1-[(2-arylthiazol-4-yl)methyl]azoles as a new class of anticonvulsants: Design, synthesis, in vivo screening, and in silico drug-like properties

Article abstract of DOI:10.1111/j.1747-0285.2011.01211.x

A series of novel thiazole incorporated (arylalkyl)azoles were synthesized and screened for their anticonvulsant properties using maximal electroshock and pentylenetetrazole models in mice. Among target compounds, 1-[(2-(4-chlorophenyl)thiazol-4-yl)methyl

Full text of DOI:10.1111/j.1747-0285.2011.01211.x

ª 2011 John Wiley & Sons A/S
doi: 10.1111/j.1747-0285.2011.01211.x
Chem Biol Drug Des 2011; 78: 844–852
Research Article
1-[(2-Arylthiazol-4-yl)methyl]azoles as a New
Class of Anticonvulsants: Design, Synthesis,
In vivo Screening, and In silico Drug-like
Properties
Nematollah Ahangar1, Adile Ayati2,
Eskandar Alipour2, Arsalan Pashapour1,
Epilepsy is the most frequent neurological disorders that are
Alireza Foroumadi3 and Saeed Emami4,*
accompanied by abnormal and excessive discharge of neurons
because of an imbalance between excitatory and inhibitory neuro-
transmitters. In these chronic disorders, recurrent and unpredict-
able occurrence of seizures can lead to lack of consciousness,
exposing the patients to possible physical injuries and social
1Department of Toxicology and Pharmacology and Pharmaceutical
Sciences Research Center, Faculty of Pharmacy, Mazandaran
University of Medical Sciences, Sari, Iran
2Department of Chemistry, Islamic Azad University, Tehran-North
restrictions (1,2).
Branch, Zafar St, Tehran, Iran
3Department of Medicinal Chemistry, Faculty of Pharmacy and
Currently available antiepileptic drugs (AEDs) in clinical practice
provide adequate seizure control in <70% of patients (3). Multi-
ple-drug therapy and lifelong medication may be required for con-
trol of epilepsy. Moreover, the current approved drugs present
some undesirable side effects such as drowsiness, ataxia, head-
ache, nausea, gingival hyperplasia, megaloblastic anemia, hepato-
toxicity, and gastrointestinal disturbance (4–6). Therefore, the
search for a newer, more effective antiepileptic agent with lower
toxicity continues to be an area of investigation into medicinal
chemistry.
Pharmaceutical Sciences Research Center, Tehran University of
Medical Sciences, Tehran, Iran
4Department of Medicinal Chemistry and Pharmaceutical Sciences
Research Center, Faculty of Pharmacy, Mazandaran University of
Medical Sciences, Sari, Iran
*Corresponding author: Dr Saeed Emami, sd_emami@yahoo.com
A
series of novel thiazole incorporated (aryl-
alkyl)azoles were synthesized and screened for
their anticonvulsant properties using maximal elec-
troshock and pentylenetetrazole models in mice.
Among target compounds, 1-[(2-(4-chlorophe-
A literature survey revealed that classical AEDs belong to different
chemical structures including hydantoines, barbiturates, iminostilb-
enes, benzodiazepines, valproate, imides, oxazolidinediones,
sulfonamides, and miscellaneous agents (7). The newer agents
include amino acids, amides (analogs of c-vinyl GABA, N-benzyla-
nyl)thiazol-4-yl)methyl]-1H-imidazole
(compound
4b), 1-[(2-phenylthiazol-4-yl)methyl]-1H-1,2,4-tria-
zole (8a), and its 4-chlorophenyl analog (compound
8b) were able to display noticeable anticonvulsant
activity in both pentylenetetrazole and maximal
electroshock tests with percentage protection
range of 33–100%. A computational study was car-
ried out for prediction of pharmacokinetics proper-
ties and drug-likeness. The structure-activity
relationship and in silico drug relevant properties
(molecular weight, topological polar surface area,
clog P, hydrogen bond donors, hydrogen bond
acceptors, and log BB) confirmed that the com-
pounds were within the range set by Lipinski’s rule-
of-five, and possessing favorable physicochemical
properties for acting as CNS-drugs, making them
potentially promising agents for epilepsy therapy.
mides,
2,6-dimethylanilides,
carboxyamides,
hydroxyamides,
alkanoamides); heterocyclic agents ((arylalkyl)azoles, pyrrolidin-2,5-di-
ones, lactams, thiosemicarbazones, quinazolin-4(3H)-ones, 2,5-disub-
stituted 1,2,4-thiadiazoles, xanthones, isatins) and enaminones, which
can prove useful for the design of future targets and development of
new drugs (8). Among these structures, (arylalkyl)azoles (Figure 1) are
distinct class of AEDs which include imidazole and 1,2,4-triazole ana-
logs. Nafimidone and denzimole are the examples of imidazole ana-
logs (9,10), and loreclezole is a representative of novel 1,2,4-triazole
anticonvulsants with broad-spectrum activity (Figure 1) (11,12).
Structure–activity relationship studies reveal the presence of one
common pharmacophoric portion in all of these molecules, which is
characterized by a lipophilic aryl ring linked by an alkylene bridge
to nitrogen of azole ring. The alkylene bridge is often substituted
by a small oxygen functional group such as carbonyl, carbamoyl,
ethylene dioxy, methoxy, acyloxy, and hydroxy substituents or a
electronegative chlorine atom (9,10,13,14).
