A Comparative Study of the Inclusion Complexes of 2-[5’-benzylidene-2’-phenyl-4’-oxo-1’, 3’-thiazolidine]-1, 3-benzothiazole and 2-[5’-( p - N,N -dimethylamino-benzylidene)-2’-phenyl-4’-oxo-1’, 3’-thiazolidine]-1, 3-benzothiazole with β -Cyclodextrin

: The compounds 2-[5’-benzylidene-2’-phenyl-4’-oxo-1’,3’-thiazolidine] -1,3-benzothiazole and 2-[5’-(p- N,N -dimethylaminobenzylidene)-2’-phenyl-4’-oxo-1’,3’-thiazolidine]-1,3-benzothiazole have been synthesized in their purest forms starting from 2-aminobenzothiazole. The inclusion complexes of the above compounds have been prepared with β -cyclodextrin to increase their solubility and bioaccessibility in polar medium. The formation of inclusion complexes have been ascertained by study of spectral characteristic before and after inclusion complex formation. The stability of inclusion complexes and nature of interaction between the host and guest are known from the determination of thermodynamic parameters. Further the antibacterial and antifungal activities of the compounds are determined which is found to increase significantly after inclusion complex formation

In the present work, an attempt has been made to synthesize 2-[5'-benzylidene-2'phenyl-4'-oxo-1', 3'-thiazolidine]-1, 3-benzothiazole(IIIA) and 2-[5'-(p-N,N-dimethylaminobenzylidene)-2'-phenyl-4'-oxo-1',3'-thiazolidine]-1,3-benzothiazole(IIIB) and to prepare their inclusion complexes with β-CD. The formation of compounds and their inclusion complexes have been ascertained by the study of spectral characteristics. Thermodynamic parameters of the inclusion complexes have been calculated to have an idea about the stability of the compounds with in β-CD cavity. Finally antibacterial and antifungal activities of the compounds have been determined to examine whether the inclusion complex formation is enhancing the bioaccesibility of the compounds or not.

Experimental
The elemental analysis of the compounds synthesized has been performed in a CHN analyzer. Electronic spectra are recorded on shimadzu UV-1700 spectrophotometers while IR spectra are recorded in KBr pallets in the range of 400-4000 cm -1 region in a shimadzu 8400 S FTIR spectrophotometer. Melting points are recorded by open capillary method.
The pure compounds have been synthesized as per the method described by Srivastava et al 33 . Equimolar solution of 2-aminobenzothiazole (5 g, 0.03 mol) and benzaldehyde (3.38 mL, 0.03 mol) with few drops of glacial acetic acid in MeOH (50 mL) was refluxed on water with bath for about 1 h. The solvent was removed in vacuo and the residue was purified over the column of silica gel using CHCl 3 .The product was recrystallized from ethanol to give 2-N-(benzyledine)-imino-1, 3-benzothiazole(I).
A mixture of the compound I (3g, 0.01 mL) and thioglycolic acid (0.91 mL, 0.01 mol) in the presence of ZnCl 2 in benzene (50 mL) is refluxed on a water bath for about 15 h. The solvent was removed in vacuo and the residue was purified over the column of silica gel using CHCl 3 as an eluent.The product was recrystallized from ethanol to afford compound 2-[2'-(phenyl)-4'-oxo-1', 3'-thiazolidine]-1, 3-benzothiazole(II).
Equimolar solution of the compound II (2 g, 0.006 mol) and benzaldehyde (0.65 mL, 0.006 mol) in dioxane (20 mL) in the presence of C 2 H 5 OK was refluxed on a water bath for about 6 h. The solvent was removed in vacuo and the residue was purified over the column of silica gel using CHCl 3 as an eluent. The product was recrystallized from ethanol to yield compound 2-[5'benzylidene-2'-phenyl-4'-oxo-1',3'-thiazolidine]-1,3-benzothiazole(IIIA). Similarly the compound IIIB was synthesized as per the procedure given above using p-N,N-dimethylaminobenzaldehyde in place of benzaldehyde. The synthesis of compound IIIA and IIIB are shown in Scheme 1.

