Practical synthesis, anticonvulsant, and antimicrobial activity of N-allyl and N-propargyl di(indolyl)indolin-2-ones

Article abstract of DOI:10.1016/j.bmcl.2011.04.117

An operation friendly protocol for the synthesis of novel di(indolyl)indolin-2-ones via Cu(OTf)₂ catalyzed bis-addition of N-allyl and N-propargyl indole with isatin was developed. This methodology allowed us to achieve the products in excellen

Full text of DOI:10.1016/j.bmcl.2011.04.117

Bioorganic & Medicinal Chemistry Letters 21 (2011) 4072–4077
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Practical synthesis, anticonvulsant, and antimicrobial activity of N-allyl
and N-propargyl di(indolyl)indolin-2-ones
Chandrasekaran Praveen a, Asairajan Ayyanar b, Paramasivan Thirumalai Perumal a,
⇑
a Organic Chemistry Division, Central Leather Research Institute, Adyar, Chennai 600 020, Tamil Nadu, India
b Department of Pharmaceutical Chemistry, Arulmigu Kalasalingam College of Pharmacy, Krishnankoil 626 190, Tamil Nadu, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An operation friendly protocol for the synthesis of novel di(indolyl)indolin-2-ones via Cu(OTf)2 catalyzed
bis-addition of N-allyl and N-propargyl indole with isatin was developed. This methodology allowed us to
achieve the products in excellent yields without requiring purification technique like column chromatog-
raphy. All the synthesized compounds were evaluated for their in vivo anticonvulsant activity against
maximal electroshock test. Six compounds showed maximum activity compared to the standard drug
phenytoin. The scope of the new molecules as antimicrobial agents were tested against two bacterial
strains (Staphylococcus aureus and Escherichia coli) and one fungal strain (Candida albicans).
Ó 2011 Elsevier Ltd. All rights reserved.
Received 26 February 2011
Revised 23 April 2011
Accepted 25 April 2011
Available online 11 May 2011
Keywords:
Copper(II) triflate
N-Allyl(propargyl)-di(indolyl)indolin-
2-ones
Anticonvulsant
Antimicrobial
Epilepsy is a chronic disease that is characterized by paroxys-
mal attacks caused by pathologic excitation of cerebral neurons.
The mechanism of action of antiepileptic drugs (AEDs) consist in
the blockade of voltage-dependent Na+ channels or T-type Ca2+
channels, inhibition of glutamatergic transmission and facilitation
(ii) This structural modification, suitable for further substitutions,
in view of controlled pharmacodynamic and pharmacokinetic test-
ing, will be useful for more detailed SAR information about this
class of molecules. Furthermore, N–CO linkage is well recognized
as pharmacophoric requirements in some of the commercial anti-
convulsant drugs with varied mechanism of action, a significant
anticonvulsant activity was also hypothesized (Fig. 1).
of c
-aminobutyric acid (GABA) inhibitory neurotransmission.1 On
the other hand, di(indolyl)indolin-2-ones are of considerable
importance due to their wide spectrum of biological activities like
antiproliferative, antibacterial, antiprotozoal and anti-inflamma-
tory.2 They have also been used as laxatives3 and lead molecules
for inhibition of translation initiation.4 Typical catalytic approach
to construct this class of molecules involve 3-indolylation of isatins
by FeCl3,5a ionic liquids,5b TfOH,5c CAN,5d Bi(OTf)3,5e silica–sulfuric
acid,5f I2,5g and KAl(SO4)2.5h,i As part of our current interest in the
synthesis of novel heterocyclic compounds,6 we attempted to
avoid expensive precursors and produce a scalable reaction for
the production of multi-gram quantities of the target di(indo-
lyl)indolin-2-ones with a reactive moiety at the indolyl N-position
(preferably allyl and propargyl). The method investigated involves
N-allylation or propargylation of indoles, followed by bis-addition
with isatin to form the desired N-allyl and N-propargyl di(indo-
lyl)indolin-2-ones. The specific use of N-allyl or N-propargyl
indoles as precursors was based on the following considerations:
(i) In order to study the effect of spacer between the heterocyclic
nitrogen and the allyl/propargyl chain of various substituents.
This letter reports the Cu(OTf)2 catalyzed efficient synthesis of
new di(indolyl)indolin-2-ones, characterized by the oxindole nu-
cleus bearing N-allyl(propargyl)indole rings in the third position.
