INTRODUCTION:

Several five membered aromatic systems having three hetero atoms at symmetrical position have been studied because of their interesting physiological properties. The derivatives of 1, 3, 4-thiadiazole was known to possess various pharmacological activities like anti-inflammatory^1-4, analgesic^5-6 , antimicrobial^7-11, anti-tubercular^12-13, anti-convulsant¹⁴ activities. Other activities that are reporting in thiadiazole containing drugs include diuretic¹⁵ , anthelmintic¹⁶ activities. 2-amino-1, 3, 4-thiadiazole are also used as antitumour, antiplatelet drugs and their acetazolamide derivatives show diuretic activity. Some of their derivatives used as carbonic anhydrase inhibitors and antiparkinsonian agents. The derivatives showed considerable promise as remedies for infection in the gastrointestinal tract. 1, 3, 4-thiadiazoles are also used as pesticidal, herbicidal, amoebicidal, CNS depressant, and antiviral.

The derivatives of 1, 3, 4-thiadiazoles are active against a panel of 3 cell line i.e. lung, breast and CNS cancer. They also showed good cytotoxicity against SI leukaemia and SF-268 CNS cancer. 2-5-Dimercapto- 1, 3, 4-thiadiazoles such as corrosion inhibition, vulcanization acceleration, prevention of sunburn and darkening of photographic developers are recorded in the patient literature.

The derivatives of 1,3,4-thiadiazoles were tested for their cytotoxic potential using A549 (lung adrenocarcinoma) cells in the presence of fetal bovine serum.

1, 3, 4-thiadiazoles also showing mild antihistaminic activity. N-[5-(amino- sulphonyl)-1,3,4-thiadiazole- 2-yl] acetamide is effective in the control of fluid secretion (glaucoma), in the treatment of convulsive disorder (epilepsy) and in the promotion of diuresis in the instances of abnormal fluid retention (cardiac oedema).

In view of the above mentioned fact we synthesized biologically important heterocyclic compounds. We are describing synthesis of Schiff bases of 1, 3, 4-thiadiazoles derivatives and evaluation of their analgesic, anti-inflammatory and antibacterial activity. Their synthesis are outlined in scheme 1. The structures of the compounds were established on the basis of their IR and ¹H NMR spectral data.

MATERIALS AND METHODS

Melting points were determined in open capillary tubes. Purity of the compounds were checked by TLC (Thin layer Chromatography) on silica gel plates and spots were visualized by exposure to iodine vapours. IR spectra (KBr, cm-¹) were recorded on Perkins Elmer Infrared-283 FTIR. ¹H NMR (CDCl3) on a Bruker 300MHz spectrometer using TMS as an internal reference (chemical shift in d ppm).

Table 1. Characterization data of Compounds

Comp.	R	R’	Mol. Formula	M.P. (°C)	Yield %	N % Found	S % Found
4A	OCH₃	OH	C₁₆H₁₆N₃O₂S	155	62 %	13.37	10.19
4B	OH	OH	C₁₅H₁₄N₃O₂S	214	58 %	14	10.66
4C	Cl	OH	C₁₅H₁₃N₃OSCl	188	45 %	13.20	10.06
4D	NO₂	OH	C₁₅H₁₃N₄O₃S	170	48 %	17.02	9.72
4E	N(CH₃)₂	OH	C₁₇H₁₉N₄OS	185	51 %	17.12	9.78
4F	OCH₃	NO₂	C₁₆H₁₅N₄O₃S	138	54 %	16.32	9.32
4G	OH	NO₂	C₁₅H₁₃N₄O₃S	194	38 %	17.02	9.72
4H	Cl	NO₂	C₁₅H₁₂N₄O₂SCl	205	43 %	16.13	9.22
4I	NO₂	NO₂	C₁₅H₁₂N₅O₄S	148	54 %	19.55	8.93
4J	N(CH₃)₂	NO₂	C₁₇H₁₈N₅O₂S	197	36 %	19.66	8.98

Synthesis of Schiff bases of 2-amino-5-aryl-1, 3, 4-thiadiazole 4(a):

A solution of 3a (0.01 м) was prepared in 20 ml alcohol in a round bottom flask. Required aldehyde (0.01 м) dissolved in 15 ml alcohol, was then added to it. The mixture was refluxed for 5-6 hr. The volume of alcohol was reduced to half by distillation under reduced pressure. The resulting solution was poured on crushed ice. The precipitate which got separated was dried and recrystallized from ethanol. 4a IR (KBr) 3385(C-H), 1157(C-C), 1691(C=N), 1567(N=C), 949 (C-S), 3201(O-H), 1096(C-O), 1674(N=O). 4a ¹H NMR (CDCl₃), δ 6.83-7.37(m, 4H, Ar-H), δ 6.8-7.4 (m, 4H, C₆H₅CH=N), δ 5.0 (s, 1H, OH), δ 8.1(s, 1H, C₆H₅CH=N), δ 3.73 (t, 3H, OCH₃). Other compounds 4(a-j) were prepared similarly and their characterization data are recorded in Table 1.