Key words: (arylalkyl)azoles, 1,2,4-triazole, 1H-imidazole, anticonvul-
sant, drug-likeness, thiazole
Received 14 December 2010, revised 9 June 2011 and accepted for
publication 2 August 2011
844

Thiazole Incorporated (arylalkyl)azoles as Anticonvulsant Agents
N
N
Cl
N
O
OH
N
N
N
N
Cl
Cl
Ph
Nafimidone
Denzimole
Loreclezole
Azole
H3C
NH2
Figure 1: Chemical structures
of some (arylalkyl)azole
anticonvulsants comprising the
azole pharmacophore, and
structure of designed compounds
as thiazole incorporated
N
N
N
S
N
N
N
N
N
Azole :
R : H, Cl
N
N
Cl
N
N
N
R
Thiazole incorporated
(arylalkyl)azoles
(arylalkyl)azoles.
In the course of investigations aiming the development of structur-
ally novel anticonvulsants, we previously described design and syn-
thesis of a series of azolylchromanones and their oxime derivatives
as conformationally constrained analogs of (arylalkyl)azole anticon-
vulsants. A number of these compounds were found to display sig-
nificant activity in different experimental models of epilepsy (15,16).
under reflux for 1–3 h. After cooling, the precipitated white crystals
was filtered and washed with acetone. The intermediate chloride
salt 2a,b was dissolved in sulfuric acid 98% (2–3 mL), and the
mixture was stirred at room temperature for 30 min. Then, cold
water (50 mL) was added to the resulting solution slowly. The pre-
cipitated white solid was separated by filtration and washed with
water to give pure compound 3a,b.
On the other hand, it is well-known that thiazole nucleus as impor-
tant pharmacophore appears extensively in various types of pharma-
ceutical agents especially in anticonvulsant agents (17–20).
Motivated by these findings, and as a part of our continuous inves-
tigation into the area of (arylalkyl)azole anticonvulsants, we
designed and synthesized several new thiazole incorporated (aryl-
alkyl)azoles (Figure 1). Thus, we report, here, synthesis, in vivo
anticonvulsant activities, and in silico physicochemical properties of
1-[(2-arylthiazol-4-yl)methyl]azoles.
4-(Chloromethyl)-2-phenylthiazole (3a)
Yield 69%; mp 53–55 ꢀC; IR (KBr, 1/cm): 3076, 1462, 1007, 755,
687, 668, 641. 1H-NMR (500 MHz, CDCl3) d: 4.78 (d, 2H,
J = 0.8 Hz, CH2), 7.33 (t, 1H, J = 0.8 Hz, Thiazole), 7.44–7.49 (m,
3H, Phenyl), 7.95–7.99 (m, 2H, Phenyl).
4-(Chloromethyl)-2-(4-chlorophenyl)thiazole (3b)
Yield 79%; mp 80–83 ꢀC; IR (KBr, 1/cm): 3101, 1451, 1397, 1261,
1091, 1004, 835, 813, 704, 651. H-NMR (250 MHz, CDCl3) d: 4.74
1
Experimental Section
(s, 2H, CH2), 7.32 (s, 1H, Thiazole), 7.41 (d, 2H, J = 8.5 Hz, H-3, H-5
Phenyl), 7.88 (d, 2H, J = 8.5 Hz, H-2, H-6 Phenyl). 13C-NMR
(125 MHz, CDCl3) d: 40.87 (CH2), 118.51 (C5-Thiazole), 127.87 (C2,
C6-Phenyl), 129.24 (C3, C5-Phenyl), 131.86 (C1-Phenyl), 135.97 (C4-
Phenyl), 153.27 (C4-Thiazole), 167.10 (C2-Thiazole). Anal. Calcd for
C10H7Cl2NS: C, 49.20; H, 2.89; N, 5.74. Found: C, 49.01; H, 2.96; N,
5.51.
Chemistry
All starting materials, reagents, and solvents were purchased from
Merck AG (Darmstadt, Germany). The purity of the synthesized com-
pounds was confirmed by thin layer chromatography (TLC) using vari-
ous solvents of different polarities. Merck silica gel 60 F254 plates
were applied for analytical TLC. Melting points were determined in
open glass capillaries using Bibby Stuart Scientific SMP3 apparatus
and are uncorrected. NMR spectra were recorded using a Bruker 500
or 250 spectrometers, and chemical shifts are expressed as d (ppm)
with tetramethylsilane as internal standard. The IR spectra were
obtained on a PerkinElmer (Norwalk, CT, USA) FT-IR spectropho-
tometer (potassium bromide disks). Elemental analyses were carried
out on a CHN-O-rapid elemental analyzer (GmbH, Hanau, Germany)
for C, H, and N, and the results are within €0.4% of the theoretical
values.
1-[(2-Phenylthiazol-4-yl)methyl]-1H-imidazole
(4a)
To a mixture of imidazole (75 mg, 1.1 mmol) and dried potassium
carbonate (276 mg, 2 mmol) in acetone (5 mL), 4-(chloromethyl)-2-
phenylthiazole (3a) (209 mg, 1 mmol) was added. The resulting mix-
ture was heated under reflux for 8 h and then allowed to cool to
room temperature. The insoluble salts were removed by filtration
and washed with acetone. The filtrate was evaporated under
reduced pressure to give yellow oil, which was dissolved in ethanol
and mixed with concentrated HCl (0.12 mL). The precipitated white
crystals was filtered and washed with diethyl ether to give hydro-
chloride salt of 4a. Yield 85%; mp 103–105 ꢀC; IR (KBr, 1/cm):
General procedure for the synthesis
of 4-(chloromethyl)thiazole derivatives 3a,b
A mixture of thiobenzamide derivatives 1a,b (2 mmol) and 1,3-di-
chloroacetone (1.27 g, 10 mmol) in acetone (25 mL) was heated
1
3094, 3068, 1560, 1418, 1398, 1276, 1004, 774. H-NMR (500 MHz,
Chem Biol Drug Des 2011; 78: 844–852
845

Ahangar et al.
