Design, synthesis and screening of quinoline-incorporated thiadiazole as a potential anticonvulsant

Article abstract of DOI:10.1111/j.1747-0285.2011.01255.x

A series of quinoline-incorporated substituted thiadiazole were designed and synthesized using appropriate synthetic route keeping in view the structural requirement of pharmacophore and evaluated for anticonvulsant and CNS activities. After intraperitoneal injection to mice, some synthesized derivatives were examined in the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazol (scPTZ)-induced seizure and neurotoxicity screens. Those found potent were also evaluated for behavioural impairment and depression activity. Among the compounds tested, 6d and 6e showed protection from seizures in both the animal models at dose level of 30mg/kg while 7f showed protection against both models at 100mg/kg dose level. These compounds exhibited lesser CNS depression and neurotoxicity compared with clinically effective drug. A series of quinoline incorporated substituted thiadiazole were designed & synthesized using appropriate synthetic route keeping in view the structural requirement of pharmacophore and evaluated for anticonvulsant and CNS activities. Among screened compounds 6d & 6e showed protection from seizures in both MES and scPTZ models at dose level (30 mg/kg).

Full text of DOI:10.1111/j.1747-0285.2011.01255.x

ª 2011 John Wiley & Sons A/S
doi: 10.1111/j.1747-0285.2011.01255.x
Chem Biol Drug Des 2012; 79: 104–111
Research Article
Design, Synthesis and Screening of
Quinoline-Incorporated Thiadiazole as a
Potential Anticonvulsant
Suresh Kumar, Darpan Kaushik†,*, Sandhya
Bawa and Suroor A. Khan
its derivatives have been synthesized and tested for their anticon-
vulsant activity (6–10). Different aryl and heteroaryl moieties have
been clubbed to the quinoline pharmacophore as hydrophobic
domain which led to the increase in the activity significantly. In this
work, we planned to attach the quinoline to the substituted
thiadiazole which has been observed to exhibit anticonvulsant
properties in experimentally maximal electroshock seizure (MES)
convulsions, as reported in previous screening data for anticonvul-
sant activity (11–17). Adding, these two active anticonvulsant moie-
ties were expected to have synergistic effect in dealing with
epilepsy.
Medicinal Chemistry Division, F/o Pharmacy, Jamia Hamdard, New
Delhi 125055, India
*Corresponding author: Darpan Kaushik, darpkaush@yahoo.com
Current address: Department of Pharmaceutical Chemistry,
Rajendra Institute of Technology & Sciences, 4th Mile Stone, Hisar
Road, Sirsa 125055, Haryana, India
A series of quinoline-incorporated substituted thi-
adiazole were designed and synthesized using
appropriate synthetic route keeping in view the
structural requirement of pharmacophore and
evaluated for anticonvulsant and CNS activities.
After intraperitoneal injection to mice, some syn-
thesized derivatives were examined in the maxi-
mal electroshock seizure (MES) and subcutaneous
pentylenetetrazol (scPTZ)-induced seizure and neuro-
toxicity screens. Those found potent were also
evaluated for behavioural impairment and depres-
sion activity. Among the compounds tested, 6d
and 6e showed protection from seizures in both
the animal models at dose level of 30 mg/kg while
7f showed protection against both models at
100 mg ⁄ kg dose level. These compounds exhibited
lesser CNS depression and neurotoxicity com-
pared with clinically effective drug.
All the synthesized titled compounds were comprised of the essen-
tial pharmacophoric elements (Figure 1) that are necessary for good
anticonvulsant activity as suggested by Unverferth et al. (18). The
essential structural features that could be responsible for an inter-
action with the active site of voltage-gated sodium channels were
a hydrophobic HP unit (R), an electron donor (D) group and a hydro-
gen donor ⁄ acceptor (HBD) unit.
Experimental
Chemistry
Melting points were determined by the open capillary method with
electrical melting point apparatus and are uncorrected. IR spectra
were recorded as KBr (pallet) on Bio Rad FT-IR spectrophotometer
and 1H and 13C-NMR spectra recorded on Bruker DPX 300 MHz
spectrophotometer using DMSO-d6 or CDCl3 as a NMR solvent.
TMS used as an internal standard and chemical shift data are
reported in parts per million (in ppm) where s, bs, d, t and m desig-
nated as singlet, broad singlet, doublet, triplet and multiplet,
respectively. Mass spectra were recorded on JEOL SX102 ⁄ DA-6000
Key words: anticonvulsant, behavioural test, neurotoxicity, quino-
line, thiadiazole
Received 8 February 2011, revised 10 August 2011 and accepted for
publication 2 October 2011
Epilepsy is one of the more common neurological disorders, affect-
ing a large section of people (1). About 20–30% of patients have
seizures that are resistant to available medical therapies. All cur-
rently approved antiepileptic drugs have dose-related toxicity and
idiosyncratic side effects (2). Therefore, the search for a novel,
highly effective and more selective agent with lesser side effects
continues to be an area of investigation of medicinal chemist's
world wide. Previously, we have reported several nitrogen-contain-
ing heterocyclic compounds based on the pharmacophoric pattern in
terms of interaction at the binding site (3–5), and the results were
encouraging enough to prompt us for further synthesizing more
derivatives and test them against the convulsant stimuli. As quino-
lines have been recognized earlier as promising nuclei, with few of
Figure 1: The essential structure elements for the pharmaco-
phore of Unverferth et al. are indicated by rectangles.
104

Design, Synthesis and Screening of an Anticonvulsant
mass spectrometer using m-nitrobenzylalcohol as a matrix and ele-
mental analysis on Vario-EL III CHNOS-Elemantar analyzer. Thin-
layer chromatography (TLC) was performed to monitor the progress
of the reaction and purity of the compounds, spot being located
under iodine vapour or UV-light.
Synthesis of 3-(Chloromethyl)-2-chloroquinoline
(20) 4
To a solution of compound 3 1.94 g (0.01 mol) in dry benzene,
SOCl2 1.54 g (0.013 mol) was added and the mixture refluxed for
4 h. Solvent was evaporated under reduced pressure, and the resi-
due so obtained was further dissolved in ether, washed with 10%
NaHCO3, followed by washing twice with water, and dried over
anhydrous Na2SO4 and concentrated in vacuo to give a residue
which was crystallized from methanol. Yield 80%; m.p. 116 ꢀC.
