Synthesis, characterization and anticonvulsant potential of 2,5-disubstituted 1,3,4-oxadiazole analogues

Article abstract of DOI:10.14233/ajchem.2019.22061

A new series of compounds in which benzimidazole, oxadiazole and quinoline were incorporated, was synthesized and investigated for their anticonvulsant activity. Some of the newly synthesized compounds have shown good anticonvulsant activity. Significant

Full text of DOI:10.14233/ajchem.2019.22061

Asian Journal of Chemistry; Vol. 31, No. 6 (2019), 1389-1397
A
SIAN
J
OURNAL OF HEMISTRY
C
https://doi.org/10.14233/ajchem.2019.22061
Synthesis, Characterization and Anticonvulsant
Potential of 2,5-Disubstituted 1,3,4-Oxadiazole Analogues
1,*,
2
RAJNISH KUMAR
and MOHD. MUSTAQEEM ABDULLAH
1Department of Pharmaceutical Chemistry, Noida institute of Engineering and Technology (Pharmacy Institute), Plot No. 19, Knowledge Park 2,
Greater Noida-201306, India
2Department of Pharmaceutical Chemistry, ANA Institute of Pharmaceutical Sciences and Research, Agras Road, Near Rubber Factory,
National Highway 24, P.O. Bhitaura, Bareilly-243501, India
*Corresponding author: E-mail: mpharm.rajnish@gmail.com
Received: 9 March 2019;
Accepted: 3 April 2019;
Published online: 29 April 2019;
AJC-19385
A new series of compounds in which benzimidazole, oxadiazole and quinoline were incorporated, was synthesized and investigated for
their anticonvulsant activity. Some of the newly synthesized compounds have shown good anticonvulsant activity. Significant anticonvulsant
potency of the prepared derivatives has been evaluated by minimal electroshock and subcutaneous pentylenetetrazole animal model
methods. The structure of synthesized compounds indicated that the introduction of strong electron donating groups like methoxy, amino
and hydroxyl group and weak electron withdrawing halogen at phenyl ring attached to 1,3,4-oxadiazole moiety causes improvement in
anticonvulsant activity. Locomotor behaviour was evaluated by actophotometer and toxicology study was also performed to evaluate their
significance as required anticonvulsant compounds.
Keywords: Benzimidazole, Quinoline, 1,3,4-Oxadiazoles, Anticonvulsant, Locomotor activity.
up in the market, the improvement of novel specialists, especially
compounds powerful against complex partial seizures, remains
a noteworthy focal point of antiepileptic medicate inquire about
epilepsy [6,7]. Nitrogen-containing heterocyclic compounds
possess the variety of pharmacological activities , among them
1,3,4-oxadiazoles, benzimidazole and quinoline derivatives are
associated with diverse biological activities, such as antibacterial
[8-10], antimalarial [11-13], anti-inflammatory [14-16] and
antifungal [17-19]. Several investigations have also revealed
that compounds consisting 1,3,4-oxadiazole, benzimidazole
and quinoline pharmacophores in their structure, constitute
vary good anticonvulsant potential [20-26]. In this study, hybrid
phamacophore approach has been used as rational drug design
process to design the new antiepileptic compounds [27]. The
hybrid pharmacophores approach aims the utilization of more
than one pharmacophores (each of them has potential pharmaco-
logical activity) in single molecule to produce compounds with
better pharmacological activity. Therefore, in this context to
increase the efficacy of the compounds as well as find out the
drugs which are effective in both MES and PTZ seizure model,
INTRODUCTION
The epilepsies are normal and every now and again obli-
terating neurological confusion with several distinct forms.
Spontaneous epileptic seizures frequently cause flashing incap-
acitate of cognizance, leaving the persons in danger of imped-
ance in their well being and also public activity. If there is any
occurrence of seizures, neither successful prophylaxis nor fix
is accessible till now as treatment is symptomatic [1,2].About
75-80 % of epileptic patients might be given satisfactory seizure
control with the assistance of regular antiepileptic drugs. Regard-
less of the advancement of a few new anticonvulsants, the medi-
cations of epilepsy still stay insufficient. Be that as it may,
over 30 % of individuals with epilepsy don't have seizure control
even with the best accessible medicine [3]. Compliance with
medicine is the big problem because epilepsy needs long-term
treatment with unwanted effects of many drugs [4,5]. Defiance
of continuous discovery of new molecules, epilepsy cannot
be treated unambiguously. Albeit older, first generation and
newer, second generation antiepileptic medications have showed
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1390 Kumar et al.
Asian J. Chem.
we clubbed three dynamic pharmacophores 1,3,4-oxadiazole,
benzimidazole and quinoline which are required to yield syner-
gistic impacts to the subsequent compounds by synthesizing
2-chloro-3-(1-(5-substituted-1,3,4-oxadiazaol-2-yl)methyl)-
1H-benzo[d]imidazole-2-yl)quinoline (6a-m), 5-{[2-(2-chloro-
quinolin-3-yl)-1H-benzimidazole-1-yl]methyl)-2,5-dihydro-
1,3,4-oxadiazole-2-thiol (7), 1,2-dihydro-1-((5-substituted
1,3,4-oxadiazaol-2-yl)methyl)-2-oxoquinoline-3-carbaldehyde
(11a-e) and 1,2-dihydro-1-((5-mercapto-1,3,4-oxadiazol-2-
yl)methyl)-2-oxoquinoline-3-carbaldehyde (12) from acetanilide.
(C-1, quinoline), 129.4 (C-6, quinoline), 128.1 ( C-5,8, quinoline),
127.2 (C-7, quinoline), 126.8 ( C-9, quinoline), 119.4 ( C-7,8,
benzimidazole), 114.2 (C-6,9, benzimidazole), 32.9 (CH2); EI-
MS (m/z): 351.08 (M+);Anal. calcd. (found) % for C18H14N5OCl
(m.w. 351.78): C, 61.46 (61.22); H, 4.01 (3.83); N, 19.91
(19.78).
General method for the synthesis of 2-chloro-3-(1-(5-
substituted-1,3,4-oxadiazaol-2-yl)methyl)-1H-benzo[d]-
imidazole-2-yl)quinoline (6a-m):A mixture of 2-[2-(2-chloro-
quinolin-3-yl)-1H-benzimidazole-1-yl]acetohydrazide (5)
(0.025 mol) and different substituted benzoic acid (0.025 mol)
was refluxed in the presence of POCl3 (10-15 mL) for 6-10 h
at 110-120 ºC.After completion of reaction, mixture was cooled
at room temperature and poured into crushed ice. On basifi-
cation of sodium bicarbonate (5 %) a solid mass was so separated
was washed with water and crystallized from ethanol.
2-Chloro-3-{1-[(5-phenyl-1,3,4-oxadiazol-2-yl)methyl]
-1H-benzimidazol-2-yl}quinoline (6a):Yield 81 %, m.p. 215-
217 ºC; IR (KBr, νmax, cm-1): 3098 (C-H, Ar), 1494 (C=C, Ar),
EXPERIMENTAL
2-Chloroquinoline-3-carbaldehyde (2): Compound 2
was synthesized from Vilsmeier-Haack reaction as described
[28]. Yield 66 %, m.p. 147 ºC.
3-(1H-benzimidazole-2-yl)-2-chloroquinoline (3): It
was prepared as described [29].Yield 79 %, m.p. 219-223 ºC.
