Expeditious Synthesis, Antimicrobial and Antimalarial Activities of Novel Heterocycles Bearing Imidazole-oxadiazole Based Hybrid Pharmacophores

Article abstract of DOI:10.1055/s-0042-112028

A facile synthesis of 2-substituted-5-amino-oxadiazole derivatives has been achieved by refluxing/sonicating a mixture of semicarbazide with various aromatic acids in conc. sulphuric acid alone. The isolated products were further condensed with p-dimethyl

Full text of DOI:10.1055/s-0042-112028

DrugRes/2016-04-1181/21.7.2016/MPS
Original Article
Expeditious Synthesis, Antimicrobial and Antimalarial
Activities of Novel Heterocycles Bearing Imidazole-
oxadiazole Based Hybrid Pharmacophores
Authors
K. Balaji*, P. Bhatt*, A. Jha
Affiliation
Department of Chemistry, GIS, GITAM University, Visakhapatnam, India
Key words
newly synthesized compounds were thoroughly
Abstract
▶
oxadiazole derivatives
antimicrobial
antimalarial
●
characterized by standard analytical techniques.
These imidazole-oxadiazole hybrid compounds
were also evaluated for their antimicrobial and
antimalarial activities. The compounds all exhib-
ited moderate to significant antimicrobial activ-
ity (6–10mm, zone of inhibition) and promising
antimalarial activity (IC50 0.037–0.100µM). This
report entails a detailed synthetic procedure,
spectroscopic elucidation and activities of the
synthesized compounds.
▼
▶
●
A facile synthesis of 2-substituted-5-amino-oxa-
diazole derivatives has been achieved by reflux-
ing/sonicating a mixture of semicarbazide with
various aromatic acids in conc. sulphuric acid
alone. The isolated products were further con-
densed with p-dimethylaminobenzaldehyde/p-
hydroxybenzaldehyde to obtain respective imino
derivatives. Finally, some potentially biologically
active imidazole analogues were obtained by
reacting ammonium acetate and 5-bromoisatin
with the synthesized imino products. All the
▶
●
▶
●
ultrasonication
Supporting Information for this article is available
online at http://www.thieme-connect.de/products
protocols which are also in sync with the current
idea of sustainable chemistry is an important
aim of a synthetic chemist [10]. Sonochemistry or
the use of ultrasonic irradiation to activate organic
reactions is one such innovative and smart strategy
of contemporary organic synthesis [11].
Introduction
▼
Owing to their widespread occurrence and phar-
maceutical potential, 5-membered heterocyclic
scaffolds with more than one heteroatom have
been an attractive target for organic and medici-
nal chemists. In particular, substituted 1,3,4-oxa-
diazoles have shown multifarious biological
activities, viz. antimicrobial [1], antituberculosis
[2], anti-inflammatory [3], anticonvulsant [4],
anti-HIV [5], and anti-tumor [6] activities. Schiff
bases [7] derived from amino oxazoles have also
been shown to possess anti-bacterial and anti-
fungal activities. Several synthetic methods for 1,
3, 4-oxadiazole [8] derivatives and related sub-
structures have been well depicted in the litera-
ture. Additionally, in recent years, the chemistry
of imidazole [9] based drugs has made good pro-
gress due to their high therapeutic value. It is
therefore considered an important pharmacoph-
ore of medicinal relevance.
Repetitive use of several important drugs has trig-
gered resistance in many pathogens and multid-
rug-resistant strains of bacteria and fungi have
emerged in the past few decades. Malaria is one
such example, where drugs such as chloroquine
(CQ) and its derivatives that traditionally formed
the first line of defence have lost their effective-
ness due to emergence of mutant forms of the
parasitic protozoan Plasmodium [12]. Artemisinin
derivatives were subsequently used to treat
malaria, but the parasites also became tolerant to
these drugs [13]. Considering these facts, an
immediate and effective solution seems to be the
diversification of the current drug arsenal and dis-
covery of new drugs based on novel chemotypes.
