Synthesis and in vitro antibacterial activity of new 2-(1-methyl-4-nitro- 1H-imidazol-5-ylsulfonyl)-1,3,4-thiadiazoles

Article abstract of DOI:10.1155/2011/642071

In the present study we report the synthesis and antibacterial activity of a new series 2-(1-methyl-4-nitro-1H-imidazol-5-ylsulfonyl)-1,3,4-thiadiazoles (6a-c). Compounds 6a-c were tested in vitro by the conventional agar dilution method against a panel of microorganisms including gram-negative and gram-positive bacteria. Compound 6b with 5-(5-nitrofuran-2-yl)-residue on 1,3,4-thiadiazole scaffold have shown promising antibacterial activities against gram-positive bacteria including Staphylococcus aureus, Staphylococcus epidermidis and Bacillus subtilis.

Full text of DOI:10.1155/2011/642071

ISSN: 0973-4945; CODEN ECJHAO
E-Journal of Chemistry
2011, 8(3), 1120-1123
http://www.e-journals.net
Synthesis and In Vitro Antibacterial
Activity of New 2-(1-Methyl-4-nitro-
H-imidazol-5-ylsulfonyl)-1,3,4-thiadiazoles
1
Ş
Ş
BAHRAM LETAFAT , NEGAR MOHAMMADHOSSEINI ,
*
ALI ASADIPOUR and ALIREZA FOROUMADI
Ş
Department of Chemistry, Islamshahr Branch
Islamic Azad University, Tehran, Iran
Department of Medicinal Chemistry
Faculty of Pharmacy and Pharmaceutics Research Center
Kerman University of Medical Sciences, Kerman, Iran
*
Department of Medicinal Chemistry
Faculty of Pharmacy and Pharmaceutical Sciences Research Center
Tehran University of Medical Sciences, Tehran, Iran
aforoumadi@yahoo.com
Received 14 November 2010; Accepted 21 January 2011
Abstract: In the present study we report the synthesis and antibacterial activity of
a new series 2-(1-methyl-4-nitro-1H-imidazol-5-ylsulfonyl)-1,3,4-thiadiazoles
(6a-c). Compounds 6a-c were tested in vitro by the conventional agar dilution
method against a panel of microorganisms including gram-negative and
gram-positive bacteria. Compound 6b with 5-(5-nitrofuran-2-yl)-residue on
1
,3,4-thiadiazole scaffold have shown promising antibacterial activities against
gram-positive bacteria including Staphylococcus aureus, Staphylococcus
epidermidis and Bacillus subtilis.
Keywords: Synthesis, Nitroimidazole, 1,3,4-Thiadiazole, Antibacterial activity
Introduction
Nitroimidazoles, such as metronidazole, misonidazole, ornidazole, secnidazole, etanidazole
and tinidazole are commonly used as therapeutic agents against a variety of protozoan and
1
bacterial infections of humans and animals . Some nitroimidazole derivatives have become
the important agents for a long time for treatment of serious infections caused by anaerobic
2
bacteria and protozoa . As pathogenic bacteria continuously evolve mechanisms of
resistance to currently use antibacterial drugs, the discovery of novel and potent antibacterial