The potential of these compounds was tested to evaluate the
in vivo anticonvulsant activity.
O
Me
N
Ph
Ph
H
N
Et
O
HN
Ph
O
N
O
Me
Me
N
H
O
O
N
O
H2N
O
H
(Oxazolidinediones)
Trimethadione
(Hydantoins)
Phenytoin
(Deoxybarbiturates) (Dibenzazepines)
Primidone
Carbamazepine
Me
N
O
O
Me
H
Ph
O
O
N
Me
N
S
HN
Et
O
N
Cl
NH Cl
O
O
N
O
Me
Et
H
Ph
(Barbiturates)
Phenobarbitone
(Succinimides)
Ethosuximide
(Benzodiazepines)
Diazepam
(Miscellaneous)
Ralitoline
⇑
Corresponding author.
E-mail address: ptperumal@gmail.com (P.T. Perumal).
Figure 1. Chemical class and examples of anticonvulsant drugs representing
–N–CO– moiety.
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.04.117

C. Praveen et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4072–4077
4073
The requisite N-allyindoles7 and N-propargylindoles8 were pre-
pared by standard procedures. Because of the economic attractive-
ness and stimulated by the growing interest in the development of
copper(II) based methods9 (and hence of their potential in large
scale reactions), we became interested in Cu(OTf)2 catalyzed syn-
thesis of di(indolyl)indolin-2-ones.10 To begin our study, indole
1a and isatin 2a was allowed to react using 5 mol % of Cu(OTf)2
in acetonitrile. The reaction went into completion within 30 min
to afford the di(indolyl)indolin-2-one 3a in 90% yield. In order to
fully examine the scope of this chemistry, various substituted
isatins and indoles were introduced and tested as substrates
(Scheme 1, Table 1).11
The corresponding di(indolyl)indolin-2-ones (3a–3m) were
formed in excellent yields, when isatins bearing electron with-
drawing group (entries 2 and 4–6) and indoles bearing electron
releasing group (entries 3–6) are used. It is worthy to mention that
we did not observe any isomerization product, when (E)-1-cin-
namyl indole 2c was reacted with isatin 1a, the corresponding
di(indolyl)indolin-2-one (3g) was provided in 85% yield with com-
plete transfer of stereochemistry (as evidenced by the coupling
constant value, J = 16.0 Hz). We next examined the possibility of
preparing N-propargyl di(indolyl)indolin-2-ones by this same
methodology. Delightfully, the desired products were obtained in
good yields (entries 10–13). Note that these substrates possessing
alkynes did not undergo isomerization to the corresponding allenyl
product.12 The structures of compounds 3a–m were confirmed by
IR, 1H and 13C NMR spectroscopy, mass spectrometry, and elemen-
tal analysis. All the compounds exhibited an IR peak between 1700
and 1725 cmÀ1 which corresponds to the stretching frequency of
amide carbonyl of the oxindole ring. All the compounds showed
a 13C peak at dC = 52.5–53.2 ppm and 175.0–179.1 ppm ascertained
the presence of quaternary and amide carbons, respectively. These
findings, confirmed the formation of di(indolyl)indolin-2-one
products 3a–m.
R3
R3
N
N
O
R2
5 mol% Cu(OTf)2
MeCN / rt
R1
N R3
R4
R1
R
2
O
N
R1
R4
O
R = H, Me
N
R3
R2
R2
R1 = allyl, prenyl, cinnamyl, propargyl
R
R
2 = H, OMe, Br
3 = H, propargyl, benzyl, CH2COOEt
R4 = H, Cl, Br, NO2
13 examples
Scheme 1. Cu(OTf)2 catalyzed synthesis of di(indolyl)indolin-2-ones.
