Synthesis of
Novel Thiazole Derivatives as Analgesic Agents
G. Saravanan*1, V. Alagarsamy2, C.R. Prakash2,
P. Dinesh Kumar2 and T. Panneer Selvam2
1Medicinal Chemistry Research Laboratory, Bapatla College of Pharmacy, Bapatla-522 101, (A.P), India.
2Medicinal Chemistry Research Laboratory, M.N.R. College of Pharmacy,
Sangareddy-502 294, (A.P), India.
*Corresponding Author E-mail: sarachem1981@gmail.com
ABSTRACT:
Thiazoles have a long history of having number of
pharmacological activities such as anti-microbial,
analgesic and anti-inflammatory activities. Pyrazoles
shows promising anti-microbial, analgesic and anti-inflammatory activities. In
the present study, novel thiazoles (8a – 8j) were synthesized by incorporation of pyrazole moiety at 2nd
position of 2-hydrazinyl-N-(4-phenylthiazol-2-yl) acetamide
(5) by
treating with chalcones (7a-7j). The chemical structures of the synthesized
compounds were confirmed by means of IR, 1H-NMR, Mass spectral and
Elemental analysis. All the spectral data were consistent with the assigned
structure. The synthesized compounds were investigated for analgesic activity
by tail immersion method in mice. All the synthesized compounds exhibited mild
to good analgesic activities. Among the synthesized compounds,
2-(5-(4-dimethylaminophenyl)-3-phenyl-4,5-dihydropyrazol-1-yl)-N-(4-phenylthiazol-2-yl)acetamide
(8c) and 2-(5-(4-methylphenyl)-3-phenyl-4,5-dihydropyrazol-1-yl)-N-(4-phenylthiazol-2-yl)acetamide
(8e) exhibited highest analgesic activity.
KEYWORDS: Thiazole, Pyrazole, Chalcone and Analgesic
activity.
INTRODUCTION:
Thiazoles and pyrazoles derivatives
are used in medicine because of their large number of potential pharmacological
activities1. According to
literature survey, Thiazoles were reported to possess
anti-microbial, analgesic, anti-inflammatory, anti-cancer, anti-tubercular, anthelmintic and diuretic activities2. Thiazoles have enhanced lipid solubility with hydrophilicity. Thiazoles are
easily metabolized by routine biochemical reactions and are non-carcinogenic in
nature. In addition, pyrazoles are reported as
anti-microbial, analgesic, anti-inflammatory, anti-hypertensive, anti-depressant and anti-cancer agents3,4. In the
view of above facts and to develop potent analgesic agents, prompted us to
synthesize the title compounds (8a
– 8j) with presumption that
incorporation of pyrazole moiety at 2nd
position of 2-hydrazinyl-N-(4-phenylthiazol-2-yl) acetamide
(5) by treating with chalcones (7a-7j). Chemical
structure of the synthesized compound was confirmed by IR, 1H-NMR,
Mass spectral and Elemental analysis. The title compounds were screened for the
analgesic activity by tail-flick method in mice.
MATERIALS AND METHODS:
The melting points were taken in open capillary tube
and are uncorrected. The IR spectra of the compounds were recorded on ABB Bomem FT-IR spectrometer MB 104 with KBr
pellets. The 1H-NMR (300 MHz) spectra were recorded on a Bruker 300 NMR spectrometer (with TMS as internal references). Mass spectra were
recorded on Shimadzu GC MS QP 5000. Microanalyses were obtained with an
elemental Analyses system GmbH VarioEL V300 element
analyzer. The purity of the compounds was checked by TLC on pre-coated SiO2
gel (HF254, 200 mesh) aluminium plates (E Merk)
using ethanol and benzene visualized in iodine chamber. The reagent grade
chemicals were purchased from the commercial sources and purified by either
distillation or recrystallisation before use.
