An Efficient Synthesis and Reactions of Novel Indolyl- Pyridazinone Derivatives with Expected Biological Activity

Reaction of 4-anthracen-9-yl-4-oxo-but-2-enoic acid (1) with indole gave the corresponding butanoic acid 2. Cyclocondensation of 2 with hydrazine hydrate, phenyl hydrazine, semicarbazide and thiosemicarbazide gave the pyridazinone derivatives 3a-d. Reaction of 3a with POCl 3 for 30 min gave the chloropyridazine derivative 4a, which was used to prepare the corresponding carbohydrate hydrazone derivatives 5a-d. Reaction of chloropyridazine 4a with some aliphatic or aromatic amines and anthranilic acid gave 6a-f and 7, respectively. When the reaction of the pyridazinone derivative 3a with POCl 3 was carried out for 3 hr an unexpected product 4b was obtained. The structure of 4b was confirmed by its reaction with hydrazine hydrate to give hydrazopyridazine derivative 9, which reacted in turn with acetyl acetone to afford 10. Reaction of 4b with methylamine gave 11, which reacted with methyl iodide to give the trimethylammonium iodide derivative 12. The pyridazinone 3a also reacted with benzene-or 4-toluenesulphonyl chloride to give 13a-b and with aliphatic or aromatic aldehydes to give 14a-g. All proposed structures were supported by IR, 1 H-NMR, 13 C-NMR, and MS spectroscopic data. Some of the new products showed antibacterial activity.


Biological Screening
The activities of some of the prepared compounds against representative Gram positive and negative bacteria were tested by the disk diffusion method [1,8,35].The results are listed in Table 5.From the data it is clear that compounds 6b, 14i possess high activity against both types of bacteria, while compound 6c displays low activity.Compounds 1 and 6b possess high activity, compounds 2, 3a-3d, 4a, 5a, 5d, 14g, 14i possess moderate activity and compounds 6c and 13a possess less activity against Gram positive strains.As far as Gram negative microorganisms are concerned, compound 14i showed high activity, while compounds 1, 2, 3a, 3b, 3d, 4a, 5a, 5d, 6b, 13a and 14g all displayed moderate activity and 3c and 6c possess less activity against such microorganisms.

Conclusions
A novel synthesis of some new indolylpyridazinone derivatives by cyclocondensation of indolylbutyric acid 2 with hydrazine hydrate and its derivatives to give pyridazinone derivatives 3a-d is described.The reactions of pyridazinone 3a with PCl 5 /POCl 3 , arylsulphonyl chloride derivatives and aliphatic or aromatic aldehydes were studied, as were the behaviors of chloropyridazine derivatives towards hydrazine hydrate, carbohydrate hydrazones and aliphatic or aromatic amines.The structures of all new synthesized compounds were established from their spectral data and elemental analysis.Additionally, the antimicrobial activity of selected compounds against Gram positive and negative bacteria is reported.I thank Dr. Malka Mehsen in Girls College of Science, Dammam, Saudi Arabia for performing the biological tests

General
Melting points were determined on Reichert hot stage microscope and are uncorrected.IR spectra were measured with a Nicolet Magna 520 instrument, using potassium bromide disks; results are given in cm -1 . 1 H-NMR and 13 C-NMR spectra were recorded at 200 and 90.56 MHz, respectively, in DMSOd 6 on a JEOL JNM-GX270 spectrometer.The chemical shifts are reported in parts per million (ppm) downfield from internal tetramethylsilane (TMS).Electron impact MS spectra were obtained on a JEOL JMS-HX 100 instrument at 70 eV.Elemental microanalysis was done on a Carlo Erba analyzer model 110.Suitable crystals were grown by slow crystallization from methanol, ethanol and benzene.

General method for the preparation of 3a-d:
Hydrazine hydrate derivatives (10 mmol) were added to a solution of 2 (10 mmol) in dry benzene (5 mL) and the resulting reaction mixture was refluxed for 6 hr.The solid that separated on cooling was recystallized from benzene to give compounds 3a-d.Their physical properties, mass spectral data and elemental analysis are given in Table 1.
General procedure for the reaction of chloropyridazine 4a with carbohydrate hydrazones.
The appropriate carbohydrate hydrazone (1 mmol) was added to a mixture of 4a (1 mmol) in ethanol (5 mL) and the reaction mixture was refluxed for 6 hr.The solid that separated on cooling was recystallized from ethanol to give compounds 5a-d.Physical properties, mass spectral data and elemental analysis for compounds 5a-d are given in Table 2.

Table 1 .
Physical properties, mass spectral data and elemental analyses for compounds 1-3.

Table 2 .
Physical properties, mass spectral data and elemental analyses for compounds 4-7.

Table 3 .
Physical properties, mass spectral data and elemental analyses for compounds 8-12.

Table 4 .
Physical properties, mass spectral data and elemental analyses for compounds 13-14.