INTRODUCTION:

The importance of triazole- derivatives lie in the field that these have occupied a unique position in heterocyclic chemistry due to their agricultural, industrial and antimicrobial activities^1,2.The 1, 2, 4- triazoles exhibit a wide range of therapeutical properties³. In view of these observations and in continuation of our earlier work^4-16 on the syntheses of some 1,2,4- and 1,2,3- triazole derivatives, we now report the synthesis of 3-alkylthio-5-pyridyl-1, 2, 4-triazoles derived from 1-picolinoylthiosemicarbazides.

MATERIAL AND METHODS:

Melting and boiling points were determined on a Gallen Kamp apparatus in open capillaries and are uncorrected. IR spectra (KBr in cm^-1) were recorded on a Jasco FT-IR 5300 spectrophotometer and proton magnetic resonance (PMR) spectra (DMSO-d6) on a Varian EM-390 spectrometer using TMS as an internal standard (chemical shift in δ ppm). Mass spectra were recorded on a Jeol JMS-D 300Mass spectrometer operating at 70eV.The purity of the compounds was confirmed by TLC using silica gel G and purified by column chromatography. For TLC, Merck silica gel 60G plate was used. For column chromatography, Merck silica gel 60 (0.063-0.200mm) was used. The necessary chemicals were obtained from Merck and Fluka. All compounds showed satisfactory elemental analyses.

General procedure for the preparation of 1-Picolinoylthiosemicarbazide (2):

Sodium (0.8 g) was added portion wise to a stirred solution of thiosemicarbazide (2.5 g) in liquid ammonia (80 mL), cooled in dry ice-acetone bath (-55⁰C). To this solution was added ethylpicolinate (4.2 g) and the mixture was stirred for 3.5 hours. After the bath was removed and the solution was allowed to evaporate at room temperature, after cooling, the precipitate was filtered and dried. The dried product was washed with water. This was recrystallized from an ethyl alcohol to afford the compound (2) and was used directly for the next step without further purification (yield 80%).

General procedure for the preparation of 3-alkylthio-5-pyridyl-1, 2, 4-triazoles (3a-c):

A suspension of corresponding alkyl halide (0.01 mol) in ethyl alcohol (10 mL), compound 2(0.01 mol) and 1N NaOH (30 mL) was stirred at room temperature for 5 hours.

The mixture was neutralized with 10% HCl. After cooling, the mixture was poured in to a beaker containing 100mL of ice-water and the precipitate was filtered and dried. The dried product was recrystallized from an appropriate solvent to afford the desired compounds 3(yield 80-90%).

3-Methylthio-5-pyridyl-1, 2, 4-triazoles (3a): Recrystallized from ethyl alcohol, (yield 80%), m.p. 145 ⁰C. Anal.Calc. for C₈H₈N₄S, C, 49.98; H, 4.19; N, 29.14 %; Found C, 50.26; H,4.23; N, 29.38% ; IR (KBr) : 3159 (NH), 1588 (C=N), 1510(C-N) and 687 cm^-1(C-S); PMR: δ 2.33 (3H, s, CH₃), 3.38 (1H, bs, SH), 7.19(2H, m, Ar-H),

7.36 (1H, m, Pyridyl-H), 7.77(1H, m, Pyridyl-H), 7.83(1H, m, Pyridyl-H) and 8.80 ppm (1H, m, Pyridyl-H); MS: m/z 280 (M⁺) other peaks observed at 148, 146, 136, 111, 97, 84, 54 and 48.

3-Benzylthio-5-pyridyl-1, 2, 4-triazoles (3b): Recrystallized from ethyl alcohol, (yield 85%), m.p. 125 ⁰C. Anal.Calc. for C₁₄H₁₂N₄S, C, 60.84; H, 7.29; N, 20.27 %; Found C, 60.80; H, 7.13; N, 20.05%; IR (KBr) : 3169 (NH), 1590 (C=N), 1512 (C-N), 732 (monosubstituted benzene) and 692 cm^-1(C-S); PMR: δ 2.42 (3H, s, CH₂), 3.42 (1H, bs, SH), 7.22 (2H, m, Ar-H), 7.33 (2H, m, Ar-H), 7.40 (1H, m, Pyridyl-H), 7.75(1H, m, Pyridyl-H), 7.85(1H, m, Pyridyl-H), and 8.82 ppm (1H, m, Pyridyl-H); MS: m/z 285(M⁺) other peaks observed at 153, 143, 135, 108, 97, 85, 57 and 52.