Results and Discussion
The synthesis of compound IIIA and IIIB have been confirmed from elemental analysis and IR data as shown in the Table 1 (Table 1).  The synthesis of inclusion complexes of compounds IIIA and IIIB have been confirmed from melting point data and spectral characteristics (UV-Vis and IR) (Table 1) The melting point of IIIA and its inclusion complex are 203 0 and 212 0 C respectively. The melting point of IIIB and its inclusion complex are 204 0 and 214 0 C respectively. A higher melting point of inclusion complexes than their compounds (IIIA and IIIB) are due to the fact that extra amount of thermal energy is required for the compound to be brought out of β-CD cavity.
. The drug recipient interactions are better identified by employing UV and IR spectrophotometry as useful tool 24 . The absorption maxima are shown to undergo a distinct blue shift of 2 nm after their inclusion complex formation with β-CD (Table 1, Figure 1.1, Figure 1.2).These observation clearly demonstrate transference of the compound from a more protic environment to a less protic environment (cavity of β-CD). The compound and β-CD interaction leading to inclusion complex formation is further supported by IR data (Table 1). It is seen that the IR stretching frequencies due to different bonds C=O, N-HC-S , C=CHAr etc in case compound IIIA and IIIB undergo a downward shift towards lower energy and the peaks become broader, weaker and smoother. Such changes in IR spectral characteristics due to the inclusion complex formation may be attributed to development of weak interactions like H-bonding van der Waals forces and hydrophobic interactions between host and guest molecules 25 . The phase solubility plots of IIIA and IIIB in a solution of β-CD is shown in the Figure 2. In both the cases, it is seen that there is a linear increase in solubility of the compounds with increasing concentration of β-CD. At a higher concentration of β-CD, a small negative deviation is observed. Since the slopes of plots are less than unity, the stoichiometry of the inclusion complexes 26 is 1:1.  The K T values for the inclusion complexes of IIIA and IIIB with β-CD are found to be 522.42 M -1 and 390.5M -1 respectively. Lower value K T for inclusion complex of IIIB than that of IIIA clearly indicates that the stability of inclusion complex of IIIA is more than that of IIIB. Further the data obtained are with in 100 to 1000M -1 (ideal values) indicating appreciable stability for the inclusion complexes 27 .
The thermodynamic parameters associated with encapsulation of compounds IIIA and IIIB with β-CD for 1:1 stoichiometries have been calculated by determining the K values at different temperatures. The K values are found to decrease with increasing temperature (deencapsulation) as expected for an exothermic process 28,29 . The plot of ln K as a function of inverse absolute temperature produced a linear plot (Figure 4). In such a case, the slope corresponds to (-∆H/ R).From these values and the value of K T at 298 K, ∆G, ∆S and ∆H have been calculated (Table 2  As can be seen from the table, ∆G values are negative for both the complexes. The data clearly demonstrates spontaneous formation of both the inclusion complexes. Secondly a negative value of ∆H and a positive value of ∆S at 298 K for compound IIIA suggest the complex formation to be an exothermic and enthalpy controlled process which may be due to the stabilization of compound with in the cavity of β-CD by weak intermolecular forces as suggested earlier [30][31][32] . In case of inclusion complex of IIIB, both ∆H and ∆S are negative which indicate the complex formation is energetically allowed but entropy forbidden. The negative value of entropy change may be due to steric hindrance with in β-CD cavity which may be correlated with its lower value of stability constant ( Table 2).
The data obtained from antibacterial and antifungal studies of compounds IIIA and IIIB suggest that both the antibacterial (E.coli) and antifungal activities (P.notatum) increase significantly after the formation of inclusion complexes (Table 3). This may be attributed to enhanced solubility of the drug. As the solubility increases, the drug becomes more bioacccessibile to specific tissues leading to increased drug activity.

Conclusion
From the above results and discussions, it is clear that the solubility of compound IIIA and IIIB can be improved by inclusion complex formation with β-CD which is a very good analytical tool for enhancing the bioavailability of drugs. Further the study furnishes information about the participation of non-covalent intermolecular forces in between the guest (drug) and host β-cyclodextrin.