Jensen) MIC method [45,46] for the
zothiazole), 1635, 1531 (2C]N, oxadiazole), 1469 (eNeCH2), 1141 measurement of MIC.
(CeN, benzimidazole), 1072 (CeOeC, oxadiazole). 1H NMR
(400 MHz, DMSOed6): d 8.60 (s, 1H, eN ¼ CH), 8.24 (s, 1H, eNH), Acknowledgements
7.91e7.70 (m, 2H), 7.51 (dd, J ¼ 8.6, 1.7 Hz, 1H), 7.40e7.26 (m, 4H,
AreH)), 4.25 (s, 2H, SeCH2), 3.82 (s, 3H, OCH3), 3.67 (s, 2H, The authors are thankful to Applied Chemistry Department of S.
eNeCH2). 13C NMR (100 MHz, DMSOe d6): d 170.02 (1C, C-2, oxa- V. National Institute of Technology, Surat for the scholarship,
diazole), 165.90 (1C, CO), 164.17 (1C, C-5, oxadiazole), 154.91 (1C, C- encouragement and facilities. The authors wish to offer their deep
2, benzothiazole), 149.46 (1C, C-2, benzimidazole), 141.19, 138.97, gratitude to Microcare Laboratory, Surat, India for carrying out the
135.67, 134.20, 132.19, 129.80, 127.34, 126.04, 123.82, 121.93, 120.01, biological screenings. We are also thankful to Centre of Excellence,
118.30 (12C, AreC), 55.90 (1C, OCH3), 45.19 (1C, NeCH2), 36.02 (1C, Vapi, India for carrying out FTeIR, 1H NMR and 13C NMR analysis.
SeCH2). Anal Calcd. for C20H16N6O3S2: C, 53.08; H, 3.56; N, 18.57;
Found: C, 52.92; H, 3.40; N, 18.31.
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Please cite this article in press as: R.V. Patel, et al., Synthesis of benzimidazolyl-1,3,4-oxadiazol-2ylthio-N-phenyl (benzothiazolyl) acetamides as
antibacterial, antifungal and antituberculosis agents, European Journal of Medicinal Chemistry (2012), doi:10.1016/j.ejmech.2012.03.033
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Please cite this article in press as: R.V. Patel, et al., Synthesis of benzimidazolyl-1,3,4-oxadiazol-2ylthio-N-phenyl (benzothiazolyl) acetamides as
antibacterial, antifungal and antituberculosis agents, European Journal of Medicinal Chemistry (2012), doi:10.1016/j.ejmech.2012.03.033