A piperazine-triazole hybrid triggers G2/M arrest in triple-negative breast Cancer cells by suppressing HDAC activity and disrupting mitochondrial membrane potential

  • Bioorg Chem. 2026 Jun 18:180:110114. doi: 10.1016/j.bioorg.2026.110114.
Hassan Moghtaderi  1 ,  Sadiq Noor Khan  1 ,  Mohammad Kamangar  1 ,  Yazdanbakhsh Lotfi Nosood  2 ,  Abdulrahman Alhinai  1 ,  Shaikh Mizanoor Rahman  1 ,  René Csuk  3 ,  Satya Kumar Avula  4 ,  Ahmed Al-Harrasi  5
Affiliations
  • 1. Natural and Medical Sciences Research Center, University of Nizwa, P.O. Box 33, Postal Code 616, Birkat Al-Mauz, Nizwa, Sultanate of Oman.
  • 2. Natural and Medical Sciences Research Center, University of Nizwa, P.O. Box 33, Postal Code 616, Birkat Al-Mauz, Nizwa, Sultanate of Oman. Electronic address: [email protected].
  • 3. Organic Chemistry, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes-Str. 2, D-06120, Halle, Saale, Germany.
  • 4. Natural and Medical Sciences Research Center, University of Nizwa, P.O. Box 33, Postal Code 616, Birkat Al-Mauz, Nizwa, Sultanate of Oman. Electronic address: [email protected].
  • 5. Natural and Medical Sciences Research Center, University of Nizwa, P.O. Box 33, Postal Code 616, Birkat Al-Mauz, Nizwa, Sultanate of Oman. Electronic address: [email protected].
PMID: 42320117 DOI: 10.1016/j.bioorg.2026.110114
Abstract

Triple-negative breast Cancer (TNBC) is an aggressive subtype with limited targeted therapies, and elevated HDAC activity contributes to tumor progression and drug resistance. In the current study, we designed and synthesised a new series of piperazine-linked 1H-1,2,3-triazole derivatives (6a-6f, 7a-7f, and 8a-8f) and evaluated their antiproliferative activities in human breast Cancer cells. All synthesised compounds were characterized using 1H NMR, 13C NMR, 19F NMR, and high-resolution mass spectrometry (HRMS-ESI + -MS) to confirm their structures. The compound 7e exhibited potent growth inhibition in MDA-MB-231 cells with an IC₅₀ of 27.59 μM, while showing low toxicity toward HUVEC cells. Cell-cycle analysis revealed significant accumulation of cells in the G2/M phase. Mechanistically, compound 7e significantly decreased HDAC activity (63% compared to control) at 30 μM, and induced mitochondrial dysfunction as evidenced by a marked loss of ΔΨm. Furthermore, Molecular docking across selected HDAC isoforms indicated that 7e can adopt favorable binding poses within conserved HDAC catalytic pockets; HDAC2 showed the best Glide XP docking score, whereas MM-GBSA refinement predicted a more favorable binding free energy for HDAC4. Collectively, these results identify this piperazine-triazole scaffold as a promising lead for TNBC therapy and support further structural optimization and preclinical investigation.

Keywords
1H-1,2,3-triazole hybrids; Anti-proliferative; Human breast cancer cells; Molecular docking studies; Piperazine-linked.
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