RESULTS AND DISCUSSION:

The newly synthesized compounds of Schiff bases of 2-amino-5-aryl-1, 3, 4-thiadiazole 4(a-j) were characterized by using IR, ¹H NMR spectroscopy. The physical data of the compounds prepared are presented in Table 1. The IR spectrum of the compounds 2(a-e) showed peaks at 3290-3271 cm-¹, N-H stretching; 2935-2932 cm-¹, C-C stretching; 1170-1157 cm-¹, C=N stretching; 1691-1624 cm-¹,C=S stretching; 1249-1216 cm-¹. The NMR spectrum of the compound 2a showed δ 6.8-7.5 (m, 4H, Ar-H), δ 3.73(t, 3H of OCH₃), δ 5.0 (s, 1H of OH), δ 2.85(t, 3H of CH₃), δ 2.0(t, 2H, NH₂). The IR spectrum of the compounds 3(a-e) showed peaks at 3201-3192 cm-¹, C-C stretching; 1170-1155 cm-¹, C=N stretching; 1624-1598 cm-¹, N=C stretching; 1567-1550 cm-¹, C-S stretching; 949-937 cm-¹, O-H stretching; 3385-3201cm-¹, C-O stretching; 1096-1027 cm-¹, N=O stretching; 1674-1633 cm-¹. The NMR spectrum of the compound 3a showed δ 6.79-7.31(m, 4H, Ar-H), δ 4.0(t, 2H, NH₂), δ 5.0(s, 1H, OH). The IR spectrum of the compounds 4(a-j) showed peaks at 3385-3290 cm-¹, C-C stretching; 1157-1150 cm-¹, C=N stretching; 1691-1649 cm-¹, N=C stretching; 1567-1552 cm-¹, C-S stretching; 949-937cm-¹ O-H stretching; 3521-3443 cm-¹, C-O stretching; 1096-1022 cm-¹, N=O stretching; 1674-1633 cm-¹. The NMR spectrum of the compound 4a showed δ 6.83-7.37 (m, 4H, Ar-H), δ 6.8-7.4 (m, 4H, C6H5CH=N), δ 5.0 (s, 1H, OH), δ 8.1(s, 1H, C6H5CH=N), δ 3.73 (t, 3H, OCH3) that indicated the presence of aromatic protons. The IR, ¹H NMR showing the various functional groups present in the synthesized compounds.

Analgesic activity:

The synthesized compounds were evaluated for their analgesic activity in Swiss albino mice by using hot plate method using Pentazocine as standard drug (Table-2).

Anti-inflammatory Activity:

The synthesized compounds were evaluated for their anti-inflammatory activity in Wister albino rats by Carrageenan induced paw edema method using Indomethacin as standard drug (Table-3).

Table: 2

Treatment

Group

Dose

(mg/kg)

Reaction time (sec)

15 (min)

30 (min)

45 (min)

60 (min)

90 (min)

Control (vehicle)

