Synthesis and antimycobacterial activity of some alkyl [5-(nitroaryl)-1,3, 4-thiadiazol-2-ylthio]propionates

Article abstract of DOI:10.1016/j.bmcl.2005.11.087

Two series of 2- and 3-[5-(nitroaryl)-1,3,4-thiadiazol-2-ylthio, sulfinyl and sulfonyl] propionic acid alkyl esters were synthesized and screened for antituberculosis activity against Mycobacterium tuberculosis H37Rv using the BACTEC 460 radiometric system. The MIC values for the compounds showing more than 90% inhibition were determined. The result of comparison between two groups of data exhibited that among the synthesized derivatives, the compound propyl 3-[5-(5-nitrothiophen-2-yl)-1,3,4-thiadiazol-2-ylthio]propionate was the most active one (MIC = 1.56 μg ml^-1).

Full text of DOI:10.1016/j.bmcl.2005.11.087

Bioorganic & Medicinal Chemistry Letters 16 (2006) 1164–1167
Synthesis and antimycobacterial activity of some alkyl
[5-(nitroaryl)-1,3,4-thiadiazol-2-ylthio]propionates
b
b
b
Alireza Foroumadi,a,b, Zahra Kargar, Amirhossein Sakhteman, Zahra Sharifzadeh,
*
Robabeh Feyzmohammadi,b Mahnoush Kazemib and Abbas Shafieea
aFaculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran
bFaculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran
Received 6 October 2005; revised 19 November 2005; accepted 25 November 2005
Available online 15 December 2005
Abstract—Two series of 2- and 3-[5-(nitroaryl)-1,3,4-thiadiazol-2-ylthio, sulfinyl and sulfonyl] propionic acid alkyl esters were syn-
thesized and screened for antituberculosis activity against Mycobacterium tuberculosis H37Rv using the BACTEC 460 radiometric
system. The MIC values for the compounds showing more than 90% inhibition were determined. The result of comparison between
two groups of data exhibited that among the synthesized derivatives, the compound propyl 3-[5-(5-nitrothiophen-2-yl)-1,3,4-thia-
diazol-2-ylthio]propionate was the most active one (MIC = 1.56 lg mlÀ1).
Ó 2005 Elsevier Ltd. All rights reserved.
Tuberculosis (TB) is a respiratory transmitted disease
affecting nearly 32% of the world’s population; it is
caused by Mycobacterium tuberculosis.1,2 The exponen-
tial increase in TB cases has been greatest in areas with
high prevalence of HIV infections.2
The use of 5-nitroheterocycles as antibacterial, anti-
protozoal, and anticancer agents is well established.5,6
In our previous studies some new compounds contain-
ing 5-nitroheterocycles and 1,3,4-thiadiazole with dif-
ferent substituents at C2 position of thiadiazole ring
were synthesized and evaluated for activity against
M. tuberculosis.7,8 To get a better structure–activity
relationship of these compounds, herein we would like
to report the synthesis and antituberculosis activity of
2- and 3-[5-(nitroaryl)-1,3,4-thiadiazol-2-ylthio, sulfinyl
and sulfonyl] propionic acid alkyl esters II and III
(Fig. 1).
The emergence of multiple drug-resistant (MDR) TB
has focused the attention of the scientific community
throughout the world on the urgent need for new antitu-
bercular drugs.1 In this regard, there have been few
additions of some promising new agents such as the
long-acting rifamycins, fluoroquinolones, oxazolodinon-
es, and nitroimidazopyrans to the existing mainline
drugs.1,2 In pursuit of this goal, our research efforts
are directed toward the discovery of new chemical enti-
ties that are effective as antituberculosis agents and to
optimize the structure to display the potent efficacy.
Reaction of nitroaryl aldehyde (1) with thiosemicarba-
zide in refluxing ethanol afforded compound 2. The
2-amino-5-(nitroaryl)-1,3,4-thiadiazole (3) was prepared
by oxidative cyclization of 5-nitroaryl carboxaldehyde
thiosemicarbazone (2).8 Diazotation of 3 in hydrochlo-
ric acid in the presence of copper powder gave 2-chlo-
ro-5-(nitroaryl)-1,3,4-thiadiazole (4).8,9 The reaction of
4 with thiourea in refluxing ethanol afforded the 2-
mercapto-5-(5-nitroaryl)-1,3,4-thiadiazole (5).9,10 Treat-
ment of the latter with 2-bromopropionic acid ethyl
ester in the presence of basic ethanol provided 2-[5-
(nitroaryl)-1,3,4-thiadiazol-2-ylthio] propionic acid
ethyl ester (6).
During recent years, there have been intense investiga-
tions of different classes of thiadiazole compounds many
of which are known to possess interesting biological
properties such as antimicrobial, anti-tuberculosis, and
anti-inflammatory activities.3,4
Keywords: Mycobacterium tuberculosis; Nitroimidazole; Nitrofuran;
Nitrothiophene; 1,3,4-Thiadiazole.
*
The purity of the synthesized compounds was confirmed
by thin-layer chromatography (TLC) using various
Corresponding author. Tel.: +98 21 66406757; fax: +98 21 66461178;
e-mail: aforoumadi@yahoo.com
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.11.087