Table 1
Copper(II) triflate catalyzed synthesis of N-allyl and N-propargyl (indolyl)indolin-2-onesa
Entry
Isatin
Indole
Di(indolyl)indolin-2-onesb
Time (min)
Yieldc (%)
H
H
N
N
O
O
N
N
2a
2a
1
30
90
O
1a
N
N
3a
H
H
N
N
O
O
O2N
O2N
2
15
95
O
N
1b
N
3b
H
MeO
MeO
H
OMe
N
N
O
O
N
3
15
95
O
1a
2b
N
N
OMe
3c
H
N
H
N
OMe
O
O
N
Cl
Cl
O
4
15
93
2b
N
1c
N
OMe
3d
(continued on next page)

4074
C. Praveen et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4072–4077
Table 1 (continued)
Entry
Isatin
Indole
Di(indolyl)indolin-2-onesb
Time (min)
Yieldc (%)
H
MeO
H
N
OMe
N
O
O
N
Br
Br
5
15
92
O
2b
2b
N
1d
N
OMe
3e
COOEt
O
MeO
COOEt
N
OMe
N
N
O
6
15
94
O
1e
N
N
OMe
3f
H
N
H
N
O
O
N
Ph
O
2c
1a
7
40
85
N
N
Ph
Ph
3g
H
N
Br
H
N
Br
O
O
N
O
1a
2d
8
45
88
N
N
Br
3h
Br
Br
N
O
N
N
O
O
2d
1f
9
45
86
N
N
Br
3i
H
N
H
N
O
O
N
2e
O
10
25
89
1a
N
N
3j
Bn
N
Bn
N
N
O
O
2e
11
40
88
O
1g
N
N
3k

C. Praveen et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4072–4077
4075
Table 1 (continued)
Entry
Isatin
Indole
Di(indolyl)indolin-2-onesb
Time (min)
Yieldc (%)
N
N
O
N
O
2e
12
45
87
O
1h
N
N
3l
H
H
N
N
Me
O
O
Me
N
N
2f
O
1a
13
20
90
Me
3m
a
All reactions were performed at 30 °C in acetonitrile using 5 mol % Cu(OTf)2.
Isolated yield without column chromatography.
b
c
All products were characterized by IR, 1H, 13C NMR and mass spectroscopy.
Table 2
The effect of compounds 3a–m on seizures induced by MES in micea
Entry
Treatment group
Dose level
Time (s) in various phases of convulsion (mean SEM)
Flexion
Extensor
Clonus
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
3ans
20 mg/kg
20 mg/kg
20 mg/kg
20 mg/kg
20 mg/kg
20 mg/kg
20 mg/kg
20 mg/kg
20 mg/kg
20 mg/kg
20 mg/kg
20 mg/kg
20 mg/kg
20 mg/kg
0.5% w/v
5.80 0.20
4.80 0.20
4.80 0.18
5.80 0.20
4.80 0.20
4.80 0.20
4.80 0.20
4.80 0.20
5.40 0.24
4.80 0.20
4.80 0.18
5.40 0.20
5.40 0.24
5.60 0.20
11.20 0.40
48.00 0.32
39.20 0.40
31.80 0.40
31.60 0.37
39.20 0.40
31.60 0.37
39.60 0.40
39.60 0.40
31.60 0.37
39.20 0.40
39.20 0.40
31.80 0.32
31.60 0.37
43.00 0.40
55.20 0.63
3.60 0.20
3.40 0.24
3.20 0.24
3.40 0.20
3.40 0.24
3.40 0.24
3.60 0.20
3.40 0.24
2.80 0.24
3.20 0.24
3.20 0.24
3.60 0.20
2.80 0.24
3.40 0.24
7.60 0.32
3b⁄
3c⁄⁄
3d⁄⁄
3e⁄
3f⁄⁄
3g⁄
3h⁄
3i⁄⁄
3j⁄
3k⁄
3l⁄⁄
3m⁄⁄
Phenytoinb
Tween 80c
Data were analyzed by one way ANNOVA followed by Dunnet’s test.
ns: not significant, P value >0.05; ⁄significant, P value <0.05; ⁄⁄highly significant, P value <0.001.
SEM: Standard error of means.
Bold values indicate the superior activity compared to the standard and other compounds.
a
Mortality = recovery.
Standard.
Control.
b
c
All the synthesized compounds were screened for their
anticonvulsant activity against Maximal Electroshock13 (MES)
induced seizure through in vivo rodent models.14 Results of anti-
convulsant activity with reference drug phenytoin are discussed
in Table 2. All the compounds were active at a dose level of
20 mg/kg which is an indicative of their ability to prevent convul-
sion spread. The MES-convulsions are divided into three phases
such as (a) tonic flexion, (b) tonic extensor and (c) clonic convul-
sions. The time (s) spent by the animal in each phase of the convul-
poor anticonvulsant activity as evidenced by high extensor time
than phenytoin.