Synthesis of 5-Sulfanyl-1,3,4-thiadiazol-2-
ylamine (19) 1
A mixture of potassium hydroxide (5.34 mmol) and carbon disul-
phide (5.52 mmol) was dissolved in anhydrous ethanol (15 mL),
later followed by addition of thiosemicarbazide (5.49 mmol) dis-
solved in anhydrous ethanol; the reaction mixture was stirred
and heated to reflux for 8 h, the ethanol was removed by evap-
oration in vacuum, and the residue was dissolved in water
(50 mL). This was slowly acidified with 5 mL of concentrated
HCl. The precipitate was further filtered to produce compound.
The crude product was washed with cold water, and this yellow
solid so obtained was further recrystallized from ethyl acetate to
give white solid.
1
IR (KBr) ⁄ cm: 1620 (C=N), 1590 (C=C), 754 (C–Cl); H-NMR (300 MHz,
CDCl3): d 4.82 (s, 2H, CH2), 7.56 (t, 1H, H-6, J = 7.2 Hz), 7.73 (t, 1H,
H-7, J = 7.5 Hz), 7.82 (d, 1H, H-5, J = 7.9 Hz), 8.01 (d,1H, H-8,
J = 8.3 Hz), 8.26 (s, 1H, H-4); 13C-NMR (CDCl3, 75 MHz): d 43.03
(CH2), 126.9, 127.3, 127.4, 128.1, 128.8, 130.8, 138.6, 147.1, 149.5;
FAB-MS : m ⁄ z 212 (M+), 214 (M + 2).
Synthesis of 5-{[(2-Chloroquinolin-3-
yl)methyl]sulfanyl}-1,3,4-thiadiazol-2-amine (21)
5
Yield, 68%; m.p. 225 ꢀC, IR (KBr) ⁄ cm: 3403, 3280, 3088, 2921,
1605, 1527, 1495, 1368, 1327, 1057; H-NMR (300 MHz, DMSO-d6):
6.4 (s, 2H, NH2), 12.99 (s, 1H, NH).
5-Sulfanyl-1,3,4-thiadiazol-2-ylamine (0.1 mol) was suspended in
water (9 mL), and 0.1 mol of KOH (85% solution) was added under
stirring at room temperature. After a few minutes, the solution was
brought to 0 ꢀC in an ice bath, and 3-(chloromethyl)-2-chloroquino-
line (0.1 mol) was dropped in with vigorous stirring. The reaction
mixture was monitored by TLC. When the reaction completed, water
(30 mL) was added, and from the crude mixture, a precipitate of 5
formed out slowly which was filtered, washed with water and crys-
tallized. Yield 67%; m.p. 194 ꢀC.
1
2-Chloro-3-formylquinoline 2 needed in the
study was also prepared previously by
Vilsmeier–Haack reaction as reported in
literature by our team (5)
Yield, 63.0%; m.p. 150–151 ꢀC; IR (KBr) ⁄ cm: 1693 (C=O), 1620
(C=N), 1595 (C=C), 752 (C–Cl); H-NMR (300 MHz, DMSO-d6): d 7.67
1
IR (KBr) ⁄ cm: 3352 (N–H), 1613 (C=N), 1587 (C=C), 754 (C–Cl); 1H-
NMR (300 MHz, CDCl3): d 4.59 (s, 2H, SCH2), 6.82 (s, 2H, NH2),
7.57, (t, 1H, H-6, J = 7.5 Hz), 7.71 (t, 1H, H-7, J = 7.2 Hz), 7.82 (d,
1H, H-5, J = 7.9 Hz), 8.02 (d,1H, H-8, J = 8.1 Hz), 8.19 (s, 1H, H-4);
13C-NMR (CDCl3, 75 MHz): d 36.03 (CH2), 117.6, 126.8, 127.8,
129.5, 131.9, 132.6, 142.9, 145.7, 146.7, 168.8; FAB-MS : m ⁄ z 309
(M+), 311 (M + 2).
(t, 1H, H-6, J = 7.4 Hz), 7.90 (t, 1H, H-7, J = 7.1 Hz), 8.01 (d, 1H, H-
5, J = 8.0 Hz), 8.09 (d,1H, H-8, J = 8.4 Hz), 8.78 (s, 1H, H-4), 10.58
(s, 1H, CHO); 13C-NMR (DMSO-d6, 75 MHz): d 125.9, 126.1, 127.3,
127.7, 129.6, 133.3, 135.0, 140.9, 148.2, 188.7 (CHO). FAB-MS: m ⁄ z
192 (M+), 194 (M + 2).
Synthesis of 2-Chloro-3-(hydroxymethyl)-
quinoline (20) 3
General procedure for synthesis of compounds
(22) (6a–e)
To a solution of 2-chloro-3-formylquinoline 1.92 g (0.01 mol) in
absolute methanol, solid sodium borohydride 0.46 g (0.012 mol) was
added portionwise over a period of 30 min with constant stirring at
room temperature. After, that solvent was evaporated under
reduced pressure and the residue was triturated with water to yield
crystalline product which was filtered, washed with water and
dried. The crude product was further recrystallized from methanol.
Yield, 86.0%; m.p. 160–162 ꢀC.
To compound 5 which was suspended in a slight excess of 10%
w ⁄ v sodium hydroxide solution, a small excess of acid chloride (a–
e) was then added in a portionwise and the mixture was vigorously
shaken in a stoppered conical flask. This facilitated acylation which
yield sparingly soluble acylated crude derivatives, which was sepa-
rated as a solid, further washed and recrystallized. The physico-
chemical data of the synthesized derivatives are summarized in
Table 1.
