Synthesis of benzothiazole derivatives having acetamido and carbothioamido pharmacophore as anticonvulsant agents

Article abstract of DOI:10.1007/s00044-011-9791-1

A new series of N-(6-chlorobenzothiazol-2-yl)-2-substituted-acetamides (3a-h) and N-(6-chlorobenzothiazol-2-yl)-2-(substituted-benzylidene) hydrazinecarbothioamides (5a-h) were synthesized and characterized by IR, ¹HNMR, mass and elemental analysis. In vivo anticonvulsant and acute toxicity screening of all the synthesized compounds showed morpholino (3f) and imidazolyl (3g) derivatives as promising anticonvulsant lead. Furthermore, In silico druglikeness parameters have also been investigated for filtering out the likelihood of poor drug absorption or brain penetration. 3D four-point pharmacophore measurements of compounds were also carried out to match these with established anticonvulsants agents. Springer Science+Business Media, LLC 2011.

Full text of DOI:10.1007/s00044-011-9791-1

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:2661–2670
DOI 10.1007/s00044-011-9791-1
ORIGINAL RESEARCH
Synthesis of benzothiazole derivatives having acetamido
and carbothioamido pharmacophore as anticonvulsant agents
•
Mohd. Amir S. Asif Israr Ali Mohd. Zaheen Hassan
•
•
Received: 1 March 2011 / Accepted: 2 September 2011 / Published online: 18 September 2011
Ó Springer Science+Business Media, LLC 2011
Abstract A new series of N-(6-chlorobenzothiazol-2-yl)-
2-substituted-acetamides (3a–h) and N-(6-chlorobenzothiazol-
2-yl)-2-(substituted-benzylidene)hydrazinecarbothioamides
(5a–h) were synthesized and characterized by IR, 1H NMR,
mass and elemental analysis. In vivo anticonvulsant and
acute toxicity screening of all the synthesized compounds
showed morpholino (3f) and imidazolyl (3g) derivatives as
promising anticonvulsant lead. Furthermore, In silico drug-
likeness parameters have also been investigated for filtering
out the likelihood of poor drug absorption or brain penetra-
tion. 3D four-point pharmacophore measurements of com-
pounds were also carried out to match these with established
anticonvulsants agents.
enormous economic trouble to patients. Therefore, devel-
opment of safer and effective antiepileptic drugs would
have an enormous socioeconomic impact (Rosaria et al.,
2006; Hong et al., 2009).
Many investigations indicated that the presence of
hydrogen bonding domain as amide (–CONH–) and their
bioisoester carbothioamide (–CSNH–) seems to be valuable
in the structure of anticonvulsants (Siddiqui et al., 2007;
Amnekar and Bhusari 2010; Siddiqui et al., 2009). More-
over, hydrophobic benzothiazoles have also an immense
interest in medicinal chemistry as these structural moieties
exist in large number of natural products (Bondock et al.,
2009) as well as in pharmaceutically active compounds
showing diverse biological properties like anticonvulsant
(Chopade et al., 2002), anticancer (Brantley et al., 2006),
anti-inflammatory (Naik et al., 1996) and antimicrobials
(Bondock et al., 2010). Riluzole (2-aminobenzothiazole
derivative) is a clinically available AED with neuroprotec-
tive effect acting on sodium channels and N-methyl-D-
aspartate (NMDA) receptors (Zarate and Manji 2008).
Encouraged by these observations and in continuation of our
interest in the synthesis of heterocyclic compounds (Amir
et al., 2008, 2010), we thought it worthwhile to synthesize a
new series of compounds having acetamide or carbothioa-
mide moieties along with benzothiazole pharmacophore
with the hope that hybridization of these bioactive moieties
will have synergistic anticonvulsant effect due to increased
lipophilicity.
Keywords Benzothiazole ꢀ Acetamide ꢀ
Carbothioamide ꢀ Drug-likeness ꢀ Anticonvulsant activity
Introduction
Epilepsy is the recurrent, serious neuropathological syn-
drome affecting about 1–2% of the world’s population,
covering over 40 different types of human seizures
(Yogeeswari et al., 2005a, b). Despite the availability of
around 20 permitted AEDs, there is an importunate demand
for newer broad spectrum antiepileptic agents to improve
the drug safety profile and to cope with uncontrolled and/or
resistant seizure patients (Lin and Kadaba 1997). Further-
more, therapeutic regimen for epilepsy often involves a
change of first line drug or polytherapy, putting an
A pharmacophore model along with physicochemical
determination provides a useful tool for designing proto-
typic molecules and explanation of plausible interactions
(Malawska 2003). In term of interaction at binding site, the
titled compounds have common structural features such as
an aromatic hydrophobic domain (A), = N– as an electron
donor atom (D), C=O or C=S as hydrogen bond acceptor
Mohd. Amir (&) ꢀ S. Asif ꢀ I. Ali ꢀ Mohd. Z. Hassan
Department of Pharmaceutical Chemistry, Faculty of Pharmacy,
Hamdard University, Hamdard Nagar, New Delhi 110062, India
e-mail: mamir_s2003@yahoo.co.in
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Med Chem Res (2012) 21:2661–2670
(HA), and N–H as hydrogen bond donor (HD) (Yogeeswari
et al., 2005b). This work also outlines the four point
pharmacophore models for the development of prototype
compound using structurally different classes of
anticonvulsants.
3.42. Moreover, the presence of additional peak due to
–NH proton at d 2.99 beside a signal of –CONH proton at d
7.18 confirmed the formation of amino-acetamide linkage.
1
The H NMR spectrum of compound 4 showed a broad
singlet at d 8.64 corresponding to –NHCSNH– group;
whereas, a signal for NH2 proton was observed at d 4.48.
The formation of compound 5a was confirmed by
appearance of a singlet at d 5.99 due to N=CH proton. The
singlets were also observed at d 9.41 and d 6.67 due to
–CSNH– and –NH protons, respectively. The elemental
analysis results were within 0.4% of the theoretical val-
ues. The physicochemical properties of the titled com-
pounds are presented in Table 1.