Attempts to understand the SAR of the molecules started with
the indole moiety. Replacement of N-allyl group (3a) with a
propargyl group (3j) increased the anticonvulsant potency signif-
icantly, indicating the importance of propargyl group. Replace-
ment of C5-hydrogen (3a) by 5-MeO group (3c) enhanced the
activity. A markedly improved potency was observed when a
small substituent like methyl was placed at the C-2 position
(3m). The presence of hydrophobic groups like cinnamyl (3g)
and prenyl (3h) offered only moderate activity. Among the sub-
stituents placed C-5 on the oxindole moiety, a chloro group
(3d) was well tolerated and offers enhanced activity over the bro-
mo counterpart (3e). Of the other substituents placed on the C-5
position, nitro group (3b) was found to exhibit higher potency
than the unsubstituted analogue (3a). The presence of N-propar-
gyl (3i) and ester (3f) groups on the oxindole ring renders the
sions is noted down.
A substance is known to possess
anticonvulsant property if it reduces or abolishes the extensor
phase of MES-convulsion. Analysis of Table 2 revealed that six
compounds (3c, 3d, 3f, 3i, 3l, and 3m) showed excellent activity
and six compounds (3b, 3e, 3g, 3h, 3j, and 3k) showed good anti-
convulsant activity. However, these compounds were found to be
more potent than the reference drug phenytoin. Compound 3a
emerged as the less attractive compound in this series showing

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C. Praveen et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4072–4077
Table 3
substituents. The antibacterial activity study revealed that four
compounds (3e, 3i, 3k, and 3m) showed maximum activity against
S. aureus and one compound (3k) showed maximum activity
against E. coli. Antifungal activity study revealed that two com-
pounds (3b and 3m) showed maximum activity against C. albicans.
However, the effect of compounds on the host cell and their mode
of action remain to be studied.
Antibacteriala and antifungalb activity of compounds 3a–m by cup plate methodc
Entry
Compounds
Zone of inhibitiond (mm)
S. aureus
E. coli
C. albicans
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
12
10
12
10
15
12
10
14
15
11
15
10
15
17
NA
12
10
10
11
14
14
14
12
15
10
17
10
15
18
NA
11
15
14
10
14
10
13
12
10
12
13
12
15
NA
16
Acknowledgments
C.P. acknowledges CSIR, New Delhi, India, for the research
fellowship. A.A. thanks Ms. R. Sabitha, Lecturer, Department of
Pharmaceutical Chemistry, Arulmigu Kalasalingam College of
pharmacy, Krishnankoil, Tamil Nadu, India for her valuable
suggestions.
3m
Amikacine
Ketoconazolef
Supplementary data
NA: not applicable.
a
Muller-Hinton agar was employed as culture media.
Sabouraud Dextrose Agar was employed as culture media.
Test concentration of 20
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2011.04.117.
b
c
l
g/mL was used with methanol as solvent control.
d
Bold value indicates the maximum antimicrobial activity among the screened
compounds.
e
References and notes
Standard antibacterial drug.
f
Standard antifungal activity.
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molecule more active than their respective unsubstituted oxin-
doles (3h and 3c). The tris-propargyl pattern also led to the
significant improvement in potency (3l).
Considering the extensive applications of di(indolyl)indolin-
2-ones in medicinal chemistry and in continuation of our ongoing
project on bio-active heterocycles,6i an attempt has been made
to evaluate the antimicrobial properties of the synthesized
compounds.
The representative compounds 3a–m were tested for their anti-
bacterial activity16 against Gram(+)ve and Gram(À)ve bacterial
strains namely Staphylococcus aureus (MSSA 22) and Escherichia coli
(K 12), respectively, by employing cup-plate method15 at a concen-
tration of 20 lg/mL of methanol in Muller-Hinton agar media. The
standard antibacterial drug Amikacin was screened under similar
conditions. Twenty microliters of these solutions were added to
each well. One of the wells was used as control by adding 20 lL
of methanol. The zone of inhibition, if any, produced by diffusion
of the compounds from the cup into the surrounding medium,
was measured after incubation at 37 °C for 24 h (Table 3). Out of
thirteen compounds, 3e, 3i, 3k, and 3m showed maximum activity
(15 mm inhibition) against S. aureus. Compound 3k showed maxi-
mum activity (17 mm inhibition) against E. coli. The in vitro anti-
fungal activities17 of the synthesized compounds were evaluated
against Candida albicans (ATCC 10231) by cup plate method at a
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concentration of 20 lg/mL of methanol in Sabouraud Dextrose
Agar Media. The standard antifungal drug Ketoconazole was
screened under similar conditions. The same procedure employed
for the evaluation of antibacterial activities was followed for anti-
fungal evaluation also. The screening data (Table 3) revealed that
compounds 3b and 3m showed maximum antifungal activity
(15 mm inhibition).
