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P. Yogeeswari et al. / IL FARMACO 60 (2005) 1–5
protection were 1a and 1b (4 h), 2c (1 h), 2d and 2e (0.5 h),
2g (2 h) and 3c (0.5 h). Compounds 1a–1b, 1d, 1e, 2d, 2f and
3e were found to be active in the scPTZ test, a test used to
identify compounds that elevate seizure threshold. In the
scPTZ screen, after administration of 1g and 2e continuous
seizure activity was noted. Death was observed after 0.5 h of
administration of compounds 2e (100 mg/kg), 3d and 3e
(300 mg/kg) and 3f (100 mg/kg). Compounds that showed
protection in both the MES and scPTZ seizure models in-
clude 1a, 1b, 1d, 1e, 2d and 2f. The MES and scPTZ tests
have become the two most widely employed seizure models
for the early identification and high-throughput screening of
investigational antiepileptic drugs. In this respect, it should
be noted that only few standard anticonvulsants exhibit a
broad spectrum of activity in these threshold models. The
present study had yielded such a broad spectrum anticonvul-
sant compounds.
Generally the isatinimino derivatives (2d–2g, 3d and 3f)
were found to show better anticonvulsant activity profile than
benzylidene or acetophenone derivatives when the 6-position
in benzothiazole moity was either methyl or methoxy. This is
in confirmation of our earlier results [15] and that isatin
derivatives have been reported to possess anticonvulsant
properties [5,13,19]. Whereas with the 6-nitro derivatives the
isatinimino (1f–1i) compounds did not show anticonvulsant
properties. These results indicate that the substitutent at
6-position of benzothiazole moiety should be an electron-
donating type in combination with isatin nucleus as an aux-
illary aryl group. In the benzylidene derivatives substitution
at para position with nitro or amino group have been found to
be beneficial in exhibiting anticonvulsant property in the
6-nitro (1d and 1e) and 6-methyl (2b) substituted benzothia-
zolyl derivatives and not in the 6-methoxy substituted deriva-
tives.
In the neurotoxicity test, compounds 1f, 1h, 1i, 2a–2d,
and 3b–3d did not show toxicity in the highest administered
dose (300 mg/kg) and all other compounds showed less
toxicity than phenytoin. Mice were unable to grasp rotorod
after administration of the following compounds viz., 1c–1e,
1g, 2e–2g, 3a and 3e (300 mg/kg). Compounds that did not
exhibit anticonvulsant activity had no neurotoxicity.
Some selected compounds (1a, 1b, 1f, 2b–2e, 2g and 3f)
were examined for activity in the rat oral MES screen and the
data are presented in Table 3. The compounds which were
inactive or showed moderate activity in the mice i.p. screen
were selected randomly as compounds could behave differ-
ently in mice and rats as reported earlier [14]. Initially a dose
of 30 mg/kg was employed. All the compounds except com-
pound 3f showed protection against seizures with no neuro-
toxicity. Compounds that exhibited greater protection than
phenytoin include 1b, 1f and 2c (0.25 h), and the compounds
that exhibited equiprotection include 1a (0.25, 2 h), 1b (2,
4 h), 1f (4 h), 2c (2 h) and 2d, 2e and 2g (0.25 h). There was
no apparent toxicity observed for these compounds in rats at
the dose level of 30 mg/kg. Compound 1f did not show
anticonvulsant activity in the mice i.p. MES screen but did
show protection in the rat oral MES screen. It is found that
this compound exhibit activity differences between mice and
rats. In the rat i.p. MES model, compound 1a at 60 mg/kg
showed 50% protection at time points 0.25–1 h intervals and
75% protection at 2 h.
Compound 1a was carried on to the next stage of evalua-
tion for quantification of activities (ED50) against MES-
induced seizures in the rat oral test model. The ED50 value
was found to be > 120 mg/kg with a time to peak effect
observed at 0.5 h.
In conclusion the present results have revealed that a
number of 6-substituted benzothiazolyl thiosemicarbazones
exhibit a range of activities in the anticonvulsant screens,
with compound 1a showing anti-MES activity in mice i.p.,
rat i.p. and rat p.o. evaluations.
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