INTRODUCTION:

The medicinal chemists have the objective of producing drug molecules having substantial therapeutic values with possessing good results. During last few decades with the significant growth of heterocyclic and pharmaceutical chemistry leads to development of many privileged structures with proven utility in medicines. The introductions of heterocyclic moieties found in the molecules have advantage in drug discovery and development on account of its extensive range of biological activities. The study of five member heterocyclic compounds is an interesting field of research work and in this context heterocyclic compounds containing nitrogen, sulfur and oxygen acquired vast importance due to their medicinal properties.

The chemistry of thiazolidinone has been recognized as one of the major fields of study and its nucleus is excellent for development of many potent therapeutic agents^1,2. Owing to its diverse structure activity relationship of the nucleus it creates an interest for pharmacist to discovery a number of lead molecules. Most of the drug formulations are based on the nature of their liophilic cavity that provides a microenvironment where drug molecules enter and helps in the formation of inclusion complex thereby leading to solubility and stability of the drug molecule. The purpose of the study is to synthesize some complexes of 4-thiazolidinone derivatives and made their inclusion complexes with β-cyclodextrin by using co-precipitation method. Although different methods are available for the preparation of inclusion complex, but it depends mainly on the nature of included compounds^3-5. The cyclodextrin is water-soluble, non-reducing and macro cyclic polymers which have glucose units those are joined by α-1, 4 linkage. Molecules forming inclusion complex with cyclodextrin should be suitable size and shape so that it can be held with the cavity of latter. It is well known that cyclodextrin from inclusion complex with various non-steroidal anti-inflammatory drugs. 4-thiazolidinone has been exhibited different biological properties like antimicrobial^6,7, antiviral⁸, anticonvulsant^9,10, anti-inflammatory^11,12, anti-cancer and anti-tumor^13-15, antitubercular^16,¹⁷etc. As the compound does not exhibit significant solubility, hence the aim of our research to achieve a reasonable yield of solubility and bio-accessibility of it. In order to get an improvement with respect to solubility, tolerability and bioavailability of the compounds, its inclusion complex has been prepared with β-cyclodextrin which is receiving as widespread acceptance and indispensable tool. Moreover, leaving the above things some other nature of β-cyclodextrin making it so popular are their easily availability, less toxicity, and cost-effective nature^18-20. To find the best encapsulation ratios between the compound and β-cyclodextrin, solubility test of the compound is performed against various concentration of β-cyclodextrin with 4-thiazolidinone derivatives. Therefore, the present communication deals with the preparation of 2-phenyl-(3-benzothiazolyl-2’) hydrazono-5-arylidene-4-thiazolidinone and four other derivatives of it. Additionally, as a part of our research work not only compounds but also inclusion complex’s properties such as physical, thermal and spectral are evaluated. Before completion of the work antibacterial activities of compounds and inclusions are also performed.

MATERIAL AND METHODS:

Apparatus and Materials:

All the chemical reagents used in the experiment are brought from Merck and Hi media Laboratories Pvt. Limited, Mumbai, India and it belongs to analytical grade. Double distilled water used as a diluted solvent made in the laboratory. Open capillary method is used to know melting point of compounds and inclusion complexes. All the synthesized compounds of 4-thiazolidinones derivatives from 4A to 4E were analyzed by UV, IR, ¹H NMR and Per kin elemental analyzer. Shimadzu UV-1700 Spectrophotometer is taken to know electronic spectra of samples. Structures are confirmed by Shimadzu 8400 FTIR spectrometer recorded using KBr pellets,¹H NMR spectra (CDCl₃) are scanned on a DRX-300 (300MHz) spectrophotometer using TMS as internal standard and chemical shifts are measured in ppm.

Synthesis of compounds:

The compounds were synthesized as per the method describe by Garnaik et.al ²¹scheme-I

Scheme

Preparation of Schiff’s Base (Compound 2):

A mixture of the compound 1(10 m mole) and benzaldehyde (10 m mole) containing 4-6 drops of piperdine in 20 ml. ethanol was refluxed in a water bath for 4hrs. The solvent was cooled at room temperature and decompose into ice cold water. The product obtained was filtered and washed with cold water. The compound so obtained dried and recrystallized from ethanol. M.P. 218^oC, yield-2.1gm (70%).

