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- dimethylaminobenzylidene)- 2'-phenyl-4'-oxo-1', 3'-thiazolidine]- 1, 3-benzothiazole with β-Cyclodextrin

Article abstract of DOI:10.1155/2011/265484

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-aminoben

Full text of DOI:10.1155/2011/265484

ISSN: 0973-4945; CODEN ECJHAO
E-Journal of Chemistry
2011, 8(3), 1030-1037
http://www.e-journals.net
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
S. PANDA* and S.K.DASH
P. G. Department of Chemistry, Berhampur University,
Bhanjabihar, Berhampur-760007, Ganjam, Odisha, India
sunakar_bu@yahoo.co.in
Received 4 September 2010; Accepted 6 November 2010
Abstract: 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
Keywords: 2-Aminobenzothiazole, Inclusion complex, β-Cyclodextrin, Antimicrobial activity.
Introduction
The derivatives of benzothiazole exhibit a wide spectrum of pharmacological activities such
as antitubercular1, antimicrobial2, antifugicidal3-5 and antiallergic6. The amino of (-NH2) group
of 2-aminobenzothiazole can be used as a very good target for condensing with 2-oxo-
azetidine and their 5-benzylidene moieties generating a series of 2-[5’-(aryldene)-2’-p-
substituted phenyl-4’-oxo-1’,3’-thiazolidine]-1,3-benzothiazole which have significant
antimicrobial activities7-16. These compounds being insoluble in polar medium may have
poor pharmacological activities17. The solubility of these compounds can be enhanced by
forming inclusion (host-guest) complexes with β-cyclodextrins (β-CD) which in turn
increase their solubility and drug efficiency18.

1031
S. PANDA et al.
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-dimethylamino-
benzylidene)-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 al33. 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 CHCl3.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 ZnCl2 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 CHCl3 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 C2H5OK 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 CHCl3 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.
N
N
SHCH COOH
2COOH
2
C6H5CHO
NH2
N=CHC 6H5
6H5
S
S
I
N
N
ArCHO
N
CHC6H5
6H5
N
CHC H
H 5
6
6 5
S
S
II
O
O
III
For IIIA Ar = C6H5-
For IIIB Ar = p-(CH3)2NC6H4-
Ar
H
Scheme 1
The aqueous phase solubility of compound IIIA and IIIB at various concentration of β -
CD have been studied by Higuchi Connors method19. Accurately weighed sample of these

A Comparative Study of the Inclusion Complexes
1032
compounds in quantities exceeding their aqueous solubility were shaken in a rotary flash
shaker at room temperature with aqueous solution of β-CD in increasing concentration in a
series of stoppered conical flasks for a period of 48 h till equilibrium is established.
The solutions were filtered through Whatman No 1 paper and were analysed in a UV-Vis
spectrophotometer at 200-400 nm range. The various values of OD at λmax have been plotted
against different concentration of β-CD. The inclusion complexes of compounds IIIA and
IIIB have been prepared as per Nayak et al32. The solutions of the synthesized compound were
prepared in required concentration (0.05 mM) and were added drop wise to previously stirred
β–CD solution. The mixture were stirred at room temperature for 48 h and filtered. Then the
contents are cooled for another 48 h in refrigerator. Finally the precipitate obtained are filtered
through G-4 crucible, washed with double distilled water and dried in air for 24 h.
The thermodynamic stability constant (KT) at room temperature of the inclusion complexes
have been calculated using Benesi-Hilderbrand relation20. The stability constant K (during
deencapsulation) of the complexes are calculated with increasing temperature. The slope of the
linear plot of ln K against 1/T gives rise to the calculation of ∆H (change in enthalpy) and then
∆S (change in entropy) was calculated using the integrated form of the van’t-Hoff equation.
ln K = (-∆H/RT) + ∆S/R
The value of ∆G was calculated from the value of KT at 298 K using the equation
∆G= -RT ln KT
The antibacterial and antifungal properties of compounds (IIIA and IIIB) and their inclusion
complexes with β-CD have been studied as per Cappuccino21 and Cooper22-23 respectively.
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.The elemental composition nearly matches with theoretical data. The
Infrared data of C=Ostr at 1689.73, C=CHArstr at 1639.38. C-N at 1294.15, N-HC-Sstrat 3049.25 etc
suggest formation of compound IIIA. The Infrared data of C=Ostr at 1685.52, C=CHArstr at
1635.37, C-N at 1319.22, N-HC-Sstr at 3323.12 etc. suggests formation of compound IIIB. In
addition, both compounds IIIA and IIIB differ significantly in their melting points (Table 1).
Table 1. Analytical data of compound (IIIA & IIIB) and their inclusion complex with β-cyclodextrin
No
M.P
oC
Elemental Analysis
Found(calculated)%
λ max
nm
IR(KBr)
cm-1
Compound
C
H
N
O/S
203 71.48 4.12 3.6 20.8 261 1689.53(C=O),cyclic
1
Compound IIIA
(71.2) (4.3) (3.4) (21.1)
1639.38(C=CHAr)
1294.15(C-N)
3049.25((N-CH-S)
259 1676.03(C=O),cyclic
1629.74(C=CHAr)
3047.32(N-CH-S)
2
3
Inclusion complex of
compound IIIA with
β-cyclodextrin
212
-
-
-
-
Compound IIIB
204 71.538 5.0 8.07 15.392 353 1685.52(C=O),cyclic
(71.1) (5.13) (7.9) (15.87)
1635.37(C=CHAr)
1319.22(C-N)
3323.12((N-CH-S)
351 1668.53 (C=O),cyclic
1627.75(C=CHAr)
1317.22(C-N)
4
Inclusion complex of
compound IIIB with
β-cyclodextrin
213
-
-
-
-
3309.62(N-CH-S)

