Antimycobacterial activity of some synthesized fluorinated benzothiazolo imidazole compounds

Article abstract of DOI:10.1155/2011/581429

4-Fluoro-3-chloroanilline treated with potassium thiocyanate in presence of glacial acetic acid and bromine was converted into 2-amino-6-fluoro-7- chlorobenzothiazole, resulting into 2-amino benzothiazole. The synthesized compound in presence of 2-phenyl-

Full text of DOI:10.1155/2011/581429

ISSN: 0973-4945; CODEN ECJHAO
E-Journal of Chemistry
2011, 8(2), 830-834
http://www.e-journals.net
Antimycobacterial Activity of Some Synthesized
Fluorinated Benzothiazolo Imidazole Compounds
B.S. SATHE*, E. JAYCHANDRAN§,
G.M SREENIVASA§ and V. A. JAGTAP
Department of Pharmaceutical Analysis
Smt. S. S. Patil College of Pharmacy, Chopda - 425 107, India
§P. G. Department of Pharmaceutical Chemistry
S. C. S. College of Pharmacy, Harapanahalli - 583 131, India
drbss1978@rediffmail.com
Received 18 July 2010; Accepted 5 September 2010
Abstract: 4-Fluoro-3-chloroanilline treated with potassium thiocyanate in
presence of glacial acetic acid and bromine was converted into 2-amino-6-
fluoro-7-chlorobenzothiazole, resulting into 2-amino benzothiazole. The
synthesized compound in presence of 2-phenyl-4-benzylidine-5-oxazolinone
refluxed in pyridine to obtain 2-(2-phenyl-4-benzylidenyl-5-oxo-imidazolin
-1-yl amino)-6-fluoro-7-substituted(1,3)benzothiazoles. The above said
compound was treated with ortho, meta and para nitroanillines, ortho, meta,
para chloroanillines, morpholino, piperazine, diphenylamine in the presence of
DMF to obtain different derivatives. Some compounds showed promising anti-
microbial activity.
Keywords: Flourine, Benzothiazole, Oxazalinone, Imidazoline, Antimycobacterial activity.
Introduction
Fluorobenzothiazoles and imidazoles exhibit the broad range of antibacterial1, antifungal2,
anthelmintic3, anti-inflammatory4 and antitubercular5 activity. In the recent years, the
chemistry of oxazolones6 has received much attention due to their use as intermediates for
synthesis of some heterocyclic systems. In the present study we made an attempt to link7-8
fluorobenzothiazoles with imidazoles for generating various derivatives, screened for
antimycobacterial activity by using in-vitro models10. Benzylidine derivatives were found to
possess MAO Inhibitory activity9, therefore in the present work we have treated oxazolones
benzothiazole ring to get potent antimycobacterial leads.