To realize this aim, we found no better source than
the heterocycles themselves because of their ver-
satile chemotherapeutic uses. Among various
known antimicrobial drugs, oxadiazole deriva-
tives [14] have appeared as an important class of
heterocyclic compounds with an excellent safety
profile and wide medicinal spectrum.
received 26.04.2016
accepted 06.07.2016
Bibliography
DOI http://dx.doi.org/
10.1055/s-0042-112028
Published online: 2016
Drug Res
© Georg Thieme Verlag KG
Stuttgart · New York
ISSN 2194-9379
Correspondence
Dr. A. Jha, Associate Professor
Department of Chemistry
GIS, GITAM University
Rushikonda
Visakhapatnam
India 530045
Tel.: +91/09490/750 597
Fax: +91/891/2790 032
anjalimanishjha@yahoo.com
Drug research is a unique multi-disciplinary sci-
ence, the success of which relies on the fast and
efficient delivery of the small molecules. In this
connection, devising smart but simple synthetic
* Both the authors contributed equally and both are co-
first authors
Balaji K et al. Biological Activities of Azole Analogues… Drug Res

DrugRes/2016-04-1181/21.7.2016/MPS
Original Article
In light of the above facts, we report herein an efficient solvent-
less synthetic protocol for a new class of substituted imidazole-
oxadiazole. This improved methodology relies on conventional/
ultrasonic (US) means to stimulate the reaction. Eventually,
these new characterized compounds were evaluated for antimi-
crobial and antimalarial activities.
thoroughly. The reaction mixture was refluxed [15] in the pres-
ence of conc. H2SO4 (10mL) without any other solvent for about
10–12h or ultrasonicated for 40–45min. The reaction mixture
was then cooled to room temperature and neutralized with
ammonia solution. The solid was filtered and washed with water
followed by minimal volume of ether. The products were recrys-
tallized from ethanol and characterized by various spectral tech-
niques.
Materials and Methods
General procedure for the preparation of 2-imino
derivative of substituted oxadiazole (5–12)
A mixture of compounds 1–4 (0.01mol) and p-dimethy-
▼
All chemicals and reagents were purchased from Across Ltd and
were used without further purification. All solvents (analytical
grade, AR.) were distilled prior to use. Melting points (uncor-
rected) were measured with a digital melting point apparatus
(Nutronics, Popular India). The ultrasonic reactions were per-
formed in an ultrasonicator bath. The solid IR spectra (using KBr
as a matrix) were obtained using a Perkin Elmer FTIR at GITAM
University, while elemental analysis were performed at the
Micro Analytical centre in Andhra University, Visakhapatnam.
The 1H and 13C NMR spectra were recorded on a Bruker 400 and
100MHz NMR at Biocon Ltd, Bangalore. 1H NMR and 13C experi-
ments utilised DMSO-d6 as a solvent and TMS as an internal ref-
erence. The antimicrobial studies were carried out at the
Department of Microbiology, GITAM University, and the antima-
larial assays were performed at TRIMS Lab, MVP Colony,
Visakhapatnam.
laminobenzaldehyde/p-hydroxybenzaldehyde (0.01mol) in etha-
▶ꢀ
nol (15mL) was refluxed with continuous stirring ( Fig. 1) for
●
about 6–8h by the conventional method. Alternatively
25–35min were required for a similar outcome under the ultra-
sonic condition. The solid products obtained from both the
methods were filtered, washed with water, and recrystallized
from ethanol. Identical TLC and melting point were observed for
the products 5–12 isolated by both the methods.
General procedure for the preparation of imidazole
derivatives of substituted oxadiazole Schiff bases (13–20)
Equimolar amounts of the above characterized Schiff’s bases
(5–12) (0.01mol, 10mL methanol) and 5-bromoisatin (0.01mol,
in 10mL methanol) were charged with an excess of ammonium
acetate (2 moles) in a round bottom flask [16]. The mixture was
▶ꢀ
General procedure for the preparation of
2-amino-5-substituted oxadiazoles (1–4)
Substituted amino oxadiazoles were prepared by the conven-
refluxed ( Fig. 2) for about 4–6h by the conventional methods.
●
A similar and comparable result was obtained with sonication
for 25–30min. Both the reaction mixtures were refrigerated
overnight, filtered, washed with water to remove excess ammo-
nium acetate and dried.