A. Foroumadi et al. / Bioorg. Med. Chem. Lett. 16 (2006) 1164–1167
1165
S(O)n CH2 COOEt
Ar
S
I
N
N
N
N
S(O)n CH COOEt
CH3
Ar
Ar
S
CH2 CH2 COOR
S
S
III
II
Figure 1.
solvents of different polarities. The structures of com-
pounds were characterized using IR, NMR, mass spec-
tra, and elemental analysis.
compound (6d) in terms of inhibition percentage and
MIC value. In contrast, dioxidation of the S moiety to
SO2 in the same compound, 6a, increased its activity
(6g; inhibition = 100%), (MIC = 3.12 lg mlÀ1). In nitro-
furan and nitrothiophene derivatives, oxidation of S to
SO has the same effect on the activity of the synthesized
compounds (6e and 6f). Unexpectedly, dioxidation of S
to SO2 could however decrease their activities (6h, inhi-
bition = 78%; 6i, inhibition = 82%) (Table 1).
The compounds were screened for antituberculosis
activity under the direction of the US National Institute
of Health, NIAID Division. Primary screening was con-
ducted at a single concentration, 6.25 lg mlÀ1 against,
M. tuberculosis H37Rv (ATCC2729) in BACTEC 12B
medium using a broth microdilution assay, the Micro-
plate Alamar Blue Assay (MABA). Compounds affect-
ing <90% inhibition in the primary screening
(MIC > 6.25 lg mlÀ1) were not generally evaluated fur-
ther. The active compounds were re-tested by serial dilu-
tion beginning at the concentration of 6.25 lg mlÀ1
against M. tuberculosis H37Rv to determine the actual
minimum inhibitory concentration (MIC) in the BAC-
TEC 460 radiometric system and BACTEC 12B medi-
um. The MIC is defined as the lowest concentration
affecting a reduction in fluorescence of 90% relative to
controls.11
Comparison of this series of compounds with previously
synthesized derivatives lacking the methyl group at Ca
position of the ester moiety7,8 (Fig. 1, compound I)
showed that introduction of methyl at Ca could largely
increase the potency of inactive thio compound contain-
ing nitrothiophene (Fig. 1, compound I, n = 0)8 to the
corresponding active compound 6c (inhibition = 92%;
MIC = 6.25 lg mlÀ1). The same modification at Ca in
sulfonyl analogue (Fig. 1, compound I, n = 2) could also
increase the inhibition percentage of the synthesized
compounds (6g–i), among which compound 6g showed
a MIC value of 3.12 lg mlÀ1
.
As it can be seen from the antituberculosis data reported
in Table 1, among the a-propionate series (6a–i), all
three thio analogues (6a–c) were active antimycobacteri-
al agents (MIC = 3.12–6.25 lg mlÀ1). Oxidation of S to
SO in compound 6a, containing nitroimidazole hetero-
cycle, could largely decrease the activity of the resultant
To realize a better structure–activity relationship for this
series of compounds, new derivatives were synthesized
by introducing a methylene group to the linker attaching
carbonyl and S moieties (Fig. 1; compound III). The
target compounds (7a–j) were prepared by treatment
Table 1. In vitro antituberculosis activity of compounds 6a–i
COOEt
S(O)n CH
Ar
S
CH3
Compound
Ar
n
Inhibition
(%)
Activity
MIC
(lg/ml)
6a
6b
1-Methyl-5-nitro-2-imidazolyl
5-Nitro-2-furyl
5-Nitro-2-thienyl
0
0
0
1
1
1
2
2
2
90
98
92
11
6
+
+
+
À
À
À
+
À
À
6.25
6.25
6c
6d
6.25
1-Methyl-5-nitro-2-imidazolyl
5-Nitro-2-furyl
5-Nitro-2-thienyl
>6.25
>6.25
>6.25
3.12
6e
6f
6g
12
100
78
82
1-Methyl-5-nitro-2-imidazolyl
5-Nitro-2-furyl
5-Nitro-2-thienyl
6h
6i
Rifampicin
>6.25
>6.25
0.5–1