Synthesis of 3-(Benzothiazolyl-2’) hydrazono-2-phenyl-4-thiazolidinone (Compound3):

A mixture of compound 2(1 m mole) was added with mercaptoacetic acid of (1m mole) with stirring in dry benzene(15ml). Continually stirred the mixture for 6 hrs. and refluxed for another 4hrs. The product formed was filtered, dried and recrystallized from ethanol to yield the product. M.P. 215^oC, yield-0.22 gm (68%).

Synthesis of 2-phenyl3-(Benzothiazolyl-2’) hydrazono-5-arylidene-4-thiazolidinone (Compound-4A):

A mixture of compound 3(1m mole), benzaldehyde (1m mole) and a pinch of anhydrous sodium acetate in glacial acetic acid of 10 ml. was refluxed for 4 hrs. The complete mixture is taken into cool condition and poured into cold water. The product thus separated was filtered, washed with water, dried and recrystallized from ethanol. M.P.210^oC, yield-0.24 gm (60%). Above systematic procedure is used to prepare compound 4A, similarly compound 4B is prepared by adopting same method but using p-anisaldehyde instead of benzaldehyde in the last step. On the same way compound 4C, 4D and 4E can be prepared by using different aldehydes in the first and last step respectively.

Compound 4A; 2-Phenyl 3-(Benzothiazolyl-2’) hydrazono- 5-arylidene-4-thiazolidinone

Compound 4B; 2-Phenyl 3-(Benzothiazolyl-2’) hydrazono- 5-p-anisilidiene-4-thiazolidinone

Compound 4C: 2-o-Chloro phenyl 3-(Benzothiazolyl-2’) hydrazono-5-arylidene-4-thiazolidinone

Compound 4D: 2-o-Chloro phenyl 3-(Benzothiazolyl-2’) hydrazono- 5-p-anisilidiene-4-thiazolidinone

Compound 4E: 2-p-Anisilidienyl 3-(benzothiazolyl-2’) hydrazono-5-p-anisilidiene-4-thiazolidinone

Aqueous phase solubility study:

The phase solubility study of derivatives of 4-Thiazolidinone compounds with β- cyclodextrin can be carried by following Hugucchi connors method²². Appropriate amount of 4-thiazolidinone derivative compounds was added with various concentration of β-cyclodextrin (0.1mM to 0.7mM) in a series of stopper conical flask. It has been shaken completely for two day and two nights on a rotary flask shaker until it attaining the point of equilibrium. The whole process has to be worked out at room temperature. The suspension were filtrated through whatmann filter paper and analyzed by UV visible spectrometer. Finally, absorbance values of λ_max were plotted against various conc. of β-cyclodextrin as shown in the figure1.

Synthesis of Inclusion complexes:

The set of compounds of 4-Thiazolidinone derivatives make inclusion complexes with β-CD by using co-precipitation method^23-26. As per the method, appropriate concentration of the solution of these compounds was added drop wise with β-cyclodextrin solution of required concentration. The solution obtained by mixing both the above is stirred for 48 hrs. and then filtered. The filtrate is cooled in refrigerator for 48 hrs. Cooling of the filtrate has to be kept in a refrigerator for 48hrs. The precipitate obtained were filtrated, washed with water and dried in open space for a complete day and night.

Evaluation of Antibacterial activity:

The antibacterial activities of original substances and their corresponding inclusion complex have been performed by using cup plate method²⁷. According to the method, Dimethyl sulphoxide (DMSO) with strength of 500μg/ml were taken and solution of compounds as well as inclusion has been prepared with same concentration. Then two bacteria E.coli and S.aureus were inoculated into 100ml of the sterile nutrient broth. Further, it has been incubated at a temperature of approximately 37⁰ C for 24 hours. The density of bacterial suspension was standardized by Mac Farland method. Standardized diameter of agar plates were used to inoculate them one after other with the test organisms aseptically. Micropipette is used to take the drug test solutions in a plate and then the plates were kept inside the refrigerator for 2 hours with a temperature maintaining at the range of 8-10 °C for right dispersal of drug into the media. Then transferred the Petri plates into incubator with a temperature of nearly 38⁰C for 22 hours. The results obtained by comparing inhibition zone of test compounds with standard drug (Tetracycline). The zone of inhibition can be found by using venire scale in the Petri plates and data is presented in table 3.