Furthermore, an In silico investigation of drug-likeness
parameters has always been a critical filter for drugs with
poor intestinal permeability or poor aqueous solubility and
hence ensuring the development of orally active drugs
(Walters et al., 1999). In present investigation all the
synthesized compounds were subjected to prediction of
molecular properties and drug-likeness parameters so as to
avoid costly late-stage preclinical and clinical failures.
Pharmacology
Results and discussion
The introduction of diverse bioactive groups at ben-
zothiazolamine and their subsequent screening led to an
understanding of electronic property, size and lipophilicity
influence at benzothiazole nucleus. The amide linkage
–NHCO– with delocalized electrons is a key determinant
of anticonvulsant activity, which would be greatly influ-
enced by the nature of adjoining substituent. Therefore,
compounds 3(a–h) were synthesized to explore the effects
of adding substituents to acetamide linkage at benzothia-
zole ring. In MES screening, all the synthesized com-
pounds having acetamide linkage were shown to have rapid
onset and long duration of action except compound 3b and
3d. The potency order for protection of hind limb tonic
extension was observed as morpholino (3f), imidazolyl
(3g) [ tert-butylamino (3a), pipredinyl (3e) [ p-fluor-
ophenylamino (3c) [ indolyl substituted derivative (3h).
Out of these, compound 3f and 3g having log P 2.32 and
2.14, respectively, showed excellent anti-generalized tonic-
clonic activity after 0.5 h and 4 h at 30 mg/kg. In the
scPTZ screen, compounds 3a, 3c, 3e, 3f, and 3g elevated
seizure threshold at dose of 100 mg/kg after 0.5 h out of
which, compound 3f and 3g were again shown to have
longer duration of action at same dose. To further evaluate
the potential of 2-aminobenzothiazole, we synthesized
hybrid compounds having hydrazinecarbothioamide phar-
macophore. In hydrazinecarbothioamide series, compound
having p-flourobenzylidene group (5d) (log P 5.22) were
shown to have rapid onset and long duration of action at
Chemistry
The synthesis of N-(6-chlorobenzothiazol-2-yl)-2-substi-
tuted acetamides (3a–h) and N-(6-chlorobenzothiazol-2-
yl)-2-(substitutedbenzylidene)hydrazinecarbothioamides
(5a–h) was carried out as presented in Scheme 1. Synthesis
of 6-chloro-2-aminobenzothiazole (1) involves the cycli-
zation of 4-chloroaniline with potassium thiocyanate and
bromine in presence of glacial acetic acid. Compound 1 on
acylation followed by treatment with various amine affor-
ded acetamide derivatives (3a–h). Furthermore, reaction of
compound 1 with CS2 and NH3 followed by treatment with
hydrazine hydrate resulted in the formation of hydra-
zinecarbothioamide derivative (4). Compound 4 on con-
densation with various aromatic aldehyde afforded
substituted benzylidene hydrazinecarbothioamides (5a–h).
The 1H NMR spectrum of 6-chlorobenzothiazol-2-
amine (1) showed a doublet at d 7.11–7.14 for aromatic
proton at 5th position. The signals for aromatic protons at
4th and 7th position were observed as a doublet at d 7.22
and 7.66, respectively, whereas a signal for two protons of
amino group was observed at d 7.57. The formation of
compound (2) was confirmed by appearance of a singlet at
d 9.73 and d 4.32 for –CONH and –COCH2 protons,
respectively, in the 1H NMR spectrum. The 1H NMR
spectrum of compound 3a, showed a singlet indicating the
presence of three CH3 groups at d 1.31 and –COCH2 at d
O
Scheme 1 Reagents and
conditions: (i) ClCH2COCl, dry
benzene, (ii) 1°/2° amine, dry
benzene, TEA (iii) CS2, NH3,
ClCH2COONa/NH2ꢀNH2 2H2O
(iv) ArCHO, EtOH, CH3COOH
O
N
S
N
S
N
S
i
ii
NH
NH
NH
N
Cl
R
Cl
Cl
Cl
2
4
3(a-h)
5(a-h)
NH2
S
S
S
N
Cl
iii
iv
1
NH
NH NH2
S
NH
N
Cl
Ar
H
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Med Chem Res (2012) 21:2661–2670
2663
Table 1 Physicochemical parameters of synthesized compounds 3a–h and 5a–h
S
N
S
O
N
S
NH
NH
NH N
H
Cl
R
5(a-h)
Cl
3(a-h)
Ar
Compound
R/Ar
Mol. formula (Mol. Wt.)
