Piperazine derivatives as anticancer agents: a medicinal chemistry review of structure, mechanism, and clinical translation.

Authors

Trapti Porwal, Rajnish Kumar, Shristi Tripathi, Salahuddin

Published in

Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents. Volume 35. Issue 6. Pages 1031-1063. Epub May 15, 2026.

Abstract

Piperazine has become essential for designing anticancer drugs because of its basicity, conformational flexibility, and capacity to serve as a solubilizing agent and molecular linker between hybrid pharmacophores. Researchers have found piperazine to function as a medicinal chemistry component that helps develop bioactive scaffolds through its capacity to control solubility, linker design, and target binding properties. The review presents a comprehensive assessment of piperazine-based anticancer drug research published between 2015 and 2025 through its evaluation of clinically relevant medicinal chemistry findings. The literature is organized based on piperazine's three main functional roles, which include its use as a linker and solubilizing/basic motif and direct target-recognition element. The study examines major cancer types through scaffold-based structure-activity relationship (SAR) analysis, which includes breast cancer, liver cancer, colon cancer, cervical cancer, prostate cancer, brain cancer, and leukemia models. The research demonstrated that various derivatives achieved IC₅₀ values in the low-nanomolar to low-micromolar range in MCF-7, HepG2, and HCT-116, HeLa, PC-3, and K562 cell lines. Researchers have demonstrated how protonatable piperazine nitrogens improve aqueous solubility and formulation development, and interactions of enzyme and kinase active sites with acidic residues, which results in better binding strength and selectivity. The review presents major translational obstacles, which include excessive dependence on 2D in vitro studies, insufficient in vivo and ADME/PK information, and limited progress in clinical applications. The research studies the development of clinically usable piperazine-based anticancer drugs through novel methods, which include green chemistry, click chemistry, molecular docking, and QSAR-focused design.

PMID:
42446683
Bibliographic data and abstract were imported from PubMed on 14 Jul 2026.

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