Syntheses of Biologically active 1-[2-(1,3-Dimethyl-2,6-Dioxo-1,2,3,6-Tetrahydro-Purin-7-Yl)-Acetyl]-3-(Substituted Phenyl)-1H-Pyrazole-4-Carbaldehyde

 

Freddy H. Havaldar* and Azadkumar S. Sharma

Nadkarny-Sacasa Research Laboratory,

Department of Chemistry, St. Xavier’s College, Mumbai - 400  001, Maharashtra, India.

ABSTRACT:

1-[2-(1,3-Dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-purin-7-yl)-acetyl]-3-(substituted phenyl)-1H-pyrazole-4-carbaldehydes (4a-e) have been synthesized by the cyclisation of (1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-purin-7-yl)-acetic acid [1-(substituted phenyl)-ethylidene]-hydrazides (3a-e) with phosphorous oxychloride in N_,N-dimethylformamide. The pyrazoles have been characterized on the basis of analytical and spectral data and screened for biological activity.

 

 

INTRODUCTION:

Xanthines such as theophylline and caffeine are well known for their antiallergic^1,2 diuretic³, cardiac stimulant⁴, antihypertensive⁵ and muscle relaxant properties. They are also the prototypes of adenosine receptor antagonists and are non-selective for A₁ and A₂ receptors^1,3-6.  Pyrazole nucleus has wide applications in medicinal chemistry. It is reported that pyrazoles exhibit antibacterial⁷, antifungal⁸ and anti-inflammatory⁹ property.  In view of this, we thought it worthwhile to synthesize some new pyrazoles containing theophylline moiety with the objective of screening them for their biological activity.

 

Theophylline on electrophilic substitution with ethyl chloroacetate gave (1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-purin-7-yl)-acetic acid ethyl ester (1)  which on amination with hydrazine hydrate afforded  (1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-purin-7-yl)-acetic acid hydrazide¹⁰ (2). Condensation of the compound (2) with various aromatic acetophenones gave (1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-purin-7-yl)-acetic acid [1-(substituted phenyl)-ethylidene]-hydrazides (3a-e) which on cyclization with Vilsmeier-Haack reagent yielded the title compounds (4a-e) (Scheme-1).

 

RESULTS AND DISCUSSION:

Biological Activity

The pyrazoles (4a-e) synthesized were screened in vitro for their antibacterial activity against Staphylococcus aureus, Escherichia coli, Bacillus subtilis and Salmonella typhosa by the ditch-plate technique¹¹ and for antifungal activity against Aspergillus niger, Candida albicans, Cryptococcus neoformans and Thielaviopsis paradoxa by paper-disc diffusion method¹² using concentrations of  2 and 5 mg/ml. Nutrient agar was employed as culture media and DMF was used as solvent control for both antibacterial and antifungal activity.

 

The antibacterial and antifungal activities displayed by compounds (4a-e) have been listed in table-2.

 

MATERIAL AND METHODS:

Melting points were taken in open capillaries and are uncorrected. IR spectra (KBr in cm^-1) were recorded on Jasco 410 plus FTIR spectrophotometer. ¹H NMR spectra were recorded on a JEOL 300 MHz FT-NMR spectrophotometer using DMSO-d₆ as solvent and TMS as internal standard (chemical shifts in δ ppm). The mass spectra of compounds were determined with Shimadzu model No. QP 2010. The elemental analysis was carried out on a Perkin Elmer C, H, N analyzer and sulphur analysis was obtained by oxygen-flask method. The purity of the compounds was monitored by thin layer chromatography. TLC was carried out on precoated 0.2 mm silica gel ₆₀F²⁵⁴ plates.                      