Ethyl-[2-(2-chloroquinoline-3-yl)-1H-benzimidazole-
1-yl)acetate (4): Ethyl chloroacetate (0.12 mol) and K2CO3
(0.20 mol) were added to a 60 mL acetone solution of 3-(1H-
benzimidazole-2-yl)-2-chloroquinoline (3) (0.1 mol), then the
solution was refluxed for 8h. After cooling to room temper-
ature, the reaction mixture was filtered. Excess acetone was
removed from the clear filtrate by distillation, and then was
added to water. The residue was washed with water, and then
dried under air. Further purification was done by recrystal-
lization from ethyl acetate to give ethyl-[2-(2-chloroquinoline-
3-yl)-1H benzimidazole-1-yl]acetate (4):Yield 75 %, m.p. 231-
234 ºC; IR (KBr, νmax, cm-1): 3098.42 (C-H, Ar), 1743 (C=O),
1494.95 (C=C, Ar), 1347 (C-N), 1292, 1163 (C-O); 1H NMR
(300 MHz, DMSO-d6) δ ppm: 8.68-8.63 (d, 2H, Ar), 8.28-8.24
(m, 4H, Ar), 8.18 (s, 1H, Ar), 7.50-7.40 (t, 4H, Ar), 3.49-3.47
(q, 2H, CH2), 2.21-2.03 (t, 3H, CH3); 13C NMR (100 MHz,
DMSO-d6) δ ppm: 166.3 (C-2, C=O), 153.3 (C-2, benzimida-
zole), 151.6 (C-2, quinoline), 146.4 (C-9, quinoline), 138.9 (C-4,
benzimidazole), 136.4 (C-10, quinoline), 134.3 (C-5, benzimi-
dazole), 130.1 (C-1,6, quinoline), 128.1 (C-8, quinoline), 126.7
(C-5,7, quinoline), 126.8 (C-4, quinoline), 123 (C-7,8, benzimi-
dazole), 115.3 (C-6,9, benzimidazole), 64.4 (CH2), 50.8 (CH2),
14.1 (CH3); EI-MS (m/z): 365.09 (M+); Anal. calcd. (found)
% for C20H16N3O2Cl (m.w. 365.81): C, 65.67 (65.47); H, 4.41
(4.24); N, 11.49 (11.18).
2-[2-(2-Chloroquinolin-3-yl)-1H-benzimidazole-1-yl]-
acetohydrazide (5): Mixture of ethyl [2-(2-chloroquinoline-
3-yl)-1H-benzimidazole-1-yl]acetate (4) and hydrazine hydrate
was refluxed in the presence of ethanol (10-15 mL) for 10-14 h
at 110-120 ºC.After completion of reaction, mixture was cooled
at room temperature and poured into crushed ice.A white solid
precipitate was obtained which was washed with water and
recrystallized from ethanol. Yield 62 %; m.p. 226-230 ºC; IR
(KBr, νmax, cm-1): 3248.69 (N-H), 3125.40 (C-H, Ar), 1650.95
(C=O), 1497.99 (C=C, Ar), 1293.06, 1184.86 (C-O); 1H NMR
(300MHz, DMSO-d6) δ ppm: 8.94 (s, 1H, CONH); 8.75-8.71
(t, 4H, Ar), 8.45 (s, 1H, Ar), 7.55-7.41 (m, 4H, Ar), 4.03 (s, 2H,
NH2), 3.86-3.85 (s, 2H, CH2); 13C NMR (100 MHz, DMSO-d6) δ
ppm: 161.7 (CONH2), 151.8 (C-2, benzimidazole), 147.2 (C-2,
quinoline), 145.9 (C-4, quinoline), 138.9 (C-4, benzimidazole),
135.9 (C-10, quinoline), 133.2 (C-5, benzimidazole), 131.4
1
1347 (C-N), 1292 (C-O); H NMR (300 MHz, DMSO-d6) δ
ppm: 8.76-8.74 (m, 3H, Ar), 8.24-8.20 (m, 3H, Ar), 7.78-7.75
(t, 1H, Ar), 7.64-7.60 (t, 2H, Ar), 7.56-7.53 (t, 2H, Ar), 7.50-
7.47 (t, 2H,Ar), 4.63 (s, 2H, CH2); 13C NMR (100 MHz, DMSO-
d6) δ ppm: 165.3, (C-5, oxadiazole), 161.6 (C-2, oxadiazole),
154.2 (C-2, benzimidazole), 147.4 (C-2, quinoline), 142.2 (C-4,
quinoline), 137.6 (C-4, benzimidazole), 136.4 (C-10, quino-
line), 134.3 (C-5, benzimidazole), 131.4 (C-1, quinoline), 130.8
(C-6, quinoline), 129.3 ( C-3, 5, phenyl), 128.8 (C-4, phenyl),
128.1 (C-8, quinoline), 127.9 (C-5, quinoline), 127.5 (C-2,6,
phenyl), 127.2 (C-7, quinoline), 126.8 (C-9, quinoline), 126.2
(C-1, phenyl), 118.9 (C-7,8, benzimidazole), 113.8 (C-6,9,
benzimidazole), 45.8 (CH2); EI-MS (m/z): 437.10 (M+);Anal.
calcd. (found) % for C25H16N5OCl (m.w. 437.88): C, 68.57
(68.32); H, 3.68 (3.43); N, 15.99 (15.74).
2-Chloro-3-(1-{[5-(4-nitrophenyl)-1,3,4-oxadiazol-2-yl]-
methyl}-1H-benzimidazol-2-yl)quinoline (6b):Yield 87 %,
m.p. 102-104 ºC; IR (KBr, νmax, cm-1): 3187 (C-H, Ar), 1610
(C-NO2), 1490 (C=C), 1315 (C-N), 1196 (C-O), 1044 (N-N);
1H NMR (300 MHz, DMSO-d6) δ ppm: 8.49 (s, 1H, Ar), 7.56-
7.53 (d, 6H, Ar), 7.55-7.47 (t, 4H, Ar), 6.57-6.53 (d, 2H, Ar),
4.52 (s, 2H, CH2); 13C NMR (100 MHz, DMSO-d6) δ ppm:
166.2 (C-5, oxadiazole), 164.6 (C-2, oxadiazole), 152.6 (C-2,
benzimidazole), 148.4 (C-2, quinoline), 147.7 (C-4, phenyl),
136.4 (C-4, quinoline), 132.7 (C-3, quinoline), 131.3 (C-1,
phenyl), 130.8 (C-7, quinoline), 130.9 (C-7, benzimidazole),
127.4 (C-2,6, phenyl), 127.2 (C-5, quinoline), 126.9 (C-8, quino-
line), 125.8 (C-6, quinoline), 121.2 (C-5,6, benzimidazole), 120.4
(C-3,5, phenyl), 115.7 (C-4, benzimidazole), 43.2 (CH2); EI-MS
(m/z): 482.08 (M+); Anal. calcd. (found) % for C25H16N5OCl
(m.w. 482.87): C, 62.18 (61.88); H, 3.13 (3.07); N, 17.40 (17.18).
2-Chloro-3-(1-((5-(4-methoxyphenyl)-1,3,4-oxadiazaol-
2-yl)methyl)-1H-benzo[d]imidazole-2-yl)quinoline (6c):Yield
92 %, m.p. 176-178 6C; IR (KBr, νmax, cm-1): 3085 (C-H, Ar),
1748 (C=O), 1485 (C=C,Ar), 1341 (C-N), 1282 (C-O); 1H NMR
(300 MHz, DMSO-d6) δ ppm: 8.51 (s, 1H, Ar), 7.78-7.75 (d,
2H, Ar), 7.64-7.60 (d, 2H, Ar), 7.57-7.53 (t, 4H, Ar), 6.50-6.48
(d, 4H, Ar), 4.53 (s, 2H, CH2), 3.52 (s, 3H, OCH3); 13C NMR
(100 MHz, DMSO-d6) δ ppm: 166.6 (C-5, oxadiazole), 164.7

Vol. 31, No. 6 (2019)
Synthesis and Anticonvulsant Potential of 2,5-Disubstituted 1,3,4-Oxadiazole Analogues 1391
(C-2, oxadiazole), 160.4 (C-4, phenyl), 152.7 (C-2, benzimida-
zole), 150.8 (C-2, quinoline), 134.6 (C-4, quinoline), 131.2 (C-7,
quinoline), 128.5 (C-2,6, phenyl), 127.6 (C-6,8, quinoline), 126.8
(C-3, quinoline), 125.9 (C-5, quinoline), 121.7 (C-5,6 benzimi-
dazole), 118.6 (C-1, phenyl), 117.5 (C-7, benzimidazole), 116.2
(C-4, benzimidazole), 114.3 (C-3,5, phenyl), 53.5 (CH2); EI-MS
(m/z): 467.11 (M+); Anal. calcd. (found) % for C26H18N5O2Cl
(m.w. 467.9): C, 66.74 (66.67); H, 3.88 (3.71); N, 14.97 (14.62).
