Synthesis and biological evaluation of N-(substituted phenyl)-2-(5H-[1,2,4]triazino[5,6-b]indol-3-ylsulfanyl)acetamides as antimicrobial, antidepressant, and anticonvulsant agents

Article abstract of DOI:10.1134/S1068162015020144

A new series of N-Aryl-2-(5H-[1,2,4]triazino[5,6-b]indol-3-ylsulfanyl)acetamides were synthesized by condensation of tricyclic compound 2,5-dihydro-3H-[1,2,4]triazino[5,6-b]indole-3-thione with chloro N-phenylacetamides. The tricyclic compound was obtaine

Full text of DOI:10.1134/S1068162015020144

ISSN 1068ꢀ1620, Russian Journal of Bioorganic Chemistry, 2015, Vol. 41, No. 2, pp. 223–230. © Pleiades Publishing, Ltd., 2015.
Synthesis and Biological Evaluation of Nꢀ(Substituted Phenyl)ꢀ2ꢀ
(5Hꢀ[1,2,4]triazino[5,6ꢀb]indolꢀ3ꢀylsulfanyl)acetamides as
Antimicrobial, Antidepressant, and Anticonvulsant Agents1
, 2
N. Shruthia, Boja Poojarya , Vasantha Kumara, Prathibha A.a, Mumtaz Mohammed Hussainb,
B. C. Revanasiddappac, and Himanshu Joshic
a Department of Chemistry, Mangalore University, Mangalagangothriꢀ574199, Karnataka, India
b Department of Pharmaceutical Chemistry, S.J.M. College of Pharmacy, Chitradurgaꢀ575501, Karnataka, India
c Department of Pharmacology, N.G.S.M. Institute of Pharmaceutical Sciences,
Paneer, Deralakatte, Mangaloreꢀ575 018, Karnataka India
Received September 8, 2014; in final form, November 3, 2014
Abstract—A new series of
sized by condensation of tricyclic compound 2,5ꢀdihydroꢀ3
chloro ꢀphenylacetamides. The tricyclic compound was obtained by condensation of Isatin with thiosemiꢀ
carbazide. Chloro ꢀphenylacetamides were obtained from different substituted anilines. Their structures
N
ꢀArylꢀ2ꢀ(5
H
ꢀ[1,2,4]triazino[5,6ꢀ
b
]indolꢀ3ꢀylsulfanyl)acetamides were syntheꢀ
H
ꢀ[1,2,4]triazino[5,6ꢀ ]indoleꢀ3ꢀthione with
b
N
N
1
were characterized by IR, H NMR, LCꢀMS and elemental analyses. Newly synthesized compounds were
screened for antimicrobial, antidepressant and anticonvulsant activities. Preliminary results indicated that
most of the compounds showed lesser MIC value than the standard drug used when tested for antimicrobial
activity. Some of the compounds were endowed with very good antidepressant and anticonvulsant activity.
Keywords: [1,2,4]triazino[5,6ꢀb]indoles, antimicrobial activities, antidepressant activities, anticonvulsant activꢀ
ities
DOI: 10.1134/S1068162015020144
2 1
INTRODUCTION
molecules. The triazino[5,6ꢀb]indole derivatives have
aroused considerable interest as a result of their high
potential of biological activities such as antibacterial,
antifungal [12], antihypertensive [13], antimalarial
[14], antihypoxic [15], antiparasitic [16] and antideꢀ
pressant [17] activities. Importantly, this tricyclic
Most of the antidepressants exert its actions on the
metabolism of monoamine neurotransmitters particuꢀ
larly on norꢀadrenaline and serotonin [1]. They are
effective and tolerated well, but noncompliance due to
the slow action, low response and a plethora of side
effects are generally observed [2–7]. Also, they inhibit
sexual behavior [8]. Epilepsy is another common neuꢀ
rological disorder characterized by unprovoked seiꢀ
zures. Phenobarbital and mephobarbital are wellꢀ
known drugs used for the treatment of epilepsy [9].
Available antiepileptic drugs are effective in controlꢀ
ling seizures of only about 70–80% of patients. But
they suffer from major side effects like sedation and
hypnosis along with drowsiness, ataxia, gastrointestiꢀ
nal disturbance, hepatotoxicity and megaloblastic
anemia and even lifeꢀthreatening conditions [10, 11].
Hence, there is a continuing demand for the new antiꢀ
convulsant and antidepressant agents as it has not been
possible to control the side effects by currently availꢀ
able drugs. Heterocyclic nucleus imparts an important
role in the field of medicinal chemistry and serves as a
key template for the development of various bioactive
structure is comparable to
pyrido[3,4ꢀ ]indole), an endogenous monoamine oxiꢀ
dase inhibitor [18]. The majority of the ꢀasꢀtriazꢀ
ino[5,6ꢀ indoles are active in vitro against a variety of
βꢀcarboline
(9Hꢀ
b
5H
b
]
viruses including several strains of rhinovirus [19].
They are used in the prophylaxis and treatment of an
extensive index of viruses and have for a long time
attracted attention in connection with the search for
new antimicrobial and anticancer agents [20, 21]. For
a search of effective small molecules with promising
biological activity, it was envisaged to synthesize a
series of
5,6ꢀ
Nꢀ(substituted phenyl)ꢀ2ꢀ(5Hꢀ[1,2,4] triazino
] indolꢀ3ꢀylsulfanyl)acetamide derivatives.
[
b
RESULTS AND DISCUSSIONS
In our present work, tricyclic compound 1,2,4ꢀtriꢀ
azino[5,6ꢀ ]indoleꢀ3ꢀthione (II) was prepared by
referring previously reported literature procedure [22].
Isatin ( ) was condensed with thiosemicarbazide in
1
b
The article is published in the original.
Corresponding author: phone/fax: +91ꢀ824ꢀ2287262/2287367;
eꢀmail: bojapoojary@gmail.com.