Antimycobacterial Activity of Some Synthesized Compounds
831
C6H5
NH2
N
Br /HAC
N
O
KSCN;
NH3
2
+
F
O
NH2
S
F
H1C
C6H5
Cl
Cl
2
Oxazolone
1
6 Hrs. reflux in pyridine
C6H5
N
N
C6H5
N
N
S
N
F
S
N
CH
C6H5
R
F
O
CH
C6H5
Cl
O
3
4 (a-i)
Experimental
Purity of compounds was checked by TLC. Melting points were determined by open
capillaries method and uncorrected. IR spectra (NaCl) are recorded on FTIR (Schimadzu-
8300) spectrophotometer using nujol mull technique. For antimycobacterial activity in vitro
by tube dilution technique using the human virulent H37RV strains of M. tuberculosis.
General Procedure
2-Amino-6-fluoro-7-chloro-(1,3)benzothiazole (1)
To the glacial acetic acid (20 mL) which is cooled below room temperature, 8 g (0.08 mol)
of potassium thiocyanate and 1.45 g (0.01 mol) of fluorochloroaniline was added. The
mixture was placed in freezing mixture of ice and salt, mechanically stirred while 1.6 mL of
bromine in 6 mL of glacial acetic acid was added, from a dropping funnel at such a rate that
the temperature never rose beyond room temperature. After all the bromine was added
(105 min), the solution was stirred for 2 h below room temperature and at room temperature
for 10 h, it was then allowed to stand over night, during which period an orange precipitate
0
settle at the bottom, water (6 mL) was added quickly and slurry was heated at 85 C on a
steam bath and filtered hot. The orange residue was placed in a reaction flask and treated
0
with 10 mL of glacial acetic acid heated again to 85 C and filtered hot. The combined
filtrate was cooled and neutralized with concentrated ammonia solution to pH 6. A dark
yellow precipitate was collected. Recrystallised from benzene-ethanol mixture (1:1) after
treatment with animal charcoal gave yellow plates of 2-amino-6-fluoro-7-chloro-(1,3)
benzothiazole. After drying in an oven at 80 0C, the dry material (1 g 51.02%) melted at 210-
0
212 C. UV 307.4, 269 nm, IR 1542 cm-1 (aromatic C=C) and 3475 cm-1 (NH2); 1456 cm-1
(thiazole), 1215 cm-1 (aromatic-F), 712 cm-1 (aromatic-Cl).
2-Phenyl- 4-benzylidine-5-oxazol-5-one (oxazolone) (2)
Redistilled benzaldehyde was treated with benzoyl glycine (Hippuric acid) in presence of
acetic anhydride (dry acetic acid) and anhydrous sodium acetate to get 4-benzylidene-2-
phenyl-oxazol-5-one(oxazolone). Upon washing with ice cold alcohol and then with boiling
0
water (Yield 80%), melted at 165-166 C, IR (NaCl) 1790 cm-1 (Lactone carbonyl) and
another bond at 1650 cm-1(C=N stretching).
2[2’- Phenyl -4’- benzidinyl- 5’- oxo- imidazoline- 1yl- amino] -6 fluoro- 7- chloro
(1,3) benzothiazoles (3)
A mixture of 0.01 mol. of 2-amino-6-fluoro-7-chloro-(1,3)benzothiazole (1) with 2-phenyl-
4-benzylidine-5-oxazol-5-one (oxazolone)(2) refluxed in pyridine for 6-8 hours. Excess of

832
B.S. SATHE et al.
pyridine was distilled off and resulting mass was poured on to crushed ice and neutralized
with dil HCl, filtered and product was recrystallised from ethanol. The dry material melted
0
at 110-112 C (72%).IR(NaCl) 3452 cm-1 (-NH stretching), 121 cm-1 (C-F), 677 cm-1(C-Cl
stretching), 3091 cm-1 (C=C stretching), 1601 cm-1 (C=O stretching).
Preparation of various derivatives (4a-i)
2[2’- Phenyl -4’- benzidinyl- 5’- oxo- imidazoline- 1yl- amino] -6 fluoro- 7- chloro (1,3)
benzothiazole (3) was treated with various aromatic amines. Refluxed for 2 h. in presence
of DMF (dimethyl formamide) yields various 2[2’- phenyl -4’- benzidinyl- 5’- oxo-
imidazoline- 1yl- amino] -6 fluoro- 7- chloro (1,3) benzothiazole derivatives (4a-i). The
solid separated was cooled and poured on to crushed ice. The solid separated was filtered
off, dried and recrystallised from benzene and super dry alcohol (1;1).
Table 1. Analytical data of the synthesized compounds (4a-i)
Comp
No
M.P. Yield
%
Elemental Analysis %
C
R
M. F.
ºC
H
N
Found 68.00 3.56 12.00
Calc. 67.50 3.54 11.66
Found 70.01 3.90 12.13
Calc. 69.67 3.87 12.04
O
N
117
80
C27H17N4O2SF
4a
NH
N
128
79
74
C27H18N4OSF
C35H23N4OSF
4b
4c
Found 74.90 4.15 10.09
Calc. 74.20 4.06 9.89
Found 65.09 3.56 13.89
-N-(C6H5)2 117
NH
NO2
116
66
68
C29H18N5O3SF
C29H18N5O3SF
4d
4e
Calc. 65.04 3.36 13.08
Found 66.00 3.89 14.02
Calc. 65.04 3.36 13.08
Found 66.09 3.45 12.80
NH
126
NO2
NH
122
70
C29H18N5O3SF
4f
Calc. 65.04 3.36 13.08
NO2
NH
Found 71.09 3.90 12.56
Calc. 71.02 3.87 11.42
Found 67.77 3.89 10.89
Calc. 66.28 3.42 10.66
Found 67.05 3.67 11.09
111
72
77
C29H19N4OSF
4g
4h
NH
85
C29H18N4OSFCl
Cl
NH
115
70
C29H18N4OSFCl
4i
Calc. 66.28 3.42 10.66
Cl