C13H16ClN3OS (297.80)
log P (C log P)a
m.p (°C)
Yield (%)
Rfb
3a
3b
3c
3d
3e
3f
Tert-butylamino
4-Chlorophenylamino
4-Fluorophenylamino
Diphenylamino
Piperidin-1yl
3.02 (3.22)
4.24 (4.57)
3.88 (4.02)
6.12 (5.88)
3.16 (3.75)
2.32 (2.43)
2.14 (2.21)
4.62 (4.74)
4.86 (4.95)
5.52 (5.71)
5.46 (5.64)
5.22 (5.16)
4.68 (4.87)
4.78 (4.70)
5.16 (5.08)
5.24 (5.12)
182
156
170
230
80
80
70
55
62
58
70
73
66
74
72
51
62
70
63
60
54
0.55
0.62
0.60
0.65
0.45
0.50
0.55
0.75
0.70
0.80
0.75
0.76
0.64
0.62
0.76
0.80
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
15H11Cl2N3OS (352.24)
15H11FClN3OS (335.78)
21H16ClN3OS (393.89)
14H16ClN3OS (309.81)
13H14ClN3O2S (311.79)
12H9ClN4OS (292.74)
17H12ClN3OS (341.81)
15H11ClN4S2 (346.86)
15H10Cl2N4S2 (381.30)
15H10Cl2N4S2 (381.30)
15H10ClFN4S2 (364.85)
15H10ClN5O2S2 (391.86)
15H11ClN4OS2 (362.86)
16H13ClN4O2 (376.88)
17H16ClN5S2 (389.93)
Morpholino
140
152
196
148
132
130
116
158
222
110
144
3g
3h
5a
5b
5c
5d
5e
5f
1H-imidazol-1-yl
1H-indol-1yl
Phenyl
4-Chlorophenyl
2-Chlorophenyl
4-Fluorophenyl
4-Nitrophenyl
4-Hydroxyphenyl
4-Methoxyphenyl
5g
5h
a
4-Dimethylamino phenyl
Log P was determined by octanol:phosphate buffer method; C log P, in parentheses was calculated using software ACD/log P 1.0
b
Solvent system: toluene/ethyl acetate/formic acid (5:4:1)
30 mg/kg (phenytoin 30 mg/kg). Also compound with
intestinal absorption, reduced molecular flexibility (mea-
sured by the number of rotatable bonds), low polar surface
area or total hydrogen bond count (sum of donors and
acceptors), are important predictors of good oral bioavail-
ability (Bakht et al., 2010). Moreover, Lipinski’s ‘‘rule of
five’’ is a heuristic approach for predicting drug-likeness
stating that molecules having molecular weight [500, log
P[5, hydrogen bond donors[5 and hydrogen bond accep-
tors[10 have poor absorption or permeation (Lipinski et al.,
1997). Therefore, all the compounds were investigated for
absorption (% ABS), molecular polar surface area (PSA) and
Lipinski’s parameters (Table 2). In this rule, any oxygen
(O) and nitrogen (N) atoms are defined as hydrogen bond
acceptors and N–H or O–H groups are considered as
hydrogen bond donors. Results of this analysis indicate that
the number of hydrogen bond donors (2–3) and hydrogen
bond acceptors (3–6) are in good agreement with ‘‘rule of
five’’. Number of rotatable bonds (NROTB) indicates the
conformational flexibility of molecule for receptors or
channels binding and should be B10 (Veber et al., 2002). All
the synthesized compounds have number of rotatable bonds
in the range of 3–6 exhibiting restrained conformational
flexibility. PSA (polar surface area) is also an important
p-nitrobenzylidene (5e) and p-hydroxybenzylidene groups
(5f) showed protection at 100 mg/kg in MES test. In scPTZ
test compounds 5d and 5e showed rapid onset and long
duration of action at dose 100 and 300 mg/kg, respectively.
Results from the rotarod motor impairment test dem-
onstrated that compounds 3f, 3g, and 3c did not show
neurotoxicity at the maximum dose administered (300 mg/
kg). Rest of the compounds showed neurotoxicity at 100 or
300 doses mg/kg. All the compounds were evaluated for
the CNS depressant effect using Porsolt’s swimming pool
test and their immobility times were compared with respect
to reference drug carbamazepine (Table 3). Compounds
3a, 3e, 3f, and 3g were found to have no significant CNS
depressant effect with respect to control. All other com-
pounds were found having CNS depressant effect as they
increased the immobility time significantly.
In silico studies and Partition coefficient
Choosing ‘‘drug-like’’ molecule from non-drug-like mole-
cules at the preliminary stage and to avoid drug with poor
oral bioavailability is the main aim of current study. Good
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Med Chem Res (2012) 21:2661–2670
predictor of absorption, defined as part of the molecular
surface that arises from oxygen or nitrogen atoms, or
hydrogen atoms attached to nitrogen or oxygen atoms.
Several studies have identified that M. Wt. of CNS active
showing several common structural features essential for
activity at sodium ion channel. Although, the chemical
diversity and various mechanisms of action of anticon-
vulsants make it difficult to identify a common pharma-
cophore, the essential structural elements in the four-point
pharmacophore model were assumed as lipophilic aryl ring
center (A), =O or =N– as an electron donor atom (D), C=O
or C=S as hydrogen bond acceptor (HA), and N–H as
hydrogen bond donor (HD) (Fig. 2) (Unverferth et al.,
1998). All the molecules are 3D optimized and were con-
formers which bring the above-mentioned groups closely
together. Table 4 shows the distances between the various
groups postulated as essential for anticonvulsant action.
Comparison of average distance requirements showed that
the compounds 3f and 3g were in good conformity with the
sodium channel blockers.
2
˚
drugs should be \450 and PSA \90 A are to be recom-
mended for the penetration of BBB (van de Waterbeemd
et al. 1998). The predicted PSA value of all the synthesized
2
compounds were found in the range of 35.58–75.14 A with
˚
M. Wt. maximum of 395.57 indicating their excellent brain
penetration which is a criterion for anticonvulsant effect.
Partition coefficient (log P) is an imperative physico-
chemical marker of drug permeability across the blood
brain barrier (BBB) for inadequate drug concentration in
crucial brain areas (Kwan and Brodie 2005). Therefore,
partition coefficients of all the compounds were determined
to establish the correlation between log P and anticonvul-
sant activity. The log P values of some of the active
compounds indicated in parentheses, viz. 3f (2.32), 3g
(2.14) and 5d (5.22). This clearly indicates that moderate
log P value (2.14–2.32) is prerequisite for showing anti-
convulsant activity without neurotoxicity.
Conclusion
Some newer acetamide and carbothiomide derivatives
having benzothiazole nucleus were synthesized with good
drug-likeness score and evaluated for anticonvulsant,
neurotoxicity, and CNS depressant activities. Structure–
activity relationship study led to presume the possible
interactions of compound with specific binding site. Ben-
zothiazole possessing acetamide derivatives showed better
protection indices than carbothiomide linkage in MES and
ScPTZ screen without any CNS depressant effect or neuro-
toxicity. Comparing the structures of acetamide series it was
Drug-likeness model score (a collective effect of phys-
icochemical properties, pharmacokinetics and pharmaco-
dynamics) of all the compounds were positive with
maximum of 1.15 therefore, the synthesized compounds
are adequate to be treated like candidate drugs. The most
active compounds 3f and 3g have also good drug-likeness
score 0.44 and 0.75 (Fig. 1).