1
121
ALIREZA FOROUMADI et al.
3
agents is the best way to overcome bacterial resistance and develop effective therapies .
Moreover, the use of nitroheterocycles as antiviral, anticancer and radio sensitizing agents is well
4-10
established . In our previous studies, some new compounds containing 5-nitroheterocycles and
,3,4-thiadiazole with different substituents at the C -position of the thiadiazole ring were
1
2
11-13
synthesized and evaluated for activity against several bacterial species and H. pylori . In
continuation to our ongoing research work on new nitroheterocyclic derivatives, herein, we
describe the synthesis and in vitro antibacterial activity of new 5-sulfonyl-1-methyl-4-nitro-1H-
imidazoles (6a-c) against a panel of gram-positive and gram-negative bacteria.
Experimental
All starting materials, reagents and solvents were purchased from merck and aldrich
chemical companies. The purity of the synthesized compounds was confirmed by thin layer
chromatography (TLC) using various solvents of different polarities. Merck silica gel
6
Merck silica gel (70-230 mesh) for purification of intermediate and final compounds.
0 F254 plates were used for analytical TLC. Column chromatography was performed on
1
H
NMR spectra were recorded using a Varian 80 spectrometer and chemical shifts are
expressed as δ (ppm) with tetramethylsilane (TMS) as internal standard. The IR spectra were
obtained on a Shimadzu 470 spectrophotometer (potassium bromide disks). Melting points
were determined on a Kofler hot stage apparatus and are uncorrected.
Chemistry
The synthesis of 5-substituted-1-methyl-4-nitro-1H-imidazole derivatives (6a-c) was achieved
with an efficient synthetic route outlined in Figure 1. The starting material 4(5)-bromo-5(4)-
11
nitroimidazole (1) was prepared according to the literature method . The reaction of 1 with
diazomethane in dry diethyl ether afforded 1-methyl-5-bromo-4-nitro-1H-imidazole 3 as
major product. Compound 3 could be also prepared from nitration of 5-bromo-1-methyl-1H-
imidazole. Treatment of 3 with appropriate arylthiols in the presence of potassium hydroxide
afforded the desired sulfides 5a-c. Oxidation of compounds 5a-c by 3 moles of m-CPBA in
dichloromethane gave 1,3,4-thiadiazole sulfones 6a-c.
NO2
Br
NO
2
N
N
N
+
Br
NO
2
Br
N
N
N
H
1
2
3
CH3
CH3
NO2
NO2
N
N
N
N
N
N
ii
N N
S
iii
3
Y
Y
N
S
S
S
S
N
O
O
H C
3
HS
Y
CH3
5
a-c
6
a-c
O N
2
Y) a : CH CONH
b:
c:
3
O N
2
N
O
N
Figure 1. Structure of 5-substituend 1-methyl-4-nitro-1H-imidazoles (6a-c) reagent and
condition: (i) CH N , dry ether; (ii) KOH, EtOH, reflux (iii) m-CPBA, CH Cl
2
2
2
2

