Design, synthesis and biological screening of some diaryl acetamide derivatives as potential cytotoxic agents on HL-60(TB) cell line

  • Bioorg Chem. 2025 Oct:165:108999. doi: 10.1016/j.bioorg.2025.108999.
Mohammed K Abdelhameid  1 ,  Mohammed A Hara  2 ,  Mohamed Ramadan  3 ,  Ehab S Taher  4 ,  Mostafa A Ramadan  5 ,  Khaled O Mohamed  6 ,  Ahmed T Negmeldin  7
Affiliations
  • 1. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt. Electronic address: [email protected].
  • 2. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Assiut, branch, 71524, Egypt.
  • 3. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Assiut, branch, 71524, Egypt. Electronic address: [email protected].
  • 4. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Assiut, branch, 71524, Egypt; Department of Medical Basic and Clinical Sciences, Faculty of Dentistry, Zarqa University, Zarqa 13110, Jordan.
  • 5. Faculty of Medicine (Kasr El-ainy), Cairo University, Cairo, Egypt.
  • 6. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Sinai University, (Arish branch), El-Arish, Egypt.
  • 7. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt; Department of Pharmaceutical Sciences, College of Pharmacy, Gulf Medical University, Ajman, United Arab Emirates. Electronic address: [email protected].
PMID: 40966779 DOI: 10.1016/j.bioorg.2025.108999
Abstract

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.

Keywords
Diaryl acetamide; Dimedone; FLT-3 kinase inhibitors; HL-60 (TB); Leukemia; Oxadiazole; Quizartinib; Thiazole; Triazole.
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