Synthesis and in vitro leishmanicidal activity of 2-(5-nitro-2-furyl) and 2-(5-nitro-2-thienyl)-5-substituted-1,3,4-thiadiazoles

Article abstract of DOI:10.1016/j.bmcl.2005.02.073

A series of 2-(5-nitro-2-furyl) and 2-(5-nitro-2-thienyl)-5-substituted-1, 3,4-thiadiazoles (5a-d and 6a-j) were synthesized and evaluated against Leishmania major promastigotes using ³H-thymidine incorporation. Most of the compounds showed activity better than the reference drug sodium stibogluconate (Pentostam). The most active compound was 6c (IC₅₀ = 0.1 μM).

Full text of DOI:10.1016/j.bmcl.2005.02.073

Bioorganic & Medicinal Chemistry Letters 15 (2005) 1983–1985
Synthesis and in vitro leishmanicidal activity of
-(5-nitro-2-furyl) and 2-(5-nitro-2-thienyl)-5-substituted-
2
1
,3,4-thiadiazoles
a
a
Alireza Foroumadi, Shirin Pournourmohammadi, Fatemeh Soltani,
a
a
Mitra Asgharian-Rezaee, Shahriar Dabiri, Arsalan Kharazmi and Abbas Shafiee
a
b
c,
*
a
Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman 76351, Iran
b
LICA Pharmaceuticals, Symbion Sciences Park, Copenhagen DK 2100, Denmark
Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran 14174, Iran
c
Received 24November 200 4; revised 18 January 2005; accepted 23 February 2005
Abstract—A series of 2-(5-nitro-2-furyl) and 2-(5-nitro-2-thienyl)-5-substituted-1,3,4-thiadiazoles (5a–d and 6a–j) were synthesized
and evaluated against Leishmania major promastigotes using H-thymidine incorporation. Most of the compounds showed activity
3
better than the reference drug sodium stibogluconate (Pentostam). The most active compound was 6c (IC50 = 0.1 lM).
ꢀ
2005 Elsevier Ltd. All rights reserved.
Leishmaniasis is a major and increasing health problem
in many parts of the world, with about 350 million peo-
ple living in areas of disease endemicity and about 2 mil-
Also the use of 5-nitrofuran and 5-nitrothiophene as
9
,10
antibacterial and antiprotozoal is well established.
Although there is a large amount of experimental work
on these heterocycles, they still remain an area of active
1
lion new cases each year. About 500,000 of these are
visceral leishmaniasis, which is nearly always fatal if left
1
1,12
research interest.
In this study we would like to
2
untreated. Chemotherapy remains the most effective
report the synthesis and in vitro antileishmaniasis
activities of some 2-(5-nitro-2-furyl) and 2-(5-nitro-2-
thienyl)-5-substituted-1,3,4-thiadiazoles (5a–d and 6a–j).
control measure for this disease. The treatment options
for leishmaniasis are limited and involve the administra-
tion of pentavalent antimonial as first line and ampho-
3
,4
tericin B and pentamidine as second line drugs.
The 2-amino-5-(5-nitro-2-furyl)-1,3,4-thiadiazole 3a was
obtained by oxidative cyclization of 5-nitrofurancarbox-
aldehyde thiosemicarbazone 2a. Diazotization of 3a in
hydrochloric acid in the presence of copper powder gave
These drugs are expensive and potentially toxic and re-
quire long-term treatment. In addition the development
of drug resistance by the pathogens especially in HIV
leishmania co-infected patients, has aggravated public
1
3
2-chloro-5-(5-nitro-2-furyl)-1,3,4-thiadiazole (4a).
5
health risks. The spread of drug resistance combined
with other shortcoming of the available antileishmanial
drugs emphasizes the importance of the development of
new, effective and safe drugs against leishmaniasis.
Reaction of compound 4a with piperidine or morpho-
line in refluxing ethanol gave compounds 5a or b,
respectively, in good yields. Similarly, the reaction of
compound 4a with piperazine, N-methylpiperazine or
N-phenylpiperazine gave the corresponding compounds
6a–c, respectively.
A great number of natural and synthetic compounds
have been tested in the recent years in antileishmanial
6
–8
assays.
Starting from 2-chloro-5-(5-nitro-2-thienyl)-1,3,4-thiadi-
1
4
azole
similarly.
compounds 5c,d and 6f–h were prepared
Keywords: 1,3,4-Thiadiazole; Nitrofuran; Nitrothiophene; Leishmani-
cidal activity.
*
Corresponding author. Tel.: +98 21 6406757; fax: +98 21 6461178;
e-mail: ashafiee@ams.ac.ir
Acetylation of 6a or f with acetic anhydride gave acetyl-
ated compound 6d and i, respectively. The reaction of 6a
0
960-894X/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.02.073