IR (KBr) ⁄ cm: 3340 (O–H), 1614 (C=N), 1592 (C=C), 765 (C–Cl); 1H-
NMR (300 MHz, DMSO-d6): d 4.77 (s, 2H, CH2), 5.45 (s, 1H, OH,
D2O-exchangeable), 7.55 (t, 1H, H-6, J = 7.0 Hz), 7.70 (t, 1H, H-7,
J = 6.9 Hz), 7.84 (d, 1H, H-5, J = 7.5 Hz), 7.99 (d,1H, H-8,
J = 8.0 Hz), 8.36 (s, 1H, H-4); 13C-NMR (DMSO-d6, 75 MHz): d 59.9
(CH2), 126.4, 127.0, 127.4, 127.7, 129.9, 133.8, 135.7, 146.0, 148.3;
FAB-MS: m ⁄ z 194 (M+), 196 (M + 2).
N-(5-{[(2-Chloroquinolin-3-yl)methyl]sulfanyl}-1,3,4-thiadiazol-2-yl)acet
amide 6a IR (KBr) ⁄ cm: 3408 (N–H), 1666 (C=O), 1604 (C=N), 1590
1
(C=C), 757 (C–Cl); H-NMR (300 MHz, CDCl3): d 2.43 (s, 3H, COCH3),
4.54 (s, 2H, SCH2), 7.53, (t, 1H, H-6, J = 7.8 Hz), 7.73 (t, 1H, H-7,
J = 7.2 Hz), 7.81 (d, 1H, H-5, J = 8.1 Hz), 8.04 (d,1H, H-8,
J = 8.1 Hz), 8.21 (s, 1H, H-4), 11.47 (bs, 1H, CONH); 13C-NMR
Chem Biol Drug Des 2012; 79: 104–111
105

Kumar et al.
Table 1: Physicochemical data of synthesized final compounds
Compound No.
R ⁄ R1
Yielda (%)
m.p. (ꢀC)
Mol. formulab
Mol. wt
6a
6b
6c
6d
6e
7a
7b
7c
7d
7e
7f
CH3
CH2CH3
C6H5
p-CH3–C6H4
p-Cl–C6H4
CH3
71
68
73
64
67
60
63
59
73
55
51
73
57
60
55
50
62
49
45
208–210
216–218
220–221
214–215
225–226
204–205
207–209
210–212
211–216
215–219
222–226
225–228
209–211
213–218
215–219
216–218
221–223
222–224
227–229
C14H11ClN4OS2
C15H13ClN4OS2
C19H13ClN4OS2
C20H15ClN4OS2
C19H12Cl2N4OS2
C14H11ClN4S2
C19H13ClN4S2
C20H15ClN4S2
C20H15ClN4OS2
C19H12Cl2N4S2
C19H12ClFN4S2
C19H12ClN5O2S2
C14H13ClN4S2
C19H15ClN4S2
C20H17ClN4S2
C20H17ClN4OS2
C19H14Cl2N4S2
C19H14ClFN4S2
C19H14ClN5O2S2
350.84
364.87
412.91
426.93
447.35
334.84
396.91
410.94
426.94
431.36
414.90
441.91
336.84
398.91
412.95
428.95
433.37
416.91
443.92
C6H5
p-CH3–C6H4–
p-OCH3–C6H4–
p-Cl–C6H4–
p-F–C6H4–
p-NO2–C6H4–
CH3
7g
8a
8b
8c
8d
8e
8f
C6H5
p-CH3–C6H4–
p-OCH3–C6H4–
p-Cl–C6H4–
p-F–C6H4–
p-NO2–C6H4–
8g
b
aRecrystallization from ethanol; Elemental analyses for C, N were within € 0.4% of the theoretical values.
(CDCl3, 75 MHz): d 22.8 (CH3), 36.6, (CH2), 117.8, 125.4, 126.5,
128.8, 129.0, 129.9, 130.7, 131.8, 132.6, 140.7, 145.9, 146.8, 166.3,
171.2; FAB-MS : m ⁄ z 351 (M+), 353 (M + 2).
General procedure for the synthesis of
compounds (23) (7a–g)
To a solution of compound 5 (0.01 mol) in 30 mL of absolute
ethanol, an equimolar amount of substituted carbaldehyde (a–g)
(0.01 mol) and 3 mL of glacial acetic acid were added. The con-
tent of the flask was refluxed for 6–8 h. The progress of the
reaction was monitored on TLC, and on completion of the reac-
tion, content of the flask was reduced to one-third and poured
in ice water after which the pH of the solution was adjusted to
neutral with dil. NaHCO3 solution, and the precipitate thus
formed was filtered off, washed with cold aqueous ethanol,
dried and crystallized from ethanol to give the compound 7a–g.
The physicochemical data of synthesized were presented in
Table 1.
N-(5-{[(2-Chloroquinolin-3-yl)methyl]sulfanyl}-1,3,4-thiadiazol-2-yl)pro-
panamide 6b IR (KBr) ⁄ cm: 3409 (N–H), 1673 (C=O), 1611 (C=N),
1576 (C=C), 754 (C–Cl); 1H-NMR (300 MHz, CDCl3): d 1.02 (t, 3H,
CH3), 2.31 (m, 2H, COCH2), 4.56 (s, 2H, SCH2), 7.50 (t, 1H, H-6,
J = 7.3 Hz), 7.75 (t, 1H, H-7, J = 7.0 Hz), 7.79 (d, 1H, H-5,
J = 8.4 Hz), 8.10 (d,1H, H-8, J = 8.1 Hz), 8.24 (s, 1H, H-4), 12.08
(bs, 1H, CONH).
N-(5-{[(2-chloroquinolin-3-yl)methyl]sulfanyl}-1,3,4-thiadiazol-2-yl)ben-
zamide 6c IR (KBr) ⁄ cm: 3387 (N–H), 1663 (C=O), 1609 (C=N), 1577
1
(C=C), 761 (C–Cl); H-NMR (300 MHz, CDCl3): d 4.58 (s, 2H, SCH2),
7.53–7.65 (m, 4H, Ar-H & H-6), 7.78–7.86 (m, 4H, Ar-H & H-5, H-7),
8.14 (d,1H, H-8, J = 7.8 Hz), 8.21 (s, 1H, H-4), 11.51 (s, 1H, CONH);
13C-NMR (CDCl3, 75 MHz): d 35.3, (CH2), 115.9, 125.6, 126.4, 127.3,
127.9, 128.6, 129.3, 129.9, 130.7, 131.6, 132.5, 136.8, 140.5, 146.3,
147.2, 165.8, 170.4.