2-Chloro-3-(1-{[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-
methyl}-1H-benzimidazol-2-yl)quinoline (6d):Yield 89 %,
m.p. 156-158 ºC; IR (KBr, νmax, cm-1): 3064 (C-H, Ar), 1492
(C=C), 1350 (C-N), 1268 (C-O), 1068 (N-N), 678 (C-Cl); 1H
NMR (300MHz, DMSO-d6) δ ppm: 8.39 (s, 1H, Ar), 8.24-8.20
(m, 4H, Ar), 7.60 (s, 1H, Ar), 7.58-7.56 (t, 2H, Ar), 7.56-7.53
(q, 4H, Ar), 7.50-7.48 (t, 2H, Ar), 3.95 (s, 2H, CH2); 13C NMR
(100 MHz, DMSO-d6) δ ppm: 165.3 (C-5, oxadiazole), 163.4
(C-2, oxadiazole), 151.6 (C-2, benzimidazole), 151.4 (C-2, quino-
line), 137.6 (C-4, quinoline), 135.7 (C-4, phenyl), 134.8 (C-7,
benzimidazole), 132.4 (C-3, quinoline), 131.6 (C-8, quinoline),
129.3 (C-3,5, phenyl), 128.8 (C-12, 13, phenyl), 128.1 (C-6,
quinoline), 127.2 (C-7, 9, quinoline), 124.1 (C-1, phenyl), 122.4
(C-5,6 benzimidazole), 115.5 (C-4, benzimidazole), 45.6 ( CH2);
EI-MS (m/z):471.06(M+);Anal. calcd. (found)%forC25H15N5OCl2
(m.w. 472.32): C, 63.57 (63.17); H, 3.20 (3.01); N, 14.83 (14.42).
2-Chloro-3-(1-{[5-(2,4-dichlorophenyl)-1,3,4-oxadiazol-
2-yl]methyl}-1H-benzimidazol-2-yl)quinoline (6e):Yield 48 %,
m.p. 234-236 ºC; IR (KBr, νmax, cm-1): 3069 (C-H, Ar), 1490
(C=C), 1350 (C-N), 1280 (C-O), 1061 (N-N), 670 (C-Cl); 1H
NMR (300 MHz, DMSO-d6) δ ppm: 8.39 (s, 1H, Ar), 8.18-8.16
(m, 2H, Ar), 7.60 (s, 1H, Ar), 7.57-7.54 (t, 2H, Ar), 7.52-7.47
(t, 2H, Ar), 4.57-4.53 (q, 4H, Ar), 1.27 (s, 2H, CH2); 13C NMR
(100 MHz, DMSO-d6) δ ppm: 164.7 (C-2, oxadiazole), 163.2
(C-5, oxadiazole), 153.3 (C-2, benzimidazole), 150.9 (C-2, quino-
line), 136.4 (C-4, quinoline), 135.7 (C-4, phenyl), 135.3 (C-1,
phenyl), 133.7 (C-2, phenyl), 131.4 (C-3, quinoline), 131.0 (C-7,
quinoline), 130.3 (C-6, phenyl), 128.1 (C-5, quinoline), 127.9
(C-8, quinoline), 127.6 (C-5, phenyl), 125.1 (C-6, quinoline),
123.8 (C-5,6, benzimidazole), 113.5 (C-4,7, benzimidazole),
46.8 (CH2); EI-MS (m/z): 505.02 (M+); Anal. calcd. (found) %
for C25H14N5OCl3 (m.w. 506.77): C, 59.25 (59.09); H, 2.78
(2.56); N, 13.82 (13.57).
2-(5-((2-(2-Chloroquinolin-3yl)-1H-benzo[d]imidazol-
1-yl)methyl)-1,3,4-oxadiazol-2-yl)phenol (6f): Yield 48 %,
m.p. 84 ºC; IR (KBr, νmax, cm-1): 3578 (O-H), 3056 (C-H, Ar),
2945 (C-H), 1487 (C=C), 1340 (C-N), 1254 (C-O), 1058 (N-N);
1H NMR (300 MHz, DMSO-d6) δ ppm: 8.31( s, 1H, Ar), 7.98-
7.68 (d, 4H, Ar), 7.54-7.43 (t, 2H, Ar), 7.29-7.22 (m, 3H, Ar),
7.01-6.79 (m, 3H, Ar), 4.85 (s, 1H, OH), 3.89 (s, 2H, CH2);
13C NMR (100 MHz, DMSO-d6) δppm: 164.5 (C-2, oxadiazole),
161.7 (C-5, oxadiazole), 155.3 (C-1, phenyl), 153.3 (C-2, benzimi-
dazole), 148.6 (C-2, quinoline), 143.9 (C-1, quinoline), 136.7
(C-4, benzimidazole), 136.2 (C-10, quinoline), 132.3 (C-5, benzi-
midazole), 131.4 (C-4, quinoline), 128.4 (C-6, quinoline),
130.2 (C-4, phenyl), 128.9 (C-6, phenyl), 128.1 (C-8, quino-
line), 127.9 (C-5,7, quinoline), 126.8 (C-9, quinoline), 123.2
(C-7,8, benzimidazole), 121.9 (C-5, phenyl), 116.4 (C-3,
phenyl), 115.3 (C-6,9, benzimidazole), 112.2 (C-2, phenyl),
45.8 (CH2); EI-MS (m/z): 453.09 (M+); Anal. calcd. (found)
% for C25H16N5O2Cl (m.w. 453.87): C, 66.16 (66.27); H, 3.55
(3.59); N, 15.43 (15.61).
2-Chloro-3-(1-((5-(2-chlorophenyl)-1,3,4-oxadiazol-2-
yl)methyl)-1H-benzo[d]imidazol-2-yl)quinoline (6g):Yield
63 %, m.p. 123-124 ºC; IR (KBr, νmax, cm-1): 3039 (C-H, Ar),
2918 (C-H), 1447 (C=C), 1354 (C-N), 1291 (C-O), 1128 (N-N);
1H NMR (300 MHz, DMSO-d6) δ ppm: 8.48 ( s, 1H,Ar), 8.15-
7.63 (d, 4H, Ar), 7.51-7.39 (t, 2H, Ar), 7.32-7.26 (d, 2H, Ar),
7.21-7.13 (t, 4H, Ar), 4.62 (s, 1H, CH2); 13C NMR (100 MHz,
DMSO-d6) δppm: 164.5 (C-2, oxadiazole), 162.6 (C-5, oxadia-
zole), 153.3 (C-2, benzimidazole), 149.8 (C-2, quinoline), 143.6
(C-1, quinoline), 138.9 (C-4, benzimidazole), 137.2 (C-1, phenyl),
136.4 (C-10, quinoline), 134.3 (C-5, benzimidazole), 132.3 (C-1,
phenyl), 131.4 (C-4, quinoline), 129.9 (C-6, quinoline), 130.2
(C-4, phenyl), 129.4 (C-3, phenyl), 128.9 (C-6, phenyl), 128.1
(C-8, quinoline), 127.9 (C-5, quinoline), 127.4 (C-5, phenyl),
127.2 (C-7,9, quinoline), 121.7 (C-7,8, benzimidazole), 117.4
(C-6,9, benzimidazole), 45.8 (CH2); EI-MS (m/z): 471.06 (M+);
Anal. calcd. (found) % for C25H15N5OCl2 (m.w. 472.32): C, 63.57
(63.32); H, 3.20 (3.04); N, 14.83 (14.72).
2-Chloro-3-(1-((5-(pyridine-3-yl)-1,3,4-oxadiazol-2-
yl)methyl)-1H-benzo[d]imidazol-2-yl)quinoline (6h):Yield
87 %, m.p. 112-123 ºC; IR (KBr, νmax, cm-1): 3142 (C-H, Ar),
3037 (C-H), 1417 (C=C), 1364 (C-N), 1268 (C-O), 1047 (N-N);
1H NMR (300 MHz, DMSO-d6) δ ppm: 8.81 (s, 1H, Ar), 8.55
(s, 1H, Ar), 8.52-7.68 (m, 5H, Ar), 7.61 (t, 3H, Ar), 7.34 (t,
2H, Ar), 4.99 (s, 2H, CH2); 13C NMR (100 MHz, DMSO-d6) δ
ppm: 166.7 (C-2, oxadiazole), 164.2 (C-5, oxadiazole), 153.3
(C-2, benzimidazole), 151.3 (C-2, quinoline), 149.1 (C-2,
pyridine), 148 (C-4, pyridine), 143.8 (C-4, quinoline), 138.9
(C-4, benzimidazole), 136.4 (C-10, quinoline), 134.3 (C-5, benzi-
midazole), 134.1 (C-6, pyridine), 131.4 (C-1, 6, quinoline),
128.1 (C-5, 8, quinoline), 127.5 (C-7, quinoline), 125.9 (C-9
quinoline), 124.5 (C-1, 5, pyridine), 122.4 (C-7,8, benzimi-
dazole), 113.8 (C-6, 9, benzimidazole), 54.4 (CH2); EI-MS
(m/z): 438.09 (M+); Anal. calcd. (found) % for C24H15N6OCl
(m.w. 438.86): C, 65.68 (65.47); H, 3.45 (3.21); N, 19.15 (19.19).