There have been several attempts to provide insight into
pharmacophore modeling of the putative MES receptor
Table 2 Calculated absorption (%ABS), polar surface area (PSA), Lipinski parameters and drug-likeness model score of the benzothiazole
derivatives
Compd.
% ABS
Mol.Vol. (A3)
PSA (A2)
NROTB
HBA
HBD
Drug-likeness
model score
3a
3b
3c
3d
3e
3f
93.31
93.66
93.66
96.72
95.74
93.01
93.01
95.97
94.60
94.60
94.60
94.60
83.07
88.64
91.70
93.57
290.44
294.45
283.17
357.95
296.80
287.04
251.80
306.19
305.44
322.64
320.11
311.36
330.43
315.99
337.29
354.95
45.45
44.46
44.46
35.58
38.41
46.32
46.33
37.76
41.73
41.73
41.73
41.73
75.14
59.00
50.12
44.70
4
4
4
5
3
3
3
3
5
5
5
5
6
5
6
6
4
3
3
3
4
5
4
3
4
4
4
4
6
5
5
4
2
2
2
1
1
1
1
1
2
2
2
2
2
3
2
2
0.94
0.24
0.42
0.60
0.62
0.44
0.75
0.16
0.89
0.87
1.09
0.99
0.20
0.97
1.15
0.76
3g
3h
5a
5b
5c
5d
5e
5f
5g
5h
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Med Chem Res (2012) 21:2661–2670
2665
Procedure for the preparation of 2-chloro-N-(6-
chlorobenzothiazol-2-yl)acetamide (2)
6-Chloro-2-aminobenzothiazole (0.05 mol, 9.22 g) and
chloroacetylchloride (0.05 mol, 3.98 ml) in dry benzene
was refluxed for 1 h. The solution was filtered and residue
was washed with benzene and then with sodium bicar-
bonate solution. Finally, it was washed with distilled water
and recrystallized from ethanol. Yield 85%; m.p. 140°C; IR
(KBr, cm-1): 3316 (NH), 2842 (CH), 1673 (C=O), 1585
(C=N). 1HNMR (CDCl3-300 MHz) d: 4.32 (s, 2H,
COCH2), 7.43 (d, 1H, 5th Ar–H, J = 8.8 Hz), 7.73 (d, 1H,
4th Ar–H, J = 8.8 Hz), 7.81 (s, 1H, 7th Ar–H), 9.73 (s,
1H, CONH). Mass (m/z): 260 (M ? 1). Anal. calcd for
C9H6Cl2N2OS: C, 41.40; H, 2.32; N, 10.73%; Found: C,
41.36; H, 2.29; N, 10.69%.
Fig. 1 Drug-likeness model score plot for compounds 3f and 3g
using Molsoft
found that substitution with morpholine (3f) and imidazolyl
(3g) group is favored over lipophilic distal phenyl ring.
Partition coefficient determinations (log P), clearly
indicate that in general the optimal hydrophobicity (log
P & 2) of the molecules is essential for anticonvulsant
activity without any neurotoxicity. These new aspects of
benzothiazolyl-acetamide molecules might be useful for
designing potential anticonvulsants.
General procedure for the preparation of N-(6-
chlorobenzothiazol-2-yl)-2-substituted-acetamides (3a–h)
To substituted amine (0.0019 mol) dissolved in dry ben-
zene (30 ml) was added triethylamine (0.0019 mol,
0.274 ml) and refluxed for 10 min. To this 2-chloro-N-(6-
chlorobenzothiazol-2-yl)acetamide (0.0019 mol, 500 mg)
was added slowly and refluxed for 6 h. The solid thus
obtained was filtered and washed with benzene and then
with distilled water and recrystallized from ethanol.
Experimental
General chemistry
2-(Tert-butylamino)-N-(6-chlorobenzothiazol-2-yl)
acetamide (3a)
The entire chemicals used in the synthesis were supplied by
E. Merck and S.D. Fine Chemicals. Melting point is deter-
mined by open capillary tube method and is uncorrected.
Purity of the compound was checked on thin layer chroma-
tography usingiodine vapors as visualizingagents. IR spectra
were obtained on a Perkin-Elmer 1720 FTIR spectrometer
IR (KBr, cm-1): 3440 (NH), 3330 (CH aromatic), 2641
(CH2), 1685 (C=O), 1592 (C=N). 1HNMR (CDCl3-
300 MHz) d: 1.31 (s, 9H, 3CH3), 2.99 (s, 1H, NH), 3.24 (s,
2H, COCH2), 7.18 (s, 1H, CONH), 7.40 (d, 1H, 5th ArH-
benzo., J = 8.7 Hz), 7.72 (d, 1H, 4th ArH-benzo.,
J = 8.7 Hz), 7.74 (s, 1H, 7th ArH-benzo.). MS (m/z): 298
(M ? 1). Anal. Calcd for C13H16ClN3OS: C, 52.43; H,
5.42; N, 14.11%; found: C, 52.47; H, 5.46; N,14.15%.
1
(KBr pellets). H-NMR spectra were obtained on a Bruker
300 MHz NMR spectrometer using Tetramethysilane (TMS)
as the internal reference (chemical shifts in d ppm). Mass
spectra were recorded at Jeol SX-102 spectrometer.
