Synthesis and screening of some novel substituted indoles contained 1,3,4-oxadiazole and 1,2,4-triazole moiety

Article abstract of DOI:10.1016/j.cclet.2013.01.001

A series of novel 3-[5-(1H-indol-3-yl-methyl)-2-oxo-[1,3,4]oxadiazol-3-yl] propionitrile (5), 3-[4-amino-3-(1H-indol-3-yl-methyl)-5-oxo-4,5-dihydro-[1,2,4] triazol-1-yl]propionitrile (6), 3-[5-(1H-indol-3-yl-methyl)-2-thioxo-[1,3,4] oxadiazol-3-yl]propionitrile (7) and 3-[4-amino-3-(1H-indol-3-yl-methyl)-5- thioxo-4,5-dihydro-[1,2,4]triazol-1-yl]propionitrile (8) were synthesized in good yields from the intermediate (1H-indol-3-yl)-acetic acid N′-(2-cyanoethyl)hydrazide (4). The chemical structures of the newly synthesized compounds were elucidated by their IR, ¹H NMR and MS. Further, all the compounds were screened for their antimicrobial activity against Gram-positive, Gram-negative bacteria and also tested their ability toward anti-inflammatory activity.

Full text of DOI:10.1016/j.cclet.2013.01.001

Chinese Chemical Letters 24 (2013) 127–130
Contents lists available at SciVerse ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Original Article
Synthesis and screening of some novel substituted indoles contained
,3,4-oxadiazole and 1,2,4-triazole moiety
1
a,
b
Hemalatha Gadegoni *, Sarangapani Manda
a
Jayamukhi College of Pharmacy, Narsampet, Warangal 506332, India
b
University College of Pharmaceutical Sciences, Kakatiya University, Warangal 506009, India
A R T I C L E I N F O
A B S T R A C T
A series of novel 3-[5-(1H-indol-3-yl-methyl)-2-oxo-[1,3,4]oxadiazol-3-yl]propionitrile (5), 3-[4-
Article history:
Received 21 August 2012
amino-3-(1H-indol-3-yl-methyl)-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl]propionitrile (6), 3-[5-(1H-
indol-3-yl-methyl)-2-thioxo-[1,3,4]oxadiazol-3-yl]propionitrile (7) and 3-[4-amino-3-(1H-indol-3-yl-
methyl)-5-thioxo-4,5-dihydro-[1,2,4]triazol-1-yl]propionitrile (8) were synthesized in good yields from
Received in revised form 13 December 2012
Accepted 20 December 2012
Available online 5 February 2013
0
the intermediate (1H-indol-3-yl)-acetic acid N -(2-cyanoethyl)hydrazide (4). The chemical structures of
1
the newly synthesized compounds were elucidated by their IR, H NMR and MS. Further, all the
Keywords:
compounds were screened for their antimicrobial activity against Gram-positive, Gram-negative
bacteria and also tested their ability toward anti-inflammatory activity.
ß 2013 Hemalatha Gadegoni. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights
reserved.
1
1
,3,4-Oxadiazols
,2,4-Triazols
Antimicrobial activity
Anti-inflammatory
1
. Introduction
The oxadiazole chemistry has been developed extensively and
stimulants sedatives, antianxiety, antimicrobial agents [16] and
antimycotic activity such as fluconazole, intraconazole, and
voriconazole [17]. Also, there are known drugs containing the
1,2,4-triazole group such as Triazolam [18], Alprazolam [19], and
Furacylin [20]. Moreover, sulphur containing heterocycles repre-
sent an important group of sulphur compounds that are promising
for use in practical applications. Among these heterocycles, the
mercapto and thione substituted 1,2,4-triazole ring systems have
been well studied and so far a variety of biological activities have
been reported for a large number of their derivatives, such as
antibacterial [21], antifungal [22], antitubercular [23], anticancer
[24], diuretic [25] and hypoglycemic [26] properties.