DMSO-d6) d: 5.62 (s, 2H, CH2), 7.50–7.51 (m, 3H, H-3, H-4, H-5 Phe-
nyl), 7.72 (br s, 1H, H-5 Imidazole), 7.83 (s, 1H, Thiazole), 7.85 (br s,
1H, H-4 Imidazole), 7.90–7.94 (m, 2H, H-2, H-6 Phenyl), 9.35 (s, 1H,
H-2 Imidazole), 14.88 (br s, 1H, Imidazolium NH). 13C-NMR
(125 MHz, DMSO-d6) d: 48.56 (CH2), 120.44 (C5-Thiazole), 120.76
(C4-Imidazole), 123.19 (C5-Imidazole), 127.04 (C2, C6-Phenyl), 130.17
(C3, C5-Phenyl), 131.50 (C4-Phenyl), 133.39 (C1-Phenyl), 136.45 (C2-
Imidazole), 151.06 (C4-Thiazole), 169.13 (C2-Thiazole). Anal. Calcd for
C13H11N3S.HCl: C, 56.21; H, 4.35; N, 15.13. Found: C, 56.01; H,
4.44; N, 15.25.
1-[(2-(4-Chlorophenyl)thiazol-4-yl)methyl]-2-
methyl-1H-imidazole (5b)
Yield 55%; mp 75–77 ꢀC; IR (KBr, 1/cm): 1526, 1499, 1450, 1090,
1
1004, 829, 737. H-NMR (500 MHz, DMSO-d6) d: 2.38 (s, 3H, CH3),
5.26 (s, 2H, CH2), 6.75 (br s, 1H, H-5 Imidazole), 7.14 (br s, 1H, H-4
Imidazole), 7.51 (s, 1H, Thiazole), 7.57 (d, 2H, J = 8.58 Hz, H-3, H-5
Phenyl), 7.93 (d, 2H, J = 8.56 Hz, H-2, H-6 Phenyl). Anal. Calcd for
C14H12ClN3S: C, 58.03; H, 4.17; N, 14.50. Found: C, 58.00; H, 4.21;
N, 14.38.
General procedure for the synthesis of
benzimidazole derivatives 6a,b
1-[(2-(4-Chlorophenyl)thiazol-4-yl)methyl]-1H-
imidazole (4b)
To a mixture of benzimidazole (130 mg, 1.1 mmol) and dried potas-
sium carbonate (276 mg, 2 mmol) in acetone (5 mL), 4-(chlorometh-
yl)thiazole derivative 3a,b (1 mmol) was added. The resulting
mixture was heated under reflux for 7–10 h and then allowed to
cool to room temperature. The insoluble salts were removed by fil-
tration and washed with acetone. The filtrate was evaporated
under reduced pressure to give waxy solid, which was washed with
water for three times. Recrystallization from methanol afforded pure
compound 6a,b.
To a mixture of imidazole (75 mg, 1.1 mmol) and dried potassium
carbonate (276 mg, 2 mmol) in acetone (4 mL), 4-(chloromethyl)-2-
(4-chlorophenyl)thiazole (3b) (224 mg, 1 mmol) was added. The
resulting mixture was heated under reflux for 10 h and then
allowed to cool to room temperature. The insoluble salts were
removed by filtration and washed with acetone. The filtrate was
evaporated under reduced pressure to give yellow solid, which
was washed with water for three times. Recrystallization from
methanol afforded pure compound 4b. Yield 59%; mp 120–
122 ꢀC; IR (KBr, 1/cm): 3094, 1497, 1451, 1089, 999, 832, 818,
752. 1H-NMR (250 MHz, DMSO-d6) d: 5.36 (s, 2H, CH2), 6.93 (s,
1H, H-5 Imidazole), 7.26 (s, 1H, H-4 Imidazole), 7.56 (d, 2H,
J = 8.5 Hz, H-3, H-5 Phenyl), 7.58 (s, 1H, Thiazole), 7.78 (s, 1H,
H-2 Imidazole), 7.94 (d, 2H, J = 8.5 Hz, H-2, H-6 Phenyl). 13C-
NMR (125 MHz, DMSO-d6) 46.52 (CH2), 119.05 (C5-Thiazole),
120.53 (C5-Imidazole), 128.63 (C2, C6-Phenyl), 129.42 (C4-Imidaz-
ole), 130.20 (C3, C5-Phenyl), 132.47 (C1-Phenyl), 135.83 (C4-Phenyl),
138.33 (C2-Imidazole), 154.27 (C4-Thiazole), 167.25 (C2-Thiazole).
Anal. Calcd for C13H10ClN3S: C, 56.62; H, 3.66; N, 15.24. Found:
C, 56.79; H, 3.58; N, 15.20.
1-[(2-Phenylthiazol-4-yl)methyl]-
1H-benzo[d]imidazole (6a)
Yield 58%; mp 80–82 ꢀC; IR (KBr, 1 ⁄ cm): 3096, 1667, 1499, 1462,
1
1265, 1006, 780, 766. H-NMR (500 MHz, DMSO-d6) d: 5.65 (s, 2H,
CH2), 7.20 (t, 1H, J = 7.3 Hz, H-5 Benzimidazole), 7.26 (t, 1H,
J = 7.3 Hz, H-6 Benzimidazole), 7.46–7.50 (m, 3H, H-3, H-4, H-5
Phenyl), 7.66 (s, 1H, Thiazole), 7.67–7.70 (m, 2H, H-4, H-7 Benzimid-
azole), 7.88–7.90 (m, 2H, H-2, H-6 Phenyl), 8.40 (s, 1H, H-2 Benz-
imidazole). Anal. Calcd for C17H13N3S: C, 70.08; H, 4.50; N, 14.42.