In summary, we have synthesized N-allyl and N-propargyl
di(indolyl)indolin-2-ones via Cu(OTf)2 catalyzed 3-indolylation of
isatin. From chemical perspective this method is simple, practical
to perform and no column chromatography required for purifica-
tion. All the synthesized compounds were screened for their anti-
convulsant and antimicrobial activity. Among the screened
compounds six compounds (3c, 3d, 3f, 3i, 3l, and 3m) exhibited
maximum anticonvulsant activity. The anticonvulsant potency of
these compounds could be attributed to the favorable structural
combination of the indole and oxindole frameworks and their
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Lett. 2006, 47, 5485; (f) Nishihara, Y.; Okamoto, M.; Inoue, Y.; Miyazaki, M.;
Miyasaka, M.; Takagi, K. Tetrahedron Lett. 2005, 46, 8661.
10. We have previously reported Cu(OTf)2 catalyzed regioselective synthesis of
phthalans, see Ref. 5h.

C. Praveen et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4072–4077
4077
11. Representative procedure for the synthesis of 3,3-bis(1-allyl-1H-indol-3-yl)-
indolin-2-one: To stirred solution of N-allylindole 2a (1.0 mmoL) in
Maximum electroshock seizure was elicited using electroconvulsiometer with
an altering current of 150 mA for 0.2 s via ear clip electrode. Each mouse was
administered the drug or control 30 min prior to receiving an electroshock. The
time (seconds) spent by the animal in different convulsion phases is noted
down.
a
acetonitrile (2 mL) was added isatin 1a (0.5 mmoL) and Cu(OTf)2
(0.05 mmoL). The resulting reaction mixture was stirred at room
temperature for 30 min. After completion of the reaction as indicated by TLC,
the reaction mixture was concentrated under reduced pressure and extracted
with ethyl acetate (3 Â 20 mL). The combined organic layers were dried over
anhydrous sodium sulfate and concentrated under reduced pressure to afford
pure product of 3,3-bis(1-allyl-1H-indol-3-yl)-indolin-2-one 3a (90%) as
yellow solid; mp 269–271 °C; IR (KBr): 3848, 3431, 2511, 2331, 2028, 1700,
(c) Statistical analysis: The obtained data were analyzed using one-way analysis
of variance (ANOVA) followed by Dunnet’s multiple comparison test. The
results are presented as mean standard error of means (SEM). Differences
between data sets were considered as significant when P <0.001.
15. Barry, A. L. The Antimicrobial Susceptibility Test, Principles and Practices, 4th
ed., ELBS, 1976; p 180.
1365 cmÀ1 1H NMR (500 MHz, DMSO-d6): dH 4.72 (s, 4H); 4.92 (d, 2H,
.
J = 16.8 Hz); 5.06 (d, 2H, J = 9.9 Hz); 5.85–5.94 (m, 2H); 6.79 (t, 2H, J = 7.6 Hz);
6.87 (s, 2H); 6.89–6.90 (m, 3H); 7.02 (t, 2H, J = 7.6 Hz); 7.22 (d, 3H, J = 8.4 Hz);
7.33 (d, 2H, J = 8.4 Hz); 10.64 (s, 1H). 13C NMR (125 MHz, DMSO-d6): dC 48.3,
52.9, 103.6, 110.6, 111.6, 114.4, 117.0, 118.2, 119.0, 121.7, 126.7, 128.0, 134.8,
134.9, 137.2, 138.9, 151.2, 159.9, 179.0. Anal. Calcd for C30H25N3O: C, 81.24; H,
5.68; N, 9.47. Found: C, 80.98; H, 5.75; N, 9.55%.
16. Experimental for antibacterial activity of compounds 3a–m: The beef extract
(30 g), casein hydrolysate (17.5 g), soluble starch (1.5 g), agar (20 g) were
taken in the above proportions and dissolved up to 1000 mL of distilled
water. The constituents were heated gently at 100 °C with agitation. The pH
of the medium was adjusted to 7.4 using sodium hydroxide. The pH was
tested using
a universal indicator paper, which showed green colour at
12. For examples of alkyne–allene isomerization, see: (a) Nandi, B.; Kundu, N. G. J.
Chem. Soc., Perkin Trans. 1 2001, 1649; (b) Fortes, C. C.; Garrote, C. F. D. Synth.
