Heterocyclic solvent. The best way for the solubility of

                   Heterocyclic structures are main backbone of
drugs and medicine. A large number of heterocyclic compounds have been prepared
after development of science and technology. Heterocyclic compound’s have their
precise necessity to human society on account of their wide application,
utilization and some specific natures. Out of available compounds few are similar
with earlier structure while some of them new to mankind. These new compounds
have been synthesized and studied for their antibacterial and other
pharmacological activities.   Synthesisation,evaluation and determination of
chemotherapeutic potential of organic compounds is the prime work of organic chemists.
Structural revisions   and elemental
analysis of the compounds can be carried out with the help of sophisticated analytical
instruments and spectroscopic techniques .Out of them, Thiazolidinone is one of
the very important pharmacore.  Thiazolidinone
is a heterocyclic compound which contains nitrogen and sulphur  in a five member ring besides a   carbonyl group. Many research works on
thiazolidinones has been done in earlier time. Different types of biological
and pharmaceutical activity possessed by this nucleus. Some of the important
biological activities are anti-histaminic 1 , anti bacterial
2,antimycobacterial3,antiHIV4,antiinflammatory5,antiprotocol6,antitubercular7,anticonvulsant
8, anticancer 9  and analgesic 10
.Our objective is to formulate three compounds of substituted 4-thiazolidinone derivative
from 2-hydrazinobenzothiazole.Since these three compounds are less soluble in
water ,hence we are making our effort to built  a supramolecule with ?-cyclodextrin to make it
better soluble in polar solvent. The best way for the solubility of the drug is
to insert it into the cavity of  ?-cyclodextrin
and to make more the bio-available which may turn out for enhanced biological functions.
Cyclodextrin’s is able to provide a conical cavity for the water insoluble thiazolidinone
to be encapsulated by using host model cavities and  makes it more water soluble.  For this reason ?-cyclodextrins  selected on account of its least toxicity, cheapness
 and 
easily availability in the market11-13. In order to prepare our required
compound ,?-cyclodextrin  has been
encapsulated with of three compounds of 2-(benzothiazolyl-2′)hyrazino-5- arylidene-4-thiazolidinone
derivatives. Authenticity of the compounds and their inclusion complexes have
been   known from their spectral and
thermal studies. Besides this, their nature towards bacterial activity has been
studied after the formation of
compounds and their inclusion complex .                                       

                                                               EXPERIMENTAL
 

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Apparatus and Materials:

                       2-hydrazinobenzothiazole
and other used chemicals are pursched from Himedia company. Preparation of
double distilled water is done on our working laboratory and it meant for  using as solvent for different purpose .Open
capillary method is used for determination of Melting points of the synthesized
compounds and their corresponding inclusions and are uncorrected. UV spectra of
compounds spectra were measured on Shimadzu UV-1700 Spectrophotometer while  at the same time IR-spectra were recorded in
KBr pellets in 400-4000 cm-1 region on a Shimadzu 8400 FTIR Spectrophotometer.
Chemical shifts are calculated  With help of TMS as internal standard 1H
NMR spectra (CDCl3) are scanned on a DRX-300 (300MHz)
spectrophotometer and ? scale. To know  Antibacterial capacity  of the synthesized compounds and their
inclusion complexes  cup plate method is
used.

Synthesis
of compounds

            Synthesis of compounds were done as
the method is given by Garnaik et.al 14 (Scheme-I)                                                                                                                                                                                                                                   

                                                    
 Compound K

Compound
K:2-(Benzothiazolyl-2′)hydrazono-5-arylidene-4-thiazolidinone

Compound
L:2-(Benzothiazolyl-2′)hydrazono-5-o-Chloroarylidene-4-thiazolidinone

Compound
M:2-(Benzothiazolyl-2′)hydrazono-5-p-Choloroarylidene-4-thiazolidinone

Step-1:
Synthesis of 1-(Benzothiazolyl-2′)thiosemicarbazide:

            To prepare 1-(Benzothiazolyl-2′)thiosemicarbazide,
Take 1.65 gm of 2-hydrazinobenzothiazole    with 2.0 gm 
of potassium thiocyanate  and add
2.0 ml of concentrated hydrochloric acid .Put the mixture into 10 ml of water taken
in the round bottom flask. Heat and Reflux the flask   slowly
for three hour and then it is cooled to room temperature, Finally, yellow solid
is formed which was filtrated  and recrystalise
by using ethanol. M.P. 141oC, yield-0.7gm (40%), (Found S, 30.20 C7H8N4S2
requires S, 30.10%)

 Step-2: Synthesis of 2-(Benzothiazolyl-2′)hydrazino-4-thiazolidinone:
 

           To prepare 2-(Benzothiazolyl-2′)hydrazino-4-thiazolidinone,Take
2.02 gm. of 1-(benzothiazolyl-2′)thiosemicarbazide  in a round bottom flask add 0.2 gm of anhydrous
sodium acetate and constant stir for 2 minute and then add with 0.9 gm of
monochloroacetic acid . Take the mixture into 15 ml.of  absolute ethanol and   refluxed for three hour. The excess of solvent
was taken out and poured into cold water. Filtration, washing and recrystalisation
with alcohol of the above obtained solid has to be done. M.P. 158-160oC,
yield-1.3 gm (69%), (Found: S, 24.21 C10H8N4OS2
requires S, 24.24%).

