Synthesis, in silico, and in vitro pharmacological evaluation of norbornenylpiperazine derivatives as potential ligands for nuclear hormone receptors

Piperazine, norbornene, and their derivatives are valuable scaffolds in rational drug design, with promising therapeutic applications in various diseases, including cancer. Given that hybridization of privileged structures is a highly effective strategy in drug development, we synthesized piperazine derivatives containing a norbornenyl fragment using a straightforward synthetic pathway. Eight synthesized norbornenylpiperazine compounds (4a–4h) were evaluated for their potential interactions with target proteins, along with an in silico assessment of their absorption, distribution, metabolism, excretion and toxicity (ADMET) profiles. In vitro cytotoxicity and genotoxicity were also assessed using Michigan Cancer Foundation (MCF)-7 breast cancer cell lines, which express the relevant target receptors. High affinity was observed for the androgen receptor, peroxisome proliferator-activated receptor gamma, and glucocorticoid receptors, with a greater number of norbornenylpiperazine compounds showing strong affinity for the latter one. The drug-likeness and ADMET properties of these compounds revealed favorable pharmacokinetic profiles and moderate toxicity. Notably, compounds 4a, 4e, and 4h significantly inhibited MCF-7 cell proliferation, underscoring their potential as cancer therapeutics. Importantly, none of the compounds induced DNA damage at non-cytotoxic concentrations, which, together with in silico predictions, indicates a low likelihood of genotoxicity. These findings provide a foundation for further development and functional evaluation of selected synthesized norbornenylpiperazine compounds.