▶ꢀ
tional method as outlined in Fig. 1. A mixture of carboxylic
●
acid (benzoic/salicylic/p-Cl-benzoic/cinnamic, 0.010mol, in a
separate reaction) and semicarbazide (0.012mol) were mixed
Fig. 1 Synthetic pathway of 1–4 and 5–12.
Fig. 2 Synthetic pathway of 13–20.
Balaji K et al. Biological Activities of Azole Analogues… Drug Res

DrugRes/2016-04-1181/21.7.2016/MPS
Original Article
Antimicrobial assay
cm− 1 and could be assigned to aromatic CH and C=C of the ring.
The additional peak at 1673cm− 1 in the IR spectra of compound
4 was attributed to CH=CH group and clearly indicative of the
condensation of cinnamic acid with semicarbazide. This was
also confirmed by the NMR spectra.
The synthesized compounds (1–20) were examined for antimi-
crobial activity against 6 bacteria [BS-Bacillus subtilis, PV-Pseu-
domonas vulgaris, EC-Escherichia coli, SF-Streptococcus faecalis,
KP-Klebsiella pneuomoniae, ML-Micrococcus luteus] and 3 fungi
[AF-Aspergillus flavus, PE-Pencillium expansom, RS-Rhizoctonia
solani] using the well diffusion method [17]. The procedure was
The 1H NMR spectral values of the 2,5-disubstituted oxadiazoles
fitted well with the proposed structures. Peaks at δ 3.2–3.9 and
6.7–7.8ppm in the NMR spectra of compounds 1–4 were attrib-
uted to the NH2 and aromatic protons. In the 13C NMR spectra
aromatic and oxadiazole carbons appeared in the region of δ
110–130ppm and δ 145–155ppm respectively [21]. The disap-
pearance of NH2 and carbonyl peaks in IR and NMR spectra
of compounds (5–12) were further supportive of the condensa-
tion between amino oxadiazoles and p-dimethylamino-
benzaldehyde/p-hydroxybenzaldehyde. The observed signals in
13C NMR spectra of compounds 5–12 in the range of δ 160–
169ppm were due the formation of azomethine carbon [22].
Further, the disappearance of C=O peak of 5-bromoisatin and
N=CH of imino derivatives (5–12) in the target compounds
(13–20) indicated the reaction between them. This was also
supported by their H and 13C NMR. Other proton and carbon
adopted from our previous work [18]. The results are shown
▶ꢀ
in Table 1.
●
Antimalarial assay
The antimalarial activity of the synthesized compounds was
evaluated against chloroquine-sensitive (NF54) and chloro-
quine-resistant (Dd2) strains of P. falciparum using the literature
method [19]. Before performing the experiment, the P. falcipa-
rum culture was synchronized by using sorbitol-induced hemol-
ysis according to the method of Lambros and Vanderberg [20] to
achieve only the ring-infected cells. They were then incubated
for 48h prior to the drug testing to avoid the sorbitol effect. The
experiments were started with synchronized suspension of
0.5–1% infected red blood cell during the ring stage. The para-
sites were suspended in the culture medium and supplemented
with 15% human serum to obtain 10% cell suspension. The para-
site suspension was taken into 96-well micro culture plates
(50μL per well); and 50μL of various test compounds were
added. The parasite suspensions were incubated at 37°C under
CO2 for 48h. The percent parasitemia of control and drug-treated
groups was examined by the microscopic technique using meth-
anol-fixed Giemsa-stained thin smear blood preparation. The
efficacy of the test compounds was evaluated by determining
the drug concentration that reduced parasite growth by 50%.
peaks were found to be consistent with the expected structures.
▶ꢀ
The results of the antimicrobial assays are summarized in Table 1
●
(zone of inhibition, mm). This table clearly indicates that all the
compounds (1–20) exhibited moderate to high antimicrobial
activity. The compounds 3, 4, and 5 displayed good antibacterial
and antifungal activities with 6–14mm and 5–10mm respec-
tively. All imidazole derivatives (13–20) also showed remarkable
activities with 10–22mm. The increased activity of these com-
pounds can be explained on the basis of Overtone’s concept [23],
the presence of unsaturation, bromine atom and imidazole ring.