 

TABLE-1 Physical data of compounds

 

Compound	Ar	M.P. (°C)	Yield (%)	Molecular  Formula	%N		IR, KBr	1HNMR (DMSO d6)	Mass ms m/z [M+]
					Requires	Found
3a	C6H5	259	86	C17H18N6O3	23.72	23.75	3275 (NH), 1707, (C=O).	2.10 (s, 3H, -CH3), 3.40 (s, 3H, -CH3),  3.50 (s, 3H, -CH3), 5.10 (s, 2H, -CH2), 7.20-7.65 (m, 5H, ArH), 8.0 (s, 1H, N-CH-N), 10.20 (s, 1H, -NH).	354
3b	4-CH3-C6H5	255	92	C18H20N6O3	22.81	22.84	3278 (NH), 1705, (C=O).	2.11 (s, 3H, -CH3), 2.31 (s, 3H, -CH3),  3.41 (s, 3H, -CH3),  3.52 (s, 3H, -CH3), 5.12 (s, 2H, -CH2), 7.25-7.7 (m, 5H, ArH), 8.05 (s, 1H, N-CH-N), 10.25 (s, 1H, -NH).	368
3c	2-OH-C6H5	244	85	C17H18N6O4	22.69	22.71	3460 (br-OH), 3282 (NH), 1710, (C=O).	2.15 (s, 3H, -CH3), 3.42 (s, 3H, -CH3),  3.54 (s, 3H, -CH3), 5.15 (s, 2H, -CH2), 7.25-7.7 (m, 5H, ArH), 8.10 (s, 1H, N-CH-N), 10.30 (s, 1H, -NH), 11.10 (s, 1H, -OH).	370
3d	4-OH-C6H5	259	88	C17H18N6O4	22.69	22.70	3450 (br-OH), 3285 (NH), 1713, (C=O).	2.11 (s, 3H, -CH3), 3.41 (s, 3H, -CH3),  3.51 (s, 3H, -CH3), 5.14 (s, 2H, -CH2), 7.20-7.65 (m, 5H, ArH), 8.05 (s, 1H, N-CH-N), 10.10 (s, 1H, -NH). 11.15 (s, 1H, -OH).	370
3e	4-OCH3-C6H5	252	81	C18H20N6O4	21.86	21.88	3290 (NH), 1711, (C=O), 1175 (C-O-C).	2.11 (s, 3H, -CH3), 3.41 (s, 3H, -CH3),  3.51 (s, 3H, -CH3), 3.85 (s, 3H, -OCH3), 5.20 (s, 2H, -CH2), 7.20-7.65 (m, 5H, ArH), 8.15 (s, 1H, N-CH-N), 10.15 (s, 1H, -NH).	384
4a	C6H5	162	62	C19H16N6O4	21.42	21.45	3280 (NH), 1700, (C=O).	3.41 (s, 3H, -CH3),  3.51 (s, 3H, -CH3), 5.10 (s, 2H, -CH2), 7.3-7.7 (m, 5H, Ar-H), 7.90 (s, 1H, N-CH-C), 8.05 (s, 1H, N-CH-N), 10.20 (s, 1H, CHO)	392
4b	4-CH3-C6H5	188	56	C20H18N6O4	20.68	20.70	3285 (NH), 1690, (C=O).	2.35 (s, 3H, -CH3), 3.45 (s, 3H, -CH3),  3.54 (s, 3H, -CH3), 5.15 (s, 2H, -CH2) 7.3-7.7 (m, 4H, Ar-H), 7.90 (s, 1H, N-CH-C), 8.10 (s, 1H, N-CH-N), 10.20 (s, 1H, CHO)	406
4c	2-OH-C6H5	144	60	C19H16N6O5	20.58	20.60	3465 (br-OH), 3289 (NH), 1708, (C=O).	3.45 (s, 3H, -CH3),  3.55 (s, 3H, -CH3), 5.20 (s, 2H, -CH2) 7.35-7.5 (m, 4H, Ar-H), 7.95 (s, 1H, N-CH-C), 8.20 (s, 1H, N-CH-N), 10.30 (s, 1H, CHO), 11.05 (s, 1H, OH).	408
4d	4-OH-C6H5	173	69	C19H16N6O5	20.58	20.61	3470 (br-OH), 3295 (NH), 1719, (C=O).	3.45 (s, 3H, -CH3),  3.55(s, 3H, -CH3), 5.30 (s, 2H, -CH2) 7.4-7.8 (m, 4H, Ar-H), 7.95 (s, 1H, N-CH-C), 8.25 (s, 1H, N-CH-N), 10.35 (s, 1H, CHO), 11.10 (s, 1H, OH).	408
4e	4-OCH3-C6H5	196	58	C20H18N6O5	19.90	19.93	3293 (NH), 1711, (C=O), 1180 (C-O-C).	3.40 (s, 3H, -CH3),  3.52 (s, 3H, -CH3), 3.95(s, 3H, -OCH3),  5.25 (s, 2H, -CH2) 7.4-7.8 (m, 4H, Ar-H), 7.95 (s, 1H, N-CH-C), 8.15 (s, 1H, N-CH-N), 10.30 (s, 1H, CHO).	422

