Antimycobacterial Activity of Some Synthesized Fluorinated Benzothiazolo Imidazole Compounds

4-Fluoro-3-chloroanilline treated with potassium thiocyanate in presence of glacial acetic acid and bromine was converted into 2-amino-6fluoro-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 antimicrobial activity.


Introduction
Fluorobenzothiazoles and imidazoles exhibit the broad range of antibacterial 1 , antifungal 2 , anthelmintic 3 , anti-inflammatory 4 and antitubercular 5 activity.In the recent years, the chemistry of oxazolones 6 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 link [7][8] fluorobenzothiazoles with imidazoles for generating various derivatives, screened for antimycobacterial activity by using in-vitro models 10 .Benzylidine derivatives were found to possess MAO Inhibitory activity 9 , therefore in the present work we have treated oxazolones benzothiazole ring to get potent antimycobacterial leads.

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 settle at the bottom, water (6 mL) was added quickly and slurry was heated at 85 0 C on a steam bath and filtered hot.The orange residue was placed in a reaction flask and treated with 10 mL of glacial acetic acid heated again to 85 0 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 0 C, the dry material (1 g 51.02%) melted at 210-212 0 C. UV 307.4,269 nm, IR 1542 cm -1 (aromatic C=C) and 3475 cm -1 (NH 2 ); 1456 cm -1 (thiazole), 1215 cm -1 (aromatic-F), 712 cm -1 (aromatic-Cl).

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.
For antimycobacterial activity in vitro by tube dilution technique using the human virulent H 37 RV strains of M. tuberculosis.
ExperimentalPurity 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.

Table 1 .
Analytical data of the synthesized compounds (4a-i)

Table 2 .
IR spectral data of the synthesized compounds (4a-i) 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 37 0 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.