A new series of pyridine and pyrimidine derivatives is designed and synthesized as potential antitumor molecules. The tested compounds show promising in vitro cytotoxic activity against HL-60 cell line as eight compounds: 4, 6, 11, 13, 14, 15, 18 and 21 exhibit potent cytotoxic activity in sub-micromolar concentration higher than the combretastatin A4 (CA-4). Compound 21 shows a cytotoxic activity 5-fold more potent than CA-4 on HL-60 cells. DNA-Flow cytometry cell cycle analysis and annexin-V assay on HL-60 cells show that compounds 4, 18 and 21 exhibit potent cell growth inhibition, cell cycle arrest at G/M phase and pro-apoptotic inducing activities. The percentage inhibition assay of β-tubulin polymerization on HL-60 cells shows that the antitumor activity of the tested compounds appears to correlate well with its ability to inhibit β-tubulin polymerization. In addition, enzyme-linked immunosorbene assay (ELlSA) measurement for compound 21 shows apoptotic inducing activities through significant up regulation of p53, Bax/Bcl-2 ratio and caspase-3 proteins parallel to down regulation of the level of survivin proteins.
II IV VII. VII . .Vilsmeier formylation of acetanilide I followed by treatment with hydroxylamine produced 2-chloroquinoline-3-carbonitrile II that was condensed with different amines to give 2substituted aminoquinolines-3-carbonitriles III. Treatment of II with thiourea yielded 2mercaptoquinoline-3-carbonitrile IV, which was converted to its potassium salt V that was condensed with some chloroacetate esters to produce 2-substituted thioquinoline-3carbonitriles VI. Hydrazinolysis of II or IV gave 1H-pyrazolo[3,4-b]quinolin-3-ylamine VII. Condensation of VII with different aryl aldehydes resulted in the corresponding imines VIII. Treatment of VII with p-chloro-benzoyl chloride afforded the amide IX. Some of the synthesized compounds were evaluated for their antibacterial and antifungal activity.
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