Anti-inflammatory and Analgesic Studies of 2-aryl-3-(5-alkyl-1, 3, 4-thiadiazol-2-yl) 4-thiazolidinones

 

Sunil Kumar*, Sandeep Jain

Drug Discovery and Research Laboratory, Department of Pharmaceutical Sciences,

Guru Jambheshwar University of Science and Technology, Hisar (Haryana), India.

 

ABSTRACT:

Any damage and bad stimulus causes pain and inflammation. The compound used for pain is known as analgesic and for inflammation is known as anti-inflammatory. The title compounds were evaluated for analgesic activity using Tail-Flick method and anti-inflammatory activity using Carrgenan Induced Rat Paw Edema. Diclofenac Sodium used as standard drug. The chloro, fluro and nitro containg derivatives showed best activity as compared to methyl, methoxy and hydroxy derivatives.

 

 

INTRODUCTION:

The study of drugs comes under the term pharmacology which includes source, physiochemical properties, knowledge of the history, mechanism of action, distribution, absorption, biochemical and physiological effects, excretion and other uses of drugs. Two main part of pharmacology are pharmacokinetics (body response to drugs) and Pharmacodynamics (drug response to body)^{1- 2}.  Thiazolidinones belong to important groups of heterocyclic compounds.  Thiazolidinones are known as 2-thiazolidinones, 4-thiazolidinones, and 5-thiazolidinones as presence of the carbonyl group at different position such as 2, 4, and 5-position. 4-Thiazolidinones shows best biological activity as compared to other thiazolidinones³. Compounds containing thiazolidinone nucleus have been reported as anti-tuberculosis⁴, antimicrobials^5-7, anti-inflammatory^8-9. The literature survey on   analgesis and anti-infilamatry evaluation  methods showed that  various articles reported in which these activities performed on different nucleus and plant based material.^10-19

 

 

MATARIAL AND METHODS:

The title compounds were synthesized according to scheme reported in article ²⁰ and evaluated for anti-inflammatory and analgesic studies using Tail- Flic methods for analgesic and Rat Paw Edima methods for anti- inflammatory.

 

Analgesic activity:

Analgesic activity was carried out by Tail-Flic method as given below.

 

Tail-Flic method:

The analgesic activity of derivatives was carried out using Tail- Flic method. The albino Wister mice having weight 20-25g were used in this methods. The instrument used in this method is hot wire analgesiometre with a facility to control overheating. Animals were divided in control, standered and test groups (6 animals in each ) and tail flick response were observed six times before introducing drugs to animals and mean of that  known as predrugs response time. By maintaining the current that 90% of animals give response in 3-5sec known as normal reaction time. The test compounds and drug is suspending in to tween 80(1% in distilled water).The standered drug (Diclofenac Sodium) dose is 0.016 mM/kg body weight and test dose is 0.064 mM/kg is given orally.In control group only vehicle is introduced and response were observed at different time intervals (1, 2, 3, and 4hr).^21-22

 

Percentage analgesic activity was calculated by using the formula.

 

PAA = (K₁-K₂) / K₁ X 100

 

K₁ is reaction time (in second) before drug admintration and K₂ after drugs administration and analyzed by one –way ANOVA followed by Tukey’s post-hoc test and statistically significance( P) was determined.The P value for all the compounds was less than 0.001.  The results are shown in Table 1.

 

Anti-inflammatory activity:

The hind paw edema method is used for the determination of  anti-inflammatory activity in Albino Wister rats using carrageen as a phologistic agent.

 

Carrageenan–Induced Rat Paw Edema:

Winter, et al described method is used and according to the methods Albino rats of the Wister strain were used. These having the weight of 120 –150g.Any of sex can be used. These were divided into control, test, and standard groups containing six animals each.The Animals were put on 12 h fast only water is allowed before the experiment. The standard compound and test were suspended in solution (tween 80, 1% w/v, in distilled water) and administered orally through gastric gavage needle to each animal. Only vehicle is given to the control group animals. Carrageenan was injected after  one hour of administration of the compounds  into right hind paw the (subplantar surface) of the of animals. In this study, the animals were administered a 0.064mM /kg (body weight) dose of the test drugs and 0.016mM/ kg (body weight) dose of the standard drug Diclofenac Sodium. The paw volume was measured immediately using a digital caliper (Yamayo). After that the paw volume was also measured after the administration of carrageenan at 1, 2, 3 and 4 hr.^23-24.

 

The percentage inhibition of the inflammation was calculated by the following formula.

 

% inhibition = (Vc-Vt) / Vc X 100

 

Where Vc and Vt are the mean relative changes in the volume of paw edema in the control and test respectively. Data was analyzed by one-way ANOVA followed by Tukey’s post-hoc test and statistically significance was denoted as P value. The P value for all the compounds was less than 0.001. The results are shown in table 2.