1984
A. Foroumadi et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1983–1985
or f with benzoyl chloride yielded compounds 6e or j in
high yield. The purity of the synthesized compounds was
confirmed by thin layer chromatography (TLC), using
various solvents of different polarities (Scheme 1).
nitrofuran derivatives (5a,b and 6a–e) have greater leish-
manicidal activities than their corresponding nitrothio-
phene derivatives (5c,d and 6f–j). However, a slight
difference in inhibitory concentration was noted for
the morpholine analogues 5b and d (IC50 = 5.2 and
10.6 lM, respectively).
The in vitro efficacy of the synthesized compounds on
promastigotes of L. major (ATCC J 774, HB-197) were
1
5
assessed by a previously described method. Promastig-
In fact, compound 5d bearing a morpholine ring was
found to be the most active compound in nitrothiophene
series.
6
otes (3 · 10 ) were cultured in medium 199 containing
1
0% heat-inactivated fetal calf serum. Incubation and
growth of the parasite were carried out at 26 ꢁC. Prom-
astigotes were harvested on day four of the culture and
used. The culture of parasite was diluted with the fresh
medium to a final concentration of 5 · 10 parasites/
Despite to the good leishmanicidal activity of nitrofuran
derivatives having piperidine (5a) or piperazine (6a)
(IC50 = 3.2 and 8.9 lM, respectively), the corresponding
nitrothiophene analogues (5c and 6f) were inactive. If
the hydrogen of piperazine ring in compound 6a, is re-
placed with a methyl (6b), phenyl (6c), acetyl (6d), or
benzoyl (6e), the activity is increased in the following
order: 6c > e > d > b > a. The nitrofuran analogue
containing N-phenylpiperazine group (6c), was found
to be the most active compound in this series
(IC50 = 0.1 lM).
6
mL. The compounds to be checked were dissolved in
DMSO (15 mM) and further diluted to appropriate con-
centrations in culture medium as given in the Table 1. In
a 96-well micro titre plate, 160 lL of the promastigotes
suspension was added to 40 lL of various concentra-
tions of each compound, medium alone, or pentavalent
antimonial Pentostam as positive control. The cultures
3
were incubated for 18 h and H-thymidine incorpora-
tion was measured and IC50 values of compounds pos-
sessing antileishmanial activity were calculated (Table
In conclusion it appears that 5-nitrofuran moiety might
be responsible for leishmanicidal activity along with
substituted piperazine ring attached to 1,3,4-thiadiazole
ring system. In addition, most of compounds were much
more active than the reference drug Pentostam. Further-
more, these compounds could represent new lead com-
pounds for further pharmacomodulation.
1
).
To ensure that the solvent had no effect on parasite
growth a control test was performed with test medium
DMSO at the same dilutions as used in the experiment.
As it could be seen from Table 1, it is clear that the
S
i
ii
O
2
N
CH(OCOCH3)
2
O N
2
CH N NH C NH
2
X
X
1
1
1
a-b
2
2
2
a-b
a: X=O
b: X=S
a: X=O
b: X=S
N
N
N
N
iii
O
2
N
NH2
O
2
N
Cl
X
S
X
S
3
3
3
a-b
4a-b
v
a: X=O
b: X=S
iv
4a: X=O
4b: X=S
N
N
N
N
N
O
2
N
N
N
R
2
O N
Y
X
S
X
S
6
6
6
6
6
6
a-j
5
5
5
a-d
a: X = O, R = H
a: X = O, Y = CH
b: X = O, Y = O
2
b: X = O, R = Me
c: X = O, R = phenyl
d: X = O, R = MeCO
e: X = O, R = PhCO
v
vi
5c: X = S, Y = CH
2
5d: X = S, Y = O
6
6
6
6
6
f: X = S, R = H
g: X = S, R = Me
h: X = S, R = Ph
i: X = S, R = MeCO
j: X = S, R = PhCO
v
vi
Scheme 1. Reagents and conditions: (i) thiosemicarbazide, EtOH, HCl, reflux, 1 h; (ii) NH
4
4
Fe(SO )
2
2
Æ12H O, H
2 2
O, reflux, 16 h; (iii) NaNO , HCl,
Cu, 0 ꢁC ! rt, 3 h; (iv) piperidine or morpholine, EtOH, reflux, 1 h; (v) piperazine or N-methylpiperazine or N-phenylpiperazine, EtOH, reflux, 1 h;
vi) Ac O, AcOH, reflux, 0.5 h; (vii) PhCOCl, pyridine, rt, 20 h.
(
2

A. Foroumadi et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1983–1985
1985
Table 1. Effect of synthesized compounds on the growth of Leishmania major promastigotes
N
N
O
2
N
R
X
S
Compound
X
O
R
IC50 (lM)
Compound
X
S
R
IC50 (lM)
>150
5
5
6
6
6
6
6
a
b
a
b
c
N
3.2
5c
N
O
O
O
O
O
O
O
N
5.2
8.9
7.3
0.1
1.1
5d
6f
6g
6h
6i
S
S
S
S
S
S
O
N
10.6
HN
Me
Ph
N
HN
Me
Ph
N
>150
N
N
N
N
102.8
N
N
N
N
105.5
48.5
11.1
d
e
CH
3
CON
N
N
CH
3
CON
N
N
PhCO
N
0.5
243.3
6j
PhCO N
Pentostam
Acknowledgments
7. Zhai, L.; Chen, M.; Blom, J.; Theander, T. G.; Christen-
sen, S. B.; Kharazmi, A. J. Antimicrob. Chemother. 1999,
4
3, 793.
. de Mello, H.; Echevarria, A.; Bernardino, A. M.; Canto-
This work was supported by grants from the research
council of Tehran University of Medical Sciences and
Iran Chapter of TWAS.
8
9
Cavalheiro, M.; Leon, L. L. J. Med. Chem. 2004, 47,
5427.
. Pires, J. R.; Saito, C.; Gomes, S. L.; Giesbrecht, A. M.;
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