CHEMISTRY:
Title compounds
(8a – 8j) were synthesized by
incorporation of pyrazole moiety at 2nd position
of 2-hydrazinyl-N-(4-phenylthiazol-2-yl) acetamide (5)
by treating with chalcones (7a-7j). The 2-hydrazinyl-N-(4-phenylthiazol-2-yl) acetamide
(5) was synthesized from 2-amino-4-phenyl thiazole (3) through 2-chloro-N-(4-phenyl thiazol-2-yl) acetamide (4)
2-Amino-4-phenyl thiazole
(3):
To a mixture5 consisting of acetophenone (0.1 mol) and thiourea
(0.2 mol), bromine (0.2 mol) were added drop wise very slowly. After the
addition of bromine the reaction mixture was heated on water bath for overnight,
and water was added to it and again heated until most of the solid has gone
into solution. The reaction mixture was filtered when it is hot and the
filtrate was cooled. It was made alkaline with concentrated ammonium hydroxide
to separate 2-amino-4-phenyl thiazole. The product
was filtered, washed with alcohol and dried over P2O5. It
was recrystallised from ethanol, as colorless needles
Yield 84 % ; m.p. 120-1220C .
2-Chloro-N-(4-phenyl thiazol-2-yl) acetamide (4):
0.05 mole of 2-amino 4-phenyl thiazole5 (3)
was dissolved in 25ml of glacial acetic acid containing a saturated
solution of sodium acetate (25ml). To the above mixture 0.06 mole of chloro acetyl chloride was added with stirring. Then the
mixture was heated on water bath for 6 hrs,
and then the reaction mixture was poured on crushed ice .The product is then
filtered, dried and recrystallised
from alcohol.
2-Hydrazinyl-N-(4-phenylthiazol-2-yl) acetamide (5):
0.01 moles of 2-chloro-N-(4-phenylthiazole
-2-yl)-acetamide5 (4) was dissolved in 25ml of alcohol. To
the above mixture 0.01 mole of hydrazine hydrate was added and the resultant
mixture was refluxed for 8 hrs. After 8 hrs the reaction mixture was poured on
the crushed ice to separate the product. (m.p. 143-145ºC)
Chalcones (7a-7j):
0.01 mole of substituted aromatic aldehyde6 and 0.01 mole of acetophenone were taken in beaker. This mixture was
dissolved in minimum quantity of ethanol and 3 to 4 drops of concentrated
sodium hydroxide is added to the above mixture. The resultant mixture was stirred
using magnetic stirrer for a period of 2 hrs. After 2 hrs, the reaction mixture
was poured over crushed ice and was placed on ice chest over night. The
precipitated product was filtered and dried.
Title compounds (8a-8j):
0.05 mole of chalcone (7a-7j) was added to the 0.1 mole of 2-hydrazinyl –N-(4-phenylthiazole -2-yl) acetamide (5) in 100 ml round bottom flask
containing 30 ml 0f N, N-dimethyl formamide. The above mixture was refluxed at 120-140ºC
for a period of 10 hrs. Then the reaction mixture was cooled and poured in to a
beaker containing ice cold water. The obtained product was separated by
filtration, dried over the filter paper and recrystallised using
butanol.
Analgesic
activity:
Test for analgesic activity was performed by tail-flick
technique7,8 using Wistar albino mice
(25-35g) of either sex selected by random sampling technique. Pentazocine at a dose level of 10 mg/kg was administered
orally as reference drug for comparision. The test
compounds at 100 mg/kg were administered orally. The reaction time was recorded
at 30 min, 1, 2 and 3h after the treatment. The cut off time was 10s. The
percent analgesic activity (PAA) was calculated by the following formula,
PAA = [(T2-T1)
/ (10-T1)] X 100
Where, T1 and T2 is the reaction
time (in sec) before and after treatment respectively.
RESULTS AND DISCUSSION:
CHEMISTRY:
IR, 1H-NMR, Mass spectra and Elemental
analysis were consistent with the assigned structures.
2-(3,5-diphenyl-4,5-dihydropyrazol-1-yl)-N-(4-phenylthiazol-2-yl)acetamide
(8a):
Yield: 76%; m.p. 88-90 °C; IR
(KBr, cm-1): 3155 (N-H), 3017 (Ar-CH), 1698 (C=O), 1580 (C=N), 1565 (C=C), 683 (C-S). 1H-NMR
(CDCl3) δ: 8.20 (s, 1H, -NH-), 7.03-7.54 (m, 15H, Ar-H), 6.54 (s, 1H, -S-CH=), 3.88 (t, 1H,
-N-CH-), 3.48 (s, 2H, -CH2-), 1.57-1.85 (d, 2H, pyrazole –CH2-). EI-MS m/z (M+):
438 (Calcd. for C26H22N4OS;
438.54). Anal. Calcd. for C26H22N4OS;
C, 71.21; H, 5.06; N, 12.78. Found: C, 71.15; H, 5.10; N, 12.76.
