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• Two series of hydrazonal and indeno[1,2- b ]pyridin-5-one bearing hydrazone and azo- groups were synthesized. • All synthesized derivatives were screened for their anti-breast cancer activity against two cell lines MCF-7 and MDA-231. • The most potent cytotoxic agents were hydrazineylidenes 4a and 4h, while other compounds were moderate to mild activity. • The cell cycle analysis data, indicated that 4a and 4h produced a 1.36- and 1.2-fold rise in the percentage of cells in s phase. • The most effective compounds, 4a and 4h, were studied for their pharmacokinetic parameters and a molecular docking study with the CDK-2 enzyme (PDB ID: 5iev) to provide a complete picture of their activity and utility as drugs. A new series of aza-indeno[1,2- b ]pyridin-5-one derivatives 6a-h was designed. The novel pyridin-5-one derivatives were constructed via cyclization of their corresponding hydrazonal precursors 4a-h with indandione. Structural elucidation of all new compounds was fully conducted. All novel hydrazonals 4a-h and indeno-pyridinone derivatives 6a-h were screened for their anti-breast cancer activity against two cell lines; MCF-7 and MDA-231. Among all screened compounds, hydrazonals 4a and 4h showed the highest cytotoxic potency. The cell cycle analysis data revealed that hydrazonals 4a and 4h caused a 1.36- and 1.2-fold increase in the proportion of cells in S phase. Annexin V-FITC apoptosis test for the same two hydrazonal derivatives 4a and 4h indicated that these molecules induce apoptosis by means of the programmed cell death pathway rather than the necrotic pathway. Pharmacokinetic parameters of these two hydrazonals as well as their molecular docking study with the CDK-2 enzyme, provided more insights of their biological activity and druggability. [ABSTRACT FROM AUTHOR]