Antimycobacterial Activity of Some Synthesized Compounds
833
Table 2. IR spectral data of the synthesized compounds (4a-i)
Comp.
Code
4a
NH
cm-1
Imidazoline ring C=N stretching C=C stretching NO2 C-F C-Cl
carbonyl cm-1
1640
1640
cm-1
1612
1673
1600
1600
1613
1640
1610
1600
1653
cm-1
1485
1460
1490
1490
1487
1400
1460
1462
1493
cm-1 cm-1 cm-1
3353
3200
3200
3300
3350
3400
3351
3350
3349
--- 1167
--- 1161
--- 1163
802 1167
799 1163
890 1167
--- 1164
---
---
---
---
---
---
---
4b
4c
1630
1640
4d
4e
1639
1630
4f
4g
4h
4i
1641
1643
1637
--- 1169 714
--- 1160 714
Screening for antimycobacterial activity (in vitro models)
Sterile Kirchner’s medium was dispensed in each borosilicate test tube (150 x 20 mm) and
to this sterile horse serum (0.5 mL) was added. The stock solution was sterile by passing
through a 0.2 mm polycarbonate sterile membrane (Nuclepore) filters. Further the serial
dilution of test compounds were carried out. Test compounds at various concentrations (250,
125, 62, 32, 16, 8, 4 and 1 µg/mL) were added to culture medium in a sterilized borosilicate
test tube and strain of M.tuberculosis was inoculated at concentration (106 bacilli/mL). The
tubes were incubated at 370 for 21 days and then examined for the presence or absence of
growth of the test organisms. All experiments were performed in triplicate. The lowest
concentration, which showed no visible growth, was taken as the end point i.e. minimum
inhibitory concentration (MIC). Rifampin and isoniazid (INH) were used as standard for
antimycobacterial activity.
Table 3. Antimycobacterial activity of synthesized compounds (4a-i)
Activity Data
Codes
H37RV strain of
M. tuberculosis 21 days
Comp. No.
01
02
20
26
4a
4b
03
04
25
13
4c
4d
05
15
21
4e
06
07
4f
4g
17
20
17
0.25
0.007
08
09
4h
4i
Standard 1
Standard 2
Rifampicin
Isoniazide
Conclusion
All the synthesized fluorinated benzothiazole imidazole compounds have given appreciable
yield with satisfactory elemental analysis. It is inferred from the Table 3 that synthesized
compounds (4a-i), have shown significant antimycobacterial activity. However, animal
study and other studies are necessary for its activity and also there is a need to elucidate its
mechanism of antimycobacterial action.

834
B.S. SATHE et al.
Acknowledgment
The authors express thanks to Dr. A.S. Bobde, Haffkine Institute, Mumbai for providing
testing facilities for Antimycobacterial activity.
References
1.
Sangal S K and Rastivona P K, Chem Abstr., 1986, 104, 34029
Gurupadiaiah B M, Jaychandran E, Nargund L V G and Shivkumar B, Indian J
Heterocycl., 1998, 7, 213-216
2.
3.
4.
5.
Labendeno N Yu, Chem Abstr., 1980, 92, 922882
Areas J J, Chem Abstr., 1991, 14, 71453
Jaychandran E, Nargund L V G, Shivkumar B and Kamal Bhatia, Oriental J Chem.,
2003, 19(1), 139-142
6.
7.
8.
9.
Vogel A I, Vogel’s Textbook of Practical Organic Chemistry; ELBS, 1978, 4, 884-885.
Merja B C, Joshi A M and Parikh K A, Oriental J Chem., 2003, 13(1), 157-160
Verma V M, Chturvedi A K and Pamar S S, J Pharm Sci., 1974, 463, 1740.
Bhusari K P, Khedkar P B, Umathe S N and Raghuramrao A, Indian J Heterocycl
Chem., 2000, 13, 798-800
10. Shieke V G and Bodade A S, Chem Abstr., 1991, 11423845r

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