2-(5-((2-(2-Chloroquinolin-3-yl)-1H-benzo[d]imidazol-
1-yl)methy)-1,3,4-oxadiazol-2-yl)benzamine (6i):Yield 42 %,
m.p. 85-87 ºC; IR (KBr, νmax, cm-1): 3176 (N-H), 3050 (C-H,
Ar), 2948 (C-H), 1609 (C=N), 1430 (C=C), 1342 (C-N), 1291
1
(C-O), 1076 (N-N); H NMR (300 MHz, DMSO-d6) δ ppm:
8.62 (s, 1H, Ar), 7.85-7.68 (m, 4H, Ar), 7.42-7.24 (t, 4H, Ar),
7.13-6.52 (m, 4H, Ar), 5.09 (s, 2H, CH2), 3.86 (s, 2H, NH2);
13C NMR (100 MHz, DMSO-d6) δ ppm: 165.2 (C-2, oxadia-
zole), 162.9 ( C-5, oxadiazole), 151.8 (C-2, benzimidazole),
147.9 (C-2, quinoline), 144.2 (C-4, quinoline), 142.1 (C-1,
phenyl), 137.4 (C-4, benzimidazole), 136.4 (C-10, quinoline),
134.3 (C-5, benzimidazole), 131.4 (C-6,9, quinoline), 129.6
(C-4, phenyl), 128.3 (C-6, phenyl), 128.1 (C-5, 8, quinoline),
127.2 (C-1,7, quinoline) , 124.4 (C-2, phenyl), 119.4 (C-7,8,
benzimidazole), 117.4 C-3, 5, phenyl), 112.6 (C-6,9, benzimi-
dazole), 52.1 (CH2); EI-MS (m/z): 452.11 (M+); Anal. calcd.
(found) % for C25H17N6OCl (m.w. 452.89): C, 66.30 (66.12);
H, 3.78 (3.52); N, 18.56 (18.47).
2-Chloro-3-(1-((5-2-methoxyphenyl)-1,3,4-oxadiazol-
2-yl)methyl)-1H-benzo[d]imidazol-2-yl)quinolone (6j):
Yield 57 %, m.p. 187-189 ºC; IR (KBr, νmax, cm-1): 3063 (C-H,

1392 Kumar et al.
Asian J. Chem.
Ar), 2959 (C-H), 1395 (C=C), 1335 (C-N), 1286 (C-O), 1064
(N-N); 1H NMR (300 MHz, DMSO-d6) δ ppm: 8.48-7.68 (m,
5H, Ar), 7.61-7.43 (t, 2H, Ar), 7.37 (d, 1H, Ar), 7.24-6.83 (m,
5H, Ar), 5.19 (s, 2H, CH2), 3.73 (s, 3H, OCH3); 13C NMR (100
MHz, DMSO-d6) δ ppm: 163.7 (C-2, oxadiazole), 159.4 (C-5,
oxadiazole), 154.6 (C-1, phenyl), 151.8 (C-2, benzimidazole),
148.2 (C-2, quinoline), 143.9 (C-1, quinoline), 137.4 (C-4,
benzimidazole), 135.4 (C-10, quinoline), 133.6 (C-5, benzimi-
dazole), 131.4 (C-4,6, quinoline), 129.8 (C-4, phenyl), 128.5
(C-6, phenyl), 128.0 (C-8, quinoline), 127.5 (C-5,7, quinoline),
125.5 (C-9, quinoline), 124.1 (C-7,8, benzimidazole), 120.1
(C-5, phenyl), 111.2 (C-6,9, benzimidazole), 114.8 (C-3, phenyl),
110.6 (C-2, phenyl), 56.2 (CH3), 48.4 (CH2); EI-MS (m/z):
467.11 (M+); Anal. calcd. (found) % for C26H18N5O2Cl (m.w.
467.90): C, 66.74 (66.81); H, 3.88 (3.63); N, 14.97 (14.58).
4-(5-((2-(2-Chloroquinolin-3-yl)-1H-benzo[d]imidazol-
1-yl)methy)-1,3,4-oxadiazol-2-yl)benzenamine (6k): Yield
83 %, m.p. 153-154 ºC; IR (KBr, νmax, cm-1): 3317 (N-H), 2950
(C-H, Ar), 2875 (C-H), 1623 (C=N), 1410 (C=C), 1354 (C-N),
1312 (C-O), 1092 (N-N); 1H NMR (300MHz, DMSO-d6) δppm:
8.39 (s, 1H, Ar), 7.86-7.65 (m, 4H, Ar), 7.51-7.35 (t, 2H, Ar),
7.21-6.57 (m, 6H, Ar), 4.89 (s, 2H, CH2), 3.48 (s, 2H, NH2);
13C NMR (100 MHz, DMSO-d6) δppm: 163.7 (C-2, oxadiazole),
159.4 ( C-5, oxadiazole), 152.6 (C-2, benzimidazole), 149.4 (C-2,
quinoline), 148.4 (C-4, phenyl), 144.5 (C-4, quinoline), 138.9
(C-4, benzimidazole), 136.4 (C-10, quinoline), 134.3 (C-5,
benzimidazole), 131.4 (C-1, 6, quinoline), 128.3 (C-2,6, phenyl),
128.1 (C-5,8, quinoline), 126.8 (C-7,9, quinoline), 119.4 (C-7,8,
benzimidazole), 116.8 (C-3,5, phenyl), 116.2 (C-1, phenyl),
112.7 (C-6, 9, benzimidazole), 43.8 (CH2); EI-MS (m/z): 452.11
(M+); Anal. calcd. (found) % for C25H17N6OCl (452.89): C,
66.30 (66.11); H, 3.78 (3.58); N, 18.56 (18.41).
157.9 (C-1, naphthalene), 151.5 (C-2, benzimidazole), 148.2
(C-2, quinoline), 145.9 (C-4, quinoline), 138.9 (C-4, benzimida-
zole), 135.7 (C-10, quinoline), 134.8 (C-9, naphthalene), 134.3
(C-5, benzimidazole), 131.4 (C-1, quinoline), 130.4 (C-6, quino-
line), 129.6 (C-3,4, naphthalene), 128.1 (C-8, quinoline), 127.9
(C-5, quinoline), 127.4 (C-5, naphthalene), 127.2 (C-7, quino-
line), 126.9 (C-3,7,8, naphthalene), 124 (C-6, naphthalene),
120.1 (C-7,8, benzimidazole), 118.8 (C-2, naphthalene), 112.4
(C-6,9, benzimidazole), 105.9 (C-10, naphthalene), 72.3 (CH2O),
42.7 (CH2); EI-MS (m/z): 517.13 (M+); Anal. calcd. (found)
% for C30H20N5O2Cl (m.w. 517.96): C, 69.56 (69.35); H, 3.89
(3.75); N, 13.52 (13.43).
5-{[2-(2-Chloroquinolin-3-yl)-1H-benzimidazole-1-yl]-
methyl)-2,5-dihydro-1,3,4-oxadiazole-2-thiol (7):A mixture
of 2-[2-(2-choloroquinolin-3-yl)-1H-benzimidazole-1-yl]-
acetohydrazide (5) (0.01 mol), KOH (0.01 mol), CS2 (4 mL)
and ethanol (15 mL) was heated under reflux until the evaluation
of hydrogen sulphide gas stoped. The resultant product was
recrystallized from methanol. Yield 67 %, m.p. 136-138 ºC;
IR(KBr, νmax, cm-1): 3191 (C-H, Ar), 2700 (S-H), 1493 (C=C),
1318 (C-N), 1282 (C-O), 1022(N-N), 750 (C-S); 1H NMR (300
MHz, DMSO-d6) δ ppm: 8.46-8.47 (s, 1H, Ar), 8.29-8.32 (t,
2H, Ar), 7.90-7.93 (t, 2H, Ar), 7.56-7.61 (m, 4H, Ar), 4.52 (s,
2H, CH2), 3.21 (s, 1H, SH); 13C NMR (100 MHz, DMSO-d6) δ
ppm: 163.2 (C-2, oxadiazole), 158.4 ( C-5, oxadiazole), 151.7
(C-2, benzimidazole), 148.3 (C-2, quinoline), 141.6 (C-4, quino-
line), 137.9 (C-4, benzimidazole), 135.8 (C-10, quinoline),
132.1 (C- 5, benzimidazole), 130.8 (C-1, 6, quinoline), 128.7
(C-5,8, quinoline), 121.5 (C-7,8, benzimidazole), 116.8 (C-6,9,
benzimidazole), 45.1 (CH2); EI-MS (m/z): 393.04 (M+);Anal.
calcd. (found) % for C19H12N5OSCl (m.w. 393.84): C, 57.94
(57.81); H, 3.07 (3.01); N, 17.78 (17.68).