2
I
223

224
SHRUTHI et al.
aqueous solution of potassium carbonate. Obtained acetate. The title compounds (IVa)–(IVq) were accomꢀ
clear solution was acidified with glacial acetic acid to plished by overnight stirring of tricyclic product (II) with
afford the condensed product (II). Different chloro appropriate chloro
Nꢀphenylacetamides (III) in dry
Nꢀphenylacetamides (III) was prepared as per the litꢀ DMSO containing anhydrous milled potassium carꢀ
erature procedure [23] involving the reaction of priꢀ bonate. The synthetic route is depicted in Scheme 1.
mary amines with chloro acetyl chloride in glacial aceꢀ Synthesized compounds were characterized by IR,
tic acid in the presence of saturated solution of sodium 1H NMR, LCꢀMS and elemental analyses.
N
O
NH
S
K CO /H O
2
3
2
S
+
O
O
N
H2N
N NH2
N
H
N
H
H
(
I)
(
II)
H
gl. acetic acid
CH COONa
N
+
Cl K CO /DMSO
2 3
R–NH2
R
3
O
Cl
Cl
(
IIIa)–(IIIq)
H
N
N
N
R
S
O
N
N
H
(IVa)–(IVq)
a: R = 3ꢀCN–C6H4;
c: R = 2ꢀCN–C6H4;
b
d
: R = 2ꢀCF3–C6H4;
: R = 4ꢀF–C6H4;
e: R = 4ꢀBrꢀ2ꢀpyridinyl;
g: R = 3ꢀCF3–C6H4; : R = 4ꢀOCF3–C6H4;
i: R = 4ꢀCNꢀ2ꢀpyridinyl; : R = 3,5ꢀCl2–C6H3;
k: R = 2,4,5ꢀCl3–C6H2; : R = 3ꢀClꢀ4ꢀFꢀC6H3;
m: R = benzothiazolyl; : R = 2,5ꢀCl2–C6H3;
o: R = 2ꢀClꢀ6ꢀCH3ꢀpyridinyl;
q: R = 5ꢀCH3ꢀ2ꢀpyridinyl
f: R = 2ꢀthiazolyl;
h
j
l
n
p: R = 2,4ꢀF2–C6H3;
Scheme 1. Synthetic route for the compounds (IVa)–(IVq).
IR spectrum of prototype compound (IVa) showed
prominent absorption bands corresponding to N–H
stretching of secondary amide near 3323 cm–1 and an
amide carbonyl at 1670 cm–1. Presence of aromatic
skeleton is confirmed by peak at 3057 cm–1 correꢀ
The newly synthesized compounds (IVa)
were screened for in vitro antimicrobial activity (minꢀ
imum inhibitory concentration) against gramꢀpositive
bacterial strains Stephylococcus aureus Enterococcus
faecalis, gramꢀnegative bacterial strains Escherichia
coli Klebsiella pneumonia and two fungal strains Asꢀ
pergillus niger and Candida albicans by tube dilution
method. Results of antimicrobial study are shown in
alpha to carbonyl group. Presence of two doublets and Table 1 and Table 2. Antibacterial studies revealed
–(IVq)
,
,
1
sponding to aromatic C–H stretching. H NMR of
(IVa) displayed singlet at δ 4.28 for methylene protons
that most of the compounds have shown good inhibiꢀ
tion against gramꢀpositive bacterial strains when
compared with reference drug used, ciprofloxacin
two triplets confirmed the presence of triazino indole
moiety. A singlet at 8.08 and multiplet at 7.47–7.57
integrating for one and three aromatic protons respecꢀ
tively affirmed the presence of 3ꢀcyanophenyl ring in
δ
δ
(MIC: 2
against E. feacalis). Compounds (IVa), (IVb), (IVc),
IVd), (IVe), (IVf), (IVh), (IVi), (IVj), (IVk), (IVl),
IVn), (IVo), (IVp) have shown more inhibition against
gramꢀpositive bacterial strains as compared to ciprofꢀ
loxacin where as compounds (IVg), (IVm) and (IVg
found to be less effective. Against gramꢀnegative bacꢀ
terial strains, compounds (IVe) and (IVi) were showed
μg/mL against S. aureus and MIC: 1.0 μg/mL
the title compound. Further, broad singlet at
revealed the presence of an amide NH proton. The
downfield broad singlet at 12.52 corresponds to inꢀ
δ 10.74
(
(
δ
dole NH proton. Formation of the compound is furꢀ
ther confirmed by the presence of M+ and M+ + 2
peaks at m/z values 360 and 362 respectively.
)
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 41
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SYNTHESIS AND BIOLOGICAL EVALUATION
225
Table 1. MIC values of in vitro antibacterial study for the analogs (IVa)–(IVq
)
MIC values (
µ
g/mL)
Compound
gramꢀpositive
Staphylococcus aureus Enterococcus faecalis
gramꢀnegative
Escherichia coli
Klebsiella
(
IVa
)
0.4
0.8
0.4
0.2
0.4
0.4
12.5
0.8
0.2
0.4
0.2
0.2
12.5
0.8
0.2
0.8
0.4
0.8
0.2
0.2
0.8
0.8
6.25
0.4
0.2
0.2
0.2
0.2
6.25
3.12
0.2
1.6
6.25
1.0
6.25
12.5
3.12
3.12
0.2
12.5
6.25
3.12
1.6
(
IVb
)
(
IVc)
(
IVd
)
)
)
(
IVe
IVf
0.8
(
3.12
3.12
3.12
0.2
6.25
12.5
12.5
0.2
(
IVg)
(
IVh
)
(
IVi
IVj
IVk
)
(
)
6.25
12.5
12.5
25
6.25
25
(
)
(
IVl
IVm
IVn
)
6.25
25
(
)
(
)
25
12.5
25
(
IVo
)
50
(
IVp
)
50
12.5
25
(
IVq
)
6.25
2.0
50
Ciprofloxacin
2.0
1.0
good inhibition than standard drug used; whereas rests
of the compounds were shown weak inhibition.