Further, the delocalization of π electrons over the whole ring
system also enhances the lipophilicity of the compounds, which
is an important factor that controls antimicrobial activity by
blocking the binding sites of the enzymes in the microorganism.
All the compounds were also tested for their antimalarial activ-
Results and Discussion
▼
The synthesis of substituted amino oxadiazole (1–4) and their
imino derivatives (5–12) was accomplished according to the
ity against P. falciparum. In vitro test results against chloroquine
▶ꢀ
▶ꢀ
steps illustrated in Fig. 1. Commercially available carboxylic
resistant strain are presented in Table 2. The results revealed
●
●
acid (benzoic/salicylic/p-Cl-benzoic/cinnamic) and semicar-
bazide were ground together in a mortar and subsequently
refluxed [15] in conc. H2SO4 (cyclizing agent). Despite good yield
under convention route, we also examined the possibility of
relatively milder condition using ultrasonic (US) irradiation.
Gratifyingly, better yields were obtained within 40–45min of
ultrasonication. This improved US methodology aligns well with
the current imperative of green chemistry, and is to be preferred
over conventional heating.
In a subsequent step, imino derivatives (5–12) were synthe-
sized by condensing products 1–4 with p-dimethylamino-
benzaldehyde/p-hydroxybenzaldehyde under US/conventional
conditions. Targeted imidazole derivatives (13–20) were then
obtained by a multicomponent reaction of imino derivatives
(5–12), 5-bromoisatin and excess ammonium acetate. Thin layer
chromatography (TLC) was used to monitor the progress of the
reactions.
that in the case of NF54, compounds 16 and 18 exhibited prom-
ising antimalarial activity with IC50 0.039 and 0.037μM while
for Dd2 strain, compounds 7, 15 and 17 were found to have sig-
nificant antimalarial activity with IC50 values of 0.080, 0.100 and
0.041μM respectively. The presence of the imidazole ring and a
bromine atom may be responsible for the promising activity of
these novel compounds. Compounds 13, 14, 19 and 20 showed
good antimalarial activity (IC50 0.068, 0.052, 0.095 and 0.051μM
respectively) against the NF5 strain. Compounds 4, 11, 14, and
18 displayed good results (IC50 0.106, 0.108, and 0.132μM
respectively) against the Dd2 strain.
Further calculations were carried out on the lipophilicity of the
newly synthesized compounds with predicted Log P values in
the range of 0.6–5.53. These values were in the acceptable range
of permeability (for drug optimization purpose, Log P value of a
▶ꢀ
compound should be 1–5). It was also evident from Fig. 3, that
●
compound 18 with IC50 value comparable to the reference drug
All novel molecules (1–20) were well characterized by spectral
techniques before their evaluation for antimicrobial and antima-
larial activities. Two strong absorption bands appeared in the
range of 3340–3200cm− 1 in the IR spectra of compounds 1–4
which were attributed to the primary amine group of substi-
tuted oxadiazole. The other major peaks observed in the IR of
these compounds were in the region of 3130–3050; 1550–1520
CQ can be a good starting point for further optimization.
In conclusion, an efficient synthesis of some oxadiazole deriva-
tives containing imidazole moiety has been achieved by conven-
tional as well as ultrasonication (US) based methods. The US
method had some significant advantages such as reduced reac-
tion times and mild reaction conditions with higher yields, thus
making it a worthwhile addition to the existing methods. The
Balaji K et al. Biological Activities of Azole Analogues… Drug Res

DrugRes/2016-04-1181/21.7.2016/MPS
Original Article
Table 1 Antimicrobial Activity (zone of inhibition in mm) of Synthesized
Table 2 Antimalarial activity of synthesized compounds.
Compounds at concentration 10µgmLꢀ−ꢀ1
.