Step-3: Synthesis of 2-(Benzothiazolyl-2′)hydrazino-5-benzylidene-4-thiazolidinone(Compound
K)

             To prepare compound K, Take 2.18
gm  of 2-(benzothiazolyl-2′)hydrazino-4-thiazolidinone
 with 0.9 gm of benzaldehyde and add 1.0
gm  fused sodium acetate. Put the entire
mixture into 15 ml. of glacial acetic acid under reflux for four hour. Then the
contents pour into ice cold water as aresult yellow solution has to be obtained
which on drying yields yellow solids.  Further,
The product obtained is to filtrated, washed with water and recrystalise by
using ethanol, M.P. 202oC ,yield-2.1 gm (59%). (Found: S, 18.15 C17H12N4OS2
requires S, 18.18%).By following same procedure ,compound L and M can be
prepared. O-chloro benzaldehyde and P-chloro 
benzaldehyde is taken is instead 
of benzaldehyde in the final step.

Preparation
 of Inclusion complexes :

               preparation of inclusion complexes of the synthesized
compounds  K ,L and M with ?-cyclodextrin  has to be carried by using co-precipitation
method 15. Necessary amount of concentrated (0.03mM) solution of the compound
is taken. Simulatenously ?-cyclodextrin solution were carried with required
concentration and mix with the solutions of compound. 48 hour  time is to be given for mixing by stirring at room
temperature and after  that the solution
is filtrated. Again 48 hour time is also given for the refrigeration of the
content.G-4 crucible is used for the precipitation of the compound, washing
have been done with distilled water and dried in air for 24 hours at the end.

Aqueous phase solubility study:

 

                  The aqueous phase solubility
of all the compounds to be performed by 
Higuchi Connors method 16 .Take a  series  of  conical flask and right amount  of the compound is put  in it. All conical flask to be shake for  48 hours in a rotary flask shaker at room
temperature until it  reached to the equilibrium
point.By using Whatmann-42 filter paper the contents in the conical flask were
filtered.Then the solutions obtained are analyzed on UV-visible
spectrophotometer in the range of 200-400nm. Absorbance values of ?-max were plotted against different concentrations
of ?-Cyclodextrin. From the phase solubility plots,
the thermodynamic stability constant (KT) of the inclusion complexes
are determined by using Benesi-Hilderbrand relation:

Where ?A is change in absorbance, ?? is
change in molar extension coefficient,Guesto is concentration of
compound in inclusion complex and ?-CDo is molar
concentration of ?-CD.

 

Evaluation of
Antibacterial activity:

               The antibacterial studies of
compounds have been performed by using cup-plate method17-18. For the testing
of compounds and their inclusions dimethyl sulphoxide (DMSO) of a strength of 500?g/ml
is prepared. The bacterial strains of E. coli (MTCC 40) ,S. aureus (MTCC 87)
and p.vulgaris (MTCC 426) were
inoculated into 100ml of the sterile nutrient broth and incubated of about 37°C
for 24 hours.  McFarland method is
adopted for the Standardization of density of the bacterial suspension. To  carry the process, take a well of uniform
diameter of 6mm consisting of agar plates, after inoculating them separately
with the test organisms aseptically. The drug (500?g/ml) and the test compounds
(500?g/ml) were introduced with the help of micropipette and the plates were
placed in the refrigerator at 8- 10°C for right diffusion of drug into the
media. After two hours of cold incubation, the Petri plates were transferred to
incubator placed at the temperature for 37°C for 18-24 hours. By using venire
scale, zone of inhibition were observed of compounds and inclusions in the
petriplates .On comparing the zone of inhibition shown by the test compounds
with standard drug (Tetracycline) results can be evaluated.

.                                                      
RESULTS
AND DISCUSSION

                Thiazolidinone
derivatives exhibits less pharmacological activities on account of their little
solubility in polar solvent like water. The formation of inclusion complex of thiazolidinone
makes the augmentation of solubility and therapeutic potential in an noticeable
amount. In an encapsulation of compound with ?-cyclodextrins, its solubility
and therapeutic activity  can be enhanced
significantly. The analytical data  of  the synthesized compounds and their inclusion
complexes are depicted in Table-I and likely the spectral data are shown in
table–II. Analysis of    the
spectral characteristics and elemental sulphur composition evidences formation  of compounds and their inclusion complexes.  

                The melting point of the
compounds K and its inclusion complex are 202oC and 208oC,
the melting point of the compounds L and its inc