Synthesis and Anti-Inflammatory Activity of 2-Amino Substituted Benzothiazoles
Shashikant R Pattan1*, VD Pujar2, Nachiket S Dighe1, Deepak S Musmade1, SN Hiremath3, HV Shinde1 and RB Laware1
1Pravara Rural College of Pharmacy, Loni, M.S. India,413736.
2KLE’S College of Pharmacy, Belgaum. India.
3College of Pharmacy, Chincholi, Nashik, M.S. India.
*Corresponding Author E-mail: shashipattan@yahoo.com
ABSTRACT:
A new series of 2-amino substituted benzothiazoles and their derivatives were prepared by multiple steps. The structures of the synthesized compounds were confirmed by Melting point, TLC, IR, and H1NMR. The compounds were screened for their anti-inflammatory activity, all the compounds shown promising anti-inflammatory activity.
KEYWORDS: 2-amino-substituted-benzothiazoles, anti-inflammatory, CHN analysis.
INTRODUCTION:
Synthesis of derivatives of drugs has been aimed at modifying the action of drugs particularly to reduce the side effects. Benzothiazoles are one such category. Benzothiazoles1 has drawn attention as promising structural units in the field of medicinal chemistry. They were reported to exhibit. Antimicrobial2, Antitubercular, Cardiovascular, Hypoglycemic3, Local anesthetic, anticancer activities and anti-inflammatory activity4. Apart from this some novel Benzothiazoles like Zopolrestat as Aldose reductase inhibitor, Lubeluzole5 as Glutamate release inhibitor and Pramipexole6 as Antiparkinson's agent are introduced into the market. An attempt has been made to enhance the activity of benzothiazoles by insulating the fluorine moiety. Several fluoro benzothiazoles7 have been synthesized and they were found to possess enhanced activities.
The activity was conducted by paw oedema method. The animals were divided into 10 groups of six animals each one group served as control, another group served as a standard (indomethacin) and the rest of the groups were used for the test drugs. The rats were dosed orally at 100mg/kg body weight, including the control and indomethacin.
Test compound and standard drug were suspended 0.5% of sodium carboxyl methylcellulose mucilage, which was used as a vehicle for the control group. A solution of 1% of carrageenan was used as an inflammatory agent. Results are listed in table 1.
EXPERIMENTAL:
Melting points were determined in open capillaries and uncorrected. Purity of the compounds was verified by percolated TLC plates. IR spectra were recorded on NICOLET Infra red spectrophotometer using KBr. The UV spectra were recorded in DMF on JASCO UV-Visible spectrophotometer between 260-400 nm. 1H NMR spectra were recorded on BRUKER amx-400 using DMSO-d6 as internal standard. Physical data and Spectral data are listed in Table 2 and Table 3.
Synthesis of 2-amino-substituted benzothiazoles 19
To glacial acetic acid (20mL) cooled below room temperature were added potassium thiocyanate (0.08 mol, 8 gm) and substituted anilines (0.01 mol). The mixture was placed in freezing mixture of ice and salt, and mechanically stirred. Bromine (1.6mL) was added in glacial acetic acid (6mL) from a dropping funnel at such a rate that the temperature never rose beyond 0°C. After all the bromine was added (15 min), the solution was stirred for 2 hr below room temperature and at room temperature for 10 hr. It was then allowed to stand over night, during which period an orange precipitate settled at the bottom, water (6mL) was added quickly and the slurry was heated to 85°C on a steam bath and filtered hot. The orange residue was placed in a reaction flask and treated with 10mL of glacial acetic acid heated again to 85°C and filtered. The combined filtrate was cooled and precipitate was collected.
Table No 1:Effect of synthesized compound and indomethacin and carrageenan induced rat paw oedema by oral administration
|
Sl. No. |
Drug (100mg/kg) |
Mean Paw Oedema Volume (ml) ± SE |
|||
|
0 hr |
1 hr |
2 hr |
4 hr |
||
|
1 |
Control |
0.389 ±0.015 |
1.09 ±0.139 |
2.12 ±0.048 |
3.26 ±0.059 |
|
2 |
Indomethacin |
3.877 ±0.363 |
4.18 ±0.2* |
3.75 ±0.21** |
3.4 ±0.23** |
|
3 |
B1 |
3.723 ±0.353 |
4.70 ±0.38 |
5.2 ±0.23* |
4.7 ±0.03** |
|
4 |
B2 |
3.62±0.086 |
5.33±0.08** |
5.39±0.44* |
4.6±0.25** |
|
5 |
B3 |
3.76±0.293 |
5.18±0.11** |
4.0±0.029 |
3.78±0.08 |
|
6 |
B4 |
4.41±0.293 |
4.97±0.17 |
4.55±0.13 |
4.34±0.09* |
|
7 |
B5 |
4.15±0.599 |
4.62±0.30 |
3.97±0.19 |
3.77±0.15** |
|
8 |
C1 |
3.64±0.374 |
4.33±0.29 |
4.78±0.199 |
4.5±0.221** |
|
9 |
C2 |
3.370 ± 1.56 |
3.26 ± 0.155 |
2.97±0.05** |
3.4±0.23** |
* P < 0.05 – moderate, ** P < 0.01 – Significant, *** P < 0.0001 (ANOVA followed by Dunnet ‘t’ test)
Table 2 - Characterization data of compounds B1-5, C1-2
|
Comp No. |
Yield % |
M.P. 0C |
Mol. wt. |
Mol. Formula |
Analysis % Calculated / Found |
||
|
C |
H |
N |
|||||
|
B1 |
60 |
147 |
273 |
C11H7N3O2S |
48.34 48.23 |
2.58 2.66 |
25.62 25.42 |
|
B2 |
57 |
165 |
273 |
C11H7N5O2S |
48.34 48.24 |
2.58 2.56 |
25.62 25.82 |
|
B3 |
62 |
158 |
246 |
C11H7N4SF |
53.65 53.64 |
2.86 2.73 |
22.75 22.58 |
|
B4 |
49 |
137 |
280 |
C11H6N4SFCl |
47.06 47.10 |
2.15 2.23 |
19.95 19.75 |
|
B5 |
64 |
162 |
256 |
C12H10N4S |
56.23 56.32 |
3.93 3.63 |
27.32 27.53 |
|
C1 |
53 |
147 |
242 |
C11H9N5S |
54.53 54.55 |
3.74 3.55 |
29.90 29.83 |
|
C2 |
47 |
128 |
261 |
C11H8N5SF |
50.56 50.73 |
3.08 3.25 |
26.80 26.62 |
Scheme
It was purified by recrystallization from benzene: ethanol (1:1) after treatment with charcoal gave yellow crystals of 2-amio-substituted-benzothiazole. The compounds were dried in an oven at 80°C.