Found: C, 69.96; H, 4.50; N, 14.67.
General procedure for the synthesis of
2-methylimidazole derivatives 5a,b
1-[(2-(4-Chlorophenyl)thiazol-4-yl)methyl]-
1H-benzo[d]imidazole (6b)
To a mixture of 2-methylimidazole (90 mg, 1.1 mmol) and dried
potassium carbonate (276 mg, 2 mmol) in acetone (5 mL), 4-(chlo-
romethyl)thiazole derivative 3a,b (1 mmol) was added. The result-
ing mixture was heated under reflux for 5–8 h and then allowed to
cool to room temperature. The insoluble salts were removed by fil-
tration and washed with acetone. The filtrate was evaporated
under reduced pressure to give yellow oil, which was washed with
water for three times. The waxy residue was crystallized from
methanol to afford pure compound 5a,b.
Yield 32%; mp 144–146 ꢀC; IR (KBr, 1 ⁄ cm): 3099, 1499, 1450, 1089,
1005, 827, 751, 733. 1H-NMR (500 MHz, CDCl3) d: 5.56 (s, 2H,
CH2), 6.96 (s, 1H, Thiazole), 7.32–7.36 (m, 2H, H-5, H-6 Benzimid-
azole), 7.45 (d, 2H, J = 8.55 Hz, H-3, H-5 Phenyl), 7.48–7.50 (m, 1H,
Benzimidazole), 7.86–7.89 (m, 1H, Benzimidazole), 7.89 (d, 2H,
J = 8.52 Hz, H-2, H-6 Phenyl), 8.13 (s, 1H, H-2 Benzimidazole). Anal.
Calcd for C17H12ClN3S: C, 62.67; H, 3.71; N, 12.90. Found: C, 62.61;
H, 3.88; N, 12.79.
4-Amino-1-[(2-phenylthiazol-4-yl)methyl]-4
2-Methyl-1-[(2-phenylthiazol-4-yl)methyl]-1
H-imidazole (5a)
H-1,2,4-triazolium chloride (7a)
A
solution of 4-(chloromethyl)-2-phenylthiazole (3a) (1047 mg,
Yield 53%; IR (KBr, 1/cm): 3076, 1501, 1462, 1438, 1277, 1004, 767.
1H-NMR (500 MHz, DMSO-d6) d: 2.47 (s, 3H, CH3), 5.33 (s, 2H,
CH2), 6.95 (d, 1H, J = 1.06 Hz, H-5 Imidazole), 7.28 (s, 1H,
J = 1.22 Hz, H-4 Imidazole), 7.49–7.52 (m, 3H, H-3, H-4, H-5 Phe-
nyl), 7.56 (s, 1H, Thiazole), 7.89–7.93 (m, 2H, H-2, H-6 Phenyl). Anal.
Calcd for C14H13N3S: C, 65.85; H, 5.13; N, 16.46. Found: C, 66.00;
H, 5.15; N, 16.31.
5 mmol) and 4-amino-1,2,4-triazole (462 mg, 5.5 mmol) in 2-propa-
nol (20 mL) was heated under reflux for 36 h, and then, it was
allowed to cool to room temperature. The precipitated salts were
filtered and washed with cold 2-propanol to give pure compound
7a. Yield 65%; mp 173–175 ꢀC; IR (KBr, 1/cm): 3252, 3099, 3081,
2988, 1464, 1438, 1166, 1002, 766. Anal. Calcd for C12H12ClN5S: C,
49.06; H, 4.12; N, 23.84. Found: C, 48.89; H, 4.15; N, 24.02.
846
Chem Biol Drug Des 2011; 78: 844–852

Thiazole Incorporated (arylalkyl)azoles as Anticonvulsant Agents
4-Amino-1-[(2-(4-chlorophenyl)thiazol-
4-yl)methyl]-4H-1,2,4-triazolium chloride (7b)
solution of 4-(chloromethyl)-2-(4-chlorophenyl)thiazole (3b)
Pharmacology
Male NMRI mice (18–22 g, 3 months old, Institute Pasteur of Iran)
were used with accommodation conditions maintained at 25 € 2 ꢀC
and a 12 h light ⁄ dark cycle. The animals were housed in standard
Plexiglas cages with free access to food (standard laboratory
rodent's chow) and water. Each animal was tested once. They were
fasted overnight and were transferred to the laboratory at least 1 h
before the start of the experiment. The experiments were per-
formed during the light portion. Pentylenetetrazole and the test
compounds were dissolved in dimethyl sulfoxide (DMSO). All com-
pounds were administered i.p. at the doses of 30, 100, and ⁄ or
300 mg ⁄ kg to four to six animals.