 

Table 1: Percentage analgesic activity of 2-aryl -3-(5-alkyl-1, 3, 4-thiadiazole-2-yl) thiazolidin-4-ones

Sr. No.	R	R1	Mean ± SD
			1 Hr	2 Hr.	3 Hr.	4Hr.
1	CH3	H	3.12   ± 0.23	4.79 ± 0.08	9.37 ± 0.51	33.54 ± 0.57
2	CH3	CH3	3.57   ± 0.30	5.88 ± 0.10	9.66 ± 0.39	34.24 ± 0.51
3	CH3	OH	4.88   ± 0.32	7.21 ± 0.08	10.61± 0.39	35.45 ± 0.51
4	CH3	OCH3	2.92   ± 0.35	4.81 ± 0.29	8.57  ± 0.14	32.84 ± 0.53
5	CH3	Cl	11.80 ± 0.24	24.67 ± 0.75	54.29 ± 0.09	76.82 ± 0.19
6	CH3	Br	9.26   ± 0.44	22.62 ± 0.65	53.01 ± 0.09	73.70 ± 0.49
7	CH3	F	13.17 ± 0.60	26.34 ± 0.73	58.53 ± 0.35	80.12 ± 0.51
8	CH3	NO2	9.87   ± 0.51	22.68 ± 0.52	53.99 ± 0.34	79.26 ± 0.51
9	CH2CH3	H	2.91  ± 0.28	5.33 ± 0.10	9.37  ± 0.42	33.75 ± 0.49
10	CH2CH3	CH3	2.70  ± 0.32	4.79 ± 0.32	8.95 ± 0.57	33.12 ± 0.69
11	CH2CH3	OH	6.42   ± 0.36	11.77 ± 0.47	18.84 ± 0.43	37.68 ± 0.44
12	CH2CH3	OCH3	4.00  ± 0.37	9.47  ± 0.39	12.84 ± 0.49	34.73 ± 0.45
13	CH2CH3	Cl	7.66  ± 0.19	20.08 ± 0.52	47.61 ± 0.53	69.77 ± 0.53
14	CH2CH3	Br	6.73  ±0.32	17.47 ±0.95	47.57± 0.10	69.05 ± 0.40
15	CH2CH3	F	6.98  ±0.12	17.45 ±0.53	49.48± 0.35	70.43 ± 0.56
16	CH2CH3	NO2	8.26  ±1.27	20.76 ±0.34	52.11± 0.29	74.15 ± 0.18
17	(CH2)2CH3	H	2.93  ±0.20	6.49  ±0.49	10.27± 0.40	34.17 ± 0.60
18	(CH2)2CH3	CH3	2.52  ±0.73	6.31  ±0.66	9.47  ± 0.41	34.10 ± 0.56
19	(CH2)2CH3	OH	7.11  ±0.61	8.78  ± 0.49	15.89± 0.40	33.68 ± 0.46
20	(CH2)2CH3	OCH3	2.62  ±0.20	4.24 ± 0.19	10.70± 0.40	27.27 ± 0.55
21	CH2CH2CH3	Cl	9.07  ±0.43	21.51 ±0.61	50.21± 0.31	72.78 ± 0.19
22	CH2CH2CH3	Br	11.77 ±0.51	23.33 ±0.60	57.11± 0.31	77.77 ± 0.14
23	CH2CH2CH3	F	11.08 ±0.80	25.43 ±0.77	56.08± 0.07	79.34 ± 0.35
24	CH2CH2CH3	NO2	12.11 ±0.20	29.51 ±0.49	57.48± 0.15	79.29 ± 0.31
Drug			11.58 ±0.23	42.91 ±0.51	64.80± 0.53	100.21± 0.81
Control			0.21± 0.40	0.63 ±0.54	0.21 ± 0.81	0.42 ± 0.81

P > 0.001, Standard drug: Diclofenac sodium

 

Table 2: Percentage inhibition of Anti-inflammatory activity of 2-aryl -3-(5-alkyl-1, 3, 4-thiadiazole-2-yl) thiazolidin- 4 ones.