Synthesis and In Vitro Antibacterial Activity
1122
General procedure for the synthesis of 5-substituend 1-methyl-4-nitro-1H-
imidazoles (6a-c)
A mixture of 5a-c (1.0 mmol), m-chloroperbenzoic acid (3.0 mmol) and NaHCO (3.0 mmol)
3
in 15 mL of dichloromethane was stirred for three days. The reaction mixture was monitored
by TLC. After consumption of the starting material, water (15 mL) was added and the organic
phase was separated. The aqueous phase was extracted with dichloromethane (2×15 mL). The
combined organic phases were washed with water and dried (Na SO ). Evaporation of the
2
4
solvent gave a solid which was recrystallized from ethanol.
N-(5-(1-Methyl-4-nitro-1H-imidazol-5-ylsulfonyl)-1,3,4-thiadiazol-2-yl)acetamide (6a)
-1
Yield 83%; m.p. 152-154 °C; IR (KBr, cm ): 1670 (C=O), 1351 (NO ), 1326, 1145 (S=O).
2
1
H NMR (80 MHz, CDCl )δ: 7.82(s, 1H, Imidazole), 3.68(s, 3H, NCH ), 2.05 (s, 3H, COCH ).
3
3
3
2-(1-Methyl-4-nitro-1H-imidazol-5-ylsulfonyl)-5-(5-nitrofuran-2-yl)-1,3,4-
thiadiazole (6b)
-1
1
Yield 82%; m.p. 148-150 °C; IR (KBr, cm ): 1555, 1357 (NO ), 1328, 1144 (S=O). H NMR
2
(80 MHz, CDCl )δ: 8.05(d, 1H, furyl, J=3.8Hz), 7.59 (s, 1H, imidazole), 7.53(d, 1H, furyl,
3
J=3.8Hz), 4.08 (s, 3H, CH3).
2-(1-Methyl-4-nitro-1H-imidazol-5-ylsulfonyl)-5-(1-methyl-5-nitro-1H-imidazol-2-
yl)-1,3,4-thiadiazole (6c)
-
1
1
Yield 85%; m.p. 82-84 °C; IR (KBr, cm ):1550, 1350 (NO ), 1324, 1142 (S=O). H NMR (80 MHz,
2
CDCl )δ: 8.13(s, 1H, 5-nitroimidazole), 7.87(s, 1H, 4-nitroimidazole), 3.70, 3.95 (2s, 6H, 2CH ).
3
3
Biological activity
Compounds 6a-c were screened for their antibacterial activity against gram-positive
Staphylococcus aureus ATCC 25923, Staphylococcus epidermidis ATCC 14940, Bacillus
(
subtilis ATCC 6051) and gram-negative (Escherichia coli ATCC 25922, Klebsiella
pneumoniae ATCC 10031, Enterobacter aerogenes PTCC 1221) bacteria by the conventional
12
agar dilution method . Twofold serial dilutions of the compounds and reference drugs were
prepared in muller hinton agar. Drugs (6.4 mg) were dissolved in DMSO (1 mL) and the
solution diluted with water (9 mL). Further progressive double dilution with melted muller-
Hinton agar was performed to obtain the required concentrations of 64, 32, 16, 8, 4, 2, 1 and
0.5 µg/mL. Petri dishes were inoculated with 1-5×104 colony-forming units (cfu) and
incubated at 37 °C for 18 h. The minimum inhibitory concentration (MIC) was defined as the
lowest concentration of the test compound, which resulted in no visible growth on the plate. To
insure that the solvent had no effect on bacterial growth, a control test was performed with test
medium supplemented with DMSO at the same dilutions as used in the experiment.
Results and Discussion
The synthesized compounds 6a-c were assessed for their antibacterial activity against a
panel of gram-positive (Staphylococcus aureus, Staphylococcus epidermidis and Bacillus
subtilis) and gram-negative (Kelebsiella pneumoniae, Escherichia coli and Enterobacter
aerogenes) bacteria using a conventional agar-dilution method. The MIC values (µg/mL)
obtained for compounds 6a-c are presented in Table 1. MIC values of the tested derivatives
indicate that compounds 6b and 6c showed a higher antibacterial activity against gram- positive
rather than gram-negative bacteria. Compounds 6b and 6c had respectable in vitro activity

1
123
ALIREZA FOROUMADI et al.
against Staphylococci and B. subtilis, but were less active than the reference drug norfloxacin.
Compound 6a showed no significant activity against gram-positive and gram-negative bacteria.
a
Table 1. In vitro antibacterial activities of compounds 6a-c against selected bacteria
Gram positive bacteria
Gram negative bacteria
Compound
S. a
S. e.
>64
8
B. s.
K. p.
>64
16
E. c.
>64
16
E. a
>64
>64
>64
0.13
6
6
a
>64
4
64
2
b
6
Norfloxacin
c
8
64
1
16
0.13
32
0.25
16
0.13
1
S. a. = Staphylococcus aureus ATCC 6538p; S. e. = Staphylococcus epidermidis ATCC 12228;
B. s. = Bacillus subtilis PTCC 1023; K. p. = Kelebsiella pneumoniae ATCC 10031;
E.c. = Escherichia coli ATCC 8739; E.a. = Enterobacter aerogenes PTCC 1221 were used for
determination of MIC.
Conclusion
We have synthesized and evaluated the antibacterial activities of a series of 1-methyl-4-
nitro-1H-imidazoles containing different arylthio or arylsulfonyl groups at the 5-position.
Compound 6b with 5-(5-nitrofuran-2-yl)- residue on 1,3,4-thiadiazole scaffold have shown
promising antibacterial activities against gram-positive bacteria including Staphylococcus
aureus, Staphylococcus epidermidis and Bacillus subtilis. The structure-activity relationship
observed from this series of compounds can be used to further optimize the structures to
obtain potent novel antimicrobial drugs.
Acknowledgment
This work was supported by grants from the Research Council of Tehran University of
Medical Sciences and Islamic Azad University, Iran.
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