Compds
LogP
Mean IC50±SD (μM)
Dd2
Cmpd
Bacteria#
Fungi##
PE
NF54
BS
PV
EC
SF
KP
ML
AF
RS
1
1.14
NA
NA
1
2
6
10
11
8
8
9
7
10
12
11
9
7
11
10
10
11
10
15
14
17
17
14
17
11
15
17
10
17
19
22
14
0
6
8
7
9
9
10
9
5
9
8
NA
5
2
1.15
2.09
1.43
1.25
0.67
3.3
NA
NA
3
NA
NA
3
14
9
9
10
8
7
4
NA
NA
4
9
NA
6
6
7
5
0.425±0.003
0.290±0.002
0.150±0.001
0.148±0.033
0.098±0.017
0.097±0.001
0.16±0.003
0.253±0.042
0.068±0.002
0.052±0.002
0.048±0.033
0.039±0.010
0.043±0.004
0.037±0.001
0.098±0.012
0.051±0.002
0.021±0.004
0.825±0.003
0.215±0.001
0.080±0.010
0.145±0.002
0.752±0.042
0.185±0.010
0.106±0.002
0.274±0.011
0.134±0.015
0.106±0.001
0.100±0.002
0.282±0.001
0.041±0.010
0.132±0.033
0.172±0.013
0.62±0.001
0.294±0.002
5
NA
9
7
8
11
9
13
10
15
13
16
11
15
17
9
10
7
6
6
8
10
11
14
12
15
18
15
11
10
12
6
NA
17
16
19
16
19
14
NA
10
19
NA
12
15
18
17
0
8
7
7
16
15
18
14
11
13
10
16
18
9
14
15
16
13
14
12
10
9
13
11
15
14
18
17
10
NA
15
9
16
19
18
16
12
14
11
13
18
8
16
11
17
09
11
08
14
NA
17
7
8
2.72
4.24
3.66
3.58
3
8
9
9
10
11
12
13
14
15
16
17
18
19
20
CQ
10
11
12
13
14
15
16
17
18
19
20
DMSO
STD
4.85
4.27
4.59
4.01
5.53
4.95
4.87
4.29
–
12
16
NA
11
17
11
18
0
16
8
17
19
18
22
0
12
17
14
18
0
18
20
17
15
0
16
18
14
19
0
13
12
17
14
0
10
13
8
15
0
CQ: Chloroquine, NA: Not active. LogP of compoundswere calculated with
Molinspiration (http://www.molinspiration.com)
30
32
33
29
30
31
29
28
25
# BS-Bacillus subtilis, PV-Pseudomonas vulgaris, EC-Escherichia coli, SF-Streptococcus
faecalis, KP-Klebsilia pneuomonia, ML-Micrococcus luteus, ##ꢀAF-Aspergillusꢀflavus,ꢀ
PE-Pencillian expasom, RS-Rhizoctonia solani, NA-Not active, STD-Ampicillin/
Nystatin
Fig. 3 Treated culture with compound 18 and
untreated control for Antimalarial assay.
newly synthesized compounds were also screened for antimi-
crobial and antimalarial activities. Initial findings are promising
and suggest that the oxadiazole analogues 13 to 20 can be fur-
ther explored. The presence of the double bond, the imidazole
group and the bromine atom seems crucial for good antimicro-
bial activity. Similarly, the presence of unsaturation, an aromatic
ring or a hetero-atom like chlorine and/or bromine significantly
improves the antimalarial activity of the synthesized oxadia-
zoles. Compound 18 with IC50 value comparable to the reference
drug CQ can be considered as a good starting point for further
optimization. Work is currently underway in our laboratory to
explore other important aspects of this study such as extensive
structure activity relationships (SARs) and the drug-likeness of
the synthesized compounds.
Acknowledgements
▼
The authors are thankful to the GITAM University for providing
the necessary instrumental facility and to the University Grants
Commission (UGC, Government of India) for the financial assis-
tance [F. No. 42–239/2013 (SR)]. We are also thankful to the
TRIMS Lab, MVP Colony Visakhapatnam for performing the anti-
malarial assay. We would also like to acknowledge the help and
suggestions of Dr. Ravinder Kaur, Research Affiliate, and Dr. Aviva
Levina, Senior Research Associate, at the School of Chemistry,
the University of Sydney, Sydney, Australia in the proofreading of
the manuscript.
Balaji K et al. Biological Activities of Azole Analogues… Drug Res

DrugRes/2016-04-1181/21.7.2016/MPS
Original Article
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Conflict of Interest
▼
The authors declare no conflict of interest.
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