5-{[(2-Chloroquinolin-3-yl)methyl]sulfanyl}-N-(ethyl-2-ylidene)-1,3,4-thia-
diazol-2-amine 7a IR (KBr) ⁄ cm: 1611 (C=N), 1583, (C=C), 763 (C–Cl);
1H-NMR (300 MHz, CDCl3): d 1.16 (d, 3H, CH3,), 4.57 (s, 2H, SCH2),
7.49 (t, 1H, H-6, J = 7.3 Hz), 7.79 (t, 1H, H-7, J = 7.2 Hz), 7.76
(d, 1H, H-5,), 8.08 (d,1H, H-8, J = 7.8 Hz), 8.18 (s, 1H, H-4), 8.51
(m, 1H, CH=N); FAB-MS : m ⁄ z 335 (M+), 337 (M + 2).
N-(5-{[(2-chloroquinolin-3-yl)methyl]thio}-1,3,4-thiadiazol-2-yl)-4-meth-
ylbenzamide 6d IR (KBr) ⁄ cm: 3392 (N–H), 1677 (C=O), 1615 (C=N),
1593 (C=C), 762 (C–Cl). 1H-NMR (300 MHz, CDCl3): d 2.37 (s, 3H,
CH3), 4.54 (s, 2H, SCH2), 7.29 (d, 2H, Ar-H, J = 7.4 Hz), 7.56 (t, 1H,
H-6, J = 7.4 Hz), 7.77–7.84 (m, 4H, Ar-H, H-5 and H-7), 8.11 (d,1H,
H-8, J = 7.5 Hz), 8.19 (s, 1H, H-4), 11.96 (bs, 1H, CONH). FAB-MS :
m ⁄ z 426 (M+), 427 (M + 1), 428 (M + 2).
5-{[(2-Chloroquinolin-3-yl)methyl]sulfanyl}-N-[-phenylmethylidene]-1,3,4-
thiadiazol-2-amine 7b IR (KBr) ⁄ cm: 1609 (C=N), 1576, (C=C), 765
1
(C–Cl); H-NMR (300 MHz, CDCl3): d 4.61 (s, 2H, SCH2), 7.45–7.64
(m, 4H, Ar-H & H-6), 7.72 (t, 1H, H-7, J = 7.2 Hz), 7.79–7.86 (m, 3H,
Ar-H & H-5), 8.05 (d,1H, H-8, J = 7.8 Hz), 8.15 (s, 1H, H-4), 8.78 (s,
1H, CH=N); 13C-NMR (CDCl3, 75 MHz): d 34.9, (CH2), 117.2, 126.4,
127.3, 128.0, 128.8, 129.5, 129.9, 131.9, 132.6, 135.0, 141.7, 146.1,
147.4, 157.9, 165.7; FAB-MS : m ⁄ z 397(M+), 399 (M + 2).
4-Chloro-N-(5-{[(2-chloroquinolin-3-yl)methyl]thio}-1,3,4-thiadiazol-2-yl)ben-
zamide 6e IR (KBr) ⁄ cm: 3385 (N–H), 1668 (C=O), 1612 (C=N), 1596
(C=C), 759 (C–Cl). H-NMR (300 MHz, CDCl3): d 4.57 (s, 2H, SCH2),
1
5-{[(2-Chloroquinolin-3-yl)methyl]sulfanyl}-N-[-(4-methylphenyl)methy-
7.54 (t, 1H, H-6, J = 7.1 Hz), 7.67–7.83 (m, 6H, Ar-H & H-5, H-7),
8.09 (d,1H, H-8, J = 7.3 Hz), 8.22 (s, 1H, H-4), 11.39 (s, 1H, CONH).
lidene]-1,3,4-thiadiazol-2-amine 7c IR (KBr) ⁄ cm: 1605 (C=N), 1579,
(C=C), 768 (C–Cl); H-NMR (300 MHz, CDCl3): d 2.37, (s, 3H, CH3),
1
106
Chem Biol Drug Des 2012; 79: 104–111

Design, Synthesis and Screening of an Anticonvulsant
4.58 (s, 2H, SCH2), 7.13 (d, 2H, Ar-H, J = 7.6 Hz), 7.49 (t, 1H, H-6,
J = 7.8 Hz), 7.69 (t, 1H, H-7, J = 7.8 Hz), 7.73–7.81 (m, 3H, Ar-H &
H-5), 8.08 (d,1H, H-8, J = 7.5 Hz), 8.14 (s, 1H, H-4), 8.89 (s, 1H,
CH=N).
NMR (CDCl3, 75 MHz): d 15.4, 35.9, (CH2), 41.5, 117.2, 126.6,
128.4, 129.2, 129.9, 130.8, 132.8, 141.3, 146.4, 147.7, 164.9. FAB-
MS : m ⁄ z 337 (M+), 339 (M + 2).
N-Benzyl-5-{[(2-chloroquinolin-3-yl)methyl]sulfanyl}-1,3,4-thiadiazol-2-
5-{[(2-Chloroquinolin-3-yl)methyl]sulfanyl}-N-[-(4-methoxyphenyl)methy-
amine 8b IR (KBr) ⁄ cm: 3375 (N–H), 1615 (C=N), 1590 (C=C), 1030
(C–N), 769 (C–Cl); H-NMR (300 MHz, CDCl3): d 3.69 (bs, 1H, NH),
1
lidene]-1,3,4-thiadiazol-2-amine 7d IR (KBr) ⁄ cm: 1610 (C=N), 1582,
1
(C=C), 759 (C–Cl); H-NMR (300 MHz, CDCl3): d 3.71, (s, 3H, OCH3),
4.03 (d, 2H, NCH2), 4.57 (s, 2H, SCH2), 7.03 (d, 2H, Ar-H,
J = 7.1 Hz), 7.34 (m, 3H, Ar-H), 7.54 (t, 1H, H-6, J = 7.6 Hz), 7.72 (t,
1H, H-7, J = 7.5 Hz), 7.82 (d, 1H, H-5, J = 7.4 Hz), 8.03 (d,1H, H-8,
J = 7.8 Hz), 8.11 (s, 1H, H-4); 13C-NMR (CDCl3, 75 MHz): d 36.4,
(CH2), 46.8, 116.8, 125.8, 126.4, 128.6, 129.1, 129.9, 130.5, 131.8,
133.2, 140.6, 142.5, 144.9, 146.5, 166.0; FAB-MS : m ⁄ z 399 (M+),
401 (M + 2).