Pentazocine

2.0 ± 0.3

4.6 ± 0.5

2.1 ± 0.4

2.2 ± 0.4

2.3 ± 0.3

1.7 ± 0.1

2.4 ± 0.3

1.5 ± 0.2

2.5 ± 0.6

2.6 ± 0.4

2.1 ± 0.3

1.9 ± 0.5

2.6 ± 0.4

6.0 ± 0.3

3.3 ± 0.4

3.0 ± 0.3

3.47 ± 0.2

2.5 ± 0.4

3.77 ± 0.3

2.1 ± 0.1

2.2 ± 0.2

2.4 ± 0.3

2.6 ± 0.5

2.5 ± 0.6

2.3 ± 0.2

6.3 ± 0.7

4.4 ± 0.2

2.7 ± 0.2

4.32 ± 0.4

2.67 ± 0.2

3.8 ± 0.1

1.8 ± 0.3

2.4 ± 0.5

2.8 ± 0.3

3.2 ± 0.2

2.9 ± 0.8

1.7 ± 0.2

8.6 ± 0.7

3.7 ± 0.8

3.4 ± 0.3

3.22 ± 0.5

3.34 ± 0.4

3.2 ± 0.4

2.4 ± 0.5

2.7 ± 0.7

3.1 ± 0.4

3.1 ± 0.2

3.2 ± 0.1

1.3 ± 0.2

10.6 ± 0.2

3.9 ± 0.4

3.2 ± 1.7

4.9 ± 0.1

3.90 ± 0.3

3.7 ± 0.2

2.3 ± 0.1

2.9 ± 0.6

2.9 ± 0.3

2.9 ± 0.4

2.7 ± 0.2

Table: 3

Groups	Dose mg/kg	Paw diameter (mm)						% of inhibition
Groups	Dose mg/kg	0 hr	1hr	2hr	3hr	4hr	5hr	% of inhibition
Control	--	0.79±0.0423	0.925±0.0223	1.3±0.018	2.062±0.033	2.358±0.042	2.568±0.020	--
Std	10	0.810±0.014	0.978±0.012	1.10±0.011	0.978±0.014	0.952±0.011	0.951±0.06	72.55
4a	30	0.775±0.013	0.915±0.025	1.240±0.038	1.523±0.033	1.830±0.015	1.638±0.038	23
4b	30	0.801±0.012	0.925±0.014	1.095±0.022	1.19±0.09	1.395±0.013	1.330±0.042	48
4c	30	0.682±0.020	0.855±0.0150	0.922±0.011	1.252±0.034	1.401±0.038	1.502±0.042	31
4d	30	0.725±0.025	1.425±0.0485	1.655±0.032	1.757±0.089	1.548±0.0455	1.422±0.035	29
4e	30	0.621±0.032	0.952±0.0425	1.28±0.018	2.238±0.033	2.445±0.0252	2.728±0.021	14
4f	30	0.752±0.014	1.102±0.0121	1.225±0.041	1.445±0.014	1.278±0.0128	1.052±0.072	43
4g	30	0.87±0.32	1.11±0.0152	1.205±0.62	1.523±0.015	1.728±0.0128	1.875±0.045	16
4h	30	0.628±0.045	0.952±0.0548	1.221±0.035	1.542±0.012	1.667±0.0212	1.438±0.055	24
4i	30	0.722±0.082	1.208±0.0221	1.432±0.052	1.566±0.043	1.732±0.0368	1.652±0.025	20
4j	30	0.998±0.528	1.118±0.0485	1.332±0.042	1.654±0.011	1.55±0.0445	1.477±0.078	35

CONCLUSION:

A total of l0 compounds were synthesized with good yields. All synthesized compounds exhibited analgesic, anti-inflammatory activity. The compound 4a, 4b, 4c and 4e were shown significant analgesic activity against Swiss albino mice. The compounds which shown good anti-inflammatory activity against Wister albino rats was compounds 4b, 4c, 4f and 4j.

Further explored of the all the compounds 4c, 4e and 4j were shown comparatively significant activity.

ACKNOWLEDGEMENT:

The authors would like to express their gratitude and thanks to the Head, Dept. of Pharmaceutical Chemistry, Nandha College of Pharmacy and research institute, Erode for necessary facilities for this research work. I would like to thank IIT, Chennai Tamilnadu for their immense help in Scanning ¹H NMR studies.

REFERENCES:

1. Kelekci N G , Goksen U S , Goktas O, Bioorganic and Medicinal Chemistry, 2007, 15, 5738-5751.

2. Palaska E, Sahin G, Kelicen P, IL FARMACO Journal, 2002, 57, 101-107.

3. Gazzar A E, Hegab M I, Bioorganic and Medicinal Chemistry Letters, 2008, 18, 4538-4543.

4. Sreenivasa A, Ghate Manjunath D, Indian Journal of Heterocyclic Chemistry, 2002, 11, 255-256

5. Barreiro E J, Varandas L S, Fraga C A, Letters in Drug Design and Discovery, 2005, 2, 62-67.

6. Moreira A, Piuvezam M R, Journal of Ethnopharmacology 1999; 67, 171–177.

7. Mishra P, Rajak H, Journal of General Applied Microbiology, 2005, 15,133-141.

8. Hussain S, Sharma J, E-Journal of Chemistry, 2008, 5, 963-968.

9. Shah V H, Vashi B S, Mehta D S, Indian Journal of Chemistry, 1996, 35B, 111-115.

10. Sharma R, Sainy J, Acta Pharma, 2008, 58, 317-326.

11. Kapoor R P, Batra H, Indian Journal of Heterocyclic Chemistry, 1997, 7, 1-4.

12. Joshi H S, Vasoya S L, Paghdar D J, Journal of Sciences, Islamic Republic of Iran, 2005, 16, 33-36.

13. Shingare M S, Shinde D B, Chowdhari B R, Indian Journal of Heterocyclic Chemistry, 1995, 4, 187-190.

14. Yadav L D S, Saigal S, Indian Journal of Chemistry, 1995, 34B, 500-503.

15. Bulbul M, Sarcoglu N, Bioorganic and Medicinal Chemistry, 2002, 10, 2561-2567.

16. Saksena R K, Puri S, Indian Journal of Heterocyclic Chemistry, 2003, 13, 127-130.

Received on 27.07.2010 Modified on 05.08.2010

Asian J. Research Chem. 4(2): February 2011; Page 278-281

R = OCH₃	R’ = OH	R = OCH₃	R’ = NO₂
R = OH	R’ = OH	R = OH	R’ = NO₂
R = Cl	R' = OH	R = Cl	R’ = NO₂
R = NO₂	R' = OH	R = NO₂	R’ = NO₂
R = N(CH₃)₂	R' = OH	R = N(CH₃)₂	R’ = NO₂