2-(5-(4-methoxyphenyl)-3-phenyl-4,5-dihydropyrazol-1-yl)-N-(4-phenylthiazol-2-yl)acetamide
(8b):
Yield: 67%; m.p. 59-60 °C; IR
(KBr, cm-1): 3159 (N-H), 3024 (Ar-CH), 1694 (C=O), 1586 (C=N), 1563 (C=C), 677 (C-S). 1H-NMR
(CDCl3) δ: 8.06 (s, 1H, -NH-), 6.75-7.63 (m, 14H, Ar-H), 6.57 (s, 1H, -S-CH=), 3.90 (t, 1H,
-N-CH-), 3.77 (s, 3H, -O-CH3), 3.45 (s, 2H, -CH2-),
1.59-1.88 (d, 2H, pyrazole –CH2-).
EI-MS m/z (M+): 468 (Calcd. for C27H24N4O2S;
468.57). Anal. Calcd. for C27H24N4O2S;
C, 69.21; H, 5.16; N, 11.96. Found: C, 69.25; H, 5.14; N, 11.91.
2-(5-(4-(dimethylamino)phenyl)-3-phenyl-4,5-dihydropyrazol-1-yl)-N-(4-phenylthiazol-2-yl)acetamide
(8c):
Yield: 73%; m.p. 72-75 °C; IR
(KBr, cm-1): 3150 (N-H), 3013 (Ar-CH), 1691 (C=O), 1579 (C=N), 1560 (C=C), 685 (C-S). 1H-NMR
(CDCl3) δ: 8.12 (s, 1H, -NH-), 6.53-7.58 (m, 14H, Ar-H), 6.55 (s, 1H, -S-CH=), 3.86 (t, 1H,
-N-CH-), 3.47 (s, 2H, -CH2-), 2.88 (s, 6H, -N(CH3)2),
1.60-1.84 (d, 2H, pyrazole –CH2-).
EI-MS m/z (M+): 481 (Calcd. for C28H27N5OS;
481.61). Anal. Calcd. for C28H27N5OS;
C, 69.83; H, 5.65; N, 14.54. Found: C, 69.87; H, 5.69; N, 14.50.
2-(5-(3-nitrophenyl)-3-phenyl-4,5-dihydropyrazol-1-yl)-N-(4-phenylthiazol-2-yl)acetamide
(8d):
Yield: 65%; m.p. 104-105 °C;
IR (KBr, cm-1): 3153 (N-H), 3018 (Ar-CH), 1687 (C=O), 1585 (C=N), 1567 (C=C), 681 (C-S). 1H-NMR
(CDCl3) δ: 8.17 (s, 1H, -NH-), 7.21-8.09 (m, 14H, Ar-H), 6.59 (s, 1H, -S-CH=), 3.93 (t, 1H,
-N-CH-), 3.51 (s, 2H, -CH2-), 1.55-1.87 (d, 2H, pyrazole –CH2-). EI-MS m/z (M+):
483 (Calcd. for C26H21N5O3S;
483.54). Anal. Calcd. for C26H21N5O3S;
C, 64.58; H, 4.38; N, 14.48. Found: C, 64.61; H, 4.36; N, 14.44.