3-(5-((5-Benzyl-1,3,4-oxadiazol-2-yl)methyl)-1H-
benzo[d]imidazol-2-yl)-2-chloroquinoline (6l):Yield 93 %,
m.p. 213-215 ºC; IR (KBr, νmax, cm-1): 3110 (C-H, Ar), 2898
(C-H), 1459 (C=C), 1360 (C-N), 1263 (C-O), 1026 (N-N); 1H
NMR (300 MHz, DMSO-d6) δ ppm: 8.64-7.48 ( m, 7H, Ar),
7.32-7.07 (t, 5H, Ar), 7.06- 6.97 ( d, 2H, Ar), 4.85 ( s, 2H,
CH2), 3.68( s, 2H, CH2); 13C NMR (100 MHz, DMSO-d6) δppm:
167.7 (C-2, oxadiazole), 165.8 (C-5, oxadiazole), 153.3 (C-2,
benzimidazole), 152.1 (C-2, quinoline), 147.6 (C-1, quinoline),
137.9 (C-4, benzimidazole), 136.8 (C-10, quinoline), 136.3
(C-1, phenyl), 134.3 (C-5, benzimidazole), 131.4 (C-4, quinoline),
131 (C-6, quinoline), 129.1 (C-2,6, phenyl), 128.7 (C-3,5, phenyl),
128.1 (C-8, quinoline), 127.9 (C-5, quinoline), 127.2 (C-7,
quinoline), 126.8 (C-9, quinoline), 125.8 (C-4, phenyl), 122.2
(C-7,8, benzimidazole), 115.3 (C-6,9, benzimidazole), 47.2
(CH2), 30.9 (CH2); EI-MS (m/z): 451.11 (M+); Anal. calcd.
(found) % for C26H18N5OCl (m.w. 451.90): C, 69.10 (69.25);
H, 4.01 (4.32); N, 15.50 (15.20).
2-Chloro-3-(1-((5-((naphthalene-2-yloxy)methyl)-1,3,4-
oxadizol-2-yl)methyl)-1H-benzo[d]imidazol-2-yl)quinoline
(6m):Yield 74%, m.p. 242-245 ºC; IR (KBr, νmax, cm-1): 3076
(C-H, Ar), 2888 (C-H), 1403 (C=C), 1355 (C-N), 1291 (C-O),
1056 (N-N); 1H NMR (300MHz, DMSO-d6) δ ppm: 8.37-7.67
(m, 9H,Ar), 7.43-7.26 (t, 4H,Ar), 7.11-6.93 (m, 3H,Ar), 5.27
(s, 2H, OCH2), 4.59 (s, 2H, CH2); 13C NMR (100 MHz, DMSO-
d6) δ ppm: 161.4 ( C-2, oxadiazole), 158.6 ( C-5, oxadiazole),
1,2-Dihydro-2-oxoquinoline-3-carbaldehyde (8): 2-Oxo-
1,2-dihydroquinoline-3-carbaldehyde was synthesized from
a suspension of 2-chloroquinoline-3-carbaldehyde in 70 %
acetic acid [29].
Ethyl-2-(3-formyl-2-oxoquinolin-1(2H)-yl)acetate (9):
In a mixture of 2-oxo-quinoline-3-carbaldehyde (0.01 mol)
in dry acetone (100 mL) and K2CO3 (2 g), ethyl chloroacetate
1.2 mL was added dropwise at room temperature for a period
of 20-30 min. The reaction mixture was stirred at room temper-
ature for 10-15 h. The solid thus obtained was filtered off and
filtrate was concentrated under reduced pressure.Yield 89 %,
m.p. 184-186 ºC; IR (KBr, νmax, cm-1): 3098 (N-H), 1748 (C=O),
1
1494 (C=C), 1347 (C-N), 1292 (C-O); H NMR (300 MHz,
DMSO-d6) δ ppm: 8.74-8.70 (d, 1H, Ar); 8.39 (s, 1H, Ar);
8.24-8.20 ( m, 3H, Ar); 7.56-7.53 (d, 2H, Ar); 7.50-7.47 (t,
1H, Ar); 4.57-4.53 (s, 2H, CH2); 1.52-1.21 (t, 3H, CH3); 13
C
NMR (100 MHz, DMSO-d6) δppm: 177.6 (C, carbonyl), 166.4
(C, carboxyl), 154.7 (C, amide), 139.2 (C-4, quinoline), 131.3
(C-6, quinoline), 129.8 (C-5, quinoline), 128.2 (C-2, quino-
line), 126.6 (C-10, quinoline), 124.9 (C-3, quinoline), 124.3
(C-9, quinoline), 121.5 (C-7, quinoline), 54.2 (2C, CH2), 24.1
(CH3); EI-MS (m/z): 259.08 (M+); Anal. calcd. (found) % for
C14H13NO4 (m.w. 259.25): C, 64.86 (64.81); H, 5.05 (5.01);
N, 5.40 (5.34).
2-(3-Formyl-2-oxoquinolin-1(2H)-yl)acetohydrazide
(10): To a mixture of 2-chloro-3-formyl-3, 4-dihydro-2H-

Vol. 31, No. 6 (2019)
Synthesis and Anticonvulsant Potential of 2,5-Disubstituted 1,3,4-Oxadiazole Analogues 1393
quinolin-1-yl)acetic acid ethyl ester (0.01 mol) and hydrazine
hydrate 98 % (0.01 mol; 0.49 mL) was added in ethanolic solution.
The reaction mixture was refluxed for 3 h. The reaction mixture
was cooled and the solid mixture thus obtained and filtered
off. Washed with cold water and recrystallized with methanol.
Yield 73 %, m.p. 213-215 ºC; IR (KBr, νmax, cm-1): 3248 (N-H),
3125 (C-H, Ar),1650 (C=O), 1497 (C=C, Ar), 1293 (C-O); 1H
NMR (DMSO-d6) δ ppm: 9.64 (s, 1H, CONH), 8.64-8.60 (s,
1H, Ar), 8.45 (s, 1H, Ar), 8.39-8.30 (d, 2H, Ar), 7.62-7.50 (m,
2H, Ar), 4.62 ( s, 2H, CH2), 3.31 (s, 3H, NH2); 13C NMR (100
MHz, DMSO-d6) δ ppm: 174.4 (1C, carbonyl), 169.2, 154.7
(2C, amide), 141.4 (C-4, quinoline), 135.4 (C-6, quinoline), 130.1
(C-5, quinoline), 127.7 (C-2, quinoline), 124.5 (C10, quino-
line), 122.2 (C-3, quinoline), 117.6 (C-9, quinoline), 115.5 (C-7,
quinoline), 51.5 (CH2); EI-MS (m/z): 245.07 (M+);Anal. calcd.
(found) % for C12H11N3O3 (m.w. 245.23): C, 58.77 (58.70); H,
4.52 (4.33); N, 17.13 (17.10).
General procedure for the synthesis of 1,2-dihydro-1-
((5-(substituted)-1,3,4-oxadiazol-2-yl)methyl)-2-oxoquino-
line-3-carbaldehyde (11a-e): An equimolar mixture of 2-(3-
formyl-2-oxoquinolin-1(2H)-yl)acetohydrazide and different
substituted benzoic acid was refluxed in the presence of POCl3
(10-15 mL) for 6-10 h at 110-120 ºC. After completion of
reaction, mixture was cooled at room temperature and poured
into crushed ice. On basification of sodium bicarbonate (5 %),
solid mass was so separated was washed with water and crysta-
llized from ethanol.