Fig. 2 Established
anticonvulsant drugs along with
synthesized compounds
showing essential
pharmacophoric elements: aryl
unit/hydrophobic domain (A),
electron donor atom (D), and
coupled hydrogen donor (HD)–
hydrogen acceptor (HA) group
HA
D
H
O
D
N
S
A
A
CH3
CH3
D
O
D
H
H
N
A
N
HN
HD
N
H3C
O
H2C
H
HA
O
N
HA
O
HD
HA
HD
S
H2N
HD
A
H
Carbamazepine
Albutoin
Phenytoin
Remacemide
HA
F
D
N
N
F
O
O
N
N
H
H
S
N
N
D
N
N
A
F
HA
D
H
H
O
N
F
A
HD
HD
N
HD
A
D
F
HA
Riluzole
N
N
S
HA
HD
S
H
Cl
O
N
A
3f
Rufinamide
3g
H
Cl
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Med Chem Res (2012) 21:2661–2670
N-(6-chlorobenzothiazol-2-yl)-2-(4-
chlorophenylamino)acetamide (3b)
300 MHz) d: 2.66 (t, 4H, CH2–N–CH2, J = 4.5 Hz), 3.28
(s, 2H, COCH2), 3.81 (t, 4H, CH2–O–CH2, J = 4.5 Hz),
7.41 (d, 1H, 5th ArH-benzo., J = 8.7 Hz), 7.70 (d, 1H, 4th
ArH-benzo., J = 8.7 Hz), 7.78 (d,1H, 7th ArH-benzo.,
J = 8.0 Hz), 10.34 (s, 1H, CONH). MS (m/z): 311 (M?).
Anal. Calcd for C13H14ClN3O2S: C, 50.08; H,4.53;
N,13.48%; found: C, 50.12; H,4.58; N, 13.52%.
IR (KBr, cm-1): 3353 (NH), 3173 (CH aromatic), 2652
(CH2), 1670 (C=O), 1598 (C=N). 1HNMR (DMSO-d6-
300 MHz) d: 3.97 (d, 2H, COCH2, J = 5.2 Hz), 5.46 (s,
1H, NH), 6.51 (d, 2H, 3&5 ArH, J = 8.0 Hz), 7.00 (d, 2H,
2&6 ArH, J = 7.6 Hz), 7.26 (1H, d, 5th Ar–H-benzo.,
J = 8.4 Hz), 7.56 (d, 1H, 4th ArH-benzo., J = 8.0 Hz),
7.69 (s, 1H, 7th Ar–H-benzo.), 11.96 (s, 1H, CONH). MS m/
z: 352 (M ? 1). Anal. Calcd for C15H11Cl2N3OS: C, 51.15;
H, 3.15; N, 11.93%; found: C, 51.19; H, 3.20; N, 11.97%.
N-(6-chlorobenzothiazol-2-yl)-2-(1H-imidazol-1-yl)
acetamide (3g)
IR (KBr, cm-1): 3342 (NH), 3034 (CH aromatic), 2609
(CH2), 1647 (C=O), 1566 (C=N). 1HNMR (DMSO-d6-
300 MHz) d: 5.11 (s, 2H, COCH2), 6.90–8.02 (m, 6H, Ar–
H), 8.07 (s, 1H, CONH). MS (m/z): 293 (M ? 1). Anal.
Calcd for C12H9ClN4OS: C, 49.23; H, 3.10; N, 19.14%;
found: C, 49.27; H, 3.18; N, 19.10%.
N-(6-chlorobenzothiazol-2-yl)-2-(4-
fluorophenylamino) acetamide (3c)
IR (KBr, cm-1): 3436 (NH), 3333 (CH aromatic), 2664
(CH2), 1655 (C=O), 1584 (C=N). 1HNMR (DMSO-d6-
300 MHz) d: 3.97 (d, 2H, COCH2, J = 5.2 Hz), 5.42 (s, 1H,
NH), 6.44–7.01 (m, 4H, ArH), 7.29 (d, 1H, 5th ArH-benzo.,
J = 8.4 Hz), 7.57 (d, 1H, 4th ArH-benzo., J = 8.0 Hz), 7.68
(1H, s, 7th Ar-H-benzo.), 11.97 (1H, s, CONH). MS (m/z):
335 (M?). Anal. calcd for C15H11ClFN3OS: C, 53.65; H,
3.30; N, 12.51%; found: C, 53.61; H, 3.32; N, 12.49%.
N-(6-chlorobenzothiazol-2-yl)-2-(1H-indol-1yl)
acetamide (3h)
Appearance—pale yellow color solid; IR (KBr, cm-1):
3442 (NH), 3217 (CH aromatic), 2606 (CH2), 1684 (C=O),
1594 (C=N). 1HNMR (DMSO-d6-300 MHz) d: 5.21 (s, 2H,
COCH2), 6.40–8.12 (m, 9H, ArH), 10.17 (s, 1H, CONH).
MS (m/z): 342 (M ? 1). Anal. calcd for C17H12ClN3OS: C,
59.73; H, 3.54; N, 12.29%; found: C, 59.78; H, 3.58; N,
12.83%.
N-(6-chlorobenzothiazol-2-yl)-2-
(diphenylamino)acetamide (3d)
IR (KBr, cm-1): 3421 (NH), 3070 (CH aromatic), 2693
(CH2), 1672 (C=O), 1594 (C=N). 1HNMR (DMSO-d6-
300 MHz) d: 5.10 (2H, s, COCH2), 6.76-8.11 (13H, m,
ArH), 10.27 (1H, s, CONH). MS (m/z): 394 (M ? 1). Anal.
calcd for C21H16ClN3OS: C, 64.03; H, 4.09; N, 10.67%;
found: C, 64.08; H, 4.13; N, 10.71%.
Procedure for the preparation of N-(6-
chlorobenzothiazol-2-yl)-hydrazinecarbothioamide (4)
6-Chloro-2-aminobenzothiazole (13.7 g, 0.1 mol) was
dissolved in ethanol (95%, 50 ml) and ammonia solution
20 ml was added slowly within 15 min with shaking and
then CS2 was added slowly. After complete addition of
CS2, the solution was allowed to stand for 1 h; sodium
chloroacetate (9.4 g, 0.1 mol) was added to it. The
reaction was exothermic with change in color from red
to yellowish green. To it 50% hydrazine hydrate (20 ml)
was added. The mixture was warmed gently filtered and
boiled to half of its volume and kept overnight. Next
day, the product thiosemicarbazide was filtered, recrys-
tallized from ethanol. Appearance—pale yellow color
solid; Yield: 75%; m.p. 175°C. IR (KBr, cm-1): 3359
(NH2), 3079 (CH), 1585 (C=N), 1175 (C=S). 1H NMR
(DMSO-d6-300 MHz) d: d 4.48 (s, 2H, NH2), 7.19 (d,
1H, 4th ArH-benzo.), 7.29 (d, 1H, 5th ArH-benzo.), 7.70
(s, 1H, 7th ArH-benzo.), 8.64 (bs, 2H, NH–CS–NH).