From structural activity relationship it was clear that
electron withdrawing group and heterocyclic substiꢀ
tuted compounds have shown good inhibition against
S. aureus and E. faecalis bacterial strains. Against
E. coli and K. pneumonia, Haloꢀpyridine substituted
derivatives were found to be potent inhibitors.
Table 2. Results of in vitro antifungal activity for the comꢀ
pounds (IVa)–(IVq
)
MIC values (
µg/mL)
Compound
Aspergillus niger Candida albicans
(
IVa
)
0.4
0.8
0.4
0.2
0.4
0.4
12.5
0.4
0.8
0.2
0.4
0.2
12.5
0.2
1.6
0.2
0.4
0.8
0.2
0.2
0.8
0.8
6.25
0.4
0.2
0.2
0.2
6.25
0.2
3.12
0.2
1.6
6.25
(
IVb
)
The reference drug flucanazole is selected as positive
control for antifungal activity assay. All the compounds
(
IVc)
(
IVd
)
)
)
have shown excellent inhibition (MIC
against C. albicans when compared with standard drug
Flucanozole (MIC: 16 g/mL). Against A. niger, exꢀ
cept (IVg) and (IVm) rest of the compounds showed
MIC value less than standard used (MIC: 8 g/mL). It
< 16 μg/mL)
(
(
IVe
μ
IVf
(
IVg)
μ
(
IVh
)
was observed that all the compounds are potent against
C. albicans and A. niger, except electron donating hetꢀ
erocyclic substituted derivatives against A. niger when
compared with Flucanazole.
(
IVi
IVj
IVk
)
(
)
(
)
Antidepressant activity of the synthesized comꢀ
pounds (IVa)–(IVq) was done by using tail suspension
test. This test is effectively used to predict the activity
of a wide variety of antidepressants such as Mao inhibꢀ
itors. During the pharmacological evaluation, only a
few of the synthesized compounds exhibited moderate
antidepressant activity in the tail suspension test, with
many exhibiting weak activity as shown in Table 3.
However, in the series, mono and dihalo substituted
(
IVl
IVm
IVn
)
(
)
(
)
(
IVo
)
(
IVp
)
(
IVq
)
6.25
8.0
Flucanazole
16.0
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226
SHRUTHI et al.
Table 3. Results of antidepressant activity for the comꢀ
pounds (IVa)–(IVq): tail suspension test
showed better activity than heterocyclic substituted
compounds and electron releasing group substituted
compounds.
Duration
Compound of immobility (s)
(mean SEM)
% decrease
in immobility
duration (%DID)
EXPERIMENTAL
Melting points were determined in open capillaries
and uncorrected (melting point apparatus: Sewell inꢀ
struments Inc., India). All solvents used were of anaꢀ
lytical grade and the reagents used were purchased
from commercial vendors. The purity of the comꢀ
pounds was checked by thin layer chromatography on
a silica coated aluminum sheet (silica gel F254). IR
spectra (KBr pellets) were recorded on a Shimadzu
FTꢀIR 157ꢀspectrophotometer. The 1H NMR spectra
were recorded on a Bruker Avance II 400 (400 MHz)
spectrometer using TMS as internal standard. Mass
spectra were determined on a Joel SX 102/Daꢀ600
mass spectrometer/data system using argon/xenon
(6 kV, 10 mA) as the FAB gas. Elemental analyses were
carried out using a CHNS elemental analyzer. The
progress and completion of the reaction was conꢀ
firmed by TLC analysis in Ethyl acetate–hexane mixꢀ
ture (4 : 6).
(
IVa
)
136.35 9.73
128.76 7.71
147.57 8.38
97.58 8.67
140.66 8.54
132.41 7.93
147.26 8.55
133.51 7.98
139.13 9.38
104.26 9.51
114.26 7.48
118.68 8.43
131.91 8.77
101.73 7.55
133.66 9.81
104.55 6.93
147.26 8.55
186.30 9.28
79.81 8.76
26.81
30.88
20.76
47.62
24.49
28.92
20.86
28.33
25.31
44.03
38.66
36.29
29.19
45.39
28.25
43.88
20.86
–
(
IVb
)
(
IVc)
(
IVd
)
)
)
(
IVe
IVf
(
(
IVg)
(
IVh
)
(
IVi
IVj
IVk
)
(
)
(
)
(
IVl
IVm
IVn
)
(
)
Synthetic procedure for the preparation
phenyl)ꢀ2ꢀ(5 ꢀ[1,2,4]triazino[5,6ꢀ ]indolꢀ3ꢀylsulfaꢀ
nyl)acetamides (IV). To a solution of 2,5ꢀdihydroꢀ3
[1,2,4]triazino[5,6ꢀ ]indoleꢀ3ꢀthione (5 mmol) in dry
DMSO (25 mL) containing anhydrous milled potassiꢀ
um carbonate (10 mmol), appropriate 2ꢀchloroꢀ
Nꢀ(sub
(
)
H
b
Hꢀ
(IVo
)
b
(IVp
)
(
IVq)
Nꢀ
substituted acetamide (5 mmol) was added. The reacꢀ
tion mixture was kept for stirring 16 h at room temperꢀ
ature. Then it was poured into the water with stirring.
The formed product was filtered, washed with water,
dried, and recrystallized from DMF–water mixture to
get pure product.
Control
Standard
57.16
Values represent the mean S.E.M. (n = 6).
N
ꢀ(3ꢀCyanophenyl)ꢀ2ꢀ(5
]indolꢀ3ꢀylsulfanyl)acetamide (IVa). Yield: 86%,
melting point: 237–239 C; IR: 3323 (–NH), 3057
(ArꢀH), 2210 (C N), 1670 (amide C=O), 656 (C–S);
1H NMR (CDCl3):
4.28 (s, 2H, ꢀCH2), 7.40 (t, 1H,
ArꢀH, = 7.6 Hz), 7.47–7.57 (m, 3H, ArꢀH), 7.66 (t,
1H, ArꢀH, = 8), 7.84 (d, 1H, ArꢀH, = 7.6 Hz), 8.08
(s, 1H, ArꢀH), 8.26 (d, 1H, ArꢀH, = 7.6 Hz), 10.74
(bs, 1H, NH), 12.52 (bs, 1H, NH); MS ( ): 360
+), 362 ( + + 2); Found for C18H12N6OS (360.39):
C, 59.92; H, 3.32; N, 23.30; S, 8.88; Anal. calc.: C,
59.99; H, 3.36; N, 23.32; S, 8.90.
