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  3. Unveiling ortho-phenolic Mannich ciprofloxacin-chalcone conjugates with potential antineoplastic activity: synthesis, mechanistic study, in silico docking and molecular dynamic simulation

Unveiling ortho-phenolic Mannich ciprofloxacin-chalcone conjugates with potential antineoplastic activity: synthesis, mechanistic study, in silico docking and molecular dynamic simulation

  • Eur J Med Chem. 2025 Oct 15:296:117891. doi: 10.1016/j.ejmech.2025.117891.
Islam M Abdel-Rahman 1,  Mohamed Abdel-Aziz 2,  Heba Ali Hassan 3,  Dalia H Abu-Baih 4,  Mohamed Badr 5,  Moustafa Fathy 6,  Ibrahim M Salem 7,  Tarek S Ibrahim 8,  Alaa M Hayallah 9,  GamalEl-Din A Abuo-Rahma 10
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Deraya University, New-Minia, Minia, Egypt.
  • 2 Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, 61519, Minia, Egypt.
  • 3 Department of Pharmacognosy, Faculty of Pharmacy, Sohag University, Sohag, Egypt.
  • 4 Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Deraya University, New Minia, 61519, Egypt; Deaya Center for Scientific Research, Deraya University, New Minia, 61519, Egypt.
  • 5 Department of Biochemistry, Faculty of Pharmacy, Menoufia University, Minia, 61519, Egypt.
  • 6 Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia, 61519, Egypt.
  • 7 Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Sphinx University, New-Assiut, 71515, Egypt.
  • 8 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Jeddah, 21589, Saudi Arabia; Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt.
  • 9 Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Sphinx University, New-Assiut, 71515, Egypt; Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Assiut University, Egypt. Electronic address: alaa.mohamed2@pharm.aun.edu.eg.
  • 10 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Deraya University, New-Minia, Minia, Egypt; Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, 61519, Minia, Egypt. Electronic address: gamal.aborahma@mu.edu.eg.
PMID: 40578251 DOI: 10.1016/j.ejmech.2025.117891
Abstract

A new series of ortho-phenolic Mannich ciprofloxacin-chalcone hybrids 5a-j were synthesized and evaluated against the NCI-60 Cancer cell lines, unveiling their promising potential as cytotoxic agents. Notably, compounds 5a, 5d and 5j exhibited notable anti-proliferative efficacy against both LOX IMVI and HCT 116 cell lines, indicating promising cytotoxic potential, with IC50 = 2.53, 2.01, 17.36, 12.23 and 3.1 μM for HCT-116 cells, respectively and IC50 = 0.73, 0.64, 3.32, 13.72 and 1.17 μM for leukemia SR cells, respectively. Mannich base 5j achieved excellent inhibitory effect on Topo IIβ in both LOX IMVI and HCT-116 cell lines with inhibition value of 75.51 % and 76.39 %. Cell cycle analysis and expression analysis of Bax, Bcl2, P53 and P21 genes were performed on LOX IMVI and HCT-116 cell lines with compound 5j and also on Caspase 3 actifundation in HCT-116 and LOX- IMIV cell lines. The docking outcomes aligned with the biological screening revealed higher affinity of the most active compound 5j against topoisomerase-I and topoisomerase-II biotargets, serving it as promising antineoplastic agent. Besides, using atomistic standard 100 ns dynamic simulation consideration, the stability of the formed complexes between compound 5j and the topoisomerase-1 and topoisomerase-2 active sites was considered under dynamic behavior. Hence, Mannich base 5j is considered a promising antineoplastic candidate that requires further in vivo investigation.

Keywords

Antiproliferative; Chalcone; Ciprofloxacin; Mannich bases; NCI cell lines.

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