Table-1. Analgesic activity of
the synthesized compounds (Tail-Flick Technique)
|
COMPOUND CODE |
DOSE (mg/kg) |
PERCENT ANALGESIC ACTIVITY |
|||
|
30 min |
60 min |
120 min |
180 min |
||
|
8a |
100 |
47.43+0.96** |
54.25+2.34* |
59.87+0.56* |
45.68+1.10* |
|
8b |
100 |
36.25+2.11* |
49.77+2.61* |
56.89+0.63** |
47.54+1.16* |
|
8c |
100 |
56.57+0.46** |
60.58+1.18*** |
72.73+0.13* |
65.23+0.26* |
|
8d |
100 |
36.46+0.85* |
39.59+1.15** |
46.24+1.34** |
33.51+1.11** |
|
8e |
100 |
46.93+1.11** |
59.42+0.48** |
63.56+1.26** |
55.27+0.38* |
|
8f |
100 |
45.92+1.07* |
51.85+0.95* |
61.79+2.05** |
42.83+1.23** |
|
8g |
100 |
43.54+3.01** |
53.73+1.56** |
54.51+0.95* |
47.36+2.15* |
|
8h |
100 |
39.67+2.24* |
51.66+1.18* |
55.84+3.28** |
36.52+1.19** |
|
8i |
100 |
49.63+2.38* |
57.87+0.66** |
57.63+0.56* |
28.55+0.38* |
|
8j |
100 |
48.82+1.56** |
56.53+1.12* |
60.14+1.12** |
47.74+0.49* |
|
control |
- |
2+0.33 |
6+0.48 |
4+0.60 |
4+0.87 |
|
Pentazocine |
10 |
65.42+0.95** |
72.64+0.67*** |
77.45+.1.03*** |
71.78+0.54* |
Each value represents the mean+S.D.
(n=6). Significance levels *p<0.5, **p<0.01, ***p<0.001 as compared
with the respective control
2-(5-(4-methylphenyl)-3-phenyl-4,5-dihydropyrazol-1-yl)-N-(4-phenylthiazol-2-yl)acetamide
(8e):
Yield: 68%; m.p. 69-72 °C; IR
(KBr, cm-1): 3157 (N-H), 3015 (Ar-CH), 1702 (C=O), 1577 (C=N), 1561 (C=C), 689 (C-S). 1H-NMR
(CDCl3) δ: 8.03 (s, 1H, -NH-), 7.15-8.00 (m, 14H, Ar-H), 6.51 (s, 1H, -S-CH=), 3.96 (t, 1H,
-N-CH-), 3.40 (s, 2H, -CH2-), 2.39 (s, 3H, -CH3),
1.60-1.87 (d, 2H, pyrazole –CH2-).
EI-MS m/z (M+): 452 (Calcd. for C27H24N4OS;
452.57). Anal. Calcd. for C27H24N4OS;
C, 71.65; H, 5.35; N, 12.38. Found: C, 71.70; H, 5.32; N, 12.36.
2-(5-(4-hydroxyphenyl)-3-phenyl-4,5-dihydropyrazol-1-yl)-N-(4-phenylthiazol-2-yl)acetamide
(8f):
Yield: 70%; m.p. 78-81 °C; IR
(KBr, cm-1): 3154 (N-H), 3011 (Ar-CH), 1693 (C=O), 1581 (C=N), 1564 (C=C), 682 (C-S). 1H-NMR
(CDCl3) δ: 8.09 (s, 1H, -NH-), 6.67-7.63 (m, 14H, Ar-H), 6.63 (s, 1H, -S-CH=), 4.95 (s, 1H, -OH),
3.82 (t, 1H, -N-CH-), 3.47 (s, 2H, -CH2-), 1.53-1.92
(d, 2H, pyrazole –CH2-). EI-MS m/z
(M+): 454 (Calcd. for C26H22N4O2S;
454.54). Anal. Calcd. for C26H22N4O2S;
C, 68.70; H, 4.88; N, 12.33. Found: C, 68.74; H, 4.85; N, 12.29.
2-(5-(4-chlorophenyl)-3-phenyl-4,5-dihydropyrazol-1-yl)-N-(4-phenylthiazol-2-yl)acetamide
(8g):
Yield: 61%; m.p. 92-94 °C; IR
(KBr, cm-1): 3160 (N-H), 3019 (Ar-CH), 1689 (C=O), 1586 (C=N), 1567 (C=C), 688 (C-S). 1H-NMR
(CDCl3) δ: 8.16 (s, 1H, -NH-), 7.09-7.67 (m, 14H, Ar-H), 6.60 (s, 1H, -S-CH=), 3.87 (t, 1H,
-N-CH-), 3.51 (s, 2H, -CH2-), 1.56-1.84 (d, 2H, pyrazole –CH2-). EI-MS m/z (M+):
472 (Calcd. for C26H21ClN4OS;
472.99). Anal. Calcd. for C26H21ClN4OS;
C, 66.02; H, 4.48; N, 7.50. Found: C, 66.08; H, 4.49; N, 7.54.