is still developing. Presently there are a number of drugs used
clinically, which comprise oxadiazole moiety in association with
various heterocyclic rings. 1,3,4-Oxadiazoles are biologically
active, synthetically useful and important heterocyclic com-
pounds. The synthesis of novel oxadiazole derivatives and
investigation of their chemical and biological behavior have
gained more importance in recent decades for biological, medicinal
and agricultural reasons. Different classes of oxadiazole com-
pounds possess an extensive spectrum of pharmacological
activities. Differently substituted oxadiazole moiety has also been
found to have other important activities such as antibacterial [1],
antimalarial [2], anti-inflammatory [3], antifungal [4], anticon-
vulsant [5], analgesic [6], antimicrobial [7], antimycobacterial [8],
anticonvulsant [9], antitumor [10], antimalarial [4], herbicidal
2. Experimental
(
1H-indol-3-yl)-acetic acid ethyl ester 2: To the solution of
indole-3-acetic acid (1) (0.01 mol) in absolute ethyl alcohol
25 mL), conc. H SO (2 mL) was added. The mixture was refluxed
[
11], vasodialatory [12], cytotoxic [13], hypolipidemic [14], and
(
2
4
antiedema [15].
for 2 h. After completion of the reaction (monitored by TLC), the
mixture was poured into ice-cold water. Crude product was
In the last few decades, the chemistry of 1,2,4-triazoles and
their fused heterocyclic derivatives has received considerable
attention owing to their synthetic and effective biological
importance. A large number of 1,2,4-triazole-containing ring
system have been incorporated into a wide variety of therapeuti-
cally interesting drug candidates including anti-inflammatory, CNS
3
collected by filtration, washed with 10% NaHCO solution, dried
and recrystallized from ethyl alcohol to get pure product 2. Data for
ꢀ1
2
: Yellow solid, yield: 82%, mp: 125–127 8C; IR (KBr, cm ):
v
3112
(
(
1
N–H, broad), 3024 (C–H, aromatic), 2962 (C–H, aliphatic), 1680
1
C 55 O), 1560 (C 55 C, aromatic); H NMR (300 MHz, DMSO-d
1.12 (s, 1H, NH), 7.85 (s, 1H, CH of indole ring), 7.62 (d, 1H,
J = 2.0 Hz, Ar–H), 7.39 (dd, 2H, J = 2.0, 8.0 Hz, Ar–H), 7.37 (d, 1H,
J = 8.0 Hz, Ar–H), 4.00 (q, 2H, OCH ), 3.45 (s, 2H, CH CO), 1.24 (t, 3H,
6
): d
*
Corresponding author.
2
2
+
E-mail address: hemagadegoni@yahoo.co.in (H. Gadegoni).
3
CH ); MS: m/z 203 (M ).
1
001-8417/$ – see front matter ß 2013 Hemalatha Gadegoni. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2013.01.001

1
28
H. Gadegoni, S. Manda / Chinese Chemical Letters 24 (2013) 127–130
1
(
1H-indol-3-yl)-acetic acid hydrazide 3: a mixture of compound 2
2260 (CBB N), 1690 (C 55 O), 1640 (C 55 N), 1570 (C 55 C, aromatic);
NMR (300 MHz, DMSO-d ): 10.25 (s, 1H, NH), 7.84 (s, 1H, CH of
indole), 7.62 (d, 1H, J = 4.5 Hz, Ar–H), 7.51 (dd, 2H, J = 7.5, 4.5 Hz,
Ar–H), 7.42 (d, 1H, J = 7.0 Hz, Ar–H), 3.72 (s, 2H, NH ), 3.57 (t, 2H,
J = 5.4 Hz, N–CH ), 3.42 (s, 2H, CH ), 2.39 (t, 2H, J = 5.4 Hz, CH );
H
(
0.01 mol) and hydrazine hydrate (0.025 mol) in ethanol (20 mL)
6
d
was refluxed for 7 h, cooled to room temperature and filtered. The
crude product was recrystallized from ethanol to give the new
intermediate 3. Data for 3: Pale yellow solid, yield: 78%, mp: 140–
2
2
+
2
2
ꢀ
1
1
42 8C; IR (KBr, cm ):
v
3330–3200 (NHNH
2
), 3125 (N–H), 3012
MS: m/z 282 (M ).