ꢀ(2ꢀTrifluoromethyl)ꢀ2ꢀ(5
]indolꢀ3ꢀylsulfanyl)acetamide (IVb). Yield: 78%, meltꢀ
ing point: 226–228 C; IR: 3265 (–NH), 3059 (ArꢀH),
1662 ( amide C=O), 650 (C–S); H NMR (CDCl3):
4.30 (s, 2H, CH2), 7.27 (t, 1H, ArꢀH; = 7.6 Hz),
7.37 (d, 1H, ArꢀH, = 7.6 Hz), 7.55 (t, 1H, ArꢀH,
= 7.6 Hz), 7.61–7.71 (m, 4H, ArꢀH), 7.89 (d, 1H,
= 8 Hz), 7.92 (d, 1H, ArꢀH, = 7.6 Hz), 8.10 (d, 1H,
= 8 Hz), 10.5 ( s, 1H, NH), 12.50 (bs, 1H, NH); MS
): 403 (
+), 405 (M+ + 2); Found for
Hꢀ[1,2,4]triazino[5,6ꢀ
derivatives showed a favorable influence on the activity
as seen in the compounds (IVd), (IVj), (IVk), (IVl),
IVn) and (IVp). Among the tested compounds, 4ꢀF
substituted derivative (IVd) is found to be more active
as it showed lesser decrease in immobility duration
than the other compounds in the series. Derivatives
with heterocyclic substitution ((IVe), (IVg), (IVi) and
b
°
(
≡
δ
J
J
J
J
(IVm)) exhibited decreased activity, where as those with
m/z
electron withdrawing group substitution showed interꢀ
mediate activity. So it can be said that, the compounds
with halogen substitution enhances the activity.
(M
M
Maximal electroshock (MES) test was used to screen
the synthesized compounds (IVa)⎯(IVq) for anticonvulꢀ
N
Hꢀ[1,2,4]triazino[5,6ꢀ
b
sant activity. The results are displayed in Table 4. The
compound (IVb) with oꢀCF3 substitution showed very
good activity with more reduced duration of extensor
tonus than the standard drug used Phenyltoin. Comꢀ
pounds (IVa) and (IVp) with mꢀCN and 2,4ꢀdifluoro
substitutions respectively showed good activity, whereꢀ
as (IVc) and (IVf) exhibited medium activity. Rest of
the compounds showed least activity. Electron withꢀ
drawing and halo substituted phenyl ring compounds
°
1
δ
−
J
J
J
J
J
J
(m
/z
M
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 41
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SYNTHESIS AND BIOLOGICAL EVALUATION
227
Table 4. Results of anticonvulsant activity for the comꢀ
pounds (IVa)–(IVq): maximal electroshock test
C18H12F3N5OS (403.38): C, 53.56; H, 2.98; N, 17.30; S,
7.92; Anal. calc.: C, 53.60; H, 3.00; N, 17.36; S, 7.95.
N
ꢀ(2ꢀCyanophenyl)ꢀ2ꢀ(5
]indolꢀ3ꢀylsulfanyl)acetamide (IVc). Yield: 80%,
melting point: 247–249 C; IR: 3320 (–NH), 3065
(ArꢀH), 2219 (C N), 1663 (amide C=O), 658 (C–S);
1H NMR (CDCl3):
4.27 (s, 2H, ꢀCH2), 7.22 (t, 1H,
ArꢀH, = 7.6 Hz), 7.30 (d, 1H, ArꢀH, = 7.6 Hz),
7.46 (m, 1H), 7.60 (t, 1H, ArꢀH, = 7.6 Hz), 7.59 –
7.68 (m, 2H), 7.89 (d, 2H, = 8 Hz), 7.88 (d, 1H, ArꢀH,
= 7.6 Hz), 8.0 (d, 1H, = 8 Hz), 10.30 ( s, 1H, NH),
12.52 (bs, 1H, NH); MS ( ): 360 (
+), 362 ( + + 2);
Hꢀ[1,2,4]triazino[5,6ꢀ
Duration of tonic hind limb
Compound
b
extensor in seconds (mean SEM)
°
(
IVa)
2.71 0.61
1.18 0.53
5.22 0.47
11.52 0.54
8.42 0.41
6.34 0.38
11.74 0.52
10.61 0.48
7.60 0.55
7.56 0.47
9.60 0.43
11.37 0.41
8.32 0.29
10.72 0.34
8.60 0.52
2.51 0.44
9.60 0.43
12.41 0.48
1.38 0.34
≡
(
IVb
)
δ
(
IVc)
J
J
J
(
IVd
)
)
)
J
(
(
IVe
J
J
IVf
m
/z
M
M
(IVg
)
Found for C18H12N6OS (360.39): C, 59.94; H, 3.34;
N, 23.31; S, 8.85. Anal. calc.: C, 59.99; H, 3.36; N,
23.32; S, 8.90.
(
IVh
)
(
IVi
IVj
IVk
)
N
ꢀ(4ꢀFluorophenyl)ꢀ2ꢀ(5
dolꢀ3ꢀylsulfanyl)acetamide (IVd). Yield: 82%, melting
point: 233 235 C; IR: 3450 (ꢀNH), 3059 (ArꢀH),
1656 (amide C=O), 1178 (ArꢀF), 653 (C–S);
1H NMR (CDCl3):
4.30 (s, 2H, –CH2), 7.17 (t, 2H,
= 8.4 Hz), 7.20 (t, 1H, ArꢀH, = 7.6 Hz), 7.32 (d,
1H, ArꢀH, = 7.6 Hz), 7.62 (t, 1H, ArꢀH, = 7.6 Hz),
7.67 7.63 (m, 2H), 7.90 (d, 2H, = 7.6), 10.10 ( s,
1H, NH), 12.50 (s, 1H, NH); MS ( ): 353 (
+),
365 (
+ + 2); Found for C17H12FN5OS (353.37): C,
57.74; H, 3.40; N, 19.80; S, 9.05; Anal. calc.: C, 57.78;
H, 3.42; N, 19.82; S, 9.07.