1,2-Dihydro-1-((5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-
yl)methyl)-2-oxoquinoline-3-carbaldehyde (11a):Yield 93 %,
m.p. 213-215 ºC; IR (KBr, νmax, cm-1): 3028 (C-H, Ar), 2843
(C-H), 1670 (C=O), 1605 (C=N), 1491 (C=C), 1280 (C-O), 1072
(N-N); 1H NMR (DMSO-d6) δ ppm: 9.12 (s, 1H, CHO), 7.81-
7.59 (m, 2H,Ar), 6.84-7.63 (m, 6H, Ar), 6.41 (s, 1H,Ar), 3.99
(s, 3H, OCH3), 2.60 (s, 2H, CH2); 13C NMR (100 MHz,
DMSO-d6) δ ppm: 181.5 (C, carbonyl), 167.2 (C, amide), 163.4
(C-5, oxadiazole), 159.7 (C-2, oxadiazole), 160.7 (C-4, phenyl),
143.3 (C-4, quinoline), 135.3 (C-6, quinoline), 131.8 (C-5,
quinoline), 128.5 (C-2,6, phenyl), 127 (C-8, quinoline), 126.6
(C-10, quinoline), 124.9 (C-3,9, quinoline), 121.5 (C-7, quino-
line), 118.5 (C-1, phenyl), 114.8 (C-3, 5, phenyl), 114.8 (C-5,
phenyl), 65.8 (CH3), 48.2 (CH2); EI-MS (m/z): 361.10 (M+);
Anal. calcd. (found) % for C20H15N3O4 (m.w. 361.35): C, 66.48
(66.26); H, 4.18 (4.12); N, 11.63 (11.43).
1,2-Dihydro-1-((5-(4-nitrophenyl)-1,3,4-oxadiazol-2-yl)-
methyl)-2-oxoquinoline-3-carbaldehyde (11b):Yield 93 %,
m.p. 213-215 ºC; IR (KBr, νmax, cm-1): 3092 (C-H, Ar), 2905
(C-H), 1655 (C=O), 1615 (C=N), 1475 (C=C), 1276 (C-O),
1035 (N-N); 1H NMR (300 MHz, DMSO-d6) δ ppm: 8.80 (s,
1H, CHO), 7.68-6.42 (m, 8H, aromatic), 6.14 (s, 1H, aromatic),
4.14 (s, 2H, CH2); 13C NMR (100 MHz, DMSO-d6) δ ppm:
176.2 (1C, carbonyl), 168.4 (1C, amide), 162.2 (C-2, oxadiazole),
160.6 (C-5, oxadiazole), 151.2 (C-4, phenyl), 141.4 (C-4, quino-
line), 136.8 (C-6, quinoline), 133.5 (C-1, phenyl), 132.8 (C-5,
quinoline), 129.5 (C-2,6, phenyl), 127.3 (C-8, quinoline), 125.9
(C-10, quinoline), 122.4 (C-3,9, quinoline), 121.5 (C-7, quino-
line), 111.5 ( C-3,5, phenyl), 53.5 ( CH2); EI-MS (m/z): 376.08
(M+); Anal. calcd. (found) % for C19H12N4O5 (m.w. 376.32):
C, 60.64 (60.38); H, 3.21 (3.04); N, 14.89 (14.81).
1,2-Dihydro-1-((5-(3,5-dinitrophenyl)-1,3,4-oxadiazol-2-
yl)methyl)-2-oxoquinoline-3-carbaldehyde (11c):Yield 93 %,
m.p. 213-215 ºC; IR (KBr, νmax, cm-1): 3010 (C-H, Ar), 2850
(C-H), 1678 (C=O), 1605 (C=N), 1468 (C=C), 1410 ( C-NO2),
1
1285 (C-O), 1052 (N-N); H NMR (DMSO-d6) δ ppm: 8.71
(s, 1H, CHO), 7.80-6.20 ( m, 7H, Ar), 6.04 ( s, 1H, Ar), 3.14 (s,
2H, CH2); 13C NMR (100 MHz, DMSO-d6) δ ppm: 176.2 (1C,
carbonyl), 166.4 (1C, amide), 161.8 (C-2, oxadiazole), 158.4
(C-5, oxadiazole), 151.2 (C-4, phenyl), 141.4 (C-4, quinoline),
136.8 (C-6, quinoline), 133.5 (C-1, phenyl), 132.8 (C-5, quino-
line), 129.5 (C-2,6, phenyl), 127.3 (C-8, quinoline), 125.9 (C-10,
quinoline), 122.4 (C-3,9, quinoline), 121.5 (C-7, quinoline),
111.5 (C-3,5, phenyl), 53.5 (CH2); EI-MS (m/z): 421.06 (M+);
Anal. calcd. (found) % for C19H11N5O7 (m.w. 421.31): C, 54.16;
H, 2.63; N, 16.62. Found: C, 53.88; H, 2.33; N, 16.42.
1-((5-(3,5-Dichlorophenyl)-1,3,4-oxadiazol-2-yl)methyl)-
1,2-dihydro-2-oxoquinoline-3-carbaldehyde (11d):Yield 93 %,
m.p. 203-212 ºC; IR (KBr, νmax, cm-1): 2982 (C-H, Ar), 2764
(C-H), 1705 (C=O), 1585 (C=N), 1491 (C=C), 1280 (C-O),
1072 (N-N), 740 (C-Cl); 1H NMR (DMSO-d6) δ ppm: 8.91 (s,
1H, CHO), 7.89-6.21 (m, 7H, Ar), 6.06 (s, 1H, Ar), 3.99 (s, 2H,
CH2);13CNMR(100MHz, DMSO-d6)δppm:182.6(1C, carbonyl),
166.5 (1C, amide), 164.2 (C-2, oxadiazole), 160.4 (C-5, oxadia-
zole), 145.3 (C-4, quinoline), 136.2 ( C-3,5, phenyl), 134.5 (C-6,
quinoline), 132.5 (C-5, quinoline), 131.1 (C-4, phenyl), 128.1
(C-1, phenyl), 128.2 (C-8, quinoline), 126.6 (C-10, quinoline),
123.9 (C-2,5, phenyl), 122.5 (C-3, quinoline), 120.3 (C-9,
quinoline), 118.9 (C-7, quinoline), 56.0 (CH2); EI-MS (m/z):
399.01 (M+); Anal. calcd. (found) % for C19H11N3O3Cl2 (m.w.
400.21): C, 57.02 (56.79); H, 2.77 (2.38); N, 10.50 (10.15).
1-((5-(2-Chloro-4-fluorophenyl)-1,3,4-oxadiazol-2-yl)-
methyl)-1,2-dihydro-2-oxoquinoline-3-carbaldehyde (11e):
Yield 93 %, m.p. 145-148 ºC; IR (KBr, νmax, cm-1): 3080 (C-H,
Ar), 2955 (C-H), 1670 (C=O), 1652 (C=N), 1522 (C=C), 1040
1
(N-N), 753 (C-Cl); H NMR (300 MHz, DMSO-d6) δ ppm:
9.05 (s, 1H, CHO), 7.81-6.26 (m, 6H, Ar), 6.10 (s, 2H, Ar), 3.45
(s, 2H, CH2); 13C NMR (100 MHz, DMSO-d6) δ ppm: 191.2
(C, carbonyl), 165.1 (C-2, oxadiazole), 162.8 (C-5, oxadiazole),
161.5 (C-4, phenyl), 158.1 (C, amide), 140.5 (C-4, quinoline),
132.6 (C-6, quinoline), 130.9 (C-2, phenyl), 128.1 (C-1, phenyl),
127.7 (C-6, phenyl), 126.9 (C-5, quinoline), 125.2 ( C-8, quino-
line), 123.6 (C-10, quinoline), 121.8 (C-3, quinoline), 119.3
(C-9, quinoline), 118.5 (C-7, quinoline), 116.1 (C-3, phenyl),
114.5 (C-5, phenyl), 43.2 (CH2); EI-MS (m/z): 383.04 (M+);
Anal. calcd. (found) % for C19H11N3O3 ClF (m.w. 383.76): C,
59.47 (59.10); H, 2.89 (2.75); N, 10.95 (10.68).
1,2-Dihydro-1-((5-mercapto-1,3,4-oxadiazol-2-yl)-
methyl)-2-oxoquinoline-3-carbaldehyde (12):A mixture of
2-(3-formyl-2-oxoquinolin-1(2H)-yl)acetohydrazide (10),
(0.01 mol), KOH (0.01 mol), CS2 (4 mL) and ethanol (15 mL)
was heated under reflux until the evaluation of H2S gas stoped.
The resultant product was recrystallized from methanol.Yield
93 %, m.p. 145-148 ºC; IR (KBr, νmax, cm-1): 3191 (C-H, Ar),
2700 (S-H), 1492 (C=C), 1318 (C-N), 1282 (C-O), 1022 (N-N),
1
750 (C-S); H NMR (300 MHz, DMSO-d6) δ ppm: 9.55 (s,
1H, CHO), 7.71-6.16 (m, 4H, Ar), 6.18 (s, 2H, Ar), 2.85 (s, 2H,
CH2); 13C NMR (100 MHz, DMSO-d6) δ ppm: 187.7 (CHO),
164.1 (CONH), 162.4 (C-2, oxadiazole), 159.3 (C-5, oxadiazole),

1394 Kumar et al.
Asian J. Chem.