(
C–H, aromatic), 2945 (C–H, aliphatic), 1640 (C 55 O),1545 (C 55 C,
3-[5-(1H-indol-3-yl-methyl)-2-thioxo-[1,3,4]oxadiazol-3-yl]-
propionitrile 7: A suspension of compound 6 (0.01 mol) and carbon
disulfide (3 mL) in pyridine (6 mL) was heated under reflux on
water bath for 20 h. The solvent was removed under reduced
pressure and the residue was washed with cold water and
neutralized with diluted HCl. The solid product obtained was
filtered off and recrystallized from petroleum ether/ethyl acetate
(2:1) to afford compound 7 in pure form. Data for 7: yellow solid,
1
aromatic); H NMR (300 MHz, DMSO-d
s, 1H, CH of indole), 7.74 (d, 1H, J = 4.5 Hz, Ar–H), 7.42 (dd, 2H,
J = 4.5, 7.5 Hz, Ar–H), 7.28 (d, 1H, J = 7.5 Hz, Ar–H), 7.70 (s, 1H,
6
): d 11.35 (s, 1H, NH), 7.75
(
+
CONH), 5.30 (s, 2H, NH
2
), 3.58 (s, 2H, CH
2
); MS: m/z 189 (M ).
0
(
1H-indol-3-yl)-acetic acid N -(2-cyano ethyl)-hydrazide 4: fresh-
ly distilled acrylonitrile (0.01 mol) was added to a suspension of
compound 3 (0.01 mol) in ethanol (10 mL). The reaction mixture
was heated under reflux for 18 h, and then the solvent was
removed under reduced pressure. The solid precipitate formed was
filtered and recrystallized from ethanol to afford compound 4. Data
ꢀ
1
yield: 74%, mp: 35–137 8C; IR (KBr, cm ):
v3224 (N–H), 3025 (C–
H, aromatic), 2925 (C–H, aliphatic), 2230 (CBB N), 1640 (C 55 N), 1540
1
3
(C 55 C, aromatic), 1160 (C 55 S); H NMR (300 MHz, CDCl ): d 11.02 (s,
ꢀ
1
for 4: brown solid, yield: 72%, mp: 165–167 8C; IR (KBr, cm ):
3290 (N–H), 3018 (C–H, aromatic), 2946 (C–H, aliphatic), 2220
1H, NH), 7.75 (s, 1H, CH of indole), 7.56 (d, 1H, J = 5.0 Hz, Ar–H),
7.48 (dd, 2H, J = 7.5, 5.0 Hz, Ar–H), 7.28 (d, 1H, J = 7.5 Hz, Ar–H),
v
1
(
CBB N), 1665 (C 55 O), 1545 (C 55 C, aromatic); H NMR (300 MHz,
DMSO-d ): 11.53 (s, 1H, NHCO), 11.27 (s, 1H, NH–CH ), 10.12 (s,
H, NH of indole), 7.65 (s, 1H, CH of indole), 7.48 (d, 1H, J = 6.0 Hz,
Ar–H), 7.27 (dd, 1H, J = 4.0, 6.0 Hz, Ar–H), 7.24 (d, 1H, J = 4.0 Hz, Ar–
H), 3.21 (s, 2H, CH CO), 3.07 (m, 2H, CH –N), 2.38 (t, 2H, CH
CBB N); MS: m/z 242 (M ).
3.42 (s, 2H, CH
J = 5.8 Hz, CH ); MS: m/z 284 (M ).
3-[4-Amino-3-(1H-indol-3-yl-methyl)-5-thioxo-4,5-dihydro-
[1,2,4]triazol-1-yl]-propionitrile 8: mixture of compound
2 2
), 3.33 (t, 2H, J = 5.8 Hz, N–CH ), 2.50 (t, 2H,
+
6
d
2
2
1
a
7
2
2
2
–
(0.01 mol) and hydrazine hydrate (5 mL) in ethanol (15 mL) was
heated refluxed for 8 h. After cooling, the solvent was removed
under reduced pressure and the residue obtained was washed with
cold water. The solid product formed was filtered off and
recrystallized from ethanol to afford compound 8. Data for 8:
+
3
-[5-(1H-indol-3-yl-methyl)-2-oxo-[1,3,4]oxadiazol-3-yl]-
0
propionitrile 5: a mixture of 4 (0.01 mol) and N,N -carbonyldiimi-
dazole (0.015 mol) in dry dioxane (20 mL) was heated under reflux
for 16 h, then the reaction mixture is allowed to cool. The solid
product 5 was filtered, washed with water, dried and recrystallized
from petroleum ether/benzene. Data for 5: colorless solid, yield:
ꢀ
1
pale yellow solid, yield: 72%, mp: 154–156 8C; IR (KBr, cm ):
3360 (NH ), 3185 (N–H), 3024 (C–H, aromatic), 2965 (C–H,
aliphatic), 2240 (CBB N), 1640 (C 55 N), 1580 (C 55 C, aromatic), 1210
v
2
ꢀ1
1
7
5%, mp: 140–142 8C; IR (KBr, cm ):
v
3195 (N–H), 3035 (C–H,
(C 55 S); H NMR (300 MHz, CDCl
CH of indole), 7.63 (d, 1H, J = 4.0 Hz, Ar–H), 7.48 (dd, 2H, J = 7.5,
4.0 Hz, Ar–H), 7.41 (d, 1H, J = 7.5 Hz, Ar–H), 5.63 (s, 2H, NH ), 3.65
(s, 2H, CH ), 3.40 (t, 2H, J = 5.4 Hz, N–CH ), 2.49 (t, 2H, J = 5.4 Hz,
CH ); MS: m/z 298 (M ).