3-Phenylthio-5-pyridyl-1, 2, 4-triazoles (3c): Recrystallized from ethyl alcohol, (yield 90%), m.p. 127 ⁰C. Anal.Calc. for C₁₃H₁₀N₄S, C, 59.51; H, 6.92; N, 21.35%; Found C, 59.68; H, 7.10; N, 21.22% IR (KBr) : 3179 (NH), 1592 (C=N), 1514 (C-N),733 (monosubstituted benzene) and 690cm^-1(C-S); PMR: δ 2.44 (3H, s, CH₂), 3.43 (1H, bs, SH), 7.25 (2H, m, Ar-H), 7.35 (2H, m, Ar-H), 7.43 (1H, m, Pyridyl-H), 7.78(1H, m, Pyridyl-H), 7.88 (1H, m, Pyridyl-H), and 8.85 ppm (1H, m, Pyridyl-H); MS: m/z 287 (M⁺) other peaks observed at 148, 141, 136, 104, 95, 86, 55 and 51.

Anti-inflammatory Activity:

Anti-inflammatory activities of three compounds were measured using formal in induced rat find paw edema technique¹⁷. Male albino rats were injected with 0.1 mL of a 1% carageenan solution in saline in to sub planter region of the left find paw. The paw was marked with ink at the level of the lateral molecules and immersed in mercury up to this mark the paw volume was measured before and 1, 2, 3, 4 and 5 hour after the injection of carageenan by mercury displacement method plethysmographically. The edema volume was determined and expressed as percentage swellings, compared with initial find paw volume of each rat. Ibuprofen was used as reference standard. The screening results revealed that showed significant anti-inflammatory activity which was comparable with Ibuprofen¹⁸. (Table 1)

Table 1 Evaluation of anti-inflammatory activity of the compounds

Compd.	Substitutent	Percentage inhibition at the end of
		1hr	3hr	5hr
3a	-CH₃	49.82	53.80	56.72
3b	-C₆H₅CH₂	52.82	55.72	59.72
3c	-C₆H₅	63.32	65.42	66.62
Ibuprofen (Standard)		64.06	68.10	72.62

RESULTS AND DISCUSSION:

In present work, 1-Picolinoylthiosemicarbazide 2 which is required as starting material were obtained in an one-pot reaction by heating ethylpicolinate and thiosemicarbazides in liquid ammonia under stirred condition for 3.5 hours. Compounds 3a-c were prepared by the alkylation and thermal cyclization of compound 2 with various alkyl halides. (Scheme 1)

The IR spectrum of the compound 3a showed characteristic absorption bands at 3159, 1588, 1510 and 687 cm^-1for NH, C=N, C-N and C-S groups respectively. The PMR spectrum of 3a exhibits a multiplet (2H) at δ 7.19 for aromatic protons, a multiplet (1H) at δ 7.36 for pyridyl protons. Mass spectra showed the expected molecular ion peaks at m/z 280, 148, 146, 136, 111, 97, 84, 54 and 48(M⁺) in agreement with their molecular formulae.

The IR spectrum of the compound 3b showed characteristic absorption bands at 3169, 1590, 1512 and 692 cm^-1for NH, C=N, C-N and C-S groups respectively. The PMR spectrum of 3b exhibits a multiplet (2H) at δ 7.22 for aromatic protons, a multiplet (1H) at δ 7.40 for pyridyl protons. Mass spectra showed the expected molecular ion peaks at m/z 285, 153, 143, 135, 108, 97, 85, 57 and 52 (M⁺) in agreement with their molecular formulae.

The IR spectrum of the compound 3c showed characteristic absorption bands at 3179, 1592, 1514 and 690cm^-1for NH, C=N, C-N and C-S groups respectively. The PMR spectrum of 3c exhibits a multiplet (2H) at δ 7.25 for aromatic protons, a multiplet (1H) at δ 7.43 for pyridyl protons. Mass spectra showed the expected molecular ion peaks at m/z 287, 148, 141, 136, 104, 95, 86, 55 and 51 (M⁺) in agreement with their molecular formulae.

All compounds containing 1, 2, 4- triazole moiety showed significant anti-inflammatory activity. The structures of all the compounds are confirmed by IR, PMR and MS spectral data (experimental part).

ACKNOWLEDGEMENTS:

The authors thank Head, RSIC, CDRI, Lucknow for the analytical and spectral data. Head of the Department of Microbiology, I.M.S. B.H.U for the biological screening and to the Head of the Chemistry Department of T.D.P.G. College, Jaunpur for providing Laboratory facilities.

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Received on 20.07.2009 Modified on 05.10.2009

Asian J. Research Chem. 2(4):Oct.-Dec. 2009 page 536-538