NHCOCH3
143.3 (C-4, quinoline), 135.3 (C-6, quinoline), 129.7 (C-5, quin-
oline), 128.2 (C-8, quinoline), 126.6 (C-10, quinoline), 122.2
(C-3,9, quinoline), 117.5 (C-7, quinoline), 51.2 (CH2); EI-MS
(m/z): 287.03 (M+); Anal. calcd. (found) % for C13H9N3O3S
(m.w. 287.29): C, 54.35 (54.31); H, 3.16 (3.10); N, 14.63 (14.36).
Biological activity:All the synthesized compounds were
evaluated for their anticonvulsant effect using male albino mice
(Swiss, 18-25 g). The qualitative evaluations were performed
in mice involved two animal model for convulsion i.e. maximal
electroshock seizure (MES) and subcutaneous pentylene-
tetrazole (scPTZ).
1
1. DMF
2. POCl
3
CHO
Cl
N
H2N
H2N
2
Maximal electroshock seizure (MES) design test: The
conduct of the animals and electrographic seizures produced
in this model were steady with the human issue as revealed
before.Animals were checked for affectability to electric stimuli
24 h preceding administration of test compounds and those
animals which neglect to indicate hind limb tonic extension
were rejected. Animals were assigned into control, standard
and test groups. The control group received polyethylene glycol
(30 % v/v, i.p.), standard group animals were given phenytoin
(25 mg/kg, i.p.) [30] and test groups were injected with comp-
ounds 6a-m, 7, 11a-e and 12 at previously selected doses. A
60 Hz cyclic current of 50 mA intensity for 0.2 s utilizing corneal
terminals evoked maximal seizures.A drop of electrolyte solution
(0.9 % NaCl) was applied to the corneal electrodes which ensure
better contact to the animal [31]. The animal were observed for
hind limb tonic extension and duration was noted i.e., prevention
or decline in the duration of hind limb extension was considered
as defensive activity.
N
N
H
N
3
Cl
Cl CH COOC H
2 5
2
N
N
N
4
Cl
C2H5OOC
NH NH . H O
2
2
2
N
N
N
5
Cl
Subcutaneous pentylenetetrazole (scPTZ) design test:The
subcutaneous pentylenetetrazole test was performed according
to the known protocol [32]. This strategy utilizes pentylene-
tetrazole (75 mg/kg) that produces seizures in > 95 % of animals
as 0.5 % solution subcutaneously in the back midline.Animals
were assigned into control, standard and test groups. The control
group received polyethylene glycol (30 % v/v) i.p., standard
group animals were given phenytoin (25 mg/kg, i.p.) and test
groups were injected with 6a-m, 7, 11a-e and 12 at previously
selected doses.After 1 h, the administration of these substances
to the respective groups, all the animals of assigned groups
were administered with pentylenetetrazole. Each animal was
observed onset of clonus and tonic convulsions after definite
period of time. Prevention or decline in the duration of onset
of convulsions was considered as defensive activity.
H2NHNOC
1. POCl
CS / KOH
2
3
2. RCOOH
N
N
N
N
N
Cl
N
O
Cl
6a-m
O
N
R
7
N
RESULTS AND DISCUSSION
N
HS
N
In the present work, the synthesis route involved for the
preparation of the compounds 6a-m and 7 is depicted in
Scheme-I and for compounds 11a-e and 12, it is depicted in
Scheme-II.Vilsmeier-Haack reaction[28] was used which involve
acetamide to synthesize 2-chloroquinoline-3-carbaldehyde (2).
Reaction of compound 2 with o-phenylene diamine yielded
3-(1H-benzimidazole-2-yl)-2-chloroquinoline (3) and reaction
with 70 % acetic acid afforded 2-oxo-1,2-dihydroquinoline-
3-carbaldehyde (8) in the conditions as described earlier [29].
Compounds 3 and 8 were refluxed with chloroacetic acid to get
ethyl [2-(2-chloroquinoline-3-yl)-1H-benzimidazole-1-yl)-
acetate (4) and ethyl 2-(3-formyl-2-oxoquinolin-1(2H)-yl)-
R = Methoxyphenyl, 4-chlorophenyl, 2, 4-dichlorophenyl, 2 –OH phenyl,
2-chlorophenyl, pyridine-3-yl, 2- aminophenyl, 2-methoxyphenyl,
4- aminophenyl, benzyl, naphthalene-2-yloxy)methyl
Scheme-I
acetate (9), respectively. Compounds 4 and 9 were refluxed with
hydrazine hydrate to give 2-[2-(2-choloroquinolin-3-yl)-1H-
benzimidazole-1-yl]acetohydrazide (5) and 2-(3-formyl-2-
oxoquinolin-1(2H)-yl)acetohydrazide (10), which on reaction
with various substituted benzoic acids in the presence of POCl3,
gives 2-chloro-3-{1-[(5-substituted-1,3,4-oxadiazol-2-yl)methyl]-
1H-benzimidazol-2-yl}quinolines (6a-m) and 1,2-dihydro-1-

Vol. 31, No. 6 (2019)
Synthesis and Anticonvulsant Potential of 2,5-Disubstituted 1,3,4-Oxadiazole Analogues 1395
CHO
Cl
also consisting singlet of proton present on C-4 of quinoline.
The presence of -CH2 and -OCH3 was confirmed by peaks in
between 3.14- 4.14 and 3.99, respectively. 13C NMR information
additionally bolstered the structures of synthesized derivatives.
So, both analytical and spectral data (IR, 1H, 13C NMR and mass)
of all the synthesized compounds were in full agreement with
the proposed structures.
N
2
70% AcOH
CHO
O
On associating the structures of all synthesized compounds
with their anticonvulsant action, it has been seen that compounds
bearing the gatherings like methoxybenzene, aminobenzene,
2-pyridyl, 2-ethoxynaphthalene, benzyl, toluidine and cresol
on oxadiazole ring have high potency in MES and scPTZ tests.
Then again, supplanting of these gatherings with nitrobenzene,
halobenzene and phenyl group on oxadiazole ring has brought
about compounds with lesser anticonvulsant potential.
Anticonvulsant activity: The evaluation of synthesized
compounds 2-chloro-3-{1-[(5-substituted-1,3,4-oxadiazol-2-
yl)methyl]-1H-benzimidazol-2-yl}quinolines (6a-m), 5-{[2-
(2-choloroquinolin-3-yl)-1H-benzimidazole-1-yl]methyl)-2,5-
dihydro-1,3,4-oxadiazole-2-thiol (7), 1,2-dihydro-1-((5-(4-
methoxyphenyl)-1,3,4-oxadiazol-2-yl)methyl)-2-oxoquino-
line-3-carbaldehydes (11a-e) and 1,2-dihydro-1-((5-mercapto-
1,3,4-oxadiazol-2-yl)methyl)-2-oxoquinoline-3-carbaldehyde
(12) for anticonvulsant activity was done by the use of two most
accepted animal models, MES [33,34] and scPTZ [35]. All
the orchestrated compounds were administered intraperitoneally
into mice utilizing dosages of 30, 100, 200 and 300 mg/kg.
The perceptions were taken into account at two diverse time
interims (0.5 and 4.0 h) and data is compiled in Table-1. Effect
on locomotor activity of the entire synthesized compounds
N
H
8
Cl CH2COOC2H5
CHO
N
O
9
COOC2H5
NH2NH2. H2O
CHO
N
O
10
CONHNH2
CS2/ KO H
1. POCl3
2. RCOOH
CHO
CHO
was determined against diazepam as reference by actophoto-
meter and the data is shown in Table-2. Acute toxicity study
(LD50) was carried out to access any chance of toxic effect of
synthesized derivatives towards increment of dose according
to the OECD Guidelines No. 423 and the data is compiled in
Table-3.