4.62 (s, 2H, SCH2), 6.98 (d, 2H, Ar-H, J = 7.3), 7.34 (d, 2H, Ar-H,
J = 7.1), 7.52 (t, 1H, H-6, J = 7.0 Hz), 7.74 (t, 1H, H-7, J = 7.5 Hz),
7.81 (d, 1H, H-5, J = 7.7 Hz), 8.10 (d,1H, H-8, J = 7.5 Hz), 8.18 (s,
1H, H-4), 8.79 (s, 1H, CH=N); 13C-NMR (CDCl3, 75 MHz): d 34.8,
(CH2), 113.8, 118.0, 126.2, 128.7, 129.3, 129.8, 130.4, 131.6, 132.4,
133.5, 136.3, 141.4, 144.8, 146.1, 156.7, 161.8, 167.2.
N-[-(4-Chlorophenyl)methylidene]-5-{[(2-chloroquinolin-3-yl)methyl]sul-
5-{[(2-Chloroquinolin-3-yl)methyl]sulfanyl}-N-(4-methylbenzyl)-1,3,4-thia-
diazol-2-amine 8c IR (KBr) ⁄ cm: 3381 (N–H), 1607 (C=N), 1593 (C=C),
1037 (C–N), 758 (C–Cl). 1H-NMR (300 MHz, CDCl3): d 2.39, (s,
3H, CH3), 3.60 (bs, 1H, NH), 3.95 (d, 2H, NCH2), 4.56 (s, 2H,
SCH2), 7.10 (d, 2H, Ar-H, J = 7.1 Hz), 7.32 (d, 2H, Ar-H,
J = 7.5 Hz), 7.51 (t, 1H, H-6, J = 7.1 Hz), 7.76 (t, 1H, H-7,
J = 7.2 Hz), 7.79 (d, 1H, H-5, J = 7.8 Hz), 8.03 (d,1H, H-8,
J = 7.5 Hz), 8.13 (s, 1H, H-4).
fanyl}-1,3,4-thiadiazol-2-amine 7e IR (KBr) ⁄ cm: 1603 (C=N), 1561,
1
(C=C), 755 (C–Cl); H-NMR (300 MHz, CDCl3): d 4.59 (s, 2H, SCH2),
7.51–7.58 (m, 3H, Ar-H & H-6), 7.71 (t, 1H, H-7, J = 7.4 Hz), 7.75–
7.81 (m, 3H, Ar-H & H-5), 8.05 (d,1H, H-8, J = 7.6 Hz), 8.16 (s, 1H,
H-4), 8.82 (s, 1H, CH=N).
5-{[(2-Chloroquinolin-3-yl)methyl]sulfanyl}-N-[-(4-fluorophenyl)methylid-
ene]-1,3,4-thiadiazol-2-amine 7f IR (KBr) ⁄ cm: 1607 (C=N), 1582,
(C=C), 763 (C–Cl); H-NMR (300 MHz, CDCl3): d 4.57 (s, 2H, SCH2),
7.51–7.59 (m, 3H, Ar-H and H-6), 7.73 (t, 1H, H-7, J = 7.0 Hz),
7.80–7.86 (m, 3H, Ar-H & H-5), 8.09 (d,1H, H-8, J = 7.0 Hz), 8.18 (s,
1H, H-4), 8.80 (s, 1H, CH=N).
1
5-{[(2-Chloroquinolin-3-yl)methyl]sulfanyl}-N-(4-methoxybenzyl)-1,3,4-
thiadiazol-2-amine 8d IR (KBr) ⁄ cm: 3358 (N–H), 1611 (C=N), 1582
(C=C), 1032 (C–N), 761 (C–Cl). 1H-NMR (300 MHz, CDCl3): d 3.58
(bs, 1H, NH), 3.79 (s, 3H, OCH3), 4.06 (d, 2H, NCH2), 4.61 (s, 2H,
SCH2), 7.03 (d, 2H, Ar-H, J = 7.2 Hz), 7.42 (d, 2H, Ar-H,
J = 7.5 Hz), 7.51 (d, 1H, H-6, J = 7.5), 7.76 (t, 1H, H-7, J = 7.4 Hz),
7.82 (d, 1H, H-5, J = 7.8 Hz), 8.03 (d,1H, H-8, J = 7.0 Hz), 8.14 (s,
1H, H-4).
5-{[(2-Chloroquinolin-3-yl)methyl]sulfanyl}-N-[-(4-nitrophenyl)methylid-
ene]-1,3,4-thiadiazol-2-amine 7g IR (KBr) ⁄ cm: 1614 (C=N), 1553,
1
(C=C), 760 (C–Cl); H-NMR (300 MHz, CDCl3): d 4.56 (s, 2H, SCH2),
7.54–7.61 (m, 3H, Ar-H and H-6), 7.73 (t, 1H, H-7, J = 7.0 Hz), 7.80
(d, 1H, H-5, J = 7.0 Hz), 8.07–8.13 (m, 3H, Ar-H and H-8), 8.16 (s,
1H, H-4), 8.83 (s, 1H, CH=N).
N-(4-Chlorobenzyl)-5-{[(2-chloroquinolin-3-yl)methyl]sulfanyl}-1,3,4-thia-
diazol-2-amine 8e IR (KBr) ⁄ cm: 3368 (N–H), 1608 (C=N), 1591 (C=C),
1
1039 (C–N), 764 (C–Cl). H-NMR (300 MHz, CDCl3): d 3.63 (bs, 1H,
NH), 4.03 (d, 2H, NCH2), 4.60 (s, 2H, SCH2), 7.34–7.42 (m, 4H, Ar-H),
7.54 (t, 1H, H-6, J = 7.5 Hz), 7.75 (t, 1H, H-7, J = 7.3 Hz), 7.81
(d, 1H, H-5, J = 7.7 Hz), 8.05 (d,1H, H-8, J = 7.6 Hz), 8.14 (s, 1H,
H-4).