A
(448 mg, 2 mmol) and 4-amino-1,2,4-triazole (185 mg, 2.2 mmol) in
2-propanol (4 mL) was heated under reflux for 24 h, and then, it
was allowed to cool to room temperature. The precipitated salts
were filtered and washed with cold 2-propanol to give pure com-
pound 7b. Yield 69.5%; mp 173–175ꢀC; IR (KBr, 1/cm): 3043, 2939,
1636, 1493, 1445, 1399, 1158, 1000, 823, 631, 617. 1H-NMR
(250 MHz, DMSO-d6) d: 5.82 (s, 2H, CH2), 7.29 (br s, 2H, NH2), 7.58
(d, 2H, J = 8.5 Hz, H-3, H-5 Phenyl), 7.95 (d, 2H, J = 8.5, H-2, H-6
Phenyl), 8.00 (s, 1H, Thiazole), 9.27 (s, 1H, H-5 Triazole), 10.60 (s,
1H, H-3 Triazole). Anal. Calcd for C12H11Cl2N5S: C, 43.91; H, 3.38;
N, 21.34. Found: C, 43.90; H, 3.33; N, 21.49.
Pentylenetetrazole (PTZ) induced seizure test
(21)
1-[(2-Phenylthiazol-4-yl)methyl]-1H-1,2,4-triazole
(8a)
At 30 min after the administration of the compounds, 100 mg ⁄ kg
pentylenetetrazole was administered i.p. The animals were placed
in individual cages and observed for 30 min. The number of death
following tonic and clonic seizures was noted. The results are
expressed as number of animal protected ⁄ number of animals
tested.
To
a vigorously stirred ice-cold suspension of 7a (846 mg,
3.2 mmol) in water (8 mL), was added concentrated HCl (1657 mg,
16.8 mmol). A solution of sodium nitrite (231 mg, 3.36 mmol) in
water (2 mL) was added dropwise to the reaction mixture at a rate
to prevent excessive foaming. The mixture was allowed to come to
room temperature and was stirred for 1 h. Upon neutralization with
K2CO3, the precipitated white solid was filtered, washed with
water, and crystallized from MeOH to give 8a. Yield 97%; mp 98–
100 ꢀC; IR (KBr, 1/cm): 3092, 1505, 1456, 1269, 1153, 1136, 1021,
Maximal electroshock (MES) induced seizure
test (22)
Maximal electroshock seizures were elicited with a 60 Hz alternat-
ing current of 50 mA intensity delivered for 0.2 seconds via ear
electrodes, 30 min after intraperitoneal administration of the tested
compounds. Saline (0.9%) was used to wet the electrodes immedi-
ately before testing to ensure good electrical contact. Mice were
manually restrained during stimulation. Immediately following stimu-
lation, mice were placed in a Plexiglas arena for behavioral obser-
vation. Abolition of the hind-leg tonic-extensor component of the
seizure indicated protection against the spread of MES-induced sei-
zures. The results are expressed as number of animal pro-
tected ⁄ number of animals tested.
1
1005, 773, 761, 695. H-NMR (500 MHz, DMSO-d6) d: 5.58 (s, 2H,
CH2), 7.47–7.52 (m, 3H, H-3, H-4, H-5 Phenyl), 7.61 (s, 1H, Thiazole),
7.88–7.92 (m, 2H, H-2, H-6 Phenyl), 8.00 (s, 1H, H-5 Triazole), 8.68
(s, 1H, H-3 Triazole). 13C-NMR (125 MHz, DMSO-d6) 49.32 (CH2),
119.20 (C5-Thiazole), 126.98 (C2, C6-Phenyl), 130.13 (C3, C5-Phenyl),
131.32 (C4-Phenyl), 133.58 (C1-Phenyl), 145.37 (C2-Triazole), 152.48
(C3-Triazole and C4-Thiazole), 168.52 (C2-Thiazole). Anal. Calcd for
C12H10N4S: C, 59.48; H, 4.16; N, 23.12. Found: C, 59.40; H, 4.33; N,
23.11.
1-[(2-(4-Chlorophenyl)thiazol-4-yl)methyl)-1
H-1,2,4-triazole (8b)
In silico calculation of physicochemical
parameters
To
a vigorously stirred ice-cold suspension of 7b (300 mg,
1.02 mmol) in water (8 mL), was added concentrated HCl (505 mg,
5.12 mmol). A solution of sodium nitrite (70 mg, 1.01 mmol) in
water (1 mL) was added dropwise to the reaction mixture at a rate
to prevent excessive foaming. The mixture was allowed to come to
room temperature and was stirred for 1 h. Upon neutralization with
K2CO3, the precipitated white solid was filtered, washed with
water, and crystallized from MeOH to give 8b. Yield 90%; mp 97–
100 ꢀC; IR (KBr, 1/cm): 3084, 3055, 1508, 1455, 1137, 1004, 830,
The physicochemical properties of the compounds such as molecular
weight (MW), clog P, log S, drug-likeness, and drug score were calcu-
lated using online Osiris property explorer.a Topological polar surface
area (TPSA) was estimated using online DAYLIGHT software.b Absorp-
tion (%ABS) was calculated by (23): %ABS = 109 ) (0.345 · TPSA).
LogBB [log (Cbrain ⁄ Cblood)] values were calculated by the equation (24):
logBB = )0.0148 · PSA + 0.152 · clog P + 0.139.
1
712, 679. H-NMR (250 MHz, DMSO-d6) d: 5.59 (s, 2H, CH2), 7.56
(d, 2H, J = 8.25 Hz, H-3, H-5 Phenyl), 7.67 (s, 1H, Thiazole), 7.92 (d,
2H, J = 8.25 Hz, H-2, H-6 Phenyl), 8.02 (s, 1H, H-5 Triazole), 8.71 (s,
1H, H-3 Triazole). 13C-NMR (125 MHz, DMSO-d6) 49.24 (CH2),
119.75 (C5-Thiazole), 128.68 (C2, C6-Phenyl), 130.19 (C3, C5-Phenyl),
132.41 (C1-Phenyl), 135.85 (C4-Phenyl), 145.40 (C5-Triazole), 152.50
(C3-Triazole), 152.62 (C4-Thiazole), 167.17 (C2-Thiazole). Anal. Calcd
for C12H9ClN4S: C, 52.08; H, 3.28; N, 20.24. Found: C, 51.89; H,
3.35; N, 20.18.