1033
S. PANDA et al.
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 2030 and 2120 C respectively. The
melting point of IIIB and its inclusion complex are 2040 and 2140 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 tool24. 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 molecules25.
Wavelength, nm
Figure 1.1. Comparison of UV spectra of IIIA (lower curve) and its inclusion complex
(upper curve)
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 complexes26 is 1:1.

A Comparative Study of the Inclusion Complexes
1034
Wavelength, nm
Figure 1.2. Comparison of UV spectra IIIB (lower curve) and its inclusion complex (upper
curve)
1.4
0.95
1.35
0.9
1.3
0.85
1.25
0.8
1.2
0.75
1.15
0.7
1.1
0.65
1.05
0.6
1
0
0.02 0.04 0.06 0.08
C (mM)
0
50
100
150
1/C
Inclusion complex of compound IIIA
Inclusion complex of compound IIIB
Inclusion complex of compound IIIA
Inclusion complex of compound IIIB
Figure 2. Phase solubility plot of compound
IIIA and IIIB
Figure 3. Plot of absorbance-1 vs. 1/[β-CD]0
of compound IIIA and IIIB
The thermodynamic stability constants (KT) of inclusion complexes are determined by
following Benesi-Hilderbrand reaction:
1/∆A=1/∆Є +1/K[guest]0 ∆Є .1/[β-CD]0
Where ∆A is change in absorbance [guest]0 is concentration of compound in
inclusion complex and [β-CD]0 is molar concentration of β-CD
A good linear correlation (Figure 3) is obtained for a plot of 1/∆A verses [1/β-CD]0 for
compounds IIIA and IIIB. The values of KT for the complexes are calculated using the relation:
KT =Intercept/Slope

1035
S. PANDA et al.
The KT 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 KT 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 complexes27.
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 process28,29. 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 KT at 298 K, ∆G, ∆S and ∆H
have been calculated (Table 2)
0.275
0.27
0.265
0.26
0.255
0.25
0.0033
0.00335
0.0034
0.00345
1/T
Inclusion complex of compound IIIA
"Inclusion complex of compound IIIB
Figure 4. Plot of ln K vs. 1/Temperature of compound IIIA and IIIB
Table 2. Thermodynamical data of inclusion complex of compound (IIIA and IIIB) at 298 K
K, M-1
No
Compound
∆G,
kJ/mol
-15.5086
∆H,
kJ/mol
∆S,
kJ/mol
1
Inclusion complex of IIIA
with β-cyclodextrin
Inclusion complex IIIB with
522.42
396.5
-0.725
-0.725
0.05199
2
-14.84
-0.00025
β-cyclodextrin
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 earlier30-32. 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

A Comparative Study of the Inclusion Complexes
1036
attributed to enhanced solubility of the drug. As the solubility increases, the drug becomes
more bioacccessibile to specific tissues leading to increased drug activity.
Table 3. Pharmacological data of compound (IIIA and IIIB) and their inclusion complex
and their inclusion complex with β-cyclodextrin
Antibacterial activity,
Antifungal activity
Conc.
µgm/mL
Zone of Inhibition of
Pencilinium Notatum
(Diameter), mm
No
Compound
Zone of Inhibition of
E.Coli (Diameter), mm
1
2
Compound IIIA
Inclusion complex of
compound IIIA With β-
cyclodextrin
0.05
0.05
9
12
7
14
3
4
Compound IIIB
0.05
0.05
10
13
11
19
Inclusion complex of
compound IIIB with β-
cyclodextrin
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.
Acknowledgement
The authors acknowledge the Principal, Institute of Pharmacy and Technology, Salepur
(Orissa) for providing laboratory facilities.
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