Phenoxytacrine derivatives: Low-toxicity neuroprotectants exerting affinity to ifenprodil-binding site and cholinesterase inhibition

0582133 - ÚEM 2025 RIV NL eng J - Journal Article
Misiachna, Anna - Svobodová, B. - Netolický, Jakub - Chvojková, M. - Kletečková, L. - Prchal, L. - Novák, M. - Hrabinová, M. - Kučera, T. - Mucková, L. - Moravcová, Z. - Karasová-Ždárová, J. - Pejchal, J. - Blažek, F. - Maliňák, D. - Hakenová, K. - Hrčka Krausová, Barbora - Kolcheva, Marharyta - Ladislav, Marek - Korábečný, J. - Pahnke, J. - Valeš, K. - Horák, Martin - Soukup, O.
Phenoxytacrine derivatives: Low-toxicity neuroprotectants exerting affinity to ifenprodil-binding site and cholinesterase inhibition.
European Journal of Medicinal Chemistry. Roč. 266, feb. (2024), č. článku 116130. ISSN 0223-5234. E-ISSN 1768-3254
R&D Projects: GA TA ČR(CZ) TO01000078; GA MŠMT(CZ) EH22_008/0004562
Institutional support: RVO:68378041
OECD category: Neurosciences (including psychophysiology
Impact factor: 6.7, year: 2022
Method of publishing: Open access
https://www.sciencedirect.com/science/article/pii/S0223523424000102?via%3Dihub https://doi.org/10.5281/zenodo.10949371 https://doi.org/10.2139/ssrn.4658299

Tacrine (THA), a long withdrawn drug, is still a popular scaffold used in medicinal chemistry, mainly for its good reactivity and multi-targeted effect. However, THA-associated hepatotoxicity is still an issue and must be considered in drug discovery based on the THA scaffold. Following our previously identified hit compound 7-phenoxytacrine (7-PhO-THA), we systematically explored the chemical space with 30 novel derivatives, with a focus on low hepatotoxicity, anticholinesterase action, and antagonism at the GluN1/GluN2B subtype of the NMDA receptor. Applying the down-selection process based on in vitro and in vivo pharmacokinetic data, two candidates, I-52 and II-52, selective GluN1/GluN2B inhibitors thanks to the interaction with the ifenprodil-binding site, have entered in vivo pharmacodynamic studies. Finally, compound I-52, showing only minor affinity to AChE, was identified as a lead candidate with favorable behavioral and neuroprotective effects using open-field and prepulse inhibition tests, along with scopolamine-based behavioral and NMDA-induced hippocampal lesion models. Our data show that compound I-52 exhibits low toxicity often associated with NMDA receptor ligands, and low hepatotoxicity, often related to THA-based compounds.
Permanent Link: https://hdl.handle.net/11104/0350209