Hꢀ[1,2,4]triazino[5,6ꢀb]inꢀ
(
)
(
)
−
°
(
IVl
IVm
IVn
)
(
)
δ
(
)
J
J
J
J
(IVo
)
−
J
(IVp
)
m/
z
M
(IVq)
M
Control
Standard
N
ꢀ(5ꢀBromopyridinꢀ2ꢀyl)ꢀ2ꢀ(5
]indolꢀ3ꢀylsulfanyl)acetamide (IVe). Yield: 69%, melting
point: 213–215 C; IR: 3455 (–NH), 3050 (ArꢀH), 1658
(amide C=O), 653 (C–S); 1H NMR (CDCl3):
4.32
(s, 2H, –CH2), 7.20 (t, 1H, ArꢀH, = 7.6 Hz), 7.32
(d, 1H, ArꢀH, = 7.6 Hz), 7.62 (t, 1H, ArꢀH, = 7.6
Hz), 7.84 (dd, = 9 Hz, 1H), 7.90 (d, 2H, = 7.6 Hz),
8.11 (d, 1H, ArꢀH, = 9.0 Hz), 8.37 (d, 1H, ArꢀH,
= 9.0 Hz), 10.17 (s, 1H, NH), 12.49 (br, 1H, NH); );
MS ( ): 415 (
+), 417 (M+ + 2); Found for
Hꢀ[1,2,4]triazino[5,6ꢀ
b
1
1668 (amide C=O), 656 (C–S); H NMR (CDCl3):
°
δ
4.30 (s, 2H, –CH2), 6.56 (d, 1H, thiazole ring,
= 8.4 Hz), 7.23 (t, 1H, ArꢀH, = 8 Hz), 7.30 (d, 1H,
= 8 Hz), 7.60 (t, 1H, ArꢀH, = 8 Hz), 7.68
(d,1H, ArꢀH, = 8 Hz) 7.73 (s, 1H, ArꢀH), 7.90 (d,
2H, = 7.6 Hz), 10.09 ( s, 1H, NH), 12.40 (bs, 1H,
NH); MS ( ): 342 (
+), 344 ( + + 2); Found for
δ
J
J
J
ArꢀH,
J
J
J
J
J
J
J
J
J
J
m/z
M
M
C14H10N6OS2 (342.4): C, 49.08; H, 2.92; N, 24.52; S,
18.71; Anal. calc. C, 49.11; H, 2.94; N, 24.54; S,
18.73.
m/z
M
C17H12BrN5OS (415.27): C, 49.25; H, 2.90; N, 16.87;
S, 7.72; Anal. calc.: C, 49.29; H, 2.92; N, 16.90; S,
7.74.
N
ꢀ(4ꢀTrifluoromethoxyphenyl)ꢀ2ꢀ(5
azino[5,6ꢀ ]indolꢀ3ꢀylsulfanyl)acetamide (IVh). Yield:
85%, melting point: 242–244 C; IR: 3265 (–NH),
3056 (ArꢀH), 1669 (amide C=O), 658 (C–S); 1H NMR
(CDCl3): 4.34 (s, 2H, CH2), 6.75 (d, 2H, ArꢀH,
= 8.6 Hz), 7.28 (t, 1H, ArꢀH, = 8 Hz), 7.37 (d, 1H,
ArꢀH, = 8 Hz), 7.63 (t, 1H, ArꢀH, = 8 Hz), 7.70
(d,1H, ArꢀH, = 8 Hz), 7.79 (d, 2H, = 8.6 Hz), 10.2
(s, 1H, NH), 12.42 (bs, 1H, NH); MS ( ): 419
+), 421(M+ + 2); Found for C18H12F3N5O2S
(419.38): C, 51.54; H, 2.86; N, 16.69; S, 7.61; Anal.
calc.: C, 51.55; H, 2.88; N, 16.70; S, 7.65.
Hꢀ[1,2,4]triꢀ
b
N
ꢀ(3ꢀTrifluoromethylphenyl)ꢀ2ꢀ(5
no[5,6ꢀ ]indolꢀ3ꢀylsulfanyl)acetamide (IVf). Yield:
72%, melting point: 238–240 C; IR: 3265 (ꢀNH),
3059 (ArꢀH), 1662 (amide C=O), 650 (C–S); H
NMR (CDCl3): 4.29 (s, 2H, –CH2), 7.17 (m, 2H,
ArꢀH), 7.20 (t, 1H, ArꢀH, = 7.6 Hz), 7.32 (d, 1H,
ArꢀH, = 7.6 Hz), 7.62 (t, 1H, ArꢀH, = 7.6 Hz),
7.64 (d, 1H, ArꢀH, = 8 Hz) 7.83 (s, 1H, ArꢀH), 7.90
(d, 2H, = 7.6 Hz), 10.10 ( s, 1H, NH), 12.43 (bs, 1H,
NH); MS ( ): 403 (
+), 405 ( + + 2); Found for
Hꢀ[1,2,4]triaziꢀ
°
b
°
1
δ
−
J
J
δ
J
J
J
J
J
J
J
m/z
J
(M
J
m/z
M
M
C18H12F3N5OS (403.38): C, 53.54; H, 2.96; N, 17.29;
S, 7.91; Anal. calc.: C, 53.60; H, 3.00; N, 17.36; S,
7.95.