3
): d 11.20 (s, 1H, NH), 7.85 (s, 1H,
aromatic), 2955 (C–H, aliphatic), 2220 (CBB N), 1770 (C 55 O), 1640
1
(
C 55 N), 1545 (C 55 C, aromatic); H NMR (300 MHz, DMSO-d
0.48 (s, 1H, NH), 7.78 (s, 1H, CH of indole), 7.47 (d, 1H, J = 4.0 Hz,
Ar–H), 7.36 (dd, 2H, J = 7.0, 4.0 Hz, Ar–H), 7.25 (d, 1H, J = 7.0 Hz, Ar–
H), 3.67 (t, 2H, J = 5.8 Hz, –NCH ), 3.42 (s, 2H, CH ), 2.46 (t, 2H,
J = 5.8 Hz, CH –CBB N); MS: m/z 268 (M ).
-[4-Amino-3-(1H-indol-3-yl-methyl)-5-oxo-4,5-dihydro-
1,2,4]triazol-1-yl]-propionitrile 6: mixture of compound
0.01 mol) and hydrazine hydrate (5 mL) in ethanol (15 mL) was
6
):
d
2
1
2
2
+
2
2
2
+
2
3. Results and discussion
3
[
a
5
The therapeutic importance of these rings prompted us to
develop selective molecules in which a substituent could be
arranged in a pharmacophoric pattern to display higher pharma-
cological activities. Inspired by the biological profile of 1,3,4-
oxadiazoles and their increasing importance in pharmaceutical
and biological fields, and in continuation of our work on the
synthesis of biologically active heterocycles, as a part of our
ongoing project, it was thought worthwhile to undertake the
(
heated under reflux for 7 h. After cooling, the solvent was removed
under reduced pressure and the residue obtained was washed with
water. The solid precipitate formed was filtered off and recrys-
tallized from ethanol to afford product 6 in pure form. Data for 6:
ꢀ
1
pink solid, yield: 70%, mp: 122–124 8C; IR (KBr, cm ):
v
3350
(NH ), 3210 (N–H), 3028 (C–H, aromatic), 2962 (C–H, aliphatic),
2
O
O
O
O
(
iii)
(i)
(ii)
NH NH
NHNH2
OH
OEt
N
H
N
H
4
N
H
N
H
3
1
2
NC
(
iv)
N
CN
CN
CN
N
(vi)
N
N
N
N
O
O
O
N
S
S
N
H
N
H
5
v)
7
(vii)
CN
(
N
N
N
O
NH
NH
2
2
N
H
N
6
8
H
0
Scheme 1. (i) EtOH, H
2
SO
4
, reflux, 2 h; (ii) NH
2
NH
2
ꢁH
2
O, EtOH, reflux, 7 h; (iii) CH
2
5CHCN, EtOH, reflux, 18 h; (iv) N,N -carbonyldiimidazole, dioxane, reflux, 16 h; (v)
NH NH O, EtOH, reflux, 7 h; (vi) CS
2
ꢁH
2 2
2
, pyridine, reflux, 20 h; and (vii) NH
2
NH O, EtOH, reflux, 8 h.