Results and Discussion
Chemistry
The synthetic routes for synthesis of key intermediates 4-(chlorom-
ethyl)thiazole derivatives 3a,b (25) and target compounds 1-[(2-aryl-
thiazol-4-yl)methyl]azoles 4–8 are outlined in Schemes 1 and 2,
respectively. Commercially available thiobenzamides 1a,b were
reacted with 1,3-dichloroacetone in refluxing acetone to afford cor-
Chem Biol Drug Des 2011; 78: 844–852
847

Ahangar et al.
Cl
Cl
Scheme 1: Preparation of the
key intermediates 4-(chlorometh-
yl)thiazole derivatives 3a,b.
Reagents and conditions: (a) 1,3-di-
chloroacetone, acetone, reflux,
1–3 h; (b) sulfuric acid 98%, rt,
30 min.
O
N
NH2
NH2
a
b
S
S
S
Cl
R
R
R
1a: R = H
1b: R = Cl
3a: R = H
3b: R = Cl
2a,b
NH2
Cl
N
N
N
Cl
N
N
N
N
N
a
d
S
S
S
R
R
Scheme 2: Preparation of tar-
get compounds 1-[(2-arylthiazol-4-
yl)methyl]azoles 4–8. Reagents and
conditions: (a) imidazole, K2CO3,
acetone, reflux, 8–10 h; (b) 2-
methylimidazole, K2CO3, acetone,
reflux, 5–8 h; (c) benzimidazole,
K2CO3, acetone, reflux, 7–10 h; (d)
4-amino-1,2,4-triazole, 2-propanol,
reflux, 24–36 h; (e) NaNO2, concen-
trated HCl, H2O, 0–5 ꢀC then rt.
R
4a,b
7a,b
3a: R = H
3b: R = Cl
b
e
c
H3C
N
N
N
N
N
N
N
N
N
N
S
S
S
R
R
R
5a,b
8a,b
6a,b
responding S-alkylated acyclic salts 2a,b. 4-(Chloromethyl)thiazole
derivatives 3a,b were obtained by cyclization of 2a,b in the
presence of sulfuric acid 98% at room temperature. Reaction of
imidazole or substituted imidazoles (2-methylimidazole and benz-
imidazole) with 4-(chloromethyl)thiazoles 3a,b in the presence of
potassium carbonate in refluxing acetone afforded the correspond-
ing imidazole derivatives 4–6. For regiospecific preparation of 1-[(2-
arylthiazol-4-yl)methyl]-1,2,4-triazoles 8a,b, 4-amino-1,2,4-triazole
was used as protected and synthetic equivalent of 1,2,4-triazole.
Thus, the quaternization of 4-amino-1,2,4-triazole with 4-(chlorom-
ethyl)thiazoles 3a,b in refluxing 2-propanol afforded pure triazolium
salts 7a,b which on subsequent deamination with nitrous acid
(generated in situ by reaction of NaNO2 and HCl) yielded exclusively
the 1-substituted 1,2,4-triazole analogs 8a,b (26).
mice weighing 18–22 g and 3 months old were utilized as experi-
mental animals. The compounds were administered intraperitoneally
(i.p) at the doses of 30, 100, and ⁄ or 300 mg ⁄ kg body weight,
30 min before the induction of seizures. For the induction of sei-
zures in MES test, mice were stimulated through ear electrodes to
50 mA current at a pulse of 60 Hz applied for 0.2 seconds. In the
PTZ test, pentylenetetrazole (100 mg ⁄ kg, i.p) was utilized to pro-
duce tonic–clonic convulsion and subsequently death in 100% of
animals. A minimal time of 30 min subsequent to the seizure induc-
tion was used for seizure detection. Table 1 presents screening
data for the anticonvulsant activity of compounds 3–8 in animals
undergoing seizures induced by PTZ and MES tests.
As shown in Table 1, (arylalkyl)azoles bearing unsubstituted imidaz-
ole or triazole ring showed moderate to good anticonvulsant activity
in the PTZ test. Compounds that were active at the dose of
100 mg ⁄ kg include 4a, 4b, 8a, and 8b. Among these compounds,
8b showed 100% protection at this dose against PTZ-induced sei-
zures. Also, compound 8b was found to be significantly active as it
showed 33% protection at the lowest dose of 30 mg ⁄ kg. In the
MES test, imidazole and benzimidazole analogs (compounds 4b and
6a, respectively) and triazole derivatives 8a,b were found to be
significantly active as they showed full protection at the dose of
100 mg ⁄ kg. Also, it could be obviously recognized that the active
compounds 4b, 6a, and 8b exerted their anticonvulsant activity at
100 mg ⁄ kg dose level; however, no activity was observed at dose
of 30 mg ⁄ kg. The results from both PTZ and MES tests revealed
that non-azole compounds 3a,b, 2-methyl imidazole derivatives
5a,b, and aminotriazolium compounds 7a,b showed no protection
against chemical and electrical induced seizures. In contrast, com-
Anticonvulsant activity
The preclinical investigations for discovery and development of new
AEDs rely heavily on the use of predictable animal models which
routinely used by most AEDs discovery programs. At the present
time, two in vivo models including MES and pentylenetetrazole
(PTZ) models are most widely used animal models in the search for
new AEDs (27).