General procedure for the synthesis of
compounds (23) (8a–g)
To a solution of (7a–g) (0.01 mol) in absolute methanol (50 mL),
solid sodium borohydride (0.015 mol, 0.46 g) was added portionwise
over a period of 30 min with constant stirring at room temperature.
After that, the content of the flask was refluxed for 4–6 h. The sol-
vent was evaporated under reduced pressure, and the residue was
triturated with water (25 mL), when the crystalline solid separated
out which was filtered, washed with water and dried. The product
was recrystallized from methanol to give colourless to cream col-
oured crystals. The physicochemical data of synthesized were pre-
sented in Table 1.
5-{[(2-Chloroquinolin-3-yl)methyl]sulfanyl}-N-(4-fluorobenzyl)-1,3,4-thia-
diazol-2-amine 8f IR (KBr) ⁄ cm: 3375 (N–H), 1613 (C=N), 1580 (C=C),
1
1028 (C–N), 770 (C–Cl). H-NMR (300 MHz, CDCl3): d 3.55 (bs, 1H,
NH), 3.98 (d, 2H, NCH2), 4.59 (s, 2H, SCH2), 7.31 (d, 2H, Ar-H,
J = 7.7 Hz), 7.53–7.60 (m, 3H, Ar-H and H-6), 7.74 (t, 1H, H-7, J =
7.0 Hz), 7.80 (d, 1H, H-5, J = 7.8 Hz), 8.03 (d,1H, H-8, J = 7.0 Hz),
8.12 (s, 1H, H-4).
5-{[(2-Chloroquinolin-3-yl)methyl]sulfanyl}-N-(4-nitrobenzyl)-1,3,4-thia-
N-Ethyl-5-{[(2-methylquinolin-3-yl)methyl]thio}-1,3,4-thiadiazol-2-amine
diazol-2-amine 8g IR (KBr) ⁄ cm: 3363 (N–H), 1613 (C=N), 1589 (C=C),
1031 (C–N), 758 (C–Cl). H-NMR (300 MHz, CDCl3): d 3.65 (bs, 1H,
NH), 4.04 (d, 2H, NCH2), 4.54 (s, 2H, SCH2), 7.41 (d, 2H, Ar-H,
J = 7.7 Hz), 7.54 (d, 1H, H-6, J = 7.4), 7.74 (d, 1H, H-7, J = 7.6 Hz),
7.82–7.7.89 (m, 3H, Ar-H and H-5), 8.04 (d,1H, H-8, J = 7.0 Hz),
8.15 (s, 1H, H-4).
1
8a IR (KBr) ⁄ cm: 3378 (N–H), 1608 (C=N), 1583 (C=C), 1034 (C–N),
1
770 (C–Cl); H-NMR (300 MHz, CDCl3): d 2.19 (s, 3H, CH3), 2.16 (s,
2H, NCH2), 3.41 (s, 1H, NH), 4.51 (s, 2H, SCH2), 7.52 (t, 1H, H-6,
J = 7.5 Hz), 7.77 (t, 1H, H-7, J = 7.3 Hz), 7.82 (d, 1H, H-5,
J = 8.0 Hz), 8.08 (d, 1H, H-8, J = 7.6 Hz), 8.17 (s, 1H, H-4); 13C-
Chem Biol Drug Des 2012; 79: 104–111
107

Kumar et al.
Table 2: Anticonvulsant and neurotoxicity screening of compounds. Evaluation of compounds in the mouse intraperitoneal maximal electro-
shock seizure (MES), scPTZ and NT screensa
MES screen
0.5 h
PTZ screen
0.5 h
Neurotoxicity screen
0.5 h
Compound No.
4 h
4 h
4 h
6b
6c
100
100
30
100
300
100
30
300
300
100
300
300
300
300
300
30
100
100
30
300
300
100
100
300
300
300
300
300
300
300
300
·
–
300
–
–
300
·
–
300
·
·
·
300
300
300
–
300
·
300
300
·
·
·
·
100
–
6d
6e
30
30
7b
7d
100
300
100
100
300
300
300
300
30
300
300
100
100
300
300
300
300
·
7f
7g
8b
8d
8e
8g
·
100
–
Phenytoin
Sodium Valporate
·
·
300
–
aDoses of 30, 100 and 300 mg ⁄ kg of the compound were administered and the protection and neurotoxicity measured after 0.5 and 4 h. The figures indicate
the minimal dose required to cause protection or neurotoxicity in 50% or more of the animals. The dash (–) indicates the absence of anticonvulsant activity or
neurotoxicity. · denotes not tested.
Pharmacology
Behavioural test
The preliminary anticonvulsant evaluation was made using reported
procedures (24–27). Male albino mice (18–25 g) were used as
experimental animals. All the test compounds were suspended in
30% PEG. The animals were kept at 25 € 2 ꢀC, in the groups of six
percentage receiving chow pellets and water. The light–dark cycle
was 12 h:12 h. Efforts were made to avoid any unnecessary dis-
tress to the animals. All the animal tests have been performed in
accordance with the institutional animal ethical committee
approval.
Some of the titled compounds (30 mg ⁄ kg) were screened for their
behavioural effects using an actophotometer at 0.5 and 1 h after
injection in each group of six animals (26). Animals were acclima-
tized to the dark environment 24 h before the test. The control
administered was 30% PEG only. The behaviour of the animal
inside the photocell was recorded as digital score. Increased score
represented good behavioural activity (Table 3).
CNS depressant study
The forced swim pool method reported earlier by Porsolt et al. (27)
was followed. Mice (six animals in each group) were placed in
chamber (diameter 45 cm, height 20 cm) containing water up to the
height of 15 cm at 25 € 2 ꢀC. Two swim sessions were conducted,
Anticonvulsant screening
Anticonvulsant evaluations were undertaken using the reported pro-
cedures (24,28). Initially, all the test compounds were administered
i.p. in a volume of 0.01 mL ⁄ g b.w. of mice at doses of 30, 100 and
300 mg ⁄ kg to 1–6 animals. Anticonvulsant activity was assessed
after 0.5-h and 4-h intervals of administration. Activity was estab-
lished using the MES and scPTZ tests, and data are summarized in
Table 2.