2
ꢁH
2

H. Gadegoni, S. Manda / Chinese Chemical Letters 24 (2013) 127–130
129
synthesis of the 3-[5-(1H-indol-3-yl-methyl)-2-oxo-[1,3,4]oxadia-
zol-3-yl]-propionitrile (5) with the view to obtain certain new
chemical entities with two active pharmacophores in a single
molecular frame work for the intensified biological activities. The
synthetic route leading to the title compounds is summarized in
Scheme 1. Accordingly, in this manuscript we describe the
synthesis of 5 from commercially available indole-3-acetic acid
(1). The (1H-indol-3-yl)-acetic acid ethyl ester (2), the key
intermediate, has been prepared under reflux of compound 1 in
ethanol for 2 h in 82% yield. The (1H-indol-3-yl)-acetic acid
hydrazide (3), intermediatefor the synthesisof the titlecompounds,
has been prepared by the condensation of compound 2 with
hydrazine hydrate in the presence of ethanol solvent at reflux for 7 h
in 78% yield. Then 3 was reacted with acrylonitrile in ethanol at
0
reflux for 18 h, to get (1H-indol-3-yl)-acetic acid N -(2-cyanoethyl)-
hydrazide (4) in 72% yield. Further, the compound 4, when reacted
0
with N,N -carbonyldiimidazole (CDI) in dioxane under reflux
temperature for 16 h afforded the title compounds, 3-[5-(1H-
indol-3-yl-methyl)-2-oxo-[1,3,4]oxadiazol-3-yl]propionitrile (5) in
75% yield. 3-[4-amino-3-(1H-indol-3-yl-methyl)-5-oxo-4,5-dihy-
dro-[1,2,4]triazol-1-yl]propionitrile(6) isobtained afterpurification
by column chromatography in 70% isolated yields through reaction
of 5 with hydrazine hydrate of under the influence of ethanol as
solvent. Thus the reaction was carried out under reflux for 7 h to
obtain compound 6. The other title compound 7 has been prepared
by the cyclization reaction of 4 with carbon disulphide, in the
presence of pyridine, under reflux for 20 h in yield 74%. Further, the
compound 7 reacted with hydrazine hydrate in the presence of
ethanolat refluxtemperature for 8 h, formedthe 3-[4-amino-3-(1H-
indol-3-yl-methyl)-5-thioxo-4,5-dihydro-[1,2,4]triazol-1-yl]pro-
pionitrile (8) in 72% yield.
3.1. Antibacterial activity
The in vitro antibacterial activity of the newly prepared
compounds was screened against three representative Gram-
positive bacteria viz., Bacillus subtilis, Staphylococcus aureus and
Micrococcus luteus, three Gram-negative bacteria viz., Proteus
vulgaris, Salmonella typhimurium and Escherichia coli by the broth
dilution method. Amphicillin was used as a standard drug, the
lowest concentration (highest dilution) required to arrest the
growth of bacteria was regarded as minimum inhibitory concen-
tration (MIC,
mg/mL), were determined and compared with the
control. The investigation of antibacterial screening data revealed
that all the tested compounds exhibited interesting biological
activity however, with a degree of variation. Compound 5 against S.
typhimurium, compound 6 toward E. coli, compounds 6 and 8
against P. vulgaris and compound 8 against B. subtilis, S. aureus is
highly active at 1.56 or 3.12
mg/mL concentration, which is equal
to the standards. Compounds 6, 7 and 8 also showed good
antibacterial activity against S. aureus, B. subtilis and M. luteus
respectively. The remaining compounds showed moderate to good
antibacterial activity (Table 1).
3.2. Anti-inflammatory activity
The anti-inflammatory activity of the target compounds 5–8 (at
a dose of 10 mg/kg body weight) was determined in vivo by the
acute carrageenan-induced paw edema standard [27]. The anti-
inflammatory properties were recorded at successive time
intervals 0.5, 1, 2, 3, and 4 h and compared with that of
Indomethacin (at a dose of 10 mg/kg body weight) which was
used as a reference standard. From the obtained results (Table 1) it
was noticed that after 1 h, all the tested compounds exhibit
considerable anti-inflammatory properties which reveal remark-
able activities, with potency (percentage edema inhibition of the

1
30
H. Gadegoni, S. Manda / Chinese Chemical Letters 24 (2013) 127–130
0
(
(
3 -pentadecylaryloxyalkyl)-1,3,4-oxadiazo-les, Eur. J. Med. Chem. 25
tested compounds relative to percentage edema inhibition of
Indomethacin) of 0.70, 0.65, 0.57 and 0.74, respectively.
1990) 541–548.
[
[
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[
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(
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