MS (m/z): 259. Anal. calcd for C8H7ClN4S2: C, 37.13;
H, 2.73; N, 21.65%; found: C, 37.17; H, 2.77; N,
21.69%.
N-(6-chlorobenzothiazol-2-yl)-2-(piperidin-1yl)
acetamide (3e)
IR (KBr, cm-1): 3414 (NH), 3286 (CH aromatic), 2672
(CH2), 1688 (C=O), 1594 (C=N). 1HNMR (DMSO-d6-
300 MHz) d: 1.69-1.49 (6H, m, (CH2)3), 2.57 (4H, t,
(CH2)2,), 3.21 (2H, s, COCH2), 6.34 (1H, s, CONH),
J = 4.8 Hz), 7.40 (1H, d, 5th ArH-benzo., J = 8.7 Hz),
7.71 (1H, d, 4th ArH-benzo., J = 8.7 Hz), 7.78 (1H, s, 7th
ArH-benzo.). MS (m/z): 310 (M ? 1). Anal. calcd for
C14H16ClN3OS: C, 54.27; H, 5.21; N, 13.56%; found: C,
54.30; H, 5.25; N, 13.60%.
N-(6-chlorobenzothiazol-2-yl)-2-morpholinoacetamide
(3f)
IR (KBr, cm-1): 3320 (NH), 3075 (CH aromatic), 2655
(CH2), 1678 (C=O), 1576 (C=N). 1HNMR (CDCl3-
123

Med Chem Res (2012) 21:2661–2670
2667
General procedure for the preparation of N-(6-
chlorobenzo[d]thiazol-2-yl)-2-substituted-
hydrazinecarbothioamides (5a–h)
(s, 1H, N=CH), 6.64 (s, 1H, NH), 6.91 (d, 1H, 5th ArH-
benzo., J = 5.0 Hz), 6.99-7.56 (m, 4H, ArH), 7.61 (s, 1H,
7th ArH-benzo.), 8.03 (d, 1H, 4th ArH-benzo.,
J = 5.7 Hz), 9.44 (s, 1H, CSNH). MS (m/z): 364 (M?).
Anal. Calcd for C15H10ClFN4S2: C, 49.38; H, 2.76; N,
15.36%; found: C, 49.43; H, 2.80; N, 15.41%.
To a solution of 6-chloro-1,3-benzothiazole-2yl-thiosemi-
carbazide (0.0019 mol) in ethanol (25 ml) an equimolar
quantity of substituted benzaldehyde in ethanol and acetic
acid (2 drops) were added. The mixture was refluxed with
stirring for 8 h and the resultant precipitate was filtered and
dried. The product was recrystallized from 95% ethanol.
N-(6-chlorobenzothiazol-2-yl)-2-(4-nitrobenzylidene)
hydrazinecarbothioamide (5e)
IR (KBr, cm-1): 3394 (NH), 3021 (CH aromatic), 1576
1
(C=N), 1158 (C=S) cm-1. HNMR (CDCl3-300 MHz) d
2-benzylidene-N-(6-chlorobenzothiazol-2-yl)
hydrazinecarbothioamide (5a)
ppm: 10.34 (s, 1H, CSNH), 8.35 (s, 1H, NH), 7.74 (s, 1H,
7th ArH-benzo.), 7.80 (d, 1H, 4th ArH-benzo.,
J = 8.7 Hz), 7.51 (d, 1H, 5th ArH-benzo., J = 8.4 Hz),
7.22 (d, 2H, 20&60 ArH, J = 5.4 Hz), 6.69 (d, 2H, 30&50
Ar–H, J = 5.4 Hz), 5.87 (s, 1H, N=CH). MS (m/z): 391
(M?). Anal. Calcd for C15H10ClN5O2S2; C, 45.98; H, 2.57;
N, 17.86%; found: C, 46.02; H, 2.62; N, 17.91%.
IR (KBr, cm-1): 3458 (NH), 3001 (CH aromatic), 1587
(C=N), 1178 (C=S). 1HNMR (DMSO-d6-300 MHz) d: 5.99
(s, 1H, N=CH), 6.67 (s, 1H, NH), 6.94 (d, 1H, 5th ArH-
benzo., J = 5.0 Hz), 7.27–7.49 (m, 5H, ArH), 7.63 (s, 1H,
7th ArH-benzo.), 8.03 (d, 1H, 4th ArH-benzo.,
J = 5.7 Hz), 9.41 (s, 1H, CSNH). MS (m/z): 346 (M?).
Anal. calcd for C15H11ClN4S2: C, 51.94; H, 3.20; N,
16.15%; found: C, 51.97; H, 3.22; N, 16.19%.
N-(6-chlorobenzothiazol-2-yl)-2-(4-
hydroxybenzylidene)hydrazinecarbothioamide (5f)
IR (KBr, cm-1) vmax: 3557 (OH), 3315 (NH), 3012 (CH
aromatic), 1590 (C=N), 1175 (C=S). 1HNMR (CDCl3-
300 MHz) d ppm: 5.87 (s, 1H, N=CH), 6.77 (d, 2H, 30&50
Ar–H, J = 5.4 Hz), 7.11 (d, 2H, 20&60 ArH, J = 5.4 Hz),
7.40 (d, 1H, 5th ArH-benzo., J = 8.4 Hz), 7.72 (d, 1H, 4th
ArH-benzo., J = 8.7 Hz), 7.78 (s, 1H, 7th ArH-benzo.),
8.24 (s, 1H, NH), 10.00 (s, 1H, CSNH), 12.18 (s, 1H, OH).
