الفهرس 
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Abstract
This study comprises a brief literature survey on cancer, its causes and treatment as well as biological activities and chemistry of pyridazine and fused pyridazine derivatives.
The Thesis involves design of some new pyridazine and fused pyridazine derivatives aiming to possess an anticancer activity through inhibition of VEGFR.
The Schemes followed for the preparation of the designed compounds are summarized asfollows:
Scheme (1) starts with the preparation of the root compound N-Carbamimidoyl-4-[(6-chloropyridazin-3-yl)amino]benzenesulphonamide (I) followed by reaction with different aromatic amines to give N-Carbamimidoyl-4-[(6-arylaminopyridazin-3-yl)amino]benzenesulphonamides IIa-f.
Scheme (2) involves nucleophilic substitution reaction of compound I with meta and para phenylenediamine to give the relevant compounds IIIa, b. Furthermore, compound IIIa was reacted with each of acetyl chloride and 3-chloropropionyl chloride to give the corresponding pyridazine derivatives IVa, b respectively. Further, compounds IIIa, b were reacted with different alkyl isothiocyanates to give the corresponding thiourea compounds Va-d and VIa-d.
On the other hand, Scheme (3A) involves the reaction of compound I with each of 2-aminophenol, different substituted anthranilic acids and 2-aminonicotinic acid to give the corresponding pyridazino[1,6-a]benzimidazole VII, pyridazino[6,1-b]quinazolines VIIIa,c,d and pyrido[2’, 3’,4,5]pyrimido[1,2-b]pyridazine VIIIb respectively.
Scheme (3B) includes the reaction of compound I with each of substituted acetophenone phenylhydrazones, thiosemicarbazide and substituted benzoic acid hydrazides to afford the corresponding hydrazinyl derivatives IXa-c, N-Carbamimidoyl-4-[(3-amino[1,2,4]triazolo[4,3-b]pyridazin-6-yl)amino] benzenesulphonamid (X) and 3-aryl [1,2,4]triazolo[4,3-b]pyridazine derivatives XIa-c respectively.
The structure elucidation of the newly synthesized compounds was supported by IR, 1HNMR, 13CNMR for some compounds, mass spectral data as well as elemental analysis.
Moreover, all the synthesized compounds were subjected to in vitro cytotoxic activity on two cell lines: human breast cancer cell line (MCF-7) and human colon cancer cell line (HCT-116) compared with imatinib as a reference anticancer drug. Compound VIIIb was the most potent against HCT-116 with IC50 10.42 μM while compound VIIIa was the most potent against MCF-7 with IC50 11.18 μM.
In addition, the antitumor activity of some synthesized compounds was tested in vivo against Ehrlich’s ascites carcinoma (EAC) solid tumor grown in mice. The antitumor activity produced by compounds IIe, IVb and Vb was greater than that produced by imatinib,
Finally, the in vitro VEGFR enzyme based inhibition assay was carried out at a single dose of 10 μM for some compounds. Percentage enzyme inhibition of IVb and Vb (89.6%, 92.0%, respectively) were more significant than that of imatinib (78.7%) against MCF-7.