Thus, in this work, azole compounds 4–8 were screened for their
preliminary anticonvulsant properties against MES and PTZ seizure
models in mice. Also, structural similarity of non-azole intermedi-
ates 3a,b to the chlormethiazole (5-(2-chloroethyl)-4-methylthiazole;
a chloroethylthiazole anticonvulsant agent) (28) prompted us to
include compounds 3a,b in anticonvulsant evaluation. Male NMRI
848
Chem Biol Drug Des 2011; 78: 844–852

Thiazole Incorporated (arylalkyl)azoles as Anticonvulsant Agents
Table 1: The anticonvulsant activities of compounds 3–8
Anticonvulsant activity
PTZa
Compound
Doses (mg ⁄ kg)
% Protection
MESb
% Protection
c
3a
30
100
300
30
–
–
0
–
–
0 ⁄ 4
–
–
0
–
0 ⁄ 6
–
–
3b
–
–
–
100
300
30
0 ⁄ 6
–
–
0
–
–
0 ⁄ 4
–
–
0
–
–
4a (HCl salt)
100
300
30
3 ⁄ 6
–
1 ⁄ 6
2 ⁄ 6
–
–
–
–
–
0 ⁄ 6
–
–
0 ⁄ 6
–
–
0 ⁄ 6
–
–
0 ⁄ 6
–
–
50
–
16.6
33.3
–
–
–
–
–
0
–
–
0
–
–
0
–
–
0
–
–
0
–
0
0 ⁄ 4
–
0 ⁄ 4
4 ⁄ 4
–
–
–
–
–
0 ⁄ 4
–
0 ⁄ 4
4 ⁄ 4
–
–
0 ⁄ 4
–
–
0 ⁄ 4
–
–
0 ⁄ 4
–
0
–
0
100
–
–
–
–
–
0
–
0
100
–
–
0
–
–
4b
5a
5b
6a
6b
7a
7b
8a
8b
100
300d
30
100e
300
30
100
300
30
100
300
30
100
300
30
100
300
30
100
300
30
100
300
10
0
–
–
0
0 ⁄ 6
–
–
0 ⁄ 6
2 ⁄ 6
6 ⁄ 6
0 ⁄ 6
2 ⁄ 6
6 ⁄ 6
–
1 ⁄ 4
4 ⁄ 4
–
25
100
–
–
0
100
–
100
33.3
100
0
33.3
100
–
–
30
0 ⁄ 4
4 ⁄ 4
–
100
300
2
Diazepam
6 ⁄ 6
100
4 ⁄ 4
aPentylentetrazole (100 mg ⁄ kg, ip) induced lethal convulsion (number of animals protected ⁄ number of animals tested).
bMaximal electroshock (MES) seizure test: 50 mA, 60 Hz, ac, 0.2 seconds (number of animals protected ⁄ number of animals tested).
cNot determined.
d,eDead following tonic extension.
pounds 4b, 8a, and 8b were able to display noticeable anticonvul-
sant activity in both the PTZ and MES tests with percentage protec-
tion range of 33–100%. Among them, chloro-triazole derivative
(compound 8b) showed maximum protection in both models. As is
shown with the comparison of compounds 4a and 4b or 8a and
8b, introduction of a para-chloro substituent on the phenyl ring
resulted in obvious improvement in the ability for control of sei-
zures. Oppositely, in benzimidazole derivatives, compound 6a bear-
ing unsubstituted phenyl ring was active in the MES test, while
para-chlorophenyl analog 6b was inactive. It was observed that the
methyl substituent at the 2-position of the imidazole ring (compound
5a versus 4a and 5b versus 4b) resulted in diminished anticonvul-
sant activity. By comparison of anticonvulsant properties of imidaz-
ole compounds 4a,b and triazole derivatives 8a,b, it can
concluded that replacement of imidazole ring with 1,2,4-triazole ring
increases anticonvulsant activity. Finally, the results obtained from
the screening tests of compounds 3–8 have revealed that anticon-
vulsant activity mainly depends on the existence of azole ring, and
the absence of the azole ring results in the lack of the activity in
compounds 3a,b.
In silico calculation of physicochemical
parameters and drug-likeness prediction
For rapidly improving the lead structures into the drug candidates,
it is important that lead compounds be of high quality or 'drug-
Chem Biol Drug Des 2011; 78: 844–852
849

Ahangar et al.
likeness,' that is, possess some significant likelihood of transfor-
mation into a small-molecule drug (29). Thus in recent years, the
definition of a lead and especially of 'drug-likeness' in physico-
chemical terms has drawn considerable attention. Physicochemical
properties of lead compounds strongly influence 'drug-likeness' by
controlling specific pharmacokinetics properties such as intestinal
absorption and central nervous system (CNS) penetration (30).
Accordingly, Lipinski published the 'rule-of-five,' which defines four
simple physicochemical parameter ranges [MW £ 500, log P £ 5,
hydrogen bond donors (HBD) £ 5, hydrogen bond acceptors
(HBA) £ 10] for oral absorption (31).
