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