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

Karine Badalyan,  Nelly Babayan,  Elena Kalita,  Narine Grigoryan,  Natalya Sarkisyan,  Ruzanna Grigoryan,  Grigor Arakelov,  Alexan Shahkhatuni,  Hovhannes Attaryan,  Davit Mkrtchyan,  Hasmik Khachatryan,  Lusine Khondkaryan   

Karine Badalyan1, Nelly Babayan2,3, Elena Kalita2,3, Narine Grigoryan2, Natalya Sarkisyan2, Ruzanna Grigoryan2, Grigor Arakelov4, Alexan Shahkhatuni5, Hovhannes Attaryan1, Davit Mkrtchyan1, Hasmik Khachatryan1, Lusine Khondkaryan2

1Laboratory of Applied Chemistry, Scientific and Technological Center of Organic and Pharmaceutical Chemistry NAS RA, Yerevan, Republic of Armenia.

2Laboratory of Cell Technologies, Institute of Molecular Biology NAS RA, Yerevan, Republic of Armenia.

3Laboratory of Experimental Biology, CANDLE Synchrotron Research Institute, Yerevan, Republic of Armenia.

4Laboratory of Computational Modelling of Biological Processes, Institute of Molecular Biology NAS RA, Yerevan, Republic of Armenia.

5Molecule Structure Research Center, Scientific and Technological Center of Organic and Pharmaceutical Chemistry NAS RA, Yerevan, Republic of Armenia.

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Published:  Apr 16, 2025

DOI: 10.7324/JAPS.2025.230239
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Abstract

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.


Keyword:     Norbornenylpiperazine derivatives synthesis computational studies ADMET prediction in vitro evaluation

Citation:

Badalyan K, Babayan N, Kalita E, Grigoryan N, Sarkisyan N, Grigoryan R, Arakelov G, Shahkhatuni A, Attaryan H, Mkrtchyan D, Khachatryan H, Khondkaryan L. Synthesis, in silico, and in vitro pharmacological evaluation of norbornenylpiperazine derivatives as potential ligands for nuclear hormone receptors. J Appl Pharm Sci. 2025. Online First. https://doi.org/10.7324/JAPS.2025.230239

Copyright: © The Author(s). This is an open-access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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