N
ꢀ(5ꢀChloropyridinꢀ2ꢀyl)ꢀ2ꢀ(5 ꢀ[1,2,4]triazino[5,6ꢀ
]indolꢀ3ꢀylsulfanyl)acetamide (IVi). Yield: 79%,
melting point: 232–234 C; IR: 3268 (–NH), 3056
(ArꢀH), 1668 (amide C=O), 656 (C–S); H NMR
H
b
°
N
ꢀ(1,3ꢀThiazolꢀ2ꢀyl)ꢀ2ꢀ(5
dolꢀ3ꢀylsulfanyl)acetamide (IVg). Yield: 66%, melting
point: 237–239 C; IR: 3268 (–NH), 3056 (ArꢀH),
Hꢀ[1,2,4]triazino[5,6ꢀb]inꢀ
1
(CDCl3):
δ
4.32 (s, 2H, –CH2), 7.20 (t, 1H, ArꢀH,
°
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 41
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228
SHRUTHI et al.
J
= 7.6 Hz), 7.32 (d, 1H, ArꢀH,
1H, ArꢀH,
(d, 2H, = 7.6Hz), 8.14 (d, 1H, ArꢀH,
8.32 (d, 1H, ArꢀH, = 9.0 Hz), 10.15 ( s, 1H, NH),
12.35 (bs, 1H, NH); MS ( ): 370 (
+); Found for
J
= 7.6 Hz), 7.62 (t, 16.27; Anal. calc.: C, 54.81; H, 3.58; N, 21.30; S,
J
= 7.6 Hz), 7.86 (dd, 1H, J = 9 Hz), 7.94 16.26.
= 9.0 Hz),
J
J
N
ꢀ(2,5ꢀDichlorophenyl)ꢀ2ꢀ(5
]indolꢀ3ꢀylsulfanyl)acetamide (IVn). Yield: 82%, meltꢀ
ing point: 237–239 C; IR: 3261 (–NH), 3052 (ArꢀH),
1663 (amide C=O), 650 (C–S); H NMR (CDCl3):
Hꢀ[1,2,4]triazino[5,6ꢀ
J
b
m/
z
M
°
C16H11ClN6OS (370.82): C, 51.54; H, 2.96; N, 22.65;
S, 8.63; Anal. calc.: C, 51.58; H, 2.99; N, 22.66; S,
8.65.
1
δ
J
J
J
4.26 (s, 2H, –CH2), 6.83 (s, 1H), 7.32 (t, 1H, ArꢀH,
= 8 Hz), 7.37 (dd, 1H, = 8.6 Hz), 7.40 (d, 1H, ArꢀH;
= 8 Hz), 7.60 (d, 1H, = 8.7 Hz), 7.65 (t, 1H, ArꢀH,
= 8 Hz), 7.70 (d, 1H, ArꢀH, = 8 Hz), 10.33 ( s, 1H,
): 404 (
+);
J
J
N
ꢀ(3,5ꢀDichlorophenyl)ꢀ2ꢀ(5
]indolꢀ3ꢀylsulfanyl)acetamide (IVj). Yield: 88%,
melting point: 235–237 C; IR: 3256 (ꢀNH), 3043
(ArꢀH), 1664 (amide C=O), 657 (C–S); H NMR
(CDCl3): 4.28 (s, 2H, ꢀCH2), 7.26 (t, 1H, ArꢀH,
= 8 Hz), 7.33 ( d, 2H, = 8.4 Hz), 7.39 (d, 1H, Arꢀ
H, = 8 Hz), 7.63 (t, 1H, ArꢀH, = 8 Hz), 7.69
(d,1H, ArꢀH, = 8 Hz), 7.73 (t, 1H, = 8.4 Hz), 7.79
(d, 2H, = 8.0 Hz), 10.23 ( s, 1H, NH), 12.38 (bs, 1H,
NH); MS ( ): 404 (
+); Found for C17H11Cl2N5OS
(404.27): C, 50.54; H, 2.76; N, 17.30; S, 7.91; Anal.
calc.: C, 50.51; H, 2.74; N, 17.32; S, 7.93.
Hꢀ[1,2,4]triazino[5,6ꢀ
b
J
°
NH), 12.28 (bs, 1H, NH); MS (
m/z
M
1
Found for C17H11N5OS (404.27): C, 50.50; H, 2.73;
N, 17.31; S, 7.92; Anal. calc.: C, 50.51; H, 2.74; N,
17.32; S, 7.93.
δ
J
J
J
J
N
ꢀ(2ꢀChloroꢀ4ꢀmethylpyridinꢀ3ꢀyl)ꢀ2ꢀ(5
azino[5,6ꢀ ]indolꢀ3ꢀylsulfanyl)acetamide
Yield: 79%, melting point: 246–248 C; IR: 3263 (ꢀNH),
3059 (ArꢀH), 1661 (amide C=O), 650 (C–S);
1H NMR (CDCl3):
2.36 ( s, 3H), 4.36 (s, 2H, –CH2),
7.36 (t, 1H, ArꢀH, = 8 Hz), 7.45 (d, 1H, ArꢀH, = 8 Hz),
7.66 (t, 1H, ArꢀH, = 8 Hz), 7.76 (d,1H, ArꢀH,
= 8 Hz), 7.83 ( d, 1H, ArꢀH, = 8.4 Hz), 7.90 (d, 1H,
= 8.4 Hz), 10.33 ( s, 1H, NH), 12.29 (bs, 1H, NH);
MS ( ): 384 (
+); Found for C17H13ClN6OS
(384.84): C, 53.05; H, 3.39; N, 21.82; S, 8.32; Anal.
calc.: C, 53.06; H, 3.40; N, 21.84; S, 8.33.
H
ꢀ[1,2,4]triꢀ
J
J
b
(IVo).