Synthesis of 2-amino [pyrazinyl]-6,7-disubstituted benzothiazoles (B)10:
2-amino substituted benzothiazoles (0.01 mol) 1 and 2-chloropyrazine (0.01 mol) was refluxed in ethanol for 2 hr. The solvent was distilled off. The solid product was removed and purified by recrystallization from ethanol.
Table 3 Spectral data of synthesized compounds B1-5, C1-2.
|
Compd |
Spectral peaks (cm-1) |
Types of Vibrations |
d Values (ppm) |
No. of Protons |
|
B1 |
3398-3400 3070 1594 719 |
Ar-NH Str Ar-CH Str C-N Str C-S Str |
7.1 7.3 7.4-7.6 7.7 |
1H of CH of thiazole 3H of Pyrazine 3H of Aryl 1H or NH
|
|
B2 |
3398 3030 1595 1525 1475 668 |
N-H Str C-H Ar Str C=C Str C-N Str NO2 Str C-S Str
|
6.8-7.1 7.3 7.7 7.4-7.6 |
1H of CH of thiazole 3H of Pyrazine 3H of Aryl 1H or NH |
|
B3 |
3427 3290 1345 1635 1527 669 |
N-H Str Ar C-H Str C-CH3 Str C=C Str C-N Str C-S Str
|
7.3 6.9 – 7.2 7.2 – 7.4 7.5 |
1H of CH of thiazole 3H of Pyrazine 3H of Aryl 1H or NH |
|
B4 |
3404 1546 1401 1193 714 685 |
N-H Str C=C Str C=N Str C-F Str C-S Str C-Cl Str
|
7.6 7.4 – 7.6 7.25 – 7.4 7.12 |
1H (s) of NH 2H of Aryl 3H (m) of Pyrazine 1H of (s) Thiazole |
|
B5 |
3387 3086 1541 1380 1193 707 |
N-H Str C-H Str C-N Str C=N Str C-F Str C-S Str
|
7.79 7.4 – 7.7 7.3 – 7.4 7.6 1.17 |
1H (s) of NH 3H (m) of Ar 3H of Pyrazine 1H of thiazole 3H of CH3 |
|
C1 |
3340 3148 1648 1530 1372 685 |
N-H Str Ar C=H Str C=C Str C-N Str C=N Str C-S Str
|
7.5 7.1 –7.4 7.48 6.5 |
1H of NH 3H of Aryl 1H of Thiazole 3H of Pyrazine |
|
C2 |
3339 2907 1656 1536 1202 677 |
N-H Str C-H Ar Str C=N Str C-N Str C-F Str C-S Str
|
7.6 6.4 7.4-7.6 7.5 |
1H of CH of thiazole 3H of Pyrazine 3H of Aryl 1H or NH |
Synthesis of 2-amino-6, 7-[pyrazinyl]-benzothiazoles (C)11:
2-amino substituted benzothiazoles (0.01 mol) 1 and 2-aminopyrazine (0.01 mol) was refluxed in ethanol for 2 hr. The solvent was distilled off. The solid product was removed and purified by recrystallization from ethanol.
2-amino [pyrazinyl]-6,7-disubstituted benzothiazoles and 2-amino-6, 7-[pyrazinyl]-benzothiazoles derivatives were synthesized by using starting material 2-amino-substitued benzothiazoles with 2-chloropyrazine and 2-aminopyrazine (scheme I, II) respectively. Their structures had been confirmed by the spectral studies. They were screened for the anti-inflammatory activity by Paw-oedema method using albino rats having 150-180 gm weight. Compounds B1, B2, B3, C1 and C2 shown significant activity in compare with Indomethacine as standard at 100mg/kg. Compound B4 shown moderate activity.
ACKNOWLEDGEMENT:
Authors wish to thank Honorable Shri. Radhakrishna Vikhe Patil, Minister for Education, Law and Justice Govt. of Maharashtra for his constant encouragement and support.
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Received on 18.09.2009 Modified on 28.11.2009
Accepted on 17.12.2009 © AJRC All right reserved
Asian J. Research Chem. 3(1): Jan.-Mar. 2010; Page 113-115