Table 3: Behavioural study on some selected compounds using
actophotometer
Posttreatment
(locomotor activity score)b
Activity score
Neurotoxicity screen
Compoundsa Control (24 h prior) 0.5 h after
1 h after
Rotarod test has been performed to detect the motor deficit in mice
(25). Animals were divided in the groups of four animals and
trained to stay on accelerating rotarod that rotates at 10 revolu-
tions per minute. The rod diameter was 3.2 cm. Trained animals
(able to stay on the rotarod for at least two consecutive periods of
90 s) were given an i.p. injection of the test compounds in the
doses of 30, 100 and 300 mg ⁄ kg. Neurological deficit was indicated
by the inability of the animal to maintain equilibrium on the rod for
at least 1 min in each of the three trials. The dose at which animal
fell off the rod was determined, and data are presented in Table 2.
6d
6e
327.17 € 12.37
289.00 € 11.16
143.33 € 9.09
119.33 € 17.43
259.00 € 13.37
294.50 € 8.80
256.17 € 21.48NS 275.50 € 13.65
7f
129.50 € 14.33
78.87 € 16.66
150.17 € 18.60NS
97.17 € 13.49
Phenytoinc
aCompounds were tested at a dose level of 100 mg ⁄ kg (i.p.).
bEach score represents the mean € SEM of six mice, significantly different
from control at p < 0.05, and NS denote the value, which were not signifi-
cant (student's t-test).
cTested at a dose level of 30 mg ⁄ kg (i.p.).
108
Chem Biol Drug Des 2012; 79: 104–111

Design, Synthesis and Screening of an Anticonvulsant
Table 4: CNS study on selected compounds in a forced swim
pool test
immobility (passive floating without struggling, making only those
movements which were necessary to keep its head above the sur-
face) during the 5 min test period was measured. This immobility
reflected state of depression. Carbamazepine was used as a refer-
ence for comparison at a dose of 30 mg ⁄ kg (i.p., in PEG). The con-
trol animals were administered 30% PEG (Table 4).
Immobility time (s)
Compoundsa
Controlb (24 h prior)
Posttreatmentc (1h after)
Vehicle
6d
160.00 € 13.37
148.17 € 7.89
139.53 € 12.61
137.33 € 10.83
143.33 € 8.42
173.50 € 11.54NS
145.83 € 9.63
143.33 € 4.57
158.50 € 6.72
169.00 € 11.63
6e
7f
Results and Discussion
Carbamazepined
Chemistry
aCompounds were tested at a dose of 100 mg ⁄ kg (i.p.).
bControl animals were administered PEG (i.p.).
The reaction sequence for the synthesis of compounds (6a–e, 7a–
g and 8a–g) is outlined in Scheme 1. The required penultimate
intermediate 5 that was prepared in moderate yield from reported
2-chloro-3-formyl quinoline 2 via its reduction with solid NaBH4 in
methanol to afford 2-chloro-3-hydroxymethyl quinoline 3, followed
by chlorination with SOCl2 in dry benzene gave 3-(chloromethyl)-2-
chloroquinoline 4, which on subsequent reaction with 5-sulfanyl-
1,3,4-thiadiazol-2-ylamine gave compound 5. The target compounds
cEach value represents the mean € SEM of six mice significantly different
from the control at p < 0.05 (NS – not significant).
dTested at 30 mg ⁄ kg (i.p.).
an initial 15 min pretest, followed by a 5-min test session 24 h
later. The animals were administered an i.p. injection (30 mg ⁄ kg) of
the test compound 30 min before the test session. The period of
S
N
N
a
NH2
H2N
H2N
NH
O
S
SH
(1)
OH
b
c
Cl
N
Cl
N
Cl
N
Cl
N
(2)
(3)
(4)
N
S
N
N
Cl
NH2
d
+
H2N
S
S
SH
N
Cl
(1)
(4)
N
Cl
(5)
f
e
N
N
N
S
R1
N
S
N
NH
N
Cl
S
S
R
(7a–f)
O
N
Cl
(6a–e)
g
R: CH3, C2H5, C6H5, p-CH3-C6H4, p-Cl-C6H4
R1: CH3, C6H5, p-CH3-C6H4, p-OCH3-C6H4, p-Cl-C6H4,
p-F-C6H4, p-NO2 -C6H4
N
N
NH
S
R1
S
N
Cl
(8a–f)
Scheme 1: Synthetic pathway of the targeted compounds 6a–e, 7a–g and 8a–g. Reagents and conditions: (a) KOH ⁄ CS2 in ethanol, r.t
8 h; (b) NaBH4 portionwise, stirring 30 min; (c) SOCl2, reflux for 4 h; (d) KOH (85% solution), stirring at 0 ꢀC in an ice bath; (e) substituted
acid chloride in 10% w ⁄ v NaOH solution; (f) substituted carbaldehyde and glacial acetic acid, reflux 6–8 h; (g) NaBH4 portionwise, stirring
30 min, then reflux 4–6 h.
Chem Biol Drug Des 2012; 79: 104–111
109

Kumar et al.
(6a–e, 7a–g and 8a–g) were obtained in moderate to good yield
All the tested compounds of this series were found to be active in
the scPTZ test, a test used to identify compounds that elevate sei-
zure threshold. Compounds 6d and 6e showed activity at a dose
of 30 mg ⁄ kg while 6b, 6c, 7f and 7g showed activity at dose of
100 mg ⁄ kg, Among the tested compounds, 6d and 6e were found
to be highly potent having rapid onset but with intermediate dura-
tion of action. Compounds 6b, 6c, 7f and 7g were found to be
having rapid onset and short duration of action as these derivatives
are effective at 0.5-h interval but required higher dose to be effec-
tive at 4 h. While the rest of compounds were found to had low
potency and short duration of action.
by following different reaction pathways (Scheme 1 and Table 1).