 

TABLE-2 Biological Activity

 

 

 

(1,3-Dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-purin-7-yl)-acetic acid [1-(substituted phenyl)-ethylidene]-hydrazide (3a-e)

 

To a mixture of (1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-purin-7-yl)-acetic acid hydrazide (2) (2.52 g, 0.01 mole) in ethanol containing a few drops of glacial acetic acid, various substituted acetophenones (0.011 mole) were added. The reaction mixture was refluxed for 3 hours and then cooled in an ice-bath. The product separated on cooling was filtered, washed with cold methanol and recrystallised from methanol to afford compounds (3a-e).

 

The melting points, yields and analytical data of compounds (3a-e) are given in table-1.

 

1-[2-(1,3-Dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-purin-7-yl)-acetyl]-3-(substituted phenyl)-1H-pyrazole-4-carbaldehyde (4a-e)

      

The compound (3) (0.004 mole) was added to the mixture of Vilsmeier-Haack reagent prepared by dropwise addition of phosphorous oxychloride (0.012 mole) in an ice-cold solution of N,N-dimethylformamide (5 cm³). The reaction mixture was warmed in a water bath for 2 hours, then poured into ice-cold water and neutralized using an excess of sodium bicarbonate solution. The product obtained was filtered, washed with water and finally recrystallised from ethyl acetate to afford compounds (4a-e).

 

The characterization and spectral data of compounds (4a-e) have been given in Table-1.

 

ACKNOWLEDGEMENT:

The authors are thankful to RSIC, IIT, Mumbai and TIFR, Mumbai for ¹H NMR spectra and Dr. (Mrs.) Vivien Amonkar, Head, Department of Microbiology, St. Xavier’s College, Mumbai for providing biological activity.

 

REFERENCES:

1.     Orange R P, Kaliner M A, Laraia P J and Austen F, Fed Proc Am Soc Exp Biol., 30 (1971) 1725.

2.     Lichtenstern LM and Margolis S, Sciences, 161 (1968) 90.

3.     Daly J W, Butts-Lamb P and Padgett W, Cell Mol Neurobiol, 3 (1983) 6.

4.     Fredholem B B and Persson C G A, Eur J Pharmacol, 8 (1982) 673.

5.     Daly J W, Padgett W, Shamim M T Butts-Lamb P and Waters J, J Med Chem, 28 (1985) 487.

6.     Jacobson K A, Shi D, Gallow-Rodriguez C, Manning M Jr, Muller C, Daly J W, Neumeyer J L, Kiriasis L and Pfleiderer W, J Med Chem, 36 (1993) 2639.

7.     V.K. Ahuwalia, B. Mittal, R.P. Singh, R.R. Mann and S.B. Singh, Indian J. Chem., 28B (1989), 150.

8.     R.B. Phatak and S.C. Bahel, J. Indian Chemical Society, 57 (1980), 1108.

9.     A.I. Eid, M.A. Kirka and H.N. Fahmy, J. Pharma (Belg)., 33 (1978), 303. (Chem. Abs., 90 (1979), 152073.

10.   Ranjana Sharma, Maqbool Ahmed and G. L. Talesara, Indian journal of heterocyclic chemistry, 15, 2005, 35.

11.   CH Collins; PM Lyne. Microbiological Methods 3^rd ed., Butterworths, London, 1970,  424.

12.   HW Seeley; PJ Van Denmark, Microbes in Action, W.H. Freeman and Co. USA, 1972.

 

 

 

Received on 31.01.2012        Modified on 21.02.2012

Accepted on 18.03.2012        © AJRC All right reserved