RESULTS AND DISCUSSION:

The five derivatives of 4-thiazolidinone compounds 4A, 4B, 4C, 4D and 4E are synthesized in their own state in pure crystalline form. With the help of β-cyclodextrin also their respective inclusion complex are prepared as usual way as described in the procedure. The change in their physical and spectral characters acknowledges the formation of inclusion complex. There is an increase in melting point of inclusion complexes as compared to the original compounds and this is due to extra heat energy is required for encapsulation from the β-cyclodextrin cavity as given in table 1.

On comparing the spectral nature between compounds and inclusion complexes, it is found to be varied and this happens due to some change in inclusion complexes. Spectral values of UV, IR and ¹H NMR of compounds and their inclusion complexes are absorbed in suitable frequency. In case of UV data, it is found that inclusion complexes are absorbed some higher frequency than the parent compound. Deviation of spectral characters of compounds with their respective inclusion complexes are given in the table 2. In case of IR data of compound 4A, it is seen that the IR frequencies are found to be formed at C-S_str 744.52 cm^-1,C-N_str at 1444.68 cm^-1,C=C_Strat 1510.26 cm^-1,C=C_strat 1625.99 cm^-1,C=O_str at 1728.32 cm^-1, Ar-H_strat 3082 cm^-1. similarly, the IR data of inclusion complexes of compound 4A show characteristics of absorption at C-S_str at 752.24 cm^-1,N-CS_str at 937.40 cm^-1, C=C_str at 1442.75 cm^-1, C=C_aroat 1612.49 cm^-1, C=O_strat1658.78 cm^-1, Ar-H_str at 2920.23 cm^-1,N-H_str at 3267.41 cm^-1. The IR data of other respective compounds and their inclusions are found to be absorbed with the proper characteristic frequency. IR frequencies of inclusion complexes changed from that of the compounds after its formation and these changes takes place due to transference of compounds into the cavity of β-cyclodextrin. These changes also accounts due to creation of weak forces such as H-bonding, van der Waals forces, hydrophobic interactions in between the two combing species i.e. host and guest molecules^28-30. Besides this, there is also change in δ values of the inclusion complexes with respect to their original compounds. This signifies shifting of PMR signals due to formation of inclusion complex which happens due to encapsulation induced shielding within the cavity of β-cyclodextrin. The inclusion complex formation makes shifting of PMR signals which happens due to encapsulation induced shielding within the cavity of β-cyclodextrin. The comparison between the δ values of compounds and their inclusion complexes revealed that the δ values of PMR signals of compounds and inclusion has been found to be varied from one compound to other.

Table 1: Physical properties of compounds and their inclusion

Compound/ Complex	Molecular Formula	COLOUR	M.P. in ^◦C	% of yield	Elemental Analysis
					Calculated (Found)
					C H N
Compound 4A	C₂₃H₁₈N₃OS₂	Yellow	170	60	66.48 04.12 10.11 (66.38) (04.02) (10.00)
Compound 4A with β-CD		Yellowish white	182	45
Compound 4B	C₂₄H₂₀N₃O₂S₂	Pale Yellow	175	62	64.69 4.29 4.43 (64.49) (4.09) (4.13)
Compound 4B with β-CD		Yellowish white	183	40
Compound 4C	C₂₃H₁₇N₃OS₂Cl	Brown	225	63	61.39 3.58 9.93 (61.25) (3.35) (9.13)
Compound 4C with β-CD		Brownish white	229	48
Compound –4D	C₂₄H₁₉N₃O₂S₂Cl	Light Brown	232	55	60.05 3.77 8.75 (60.00) (3.67) (8.63)
Compound 4D with β-CD		Reddish white	237	40
Compound 4E	C₂₅H₂₂N₃O₃S₂	Pale red	180	60	63.14 4.45 8.83 (63.02) (4.34) (8.73)
Compound 4E with β-CD		Reddish white	187	45

