الفهرس 
INTRODUCTIONOnly 14 pages are availabe for public view
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Abstract
Synthesis, in silico studies and Biological Evaluation of Nitrogen Containing Heterocyclic Compounds Background: The present study deals with the synthesis of a new series of 2-alkoxy-4-substituted phenyl-6-(p-tolyl)nicotinonitriles, 2-alkoxy-4-substituted phenyl-6-(1H-indol-3-yl)nicotinonitriles, and 4,5-dihydro-1H-pyrazole derivatives. Also, outlines how anticancer drugs are categorized according to their therapeutic targets. It additionally provides examples from recent research illustrating the anticancer action of several series of cyanopyridine and 4,5-dihydro-1H-pyrazole derivatives.Methods: includes the synthetic procedures followed to obtain the target compounds, the adopted techniques in antitumor screening, EGR, HER2, and DHFR inhibitory activities, cell cycle arrest analyses, in vivo anti-breast cancer activity, and molecular modeling studies including pharmacophore prediction, flexible alignment, and molecular docking, finally, in silico studies and preadmet parameters were performed.Results: compounds 3a, 4b, 4c, 7a, 8d, 11b, and 11c demonstrated superior anticancer efficacy with elevated safety profiles and selectivity indices, particularly against MCF7 breast cancer. For exploration of their mechanism of action, assays for inhibition of EGFR, HER2 kinase, and DHFR were performed. The promising synthesized compounds exhibited potent dual kinase EGFR/HER2 inhibitory activity with IC50 values of 0.248/0.156 μM for 4b and 0.138/0.092 μM for 4c. Additionally, with IC50 values of 0.138 and 0.193 M, respectively, 4b and 4c had the greatest DHFR inhibitory activity that was comparable to methotrexate. In the MCF7 breast cancer cell line, they caused arrest at the S phase of the cell cycle and exhibited apoptosis induction activity. With restored caspase-3 immunoexpression, the anti-breast cancer assay performed in vivo of 4b and 4c demonstrated a substantial decrease in tumor volume Conclusion: Among synthesized compounds, 4b and 4c were proved to be the most active as they exhibited broad spectrum anticancer activity, strong EGFR, HER2, and DHFR inhibitory activity, they induce cell cycle arrest at S phase, their in vivo results showed remarkable tumor and body weight reduction, results of molecular modeling are compatible with biological assays and they obey Lipinski’s rule of five with satisfactory ADMET data.