J
°
m/z
M
δ
J
J
J
N
ꢀ(2,4,5ꢀTrichlorophenyl)ꢀ2ꢀ(5 ꢀ[1,2,4]triaziꢀ
no[5,6ꢀ ]indolꢀ3ꢀylsulfanyl)acetamide (IVk). Yield:
88%, melting point: 217–219 C; IR: 3268 (–NH),
3054 (ArꢀH), 1660 (amide C=O), 647 (C–S);
1H NMR (CDCl3):
4.26 (s, 2H, –CH2), 7.27 (t,
1H, ArꢀH, = 8 Hz), 7.39 (d, 1H, ArꢀH, = 8 Hz),
7.48 (s, 1H), 7.60 (t, 1H, ArꢀH, = 8 Hz), 7.70
(d,1H, ArꢀH, = 8 Hz), 7.89 (s, 1H), 10.33 ( s, 1H,
NH), 12.28 (bs, 1H, NH); MS ( ): 438.72 (
+),
440.21 (
+ + 2); Found for C17H10Cl3N5OS: C, 46.53;
H, 2.32; N, 15.95; S, 7.33; Anal. calc.: C, 46.54; H,
2.30; N, 15.96; S, 7.31.
ꢀ(3ꢀChloroꢀ4ꢀfluorophenyl)ꢀ2ꢀ(5
ino[5,6ꢀ ]indolꢀ3ꢀylsulfanyl)acetamide (IVl). Yield:
83%, melting point: 232–234 C; IR: 3266 (–NH),
3053 (ArꢀH), 1663 (amide C=O), 654 (C–S);
1H NMR (CDCl3):
4.26 (s, 2H, ꢀCH2), 7.13 (t, 1H,
Ar–H, = 9.0 Hz), 7.27 (t, 1H, ArꢀH, = 8 Hz), 7.31–
7.37 (m, 1H, Ar–H), 7.39 (d, 1H, ArꢀH, = 8 Hz),
7.60 (t, 1H, ArꢀH, = 8 Hz), 7.70 (d,1H, ArꢀH, = 8
Hz), 7.72–7.75 (m, 1H, Ar–H), 7.89 (s, 1H), 10.33(
s, 1H, NH), 12.28 (bs, 1H, NH); MS ( ): 387 (
+);
H
J
J
J
b
°
m/z
M
δ
J
J
J
N
ꢀ(2,4ꢀDifluorophenyl))ꢀ2ꢀ(5 ꢀ[1,2,4]triazino[5,6ꢀ
]indolꢀ3ꢀylsulfanyl)acetamide (IVp). Yield: 89%,
melting point: 226–228 C; IR: 3268 (–NH), 3056
(ArꢀH), 1662 (amide C=O), 657 (C–S); H NMR
(400 MHz, DMSO, ppm); 4.32 (s, 2H, –CH2), 7.36
(t, 1H, ArꢀH, = 8 Hz), 7.39 (d, 1H, ArꢀH, = 8 Hz),
7.52–7.57 ( m, 3H, ArꢀH), 7.66 (t, 1H, ArꢀH, = 8 Hz),
7.76 (d,1H, ArꢀH, = 8 Hz), 10.38 (s, 1H, NH), 12.24
(s, 1H, NH); MS ( ): 371 (
+); Found for
H
J
b
m/z
M
°
1
M
δ
J
J
J
N
Hꢀ[1,2,4]triazꢀ
J
b
m/
z
M
°
C17H11F2N5OS (371.36): C, 54.95; H, 2.98; N, 18.85;
S, 8.62. Anal. calc.: C, 54.98; H, 2.99; N, 18.86; S,
8.63.
δ
J
J
J
N
ꢀ(4ꢀMethylpyridinꢀ3ꢀyl)ꢀ2ꢀ(5
ino[5,6ꢀ ]indolꢀ3ꢀylsulfanyl)acetamide (IVq). Yield:
77%, melting point: 250 C; IR: 3266 (–NH),
3052(ArꢀH), 1669 (amide C=O), 651 (C–S);
1H NMR (CDCl3):
2.33 ( s, 3H), 4.39 (s, 2H, –CH2),
7.38 (t, 1H, ArꢀH, = 8 Hz), 7.45 (d, 1H, ArꢀH,
= 8 Hz), 7.68 (t, 1H, ArꢀH, = 8 Hz), 7.76 (d,1H,
ArꢀH, = 8 Hz), 7.83 ( d, 1H, ArꢀH, = 8.4 Hz), 7.90
(d, 1H, = 8.4 Hz), 8.54 (s, 1H, ArꢀH), 10.33 ( s, 1H,
NH), 12.29 (bs, 1H, NH); MS ( ): 350 (
+);
Hꢀ[1,2,4]triazꢀ
J
J
b
>
°
m/z
M
Found for C17H11ClFN5OS (387.82): C, 52.64; H,
2.85; N, 18.05; S, 8.26; Anal. calc.: C, 52.65; H, 2.86;
N, 18.06; S, 8.27.
δ
J
J
J
J
J
N
ꢀ(1,3ꢀBenzothiazolꢀ2ꢀyl))ꢀ2ꢀ(5
no[5,6ꢀ ]indolꢀ3ꢀylsulfanyl)acetamide (IVm). Yield:
80%, melting point: 233–235 C IR: 3265 (–NH),
3052 (ArꢀH), 1666 (amide C=O), 651 (C–S);
1H NMR (CDCl3):
4.44 (s, 2H, –CH2), 7.29 (t, 1H,
Ar H, = 8 Hz), 7.38–7.50 (m, 2H, benzothiazole–
H),7.58 (d, 1H, ArꢀH, = 8 Hz), 7.67 (t, 1H, ArꢀH,
= 8 Hz), 7.77 (d,1H, ArꢀH, = 8 Hz), 7.95 (d, 1H,
= 8 Hz), 8.27 (d, 1H, = 8 Hz), 10.63 ( s, 1H, NH),
12.78 (bs, 1H, NH); MS ( ): 394 (
+); Found for (1 mmol) and K2CO3 (150 mmol) in 500 mL of water
C18H14N6OS2 (394.47): C, 54.84; H, 3.59; N, 21.28; S,
Hꢀ[1,2,4]triaziꢀ
J
b
m/z
M
°
Found for C17H14N6OS (350.05): C, 58.05; H, 4.02;
N, 23.96; S, 9.12; Anal. calc.: C, 58.07; H, 4.03; N,
23.98; S, 9.15.