Table 2: Spectral data of synthesized compounds and their inclusions

Compound/ Inclusion complex	UV_λmax	IR(KBr) cm^-1	¹H NMR
Compound/ Inclusion complex	UV_λmax	IR(KBr) cm^-1	¹H NMR
Compound –4A	298	744.52(CSstr),1166.93,1444.68(C-Nstr)1510.26(C=C Str), 1625.99(C=Cstr), 1728.22(C=Ostr), 3082.25,2916.37(Ar-Hstr)	¹H NMR (CDCl₃) : d 6.93-8.02 (d, 6H, Ar-H), 4.02(s,1H,C-NH),7.56(s,1H,C-H),7.31-7.68 (t,8H, Ar-H)
Compound-4A with β-CD	285	752.24(C-Sstr),937.40(N-C-Sstr)1442.75 (C=Cstr), 1612.49(C=C aro),1658.78 (C=Ostr),2920.23(Ar-H str),3267.41(N-H str)	¹H NMR (CDCl₃): d 6.94-8.01 (d, 6H, Ar-H), 3.87 (s,1H,C-NH),7.15(s,1H,C-H),6.96-7.96 (t,8H, Ar-H)
Compound –4B	278	744.52(C-Sstr),894.97(C Nstr)1573.91(C=C Str), 1691.57(C=Nstr),2916.37(Ar-Hstr) 1759.08(C=O str),3360.00(N-H str)	¹H NMR (CDCl₃) : d 6.96-8.01 (d, 6H, Ar-H), 3.87(s,1H,C-NH),7.70(s,1H,C-H),7.18-7.70 (t,8H, Ar-H)
Compound -4Bwith β-CD	267	738.74(C-Sstr),943.19(N-C Sstr),1251.80(C Nstr), 1510.26(C=CStr),1610.20(C=Nstr), 3174.83(N-H str	¹H NMR (CDCl₃): d 6.93 -7.67 (d, 6H, Ar-H), 3.9 (s,1H,C-NH),7.28(s,1H,C-H),6.96-7.39 (t,8H, Ar-H)
Comp –4C	277	655.80(C-Clstr),738.74(C-Sstr),1367.53(C-Nstr), 1573.91,1510.26(C=CStr),1610.56(C=Nstr),1658.78(C=Ostr),3190.26(N-H str)	¹H NMR (CDCl₃) : d 7.26-8.25 (d, 6H, Ar-H), 4.62(s,1H,C-NH),7.50(s,1H,C-H),7.3-7.8 (t,8H, Ar-H)
Comp –4C with β-CD	267	705.95(C-Clstr),734.88(C-Sstr),939.33(N-C Sstr), 1321.24(CNstr),1512.19(C=CStr),1610.56(C=Nstr),3217.27(N-Hstr)	¹H NMR (CDCl₃): d 7.21-8.03 (d, 6H, Ar-H), 3.59 (s,1H,C-NH),7.28(s,1H,C-H)
Comp –4D	273	659.66(C-Clstr),705.96(C-S str),1321.26(C-Nstr), 1510.26(C=CStr),1610.56(C=Nstr),2929.87(Ar-Hstr),3224.89(N-H str)	¹H NMR (CDCl₃): d 7.18-8.45 (d, 6H, Ar-H), 3.86 (s,1H,C-NH),7.32(s,1H,C-H),6.94-8.08 (t,8H, Ar-H)3.86 (s,3H,OCH₃)
Comp4D-with β-CD	265	674.01(C-Clstr),736.31(C-Sstr),945.12(N-C-Sstr), 1510.26(C=CStr),1610.56(C=Nstr),1658.78(C=Ostr),2929.87(Ar-Hstr),3201.83(N-H str)	¹H NMR (CDCl₃):d 7.18-8.44 (d, 6H, Ar-H),3.87 (s,1H,C-NH),7.28(s,1H,CH),6.69-7.71 (t,8H, Ar-H)3.87 (s,3H,OCH₃)
Compound –4E	297	692.44(C-Clstr),746.45(C-S str),1489.05(C=CStr), 1539.20(C=Nstr),1714.72(C=Ostr),3030.17(ArHstr),3325.28,3194.12(N-H str)	¹H NMR (CDCl₃) : d 6.89-8.18 (d, 5H, Ar-H), 4.0(s,1H,C-NH),7.60(s,1H,C-H),7.30-7.63 (t,8H, Ar-H)
Compound 4E with β-CD	299	748.38(CSstr),1425.40(C=Nstr),1494.83(C=CStr),1593.20(C=Nstr),1712.97(C=O),3062.96(Ar-HStr	¹H NMR (CDCl₃) : d 6.93-7.97 (d, 5H, Ar-H), 4.1(s,1H,C-NH),7.63(s,1H,C-H),7.34-7.61 (t,8H, Ar-H)