1
Both analytical and spectral data (IR, H & 13C-NMR and Mass) of
all the synthesized compounds were in full agreement with the pro-
posed structures. In the IR spectra of compounds (6a–e), the band
representing N–H and CO of –NHCO– appeared at 3385–3409 and
1663–1677 ⁄ cm, respectively. In 1H-NMR spectra of compounds
(6a–e), the characteristics peak of-NHCO– was observed as singlet
to broad singlet at d 11.39–12.08 ppm equivalent to one proton of
NH, while in 13C-NMR spectra, the carbonyl carbon of –NHCO–
1
was resonated at d 171.2 in compound 6a. In H-NMR spectra of
compounds (7a–g), the azomethine proton was appeared as singlet
integrating for one proton at d value ranging 8.51–8.89 ppm. The
transformation of azomethines (7a–g) into secondary amines was
accomplished using NaBH4, and characteristic methylene amine
Two general trends may be discerned. First, data for the MES and
scPTZ tests revealed that 33% and 50%, respectively, of the com-
pounds had greater activity at the end of 0.5 h than after 4 h.
Thus, in general, these compounds are short-acting anticonvulsant.
Secondly, protection was afforded by all the tested compounds in
the MES and scPTZ screen, respectively. No compound showed
greater activity in the scPTZ screen rather than MES test, while 6e
showed better activity in the MES model.
1
function was identified by H-NMR in which two new signals at d
value ranging from 3.41–3.69 to 2.16–4.06 arises owing to –NH
and –CH2– function, respectively. The disappearance of azomethine
group also supported the fact. Furthermore, in 13C-NMR spectra, –
NHCH2 carbon of compound 8a and 8b was observed at d 35.9
and 36.4 respectively. This is considered to be a strong confirmation
for the synthesis of compounds (8a–g). The confirmation of synthe-
sis of compounds was also supported by the FAB-MS spectrometry
of some selected compounds 6a, 6d, 7a, 7b and 8a, which regis-
tered molecular ion peak at m ⁄ z 351, 426, 335, 397 and 337
respectively. The spectral details of individual compound have been
given in experimental section.
In neurotoxicity screen, compound 6e did not show neurotoxicity in
the maximum administered dose (300 mg ⁄ kg), and the remaining
compounds were found to be less neurotoxic as compared to phe-
nytoin.
In the behavioural study, using actophotometer, the compounds 6e
and 7f showed no behavioural despair effect when compared to
phenytoin as represented in Table 3. Compound 6d showed
decreased locomotor activity in the 0.5-h interval but no significant
effect on behavioural despair was observed during 1-h time period.
Similarly, results obtained in Porsolt's swim pool test with com-
pound 7f, in which an increase in the slight immobility time by the
compounds indicated the CNS depressant effect. Rest of the tested
compounds showed no significant variation from control.
Pharmacology
Some of the new derivatives obtained by the above-mentioned proce-
dure were undertaken for the initial anticonvulsant studies by the
anticonvulsant drug development (ADD) programme protocol (28). The
profile of anticonvulsant activity was established after i.p. injections
into mice and evaluated in the MES, subcutaneous pentylenetetrazole
(scPTZ) and neurotoxicity screens, using doses of 30, 100 and
300 mg ⁄ kg at two different time intervals. These data are presented
in Table 2. Those found potent on initial preliminary screening were
evaluated for their CNS behavioural activity in mice using actopho-
tometer and CNS depressant study using Porsolt's forced swim pool
test. The results are presented in Tables 3 and 4, respectively.
Conclusion
As observed through data analysis, the compounds with amido link-
age are more potent than having azomethine linkage which in turn
better than substituted amino derivative as can be observed that none
of 8a–g does not produced fruitful result, so this might be due to
involvement and binding of certain groups on thiadiazole with the
receptor site, so probably amido derivate (6a–e) that are most potent
might be playing role in hydrogen bonding, i.e., interaction with recep-
tor site; thus, pharmacophoric features that are essential for a ligand
to interact with receptor site to elicit action were achieved through
the presence of amido group in designed molecules.
Anticonvulsant activity
All the tested compounds showed protection against MES test
indicative of their ability to inhibit the seizure spread. Compounds
6d and 6e showed protection against the MES model at 30 mg ⁄ kg
while some compounds 6b, 6c, 7b, 7f and 7g showed protection
at dose level of 100 mg ⁄ kg. The compound 6e showed activity at
both 0.5- and 4-h period at dose level of 30 mg ⁄ kg indicating the
compound to be highly potent and long acting. Similarly compound
6d was also found to be highly potent but short acting as 4-h pro-
tection requires the dose of 100 mg ⁄ kg. The compounds 6b and 7f
showed activity both at 0.5- and 4-h period at dose level of
100 mg ⁄ kg, indicating that the compounds are potent and long act-
ing while compounds 6c, 7b and 7g showed activity only at 0.5 h
at 100 mg ⁄ kg dose, indicating that these are having rapid onset
and shorter duration of action.
Acknowledgements
Authors are thankful to Hamdard University, New Delhi for genera-
tion of FT-IR and elemental analysis data. The authors are really
grateful to CDRI, Lucknow, for the generation of FABMS and to IIT,
1
New Delhi and Hamdard University, New Delhi, for providing the H
NMR spectra. The authors also record their appreciation of extraor-
110
Chem Biol Drug Des 2012; 79: 104–111

Design, Synthesis and Screening of an Anticonvulsant
dinary assistance of Lalit kumar of Pharmacology Dept., Jamia Ham-
dard. One of the authors S.K is thankful to UGC for the grant of fel-
lowship for carrying out the research.
14. Pattanayak P., Sharma R. (2010) 2-Amino-5-sulphanyl-1,3,4-thi-
adiazole derivatives as anticonvulsant agents: synthesis and
evaluation. Indian J Chem;49B:1531–1534.
15. Pattanayak P., Sharma R., Sahoo P.K. (2009) Synthesis and evalu-
ation of 2-amino-5-sulfanyl-1,3,4-thiadiazoles as antidepressant,
anxiolytic, and anticonvulsant agents. Med Chem Res;18:351–
361.
Conflict of Interest
16. Thareja S., Aggarwal S., Verma A., Bhardwaj T.R., Kumar M.
(2010) 3D QSAR studies on 1, 3, 4-thiadiazole derivatives: an
approach to design novel anticonvulsants. Med Chem;6:233–
238.
The authors declared that there are no conflicts of interest.
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