Simple and Efficient Methods for the Synthesis of New Biologically Active Heterocycles

Abstract

In this study we reported the synthesis of new heterocyclic compounds containing pyridazine moiety of expected biological activity and investigate its reactivity towards some nucleophiles. 6-Aryl-4-(2-methoxybenzyl)pyridazin-3(2H)-ones(31a-c)were synthesizedvia the base catalyzed condensation of 6-aryl-4,5-dihydropyridazin3(2H)-ones (30a-c) with 2-methoxybenzaldehyde. Oxidationof (31a-c)by selenium dioxide yielded 6-aryl-4-(2-methoxybenzoyl)pyridazin-3(2H)-ones (110a-c). Reaction of some nucleophilic reagent such as hydrazine hydrate, phenyl hydrazine and hydroxyl amine hydrochloride with (110a-c) under basic conditions gave 3-(2-methoxyphenyl)-7-aryl-1H-pyrazolo[4,3-d]pyridazin-4(5H)-ones (166a-c), 3-(2-methoxyphenyl)-1-phenyl-7-aryl-1H-pyrazolo[4,3-d]pyridazin-4(5H)-ones (167a-c) and 3-(2-methoxyphenyl)-7-arylisoxazolo[4,5-d]pyridazin-4(5H)-ones (168a-c) respectively. 4-Chloro pyridazine derivatives (169a-c), (170a-c) and (171a-c)were formed via reaction of the pyridazinonederivatives (166a-c),(167a-c) and (168a-c) with phosphorus oxychloriderespectively. Condensation reaction of 4-chloro pyridazine compounds (169a-c), (170a-c) and (171a-c) with different sulfonamides such as sulfanilamide, sulfaguanidine and sodium sulfacetamide in refluxing acetic acid yielded the corresponding sulfonamide derivatives (172a-c – 180a-c) respectively. Also, the reaction of 4-chloro pyridazine derivatives (169a-c), (170a-c) and (171a-c)with sodium azide in refluxing dimethylformamide yielded the corresponding tetrazoloderivatives (181a-c), (182a-c) and (183a-c) respectively. Treatment of 4-chloro pyridazine compounds (169a-c), (170a-c) and (171a-c)withthiourea in refluxing ethanol afforded the corresponding thiol compounds (184a-c), (185a-c) and (186a-c) respectively. The reaction of thiol compounds (184a-c), (185a-c) and (186a-c) with hydrazine hydrate under refluxing in ethanol yielded the hydrazino products (187a-c), (188a-c) and (190a-c).Compound (188a)formation wasconfirmed chemically by reaction with benzaldehyde to give the corresponding Schiff product (189). This study was extended to investigate the reaction of the hydrazino compound (188a) with some aliphatic acids and aldehydes. The reaction of 1-(3-(2-methoxyphenyl)-1-phenyl-7-phenyl-1H-pyrazolo[4,3-d]pyridazin-4-yl)hydrazine (188a) with formic acid yielded the unexpected formohydrazide product (191) namely 3-(2-methoxyphenyl)-1,7-diphenyl-1H-pyrazolo[4,3-d]pyridazin-4-yl)formohydrazide,which confirmed chemically by reaction with hydrazine hydrate to give the corresponding Schiff product (192). Moreover the reaction of hydrazino compound (188a) with acetic acid yielded acetohydrazide product (193) 3-(2-methoxyphenyl)-1,7-diphenyl-1H-pyrazolo[4,3-d]pyridazin-4-yl)acetohydrazide. Also, refluxing ofhydrazino compound (188a) with benzoyl chloride give the corresponding benzohydrazide product (194) 3-(2-methoxyphenyl)-1,7-diphenyl-1H-pyrazolo[4,3-d]pyridazin-4-yl)benzohydrazide. While reaction of hydrazino compound (188a) with p-nitrobenzaldehyde in ethanol yielded 1-(4-nitrobenzylidene)-2-(3-(2-methoxyphenyl)-1,7-diphenyl-1H-pyrazolo[4,3-d]pyridazin-4-yl)hydrazine (195), which chemically confirmed by reaction with N-acetyl glycine to give the expected product1-acetyl-2-(3-(2-methoxyphenyl)-1,7-diphenyl-1H-pyrazolo[4,3-d]pyridazin-4-ylamino)-3-(4-nitrophenyl)pyrazolidin-4-one (196). All the structures of the new products were established using spectral data (IR, Mass, 1HNMR and 13C-NMR spectra). Six of the new synthesized compounds (182c , 187c , 188a-c and 190c) were selected and tested in , Al-Azhar University, Cairo, Egypt against a panel human tumor cell line HCT-116 (colon cancer) using Imatinib as standard drug. The cytotoxicity data of the tested compounds 1-(3-(2-methoxyphenyl)-1-phenyl-7-methoxyphenyl-1H-pyrazolo[4,3-d]pyridazin-4-yl)hydrazine (188c) and 1-(3-(2-methoxyphenyl)-7-methoxyphenylisoxazolo[4,5-d]pyridazin-4-yl)hydrazine (190c) virus Imatinib in means of IC50 values showed high reactivity towards cell line HCT-116 (colon cancer) more than the standard drug Imatinib. Furthermore the synthesized compounds (172c -183c) were tested for their in vitro antibacterial activity against Gram-positive bacteria (Bacillissubtilis (RCMB 010067), Streptococcus pneumonia (RCMB 010010)), Gram-negative bacteria (Pseudomonas aeruginosa (RCMB 010043), Escherichia coli (RCMB 010052)) againt( Aspergillusfumigatus(RCMB 02568) and Candida albicans (RCMB 05036)). Most of the new compounds showed significant antibacterial and antifungal activity.