Commun. 1997, 27, 3917; (c) Noguchi, M.; Okada, H.; Watanabe, M.; Okuda, K.;
Nakamura, O. Tetrahedron 1996, 52, 6581; (d) Abbiati, G.; Canevari, V.; Caimi,
S.; Rossi, E. Tetrahedron Lett. 2005, 46, 7117.
13. (a) Kulkarni, S. K. Arch. Int. Pharmacodyn. 1981, 252, 124; (b) Unverferth, K.;
Engel, J.; Hofgen, N.; Rostock, A.; Gunther, R.; Lankau, H.; Menzer, M.; Rolfs, A.;
Liebscher, J.; Muller, B.; Hofmann, H. J. Med. Chem. 1998, 41, 63; (c) Yogeeswari,
P.; Sriram, D.; Thirumurugan, R.; Raghvendran, J.; Sudan, K.; Pavana, R.; Stables,
J. J. Med. Chem. 2005, 48, 6202.
pH 7.4. Then it was transferred to boiling tubes in hot condition and sealed
with non-absorbent cotton and sterilized by autoclaving at 121 °C (15 lbs
pressure) for 15 min. Then poured aseptically into sterile Petri dishes. The
sterilized Muller-Hinton agar media was heated on a water bath to melt the
media. When the media was lukewarm, the organism (E. coli or S. aureus)
were inoculated separately and poured aseptically into sterile Petri dishes
and allowed to solidify. The standard drug Amikacin disc was placed on the
media. These vials were kept in hot air oven at 160 °C for 30 min for
sterilization using methanol as solvent control. The synthesized compounds
(20 lg/mL) were then added by sterile micro pipette into each cup. Initially it
14. Typical experimental procedure for the evaluation of anticonvulsant activity of
the synthesized compounds by MES induced convulsion method: (a) Animals
and experimental conditions: Inbred albino mice (Swiss strain) of both genders
weighing 25–30 g were used for the study. The mice were kept in clean
polypropylene cages with free access to standard pellet diet and water (ab
libitum), under standardized housing conditions (natural light–dark cycle,
temperature 25 1 °C, relative humidity 55 5%). After 7 days of adaptation to
laboratory conditions, the animals were randomly assigned to 12 experimental
was kept in the refrigerator for 1 h to facilitate uniform diffusion of the drug
and later kept in the incubator for a period of 24 h at 37 °C. Observations
were made for the zone of inhibition around the test compounds and
compared with that of standard.
17. Experimental for antifungal activity of compounds 3a–m: Glucose (40 g),
peptone (10 g) and agar (15 g) were taken in the above proportions at 100 °C
with agitation. The pH of the medium was adjusted to 5.4. Then it was
transferred to boiling tubes in hot condition and sealed with non-absorbent
cotton and sterilized by autoclaving at 121 °C (15 lbs pressure) for 15 min.
Then it was poured aseptically into sterile Petri dishes. The sterilized
Sabouraud dextrose agar was heated on a water bath to melt the media.
When the media was lukewarm, the C. albicans spores were inoculated
separately and poured aseptically into sterile Petri dishes and allowed to
solidify. The standard drug Ketoconazole was placed on the media. These vials
were kept in hot air oven at 160 °C for 30 min for sterilization using methanol
groups of
5 mice each. Each mouse was used only once. All tests were
performed between 10:00 and 16:00. All efforts were made to minimize
animal suffering and to use only the number of animals necessary to produce
reliable scientific data. The experimental protocols and procedures listed
below conformed to the Guide for the Care and Use of Laboratory Animals and
approved by the Institutional Ethics Committee.
(b) MES induced seizure: Group-I was treated with 0.5% aqueous solution of
Tween 80 (polyoxyethylene sorbitan mononucleate) and served as control.
Phenytoin was suspended in a 0.5% Tween 80 solution and administered
intraperitoneally (ip) to group-II (20 mg/kg) and served as standard. All the test
compounds were suspended in a 0.5% Tween 80 solution and administered
intraperitoneally (ip) to group-III (20 mg/kg) 30 min before seizure induction.
as solvent control. The synthesized compounds (20 lg/mL) were then added by
sterile micro pipette into each cup. Initially it was kept in the refrigerator for
1 h to facilitate uniform diffusion of the drug and later kept in the incubator for
a period of 24 h at 28 °C. Observations were made for the zone of inhibition
around the test compounds and compared with that of standard.