MS (m/z): 362 (M?). Anal. Calcd for C15H11ClN4OS2; C,
49.65; H, 3.06; N, 15.44%; found; C, 49.69; H, 3.10; N,
15.49%.
N-(6-chlorobenzothiazol-2-yl)-2-(4-
chlorobenzylidene)hydrazinecarbothioamide (5b)
IR (KBr, cm-1): 3384 (NH), 3029 (CH aromatic), 1613
(C=N), 1197 (C=S). 1HNMR (DMSO-d6-300 MHz) d: 5.97
(s, 1H, N=CH), 6.79 (d, 2H, 30&50 Ar–H, J = 5.4 Hz), 7.12
(d, 2H, 2’&6’ ArH, J = 5.4 Hz), 7.41 (1H, d, 5th ArH-
benzo., J = 8.4 Hz), 7.70 (1H, d, 4th ArH-benzo.,
J = 8.7 Hz), 7.72 (s, 1H, 7th ArH-benzo.), 8.34 (s, 1H,
NH), 10.12 (s, 1H, CSNH). MS (m/z): 380 (M?). Anal.
calcd for C15H10Cl2N4S2: C, 47.25; H, 2.64; N, 14.69%;
found: C, 47.29; H, 2.70; N, 14.75%.
N-(6-chlorobenzothiazol-2-yl)-2-(4-methoxy
benzylidene)hydrazinecarbothioamide (5g)
N-(6-chlorobenzothiazol-2-yl)-2-(2-
chlorobenzylidene)hydrazinecarbothioamide (5c)
IR (KBr, cm-1): 3420, (NH), 3004 (CH aromatic), 1586
(C=N), 1127 (C=S). 1HNMR (CDCl3-300 MHz) d: 3.88 (s,
3H, OCH3), 6.64 (s, 1H, N=CH), 6.90-7.80 (m, 7H, ArH),
7.83 (s, 1H, NH), 9.19 (s, 1H, CSNH). MS (m/z): 376
(M?). Anal. calcd for C16H13ClN4OS2: C, 50.99; H, 3.48;
N, 14.87%; found: C, 51.02; H, 3.52; N, 14.91%.
IR (KBr, cm-1): 3453 (NH), 3068 (CH aromatic), 1597
(C=N), 1155 (C=S). 1HNMR (DMSO-d6-300 MHz) d: 5.98
(s, 1H, N=CH), 6.68 (s, 1H, NH), 6.94 (d, 1H, 5th ArH-
benzo., J = 5.0 Hz), 7.26–7.46 (m, 4H, ArH), 7.63 (s, 1H,
7th ArH-benzo.), 8.02 (d, 1H, 4th ArH-benzo.,
J = 5.7 Hz), 9.40 (s, 1H, CSNH). MS (m/z): 380 (M?).
Anal. calcd for C15H10Cl2N4S2: C, 47.25; H, 2.64; N,
14.69%; found: C, 47.31; H, 2.68; N, 14.76%.
N-(6-chlorobenzothiazol-2-yl)-2-(4-(dimethyl-
aminobenzylidene)hydrazinecarbothioamide (5h)
IR (KBr, cm-1): 3353 (NH), 2906 (CH aromatic), 2477
(CH3), 1598 (C=N), 1217 (C=S). 1HNMR (CDCl3-
300 MHz) d ppm: 3.28 (s, 6H, (CH3)2), 5.86 (s, 1H,
N=CH), 6.75 (d, 2H, 30&50 ArH, J = 5.4 Hz), 7.12 (d, 2H,
20&60 ArH, J = 5.4 Hz), 7.41 (d, 1H, 5th Ar–H-benzo.,
N-(6-chlorobenzothiazol-2-yl)-2-(4-
fluorobenzylidene)hydrazinecarbothioamide (5d)
IR (KBr, cm-1): 3394 (NH), 3000 (CH aromatic), 1560
(C=N), 1188 (C=S). 1HNMR (DMSO-d6-300 MHz) d: 6.02
123

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Med Chem Res (2012) 21:2661–2670
J = 8.4 Hz), 7.73 (d, 1H, 4th ArH-benzo., J = 8.7 Hz),
8.26 (s, 1H, NH), 7.78 (s, 1H, 7th ArH-benzo.), 10.34 (s,
1H, CSNH). MS (m/z): 389 (M?). Anal. calcd for
C17H16ClN5S2: C, 52.36; H, 4.14; N, 17.96%; found: C,
52.40; H, 4.18; N, 18.01%.
CNS depressant activity was carried out by Porsolt’s swim
test (1978). The results are presented in Table 3.
Maximum electroshock (MES) test
The anticonvulsant activity in MES test was indicated by the
lower dose which protected the hind limb tonic extension in
more than half of the animals (n = 4). Each animal received
i.p. injection of the test compounds (30/100/300 mg/kg)
followed by electroshock with 60 cycle altering current of
50 mA for 0.25 s via ear clip electrode through electrocon-
vulsometer as per the reported procedure and activity was
assessed at 0.5 h and 4 h after administration (Anticonvul-
sant Screening Project, 1978; Krall et al., 1978).
Pharmacology
The anticonvulsant screening of all the newly synthesized
compounds were performed according to the standard
protocol provided by epilepsy branch of the National
Institute of Neurological Disorders and Stroke (NINDS)
following the protocol adopted by Antiepiletic Drug
Development (ADD) program.
The preliminary anticonvulsant screening were carried
out by maximal electroshock test (MES) (Krall et al., 1978)
and subcutaneous pentylenetetrazole (ScPTZ) (Swinyard
et al., 1989). Minimal motor impairment was assessed by
rotorod method (Dunham and Miya 1957). Compounds
were administered intra peritoneal as a solution in poly-
ethyleneglycol (PEG) and tested using three graded doses
of 30, 100, and 300 mg/kg at two different time intervals.
