2. Academic Validation
  3. Design, synthesis and mechanistic study of N-4-Piperazinyl Butyryl Thiazolidinedione derivatives of ciprofloxacin with Anticancer Activity via Topoisomerase I/II inhibition

Design, synthesis and mechanistic study of N-4-Piperazinyl Butyryl Thiazolidinedione derivatives of ciprofloxacin with Anticancer Activity via Topoisomerase I/II inhibition

  • Sci Rep. 2024 Oct 15;14(1):24101. doi: 10.1038/s41598-024-73793-y.
Hossameldin A Aziz 1 2,  Ahmed M El-Saghier 3,  Mohamed Badr 4,  Bakheet E M Elsadek 5,  Gamal El-Din A Abuo-Rahma 6 7 8,  Mai E Shoman 9
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, New Valley University, New Valley, 72511, Egypt.
  • 2 Department of Medicinal Chemistry, Minia University, Minia, 61519, Egypt.
  • 3 Department of Chemistry, Faculty of Science, Sohag University, Sohag, 82524, Egypt.
  • 4 Department of Biochemistry, Faculty of Pharmacy, Menoufia University, Menoufia, Egypt.
  • 5 Department of Biochemistry and Molecular Biology, Faculty of pharmacy, Assiut Branch, Al-Azhar University, Assiut, 71524, Egypt.
  • 6 Department of Medicinal Chemistry, Minia University, Minia, 61519, Egypt. gamal.aborahma@mu.edu.eg.
  • 7 Department of Pharmaceutical Chemistry, Deraya University, New Minya, 61768, Minia, Egypt. gamal.aborahma@mu.edu.eg.
  • 8 Department of pharmaceutical chemistry, Deraya University, New Minia, 61768, Egypt. gamal.aborahma@mu.edu.eg.
  • 9 Department of Medicinal Chemistry, Minia University, Minia, 61519, Egypt. mai_shoman@mu.edu.eg.
PMID: 39406816 DOI: 10.1038/s41598-024-73793-y
Abstract

A new group of thiazolidine-2,4-dione derivatives of ciprofloxacin having butyryl linker 3a-l was synthesized via an alkylation of thiazolidine-2,4-diones with butyryl ciprofloxacin with yield range 48-77% andfully characterized by various spectroscopic and analytical tools. Anti-cancer screening outcomes indicated that 3a and 3i possess antiproliferative activities against human melanoma LOX IMVI Cancer cell line with IC50 values of 26.7 ± 1.50 and 25.4 ± 1.43 µM, respectively, using doxorubicin and cisplatin as positive controls with an IC50 of 7.03 ± 0.40 and 5.07 ± 0.29 µM, respectively. Additionally, compound 3j showed promising Anticancer activity against human renal Cancer A498 cell line with IC50 value of 33.9 ± 1.91 µM while doxorubicin and cisplatin showed IC50 values of 3.59 ± 0.20 and 7.92 ± 0.45, respectively. On the Other hand, compound 3i did not show considerable anti-bacterial activity against S. aureus, E. coli and P. aeruginosa, and only moderate activity against K. pneumoniae with only a tenth of the activity of ciprofloxacin, confirming the cytotoxicity observed. Mechanistically, compound 3i inhibited both Topoisomerase I and II with IC50 of 4.77 ± 0.26 and 15 ± 0.81 µM. Furthermore, it induced cell cycle arrest at S phase in melanoma LOX IMVI cells. Moreover, 3i provoked substantial levels of early, late Apoptosis and necrosis in melanoma LOX IMVI cell line comparable to that induced by doxorubicin. Furthermore, compound 3i increased the expression level of active Caspase-3 by 49 folds higher in LOX IMVI cell, increased protein expression level of Bax more than the control by 3 folds and inhibited PARP-1by 33% in LOX IMVI. All results were supported by theoretical docking studies on both tested Enzymes confirming potential cytotoxicity for the synthesized hybrids.

Keywords

Anti-cancer; Fluoroquinolones; Thiazolidinedione-2,4-dione; Topoisomerase inhibitors.

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