1166
A. Foroumadi et al. / Bioorg. Med. Chem. Lett. 16 (2006) 1164–1167
of 2-mercapto-5-(nitroaryl)-1,3,4-thiadiazole (5) with al-
kyl 3-bromopropionates in the presence of basic ethanol
(Scheme 1). Their antituberculosis activities were evalu-
ated with the above-described method (Table 2).
ty in the nitrothienyl series, propyl and butyl substitu-
tion led to the active compounds 7i (MIC = 1.56
lg mlÀ1) and 7j (MIC = 6.25 lg mlÀ1), respectively. In
contrast, the same modification in nitrofuryl derivatives
led to totally inactive compounds 7d and 7e
(inhibition = 0%).
Comparison of the ethyl esters 7c, and 7h, with the cor-
responding counterparts in Table 1, showed a large
decrease in the activity of the resultant compounds
(inhibition = 14% and 26%, respectively).
Hydrolyzing the ester group had different effects in
nitrothienyl and nitrofuryl series. Despite observing a
large decrease in the activity of hydrolyzed nitrothienyl
analogue 7f (inhibition = 0%) the active compound 7a
(MIC = 6.25) was obtained by hydrolyzing the corre-
sponding nitrofuryl ester.
This decreasing effect could be compensated and even
reversed by a proper modification of the ester moiety.
Among the different groups replaced at the ester moie-
S
ii
iii
i
Ar
Cl
CH
N
NH
C
NH2
CHO
Ar
Ar
NH2
Ar
S
S
1a-c
4a-c
2a-c
3a-c
N
N
N
N
iv
vii
Ar
SH
Ar
S
CH2 CH2 COOR
S
5a-c
S
7a-j
v
CH3
N
N
N
N
CH3
vi
Ar
S
CH COOEt
Ar
S(O)n
CH COOEt
S
S
6a-c
6d-i
n=1,2
N
,
,
NO
NO2
Ar=
NO2
2
N
O
S
CH3
Scheme 1. Synthesis of compounds 6 and 7. Reagents and conditions: (i) thiosemicarbazide, EtOH, HCl, reflux; (ii) ammonium ferric sulfate, H2O,
reflux; (iii) NaNO2, HCl, Cu; (iv) thiourea, EtOH, reflux; (v) ethyl 2-bromopropionate, KOH, EtOH; (vi) MCPBA, NaHCO3, CH2Cl2, rt; (vii) alkyl
3-bromopropionate, KOH, EtOH, rt.
Table 2. In vitro antituberculosis activity of compounds 7a–j
Ar
S
CH2
CH2
COOR
S
Compound
Ar
R
H
Inhibition (%)
Activity
MIC (lg/ml)
7a
7b
5-Nitro-2-furyl
5-Nitro-2-furyl
5-Nitro-2-furyl
5-Nitro-2-furyl
5-Nitro-2-furyl
5-Nitro-2-thienyl
5-Nitro-2-thienyl
5-Nitro-2-thienyl
5-Nitro-2-thienyl
5-Nitro-2-thienyl
95
64
14
0
+
6.25
>6.25
>6.25
>6.25
>6.25
>6.25
>6.25
>6.25
1.56
Methyl
Ethyl
À
À
À
À
À
À
À
+
7c
7d
n-Propyl
n-Butyl
H
7e
0
7f
7g
0
Methyl
Ethyl
76
26
98
98
7h
7i
n-Propyl
n-Butyl
7j
Rifampicin
+
6.25
0.5–1

A. Foroumadi et al. / Bioorg. Med. Chem. Lett. 16 (2006) 1164–1167
1167
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In conclusion, among two series of 2- and 3-[5-(nitroa-
ryl)-1,3,4-thiadiazol-2-ylthio, sulfinyl and sulfonyl] pro-
pionic acid alkyl esters, the high antimycobacterial
activity of the compound 7i makes it a suitable lead
for further in vitro and in vivo evaluations.
5. Foroumadi, A.; Pournourmohammadi, S.; Soltani, F.;
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Acknowledgments
The antimycobacterial data were provided by the Tuber-
culosis Antimicrobial Acquisition and Coordinating
Facility (TAACF), through a research and development
contract with the U.S. National Institute of Allergy and
Infectious Disease.
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