N
O
O
N
O
O
R
SH
12
N
N
N
N
11a-e
R = 4-methoxyphenyl, 4-nitrophenyl 3,5-dinitrophenyl,
3,5-dichlorophenyl, 2-chloro-4-fluorophenyl
In maximal electroshock seizure (MES) test, among all
the synthesized compounds 6h, 6k, 6l, 6m and 11a had been
found with very good anticonvulsant potential as all had shown
protection at the dose level of 30 mg/kg against the seizure
spread at both the time intervals 0.5 and 4 h while in scPTZ
test, protection was shown at 100 mg/kg after 4 h. Compounds
6c, 6f, 6i, 6j, 7 and 12 had shown moderate activity in which
compounds 6c and 6f had started showing protection at the
dose level of 30 mg/kg after 0.5 h, but 100 mg/kg and 300 mg/kg
were required after 4 h in MES and scPTZ, respectively which
indicated rapid onset but shorter duration of action. Compounds
6I, 6j, 7 and 12 shown protection at the dose level of 100 mg/kg
after 0.5 h and at 300 mg/kg after 4 h in both the animal models
which indicated about longer onset and shorter duration of
action. Compounds 6a, 6b, 6d, 6g, 11a, 11d and 11e have shown
very little activity as they shown protection at the dose level
of 300 mg/kg in both the time interim in MES and in scPTZ
test, they don't show protection after 4 h. Compounds 6e and
11c were found inactive due to heavy presence of electronegative
substitute on phenyl ring.
Scheme-II
((5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl)methyl)-2-
oxoquinoline-3-carbaldehydes (11a-e). On the other hand,
refluxing compounds 5 and 10 in the presence of CS2 and KOH
yielded thiazole derivatives 7 and 12, respectively.
All the newly synthesized compounds were isolated in
moderate to good yield and the structures of all the compounds
were established through spectroscopic (IR, 1H NMR and mass)
as well as elemental analyses data. In general, IR spectra of
newly synthesized compounds 6a-m revealed C-H Ar, C=C,
C-N, C-O (oxadiazole) and N-N peaks near 3050, 1450, 1350,
1260 and 1050 cm-1, respectively. In 1H NMR spectra, signals
of respective protons of newly synthesized compounds showed
the peaks for aromatic protons in between δ8.7-6.5 and presence
of -OCH2, -OH, -CH2, -NH2 and -OCH3 were confirmed by the
presence of singlets at δ5.27, 4.85, 4.5, 3.8 and 3.73, respectively.
The appeared signals of IR spectra for compounds 11a-e
were 3050, 1670, 1600, 1470 and 1050 for C-HAr, C=O, C=N,
C=C and N-N str. vibrations while in 1H NMR spectra, signals
appeared for aromatic protons in between 7.89-6.04 which
Locomotor activity: Every animal was kept in actophoto-
meter for 5 min and basal movement score was recorded for

1396 Kumar et al.
Asian J. Chem.
TABLE-1
ANTICONVULSANT ACTIVITY OF SYNTHESIZED COMPOUNDS 6a-m
,
7, 11a-e AND 12
Intraperitoneal injectionin micea
MES screen
HLTE (s)
ScPTZ
Compounds
Onset of clonus(s)
0.5 h
Onset of tonic(s)
0.5 h
300
300
30
100
–
4 h
300
300
100
300
–
4 h
–
–
0.5 h
300
300
30
4 h
–
–
300
–
–
6a
6b
6c
6d
300
300
30
300
–
300
–
300
–
6e
–
6f
6g
6h
6i
6j
6k
6l
6m
7
11a
11b
11c
11d
30
300
30
100
100
30
30
30
100
30
300
–
100
–
30
300
30
100
100
30
30
30
100
30
300
–
300
–
30
300
30
100
100
30
30
30
100
30
300
–
300
–
30
300
300
30
30
30
300
30
–
–
–
–
300
30
–
100
300
300
100
100
100
300
100
100
300
300
100
100
100
300
100
–
–
–
–
300
300
100
30
300
300
100
–
300
300
100
–
11e
12
300
–
100
300
–
100
Phenytoin
Carbamazepine
–
100
100
aAdministered doses were 30, 100, 200 and 300 mg/kg and above data indicate the minimum dose whereby bioactivity was exhibited down the
middle or a greater amount of the mice. The tested mice were examined at 0.5 and 4 h. The (–) indicates an absence of activity at maximum dose
administered (300 mg/kg).
TABLE-2
TABLE-3
LOCOMOTOR ACTIVITY DATA OF SYNTHESIZED
ACUTE TOXICITY DATA OF SYNTHESIZED
COMPOUNDS 6a-m, 7, 11a-e AND 12
COMPOUNDS 6a-m, 7, 11a-e AND 12
% Reduction in
locomotor
activity
Number of animals dead/total
number of animals tested
Basal
Mean SEM
After treatment
Mean SEM
Compd.
No.
Compounds
Dose (mg/kg), i.p.
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
7
11a
11b
11c
11d
11e
12
404.6 2.31
400 2.022
399.6 2.50
396.2+2.24
404 3.05
407.2 2.47
397.6 1.20
398.8 2.57
407.2 2.15
406.6 2.31
405.2 2.22
399 1.51
407.4 2.08
401.4 0.92
408 1.64
411.8 1.98
398 2.34
389.0 1.73ns
387.0 0.77**
383.4 1.16**
384.2 2.08**
389.0 0.70*
386.6 1.43*
390.0 0.70ns
387.8 1.82*
380.0 0.70**
387.8 1.28*
389.0 0.70*
389.0 1.73ns
390.2 1.39ns
388.0 1.14*
386.6 1.43*
386.2 1.06**
388.8 0.48*
379.8 0.80*
380.0 0.70**
389.0 1.73ns
378.4 3.64
3.85
3.25
4.05
3.02
3.71
5.05
1.91
2.25
6.67
4.62
3.99
2.50
4.22
3.33
5.24
6.21
2.31
6.45
4.52
2.01
1.56
80.10
20
50
100
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
200
0/3
0/3
0/3
1/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
1/3
0/3
1/3
1/3
0/3
0/3
1/3
0/3
0/3
400
0/3
0/3
0/3
2/3
1/3
1/3
0/3
1/3
1/3
1/3
0/3
1/3
1/3
0/3
2/3
1/3
2/3
2/3
1/3
1/3
2/3
2/3
2/3
Control
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
7
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
406 0.83
398 2.09
397 2.60
384.4 2.58
382.2 4.76
11a
11b
11c
11d
11e
12
PEG-400
Diazepam
76.0 2.58**
n = 5; Time span 5 min; The percent inhibition for each group was
calculated by comparison with the control group. Dose = 30 mg/kg
(p.o); All values expressed as mean SEM (n = 5). *P ≤ 0.05, **P ≤
0.01 as compared with control. Data was analyzed by one-way
ANOVA followed by Dunnett’s test).
Phenytoin
Carbamazepine

Vol. 31, No. 6 (2019)
Synthesis and Anticonvulsant Potential of 2,5-Disubstituted 1,3,4-Oxadiazole Analogues 1397
6. B.N. Prasanna Kumar, K.N. Mohana and L. Mallesha, J. Chem., 2013,
all. After 0.5 h of the various administered doses, animal′s
locomotor conduct was checked utilizing same actophotometer
[36]. Deceased action score was taken as file of CNS dejection
and percentage reduction in locomotor activity was compiled
in Table-2. It was found that no significant reduction caused
by active synthesized compounds.
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Conclusion
The present results have revealed that synthesized 2-
chloro-3-(1-(5-substituted-1,3,4-oxadiazaol-2-yl)methyl)-1H-
benzo[d]imidazole-2-yl)quinoline (6a-m) and 1,2-dihydro-1-
((5-substituted-1,3,4-oxadiazaol-2-yl)methyl)-2- oxoquino-
line-3-carbaldehyde (11a-e) exhibit a range of activity in anti-
convulsant screening in dose dependent manner. Compounds
6h, 6k, 6l, 6m and 11a are found to be most prominent as they
cause abolition of the hind limb tonic extensor component in
MES test and increased both onset of clonus and onset of tonic
convulsions in scPTZ test. These compounds can be tools for
ligand-based drug design purposes, which can further explore
the chances of discovery of more potent molecule for the treat-
ment of convulsion in human in near future.
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ACKNOWLEDGEMENTS
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Pharm. Sci., 10, 254 (2007).
The authors are highly thankful to Prof. Dr. O.P.Agarwal,
Managing Director, Noida Institute of Engineering &Technology,
Greater Noida, India, for providing the necessary research
facilities. The authors are also grateful to Dr.Avijit Mazumder,
Director, NIET Pharmacy Institute, Greater Noida, India for
his continuous motivation.
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CONFLICT OF INTEREST
The authors declare that there is no conflict of interests
regarding the publication of this article.
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