الفهرس 
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Abstract
Tumor is one of the most dangerous problems that world population can face. Many enzymes are overexpressed in a variety of tumor types so, inhibition of such enzymes is considered an important target in antitumor drug discovery. This dissertation is divided into two chapters; chapter 1 is concerned with the design, synthesis and molecular modeling of some new phenyldihydropyridazinone derivatives as B-Raf inhibitors beside the evaluation of their anticancer activity. While, chapter 2 illustrates design, synthesis and molecular modeling of some new phenylpyrimidinone derivatives as Eg5 inhibitors beside the evaluation of their anticancer activity. Chapter 1: Considering several literatures enlightening the anticancer activity of pyridazine scaffolds, twenty-four new phenyl-4,5-dihydropyridazinone derivatives 1.54b; 1.69a, b; 1.70a, b; 1.71; 1.72; 1.99a-h; 1.100a-e and 1.101a-d have been designed, synthesized and evaluated for their anticancer activity against different cancer cell lines. Nine compounds showed strong cytotoxic activity, among which compound 1.101b exhibited potent activity against PC-3 cell line with IC50 value of 7.83 μM in comparison to sorafenib (IC50 11.53 μM). Compounds 1.70a, 1.71, 1.99f-h and 1.101a-d were further screened for their B-Raf inhibitory activity where seven compounds 1.99f-h and 1.101a-d showed high B-Raf inhibition with ranges of IC50 values 70.65–84.14 nM and 24.97–44.60 nM, respectively when compared to sorafenib (IC50 44.05 nM). Among the tested compounds, 1.101b was the most potent B-Raf inhibitor with IC50 value of 24.79 nM. Cell cycle analysis of MCF-7 cells treated with 1.101b showed cell cycle arrest at G2 M phase with significant apoptotic effect. Virtual screening was carried out through molecular modeling evaluation of all the designed compounds using molecular operating environment (MOE) to understand the binding mode of the most active synthesized compounds with B-Raf enzyme. The structures of the synthesized compounds were elucidated through microanalysis, IR, 1H-NMR, APT, 13C-NMR, elemental analysis and Mass spectro-scopy. Chapter 2: In this chapter we aimed to attack cancer cells by another mechanism. According to our study of the anticancer nature of pyrimidine scaffolds, sixteen new phenyl- dihydropyrimidinone derivatives 2.38a-e and 2.55a-k have been designed, synthesized and evaluated for their anticancer activity against different cancer cell lines. Four compounds showed strong cytotoxic activity among which, compound 2.55j showed potent cytotoxic activity against four cancer cell lines with IC50 value at the range of 3.75–5.13 µM in comparison to 5-flourouracil (IC50 range 4.92–7.98µM). Compounds 2.38d, 2.38e and 2.55h-j were further screened for their Eg5 inhibitory activity where 2.38d and 2.55h-j showed high Eg5 inhibition with IC50 values of 28.48, 24.22, 18.90 and 12.89 µM respectively when compared to monastrol (IC50 14.89 µM). Among the tested compounds, 2.55j was the most potent Eg5 inhibitor with IC50 value of 12.89 µM. Cell cycle analysis of HCT-116 cells treated with 2.55j showed cell cycle arrest at G2-M phase which characterize the Eg5 inhibitors. Furthermore, 2.55j showed a significant apoptotic effect. Virtual screening was carried out through molecular modeling evaluation of all the designed compounds using MOE to understand the binding mode of the most active synthesized compounds with Eg5 enzyme.