Sr. No.	R	R1	Mean ± SD
			1 Hr	2 Hr.	3 Hr.	4Hr.
1	CH3	H	1.18   ± 0.23	9.23  ± 0.08	4.55 ± 0.51	15.62  ± 0.57
2	CH3	CH3	1.08   ± 0.30	8.46  ± 0.10	3.23 ± 0.39	14.9 2 ± 0.51
3	CH3	OH	1.63   ± 0.32	8.92  ± 0.08	3.96 ± 0.39	15.06 ± 0.51
4	CH3	OCH3	0.54   ± 0.35	6.15  ± 0.29	3.08  ± 0.14	13.66  ± 0.53
5	CH3	Cl	3.08  ± 0.24	12.15  ± 0.75	8.66 ± 0.09	24.26  ± 0.19
6	CH3	Br	2.54   ± 0.44	10.76 ± 0.65	7.78 ± 0.09	23.29  ± 0.49
7	CH3	F	3.81 ± 0.60	12.76  ± 0.73	8.95 ± 0.35	23.80  ± 0.51
8	CH3	NO2	3.62    ± 0.51	11.69  ± 0.52	8.37 ± 0.34	23.57  ± 0.51
9	CH2CH3	H	2.17 ± 0.28	8.92  ± 0.10	3.81  ± 0.42	15.34  ± 0.49
10	CH2CH3	CH3	0.54  ± 0.32	8.30 ± 0.32	3.08 ± 0.57	14.22  ± 0.69
11	CH2CH3	OH	1.45   ± 0.36	8.76  ± 0.47	3.67 ± 0.43	13.94  ± 0.44
12	CH2CH3	OCH3	0.36  ± 0.37	5.69  ± 0.39	2.64 ± 0.49	13.52 ± 0.45
13	CH2CH3	Cl	2.72  ± 0.19	11.69 ± 0.52	8.51 ± 0.53	23.98 ± 0.53
14	CH2CH3	Br	1.99  ± 0.32	10.30  ± 0.95	7.63 ± 0.10	22.59 ± 0.40
15	CH2CH3	F	3.26  ± 0.12	12.46  ± 0.53	7.92 ± 0.35	23.01 ± 0.56
16	CH2CH3	NO2	3.08  ± 1.27	11.38  ± 0.34	8.22 ± 0.29	23.01 ± 0.18
17	(CH2)2CH3	H	1.99  ± 0.20	9.07  ± 0.49	4.69 ± 0.40	15.48 ± 0.60
18	(CH2)2CH3	CH3	0.36  ± 0.73	8.15  ± 0.66	3.37  ±  0.41	14.08 ± 0.56
19	(CH2)2CH3	OH	0.90  ± 0.61	8.61 ± 0.49	4.11 ± 0.40	13.94 ± 0.46
20	(CH2)2CH3	OCH3	0.72  ± 0.20	5.38  ± 0.19	2.49 ± 0.40	13.38 ± 0.55
21	CH2CH2CH3	Cl	2.17  ± 0.43	11.53 ± 0.61	8.22 ± 0.31	23.84 ± 0.19
22	CH2CH2CH3	Br	1.81 ± 0.51	10  ±  0.60	7.19 ± 0.31	21.89 ± 0.14
23	CH2CH2CH3	F	3.08 ± 0.80	12.30  ± 0.77	7.63 ± 0.07	23.15 ± 0.35
24	CH2CH2CH3	NO2	2.72  ± 0.20	10.92  ± 0.49	7.92 ± 0.15	23.01 ± 0.31
Drug			9.25  ± 0.23	19.23  ± 0.51	18.50  ± 0.53	29.98 ± 0.81

P < 0.001, Standard drug: Diclofenac sodium

 

 

RESULTS AND DISCUSSION:

The analgesic activity of the synthesized compounds was evaluated by using tail flick method in albino Wister mice (20-25g) of either sex. The anti-inflammatory activity of the synthesized compounds was evaluated by the method Carrageenan–Induced Rat Paw Edema in albino Wister rats. Diclofenac sodium is used as standared drug.

 

The percentage analgesic activity of title compounds are reported in Tables 1. The percentage inhibition of Anti-inflammatory activity results of title compounds are given in Table 2.

 

The derivatives containing nitro and fluoro group at para position of phenyl ring exhibeted better analgesic activity as compared to other compounds probably. The chloro derivatives more active than bromo derivatives The methyl, hydroxyl and methoxy groups are electron releasing groups which have modrate to weak activites. The order of activity is F > NO₂ >Cl > Br > H > CH₃> OH > OCH_3.

 

CONCLUSION:

The work describes anti-infilammtory and analgesic studies of   2-aryl-3-(5-alkyle -1, 3, 4-thiadiazol-2-yl) thiazolidin-4-ones using Carrageenan–Induced Rat Paw Edema method and Tail Flic method respectively. The results of anti-inflammatory and analgesic showed that compounds containing fluro, nitro and chloro groups were found to be more active than the compounds containing methoxy, hydroxyl and methyl.

 

ACKNOWLEDGEMENTS:

The authors are thankful to Department of Pharmaceutical Sciences and Central Instrument Laboratory, Guru Jambheshwar University of Science and Technology, Hisar (Haryana) India for providing necessary facilities to carry out this work and spectral analysis respectively.

 

CONFLICT OF INTEREST:

No.

 

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Accepted on 06.08.2022           © RJPT All right reserved

Research J. Pharm. and Tech 2022; 15(12):5555-5558.