Design, synthesis and biological screening of some diaryl acetamide derivatives as potential cytotoxic agents on...

In this study, novel diaryl acetamide derivatives were designed and evaluated as potential cytotoxic agents against the leukemic cells HL-60 (TB) with tyrosine kinase FMS-3(FLT-3) enzyme inhibitory activity. The designed molecules were synthesized and investigated for the FLT-3 enzyme inhibition. Compounds 5a, 15b, and 16b showed significant inhibitory activity against the FLT-3 enzyme. Assessment of cytotoxicity on HL-60 cells revealed that compound 15b exhibited superior activity than Quizartinib (AC220). Additionally, compounds 5a and 15b effectively arrested the cell cycle at the G₁ phase upon testing on HL-60 cells, suggesting potential abilities in blocking HL-60 cells' proliferation. The annexin-V stain assay demonstrated that compounds 5a, 15b, and 16b induced apoptosis in HL-60 cells. Furthermore, the ELISA assay showed that the blocking of cell cycle proliferation of HL-60 cells was mediated via the induction of cell cycle regulatory proteins p53 and p21. Meanwhile, the observed apoptosis induction was mediated by increasing apoptotic mediators, Bax/Bcl-2 ratio, and up-regulating caspase-3. Molecular docking studies revealed the binding affinities and interactions of the newly synthesized compounds, along with the reference compound Quizartinib, with the FLT-3 enzyme binding site.