2-(5-(4-nitrophenyl)-3-phenyl-4,5-dihydropyrazol-1-yl)-N-(4-phenylthiazol-2-yl)acetamide
(8h):
Yield: 69%; m.p. 100-102 °C;
IR (KBr, cm-1): 3152 (N-H), 3016 (Ar-CH), 1695 (C=O), 1587 (C=N), 1562 (C=C), 686 (C-S). 1H-NMR
(CDCl3) δ: 8.11 (s, 1H, -NH-), 7.14-8.07 (m, 14H, Ar-H), 6.58 (s, 1H, -S-CH=), 3.91 (t, 1H,
-N-CH-), 3.49 (s, 2H, -CH2-), 1.51-1.86 (d, 2H, pyrazole –CH2-). EI-MS m/z (M+):
483 (Calcd. for C26H21N5O3S;
483.54). Anal. Calcd. for C26H21N5O3S;
C, 64.58; H, 4.38; N, 14.48. Found: C, 64.55; H, 4.41; N, 14.42.
2-(3-phenyl-5-(3,4,5-trimethoxyphenyl)-4,5-dihydropyrazol-1-yl)-N-(4-phenylthiazol-2-yl)acetamide
(8i):
Yield: 73%; m.p. 62-65 °C; IR
(KBr, cm-1): 3156 (N-H), 3012 (Ar-CH), 1689 (C=O), 1574 (C=N), 1563 (C=C), 673 (C-S). 1H-NMR
(CDCl3) δ: 8.01 (s, 1H, -NH-), 6.05-7.59 (m, 12H, Ar-H), 6.53 (s, 1H, -S-CH=), 3.85 (t, 1H,
-N-CH-), 3.70 (s, 9H, -(OCH3)3), 3.46 (s,
2H, -CH2-), 1.59-1.92 (d, 2H, pyrazole
–CH2-). EI-MS m/z (M+): 528 (Calcd.
for C29H28N4O4S; 528.62). Anal. Calcd. for C29H28N4O4S;
C, 65.89; H, 5.34; N, 10.60. Found: C, 65.94; H, 5.33; N, 10.56.
2-(5-(4-hydroxy-3-methoxyphenyl)-3-phenyl-4,5-dihydropyrazol-1-yl)-N-(4-phenylthiazol-2-yl)acetamide
(8j):
Yield: 62%; m.p. 83-85 °C; IR
(KBr, cm-1): 3163 (N-H), 3024 (Ar-CH), 1692 (C=O), 1588 (C=N), 1560 (C=C), 679 (C-S). 1H-NMR
(CDCl3) δ: 8.15 (s, 1H, -NH-), 6.41-7.68 (m, 13H, Ar-H), 6.57 (s, 1H, -S-CH=), 5.06 (s, 1H, -OH),
3.89 (t, 1H, -N-CH-), 3.76 (s, 3H, -OCH3), 3.43 (s,
2H, -CH2-), 1.63-1.94 (d, 2H, pyrazole
–CH2-). EI-MS m/z (M+): 484 (Calcd.
for C27H24N4O3S; 484.57). Anal. Calcd. for C27H24N4O3S;
C, 66.92; H, 4.99; N, 11.56. Found: C, 66.96; H, 5.03; N, 11.52.
The results of analgesic activity indicate that all the
test compounds exhibited significant activity. When compared with standard drug
(Pentazocin, 10 mg/kg) the compounds 8c and 8e exhibited comparable analgesic activity at 100 mg/kg. Compounds 8f, 8j, 8a and 8b exhibited moderate analgesic activity. Among the compounds
synthesized compound 8d exhibited
lowest analgesic activity. From the above results it may concluded that
compounds containing electron donating groups exhibits better activity than
electron withdrawing groups.
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Received on 13.11.2011 Accepted on 14.12.2011
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