As a part of our study, a computational study for prediction of bio-
availability and drug-likeness of compounds was performed. The
physicochemical parameters of the compounds such as MW, clog P,
log S (solubility), drug score, and drug-likeness of the compounds
were calculated using online Osiris property explorer (Table 2).a
Hydrogen-bonding capacity was estimated by taking the number of
Table 2: In silico physicochemical properties of compounds 3–8
R'
N
S
R
Compound
3a
3b
R
H
Cl
R'
Cl
Cl
TPSAa (ꢀ2)
12.89
12.89
log S
)3.08
)3.82
clog P
3.74
4.35
MW
209
234
HBD
0
0
HBA
1
1
logBB
0.52
0.61
Lipinski's violations
0
0
Drug-likeness
)0.32
1.1
Drug score
0.58
0.63
N
N
4a
H
30.71
)1.24
2.62
241
0
2
0.083
0
2.12
0.88
N
N
4b
5a
Cl
H
30.71
30.71
)1.97
3.23
2.82
275
255
0
0
2
2
0.176
0.114
0
0
3.24
0.6
0.86
0.76
H3C
N
0.86
N
5b
6a
Cl
H
H3C
N
30.71
30.71
)1.6
3.44
4.22
289
291
0
0
2
2
0.208
0.326
0
0
1.92
0.66
0.81
0.52
N
N
)2.63
N
N
6b
7a
7b
Cl
H
30.71
60.61
60.61
)3.37
ndb
4.83
nd
325
nd
0
1
1
2
3
3
0.419
nd
0
1.97
nd
0.5
nd
nd
N
NH2
Cl
nd
nd
N
N
N
N
N
N
NH2
Cl
Cl
nd
nd
nd
nd
nd
N
N
N
N
8a
8b
H
43.60
43.60
)1.9
2.62
3.23
242
276
0
0
3
3
)0.108
)0.015
0
0
0.72
2.05
0.61
0.65
N
N
Cl
)2.64
aTPSA, topological polar surface area; log S, logarithm of aqueous solubility measured in M; clog P, calculated lipophilicity; MW, molecular weight; HBD, number
of hydrogen bond donor; HBA, number of hydrogen bond acceptor; logBB, logarithm of (Cbrain ⁄ Cblood) which is the ratio of the steady-state concentrations of the
drug molecule between the brain and the blood.
bNot determined.
850
Chem Biol Drug Des 2011; 78: 844–852

Thiazole Incorporated (arylalkyl)azoles as Anticonvulsant Agents
nitrogen and oxygen atoms in the chemical structure as the number
Conclusion
of HBA. The number of HBD atoms was the sum of hydrogen atoms
bound to oxygen and to nitrogen atoms (HBD) (31). In addition, TPSA,
i.e., surface belonging to polar atoms, was calculated using online
DAYLIGHT software.b This descriptor has been linked to drug bioavail-
ability and shown to correlate well with passive molecular transport
through membranes and, therefore, allows prediction of transport
properties of drugs in the intestines and blood-brain barrier (BBB)
crossing (32). The calculated descriptors are presented in Table 2.
In conclusion, as a part of our continuous investigation into the area
of (arylalkyl)azole anticonvulsants, we designed and synthesized sev-
eral new thiazole incorporated (arylalkyl)azoles bearing (un)substi-
tuted imidazole or triazole motifs. Target compounds were screened
for their anticonvulsant properties using MES and PTZ models in mice.
Among them, 1-[(2-(4-chlorophenyl)thiazol-4-yl)methyl]-1H-imidazole
(compound 4b), 1-[(2-phenylthiazol-4-yl)methyl]-1H-1,2,4-triazole (8a),
and its 4-chlorophenyl analog (compound 8b) were able to display
noticeable anticonvulsant activity in both PTZ and MES tests with per-
centage protection ranging from 33% to 100%.
The results disclosed in Table 2 reveal that all compounds are
within the range set by Lipinski's rule-of-five (low MW, favorable
clog P, favorable hydrogen bond-donating and accepting capabili-
ties). On the other hand, passively absorbed compounds with a PSA
>140 ꢀ2 are thought to have poor oral bioavailability (33). According
to the equation: %ABS = 109 ) (0.345 · TPSA), as reported by
Zhao et al. (23), it can be predicted that all target compounds (pos-
sessing TPSA < 45) exhibited absorption (ABS) >90%.
A computational study was carried out for prediction of pharmacoki-
netic properties and drug-likeness. The structure-activity relationship
and in silico drug relevant properties (MW, TPSA, clog P, HBDs,
HBAs, and log BB) confirmed that the new (arylalkyl)azoles prepared
in this work possess good physicochemical properties that qualify
them to have good pharmacokinetics and drug bioavailability. They
are fully compatible with Lipinski's rule-of-five (low MW, favorable
clog P, favorable hydrogen bond-donating and accepting capabili-
ties). These results revealed that thiazole incorporated (arylalkyl)az-
oles 4b, 8a, and 8b which showed good protection in both
models of epilepsy (PTZ and MES) can be regarded as promising
candidate for future investigations.
The drug-likeness prediction in Osiris calculations is fragment-
based approach. The occurrence frequency of every one of the
fragments was determined within the collection of traded drugs
and within the supposedly non-drug-like collection of commer-
cially available chemicals. A positive drug-likeness value states
that a molecule contains predominantly fragments which are fre-
quently present in commercial drugs.a Osiris study revealed that
the active compounds 4a,b, 6a, and 8a,b had positive drug-
likeness values, and the fragments of these compounds had a
contribution for drug-like activities. The drug-score prediction pro-
cess in Osiris explorer relies on the combination of drug-likeness,
clog P, log S, MW, and toxicity risks (mutagenicity, tumorogenici-
ty, irritation, reproduction) in one handy value than may be used
to judge the compound's overall potential to qualify for a drug.a
The active compounds showed moderate to good drug score that
disclosed their potential as safe leading compounds.
Acknowledgment
This work was supported by a grant from the Research Council of
Mazandaran University of Medical Sciences, Sari, Iran.
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