δ
ꢀ
J
J
Synthetic procedure for the preparation 2,5ꢀdihyꢀ
J
J
J
droꢀ3Hꢀ[1,2,4]triazino[5,6ꢀb]indoleꢀ3ꢀthione (II). A
J
mixture of Isatin (100 mmol), thiosemicarbazide
m/z
M
was refluxed with stirring for 3 h. On cooling the mixꢀ
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 41
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2015

SYNTHESIS AND BIOLOGICAL EVALUATION
229
ture was filtered and precipitated by acidification with of the tail. After the initial escapeꢀoriented moveꢀ
acetic acid. The solid was washed with water and dried ments, mice develop an immobile posture when
to obtain as yellow solid. Yield: 92%, melting point: placed in an inescapable stressful situation. This
stressful situation involved haemodynamic stress of
196–298
(CDCl3):
1H, ArꢀH,
7.92 (d, 1H, ArꢀH,
exchangeable with D2O), 14.54 (bs, 1H, NH; exꢀ
changeable with D2O); MS ( ): 202 (
+); Found
for C9H6N4S (202.02): C, 53.40; H, 2.96; N, 27.72; S,
15.86; Anal. calc.: C, 53.45; H, 2.99; N, 27.70; S,
15.86.
°
C; IR: 3108 (–NH), 3051 (ArꢀH); 1H NMR
being hung in an uncontrollable fashion by their tail.
The total duration of immobility induced by tail susꢀ
pension was measured. Immobility time was recorded
during a 6ꢀmin period. The animal was immobile only
when they hung passively and completely motionless.
The synthesized compounds (25 mg/kg), and fluoxetꢀ
ine hydrochloride, as a reference drug (30 mg/kg) were
suspended in a 10% aqueous solution of Tween 80. The
percentage decrease in immobility duration (%DID)
for the test and standard drugs was calculated using
following formula:
δ
J
7.27 (t, 1H, ArꢀH,
= 7.6 Hz), 7.55 (t, 1H, ArꢀH,
= 7.6 Hz), 12.43 (bs, 1H, NH;
J
= 7.6 Hz), 7.37 (d,
J
= 7.6 Hz),
J
m/z
M
Antibacterial and Antifungal Activities
%DID = [(A – B)/A] × 100.
Determination of minimum inhibitory concentration
(MIC). The MIC of the samples in DMF was deterꢀ
mined by using different concentrations of extracts in
Brain Heart Infusion Broth for bacteria and fungi by
macro dilution method following NCCLS recomꢀ
mendations [24, 25]. The lowest concentration of the
sample in DMF inhibiting the visible growth of microꢀ
organisms was considered as MIC. The Tube dilution
test is used to determine the minimum inhibitory conꢀ
centration (MIC) of the synthesized compounds
Where A is the duration of immobility(s) in the
control group and B is the duration of immobility(s) in
test groups.
Maximal Electroshock (MES) Test
In the MES test [27, 28], the mice were subjected
to 50 mA alternating current from a convulsiometer
for 0.2 s through a pair of electrodes attached to each
ear. The duration of the tonic hind limb extensor
phase, and the number of animals protected from conꢀ
vulsions were noted. Phenytoin (40 mg/kg) was used
as standard drug.
(
IVa
as diluents. The 24 h old cultures of the test bacteria
S. aureus, E. fecalis E. coli and K. pneumoniae and the
test fungi C. albicans and A. niger were diluted
100 folds in nutrient broth (NB) (100 L bacterial culꢀ
tures in10 mL NB). The stock solution of the syntheꢀ
sized compounds with concentration 1000 g/10
was prepared in DMF. Different concentrations of the
test samples (0.2, 0.4, 0.8, 1.6, 3.125, 6.25, 12.5, 25, 50
and 100 g/mL) were added to the test tubes containꢀ
ing the bacterial and fungal cultures. All the tubes were
incubated at 37 C for 24 h for bacteria and at 28 C for
)–(IVq). Freshly prepared nutrient broth was used
,
μ
CONCLUSION
μ
μL
A new series of
[1,2,4]triazino[5,6ꢀ
N
ꢀ(substituted phenyl)ꢀ2ꢀ(5
Hꢀ
b
]indolꢀ3ꢀylsulfanyl) acetamides
μ
were synthesized in good yields and characterized
well. Most of the derivatives showed good inhibition
against bacterial and fungal strains. Halogen substiꢀ
tuted derivatives showed preferential increase in the
both antidepressant and anticonvulsant activity.
Among the synthesized newer compounds, it is conꢀ
ceivable that some of the derivatives showed promising
biological and pharmacological activities which can be
further modeled to exhibit better potency than the
standard drugs.
°
°
48 h for fungi. The tubes were examined for visible turꢀ
bidity and using NB as a control. Control without test
samples and with solvent was assayed simultaneously.
The lowest concentration that inhibited visible growth
of the tested organisms was recorded as MIC.
Tail Suspension Test (TST)
For the purpose of biological evaluation of syntheꢀ
sized compounds, adult male Swiss Albino mice
(22 2 g) were used. Animals were maintained in huꢀ
midity and temperature controlled room with day–
night cycle. They were allowed to acclimatize to the
environment for one week before commencement of
the experiments. Free access to food and water was
permitted. The mice were housed in Plexiglass cages
with six animals for each cage. Title compounds were
screened for antidepressant activity employing tail
suspension test (TST) [26]. In this test, mice were susꢀ
pended on the edge of a table 50 cm above the floor by
adhesive tape placed approximately 1 cm from the tip
ACKNOWLEDGMENTS
We are grateful to Indian Institute of Science
(IISc), Bangalore and MIT, manipal for providing the
spectral analyses. Ms. SN is thankful to DSTꢀPURSE
for providing financial assistance.
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