Subcutaneous pentylenetetrazole (scPTZ) seizure
threshold test
For anticonvulsant screening test compounds were admin-
istered 0.5 h before the scPTZ treatment and protection was
detected in terms of failure to observe an episode of clonic
spasms for 5 s duration. The control group received subcu-
taneous PTZ solution (in 0.9% sodium chloride) in the
Table 3 Anticonvulsant Activity, Neurotoxicity and CNS depressant effect of synthesized compounds
Compound
Intraperitoneal injection in micea
Mean average immobility timeb(s)
MES screen Sc PTZ screen
Neurotoxicity screen
Mean SEM
0.5 h
4.0 h
0.5 h
4.0 h
0.5 h
4.0 h
Control (24 h before)
Post-treatment (60 min after)
3a
30
100
–
100
–
300
–
–
300
100
–
118 7.57
113 4.22
116 5.98
109 6.13
119 9.70
122 5.49
126 7.62
120 9.12
108 5.70
116 7.87
110 6.91
143 8.35
111 7.43
110 8.00
120 6.09
112 6.83
NT
129 9.59NS
161 8.16
169 9.79
196 8.16
145 4.16NS
140 8.05NS
137 4.49NS
152 7.30
162 8.18
191 4.02
177 5.39
188 7.08
157 8.05
169 9.79
181 8.70
172 7.97
NT
3b
100
100
300
30
–
3c
100
–
100
–
300
–
–
3d
300
–
–
3e
100
30
30
300
300
–
100
100
100
–
–
300
–
3f
30
100
100
300
–
–
3g
30
–
–
3h
100
–
100
300
300
–
300
300
–
5a
–
5b
300
300
30
–
–
5c
–
–
–
100
100
300
100
300
100
100
300
5d
30
–
100
300
100
–
100
300
–
100
300
–
5e
100
100
–
5f
–
5g
300
–
–
100
100
100
100
5h
–
–
–
Phenytoin
30
30
100
–
–
Carbamezepine
30
100
100
111 6.51
179 8.62
a
Doses of 30, 100, and 300 mg/kg were administered. The data indicate the minimum dose whereby protection was demonstrated in more than
half of the mice (four in each group). The animals were examined at 0.5 and 4.0 h. A dash indicates the absence of anticonvulsant activity and
neurotoxicity at the maximum dose administered (300 mg/kg)
b
Each value represents the mean SEM of six mice, significantly different from the control at P \ 0.05, and NS denotes not significant at
P \ 0.05 (Student’s t test)
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Med Chem Res (2012) 21:2661–2670
2669
posterior midline of the mice and the onset and severity of
Table 4 Calculated distance ranges between the pharmacophoric
elements
convulsion was noted (Swinyard et al., 1989).
O
.
.
S
.
N
Neurotoxicity screening
.
D
The neurotoxicity of all the test compounds was evaluated
using rotarod test. Mice were trained to balance on the
rotating rod (3.2 cm diameter) that rotates at 6 rpm. Trained
animals were treated with test compounds at a dose of
20–1000 mmol/kg administered intraperitoneally. Neuro-
toxicity was determined by the inability of the animal to
remain on the rod for 1 min (Dunham and Miya 1957).
A
HA
O
S
.
.
Porsolt’s swim test
N
HD
Behavioral depression was measured by evaluating the
immobility time of the mice during swimming phase.
Before starting test the animals were trained for swimming
(24 h before). Then the trained animals were given an i.p.
injection (100 mg/kg) of the test compounds 60 min before
the test session. The duration of passive floating without
struggling was recorded during the last 4 min of the 6 min
testing period as the immobility time (Porsolt et al., 1978).
H
Compound
Albutoin
A–HA A–HD A–D HA–HD HD–D HA–D
5.02
2.87
3.99
3.76
6.92
3.77
6.51
4.63
3.91
3.89
3.34 3.08
3.79 2.35
4.12 2.39
3.96 3.32
2.74 2.44
3.91 2.37
3.64 2.65
2.36 2.33
2.36 2.30
4.84
5.27
3.66
3.26
7.37
4.52
4.82
2.54
2.51
5.35
4.21
4.69
2.32
5.47
4.58
4.43
2.79
2.37
Carbamazepine 3.77
Phenytoin
Remacemide
Riluzole
Rufinamide
Av. distance
3g
4.56
5.49
2.73
5.34
4.48
5.05
4.67
In silico studies
The partition coefficient (log P) between octanol and
phosphate buffer was determined by the procedure
described in literature (Farrar et al., 1993). The calculated
log P (C log P) values were taken from the software ACD/
log P 1.0 and the results are shown in Table 1. The
experimental data were in agreement with the calculated
log P values. Christopher Lipinski’s rule-of-five analysis
provides a useful tool for filtering out molecules likely to
have poor oral absorption. Therefore, for the confirmation
whether molecules are more or less drug-like, synthesized
compounds were subjected to molecular properties and
drug-likeness prediction using Molinspiration and Molsoft
molecular processing programs. The analysis was done
considering pharmacokinetic (ADME) related descriptors
like molecular weight, log P, number of H-bond donors,
and number of H-bond acceptors while pharmacodynamic
related descriptors employed total polar surface area, and
number of rotatable bonds. Results clearly showed that
compounds 3f and 3g passed the rule of five status
(Table 2). The 4-point pharmacophore group’s distance
estimations were done on 3D optimized structures using
ACD/Chemsketch/3-D viewer 2.0 version program
(Brooks et al., 1983). Our analyses of the distance rela-
tionship showed that the synthesized compounds 3f and 3g
did fulfill the essential demands of the pharmacophore
when compared to the average distance requirement
(Table 4).
3f
Acknowledgments The author Asif S. deeply acknowledges the
University Grants Commission, India, for providing the Junior
Research Fellowship. The authors also wish to express their thanks to
Hamdard University, New Delhi, India for providing animal research
facilities.
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