The thermodynamic stability constants of inclusion complexes can be determined by using Benesi-Hilderband relation³¹. The relation is 1/ΔA = 1/ ΔЄ + 1/ K_T [Guest] oΔЄ. [β-CD]_o. Where ΔA is change in absorbance, ΔЄ is change in molar extension coefficient, [Guest]_o is concentration of compound in inclusion complex and [β-CD]_o is concentration of β-CD. A plot of 1/ΔA verses [β- CD]_owere drawn where good linear correlations were obtained for compounds obtained as shown in figure.2. Using the relation K_T = Intercept/Slope, K_T values for all the complexes were found. The K_T values of inclusion complexes of compounds 4A, 4B, 4C, 4D and 4E were calculated as 773.76, 839.09, 802.21, 894.17 and 165.00 M^-1 respectively as given in Table-3. It is found to be remained in the range of 100 to 1000 M^-1indicating considerable stabilities for the inclusion complexes by the way of host-guest interaction like vander Waal’s force, hydrophobic interaction etc.^28-30. The free energy of activation of five different compounds is obtained as -14.791, -15.349, -15.028, -15.881 and -11.652 kJ/mole as given in Table-3. ∆G⁰ is the change in Gibb’s free energy and it is the standards to do some useful work. The reaction will become favourable with negative value of ∆G⁰. By using the equation at 298 K, ΔG = -2.303RT log K, free energy of inclusion complex is determined. There is thermodynamic acceptability of inclusion complex formation because free energy change is –ve value.

Table 3: Equilibrium constant and free energy change of inclusion complexes

SI. No	Inclusion complex of Compound	Equilibrium Constant (K_T)	∆G(kJ/mole)
1	4A	773.76	-14.791
2	4B	839.04	-15.349
3	4C	802.21	-15.028
4	4D	894.17	-15.881
5	4E	165.00	-11.652

Figure 1: Variation of absorption with concentration

Figure 2: Variation of 1/ absorption with 1/concentration

From the antibacterial studies against two selected bacterial strains like E. coli, S. aureus, it’s found that the diameter of the zone of inhibition of inclusion complexes noticeably high as compared to the compounds against which it’s tested as shown in Figure 3 and 4. Among the tested substances the inclusion complex of compound 4C exhibited maximum activity against E. coli than that of other complexes whereas compound 4A shows maximum activity towards S.aureus with relevance to other complexes. The noticeable improvement of antibacterial activity of the inclusion complexes on account of more solubility of compounds within the aqueous medium that creating them more bio-accessible and effective towards specific tissues as a result which efficiency of drug increased.

Table 4: Antibacterial studies of the compounds and their inclusion complexes

Sl. No.	Compounds/complexes	Diameter of zone of inhibition (mm)
Sl. No.	Compounds/complexes	*E. coli*	*S.aureus*
1.	Compound 4A	11	9
2.	Inclusion complex of comp. 4A	13	11
3.	Compound 4B	10	10
4.	Inclusion complex of comp. 4B	12	11
5.	Compound 4C	09	12
6.	Inclusion complex of comp. 4C	12	14
7	Compound 4D	10	11
8	Inclusion complex of comp. 4D	13	13
9	Compound 4E	10	12
10	Inclusion complex of comp. 4E	11	14
11	Control	-	-
12	Standard	28	27

Figure 3: Antibacterial activity of the test substances against E.Coli

Figure 4: Antibacterial activity of the test substances against S.aureus

CONCLUSION:

This work involved with preparation some of the compounds of 4-thiazolidinone and their inclusion complex with β-cyclodextrin and characterized by their spectral, thermal and antibacterial nature. Proper molecular interactions have leaded the formation of complex which is found to point out more active nature than the original compounds. Complex formation with β-cyclodextrin is an excellent process to get better aqueous dissolution of inadequately water-soluble drugs. Thus, inclusion complexes show more bio-accessibility of the drug as a result of which it minimizes drug doses and its related ill effect.

ACKNOWLEDGEMENT:

The author thankful to Dr. Gyanaranjan Panda, professor in Roland Institute of Pharmaceutical Science for helping study of antibacterial activities of compounds and inclusions. The author is also thankful to principal and management of Roland Institute of Technology for encouraging research work.

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Received on 27.12.2021 Modified on 03.01.2022

Asian J. Research Chem. 2022; 15(1):65-70.

DOI: 10.52711/0974-4150.2022.00010