RT Journal Article
T1 In Vitro and  In Silico ADME-Tox Profiling and Safety Significance of Multifunctional Monoamine Oxidase Inhibitors Targeting Neurodegenerative Diseases.
A1 Więckowska, Anna
A1 Szałaj, Natalia
A1 Góral, Izabella
A1 Bucki, Adam
A1 Latacz, Gniewomir
A1 Kiec Kononowicz, Katarzyna
A1 Bautista Aguilera, Òscar M
A1 Romero Martínez, Manuel Alejandro
A1 Ramos Alonso, Eva
A1 Egea, Javier
A1 Farré Alíns, Victor
A1 González Rodríguez, Águeda
A1 López Muñoz, Francisco
A1 Chioua, Mourad
A1 Marco Contelles, José Luis
AB Herein we report  metabolic stability in human liver microsomes (HLMs), interactions with cytochrome P450 isoenzymes (CYP3A4, CYP2D6, and CYP2C9), and cytotoxicity analyses on HEK-293, HepG2, Huh7, and WTIIB cell lines of our most recent multitarget directed ligands PF9601N, ASS234, and contilisant. Based on these results, we conclude that (1) PF9601N and contilisant are metabolically stable in the HLM assay, in contrast to the very unstable ASS234; (2) CYP3A4 activity was decreased by PF9601N at all the tested concentrations and by ASS234 and contilisant only at the highest concentration; CYP2D6 activity was reduced by ASS234 at 1, 10, and 25 μM and by PF9601N at 10 and 25 μM, whereas contilisant increased its activity at the same concentrations; CYP2C9 was inhibited by the three compounds; (3) contilisant did not affect cell viability in the widest range of concentrations: up to 10 μM on HEK-293 cells, up to 30 μM on Huh7 cells, up to 50 μM on HepG2 cells, and up to 30 or 100 μM on WTIIB cells. Based on these results, we selected contilisant as a metabolically stable and nontoxic lead compound for further studies in Alzheimer's disease therapy.
PB ACS American Chemical Society
SN 1948-7193
YR 2020
FD 2020-11-18
LK https://hdl.handle.net/20.500.14352/120425
UL https://hdl.handle.net/20.500.14352/120425
LA eng
NO Więckowska, A., Szałaj, N., Góral, I., Bucki, A., Latacz, G., Kiec-Kononowicz, K., Bautista-Aguilera, Ò. M., Romero, A., Ramos, E., Egea, J., Farré Alíns, V., González-Rodríguez, Á., López-Muñoz, F., Chioua, M., & Marco-Contelles, J. (2020). In Vitro and In Silico ADME-Tox Profiling and Safety Significance of Multifunctional Monoamine Oxidase Inhibitors Targeting Neurodegenerative Diseases. ACS chemical neuroscience, 11(22), 3793–3801. https://doi.org/10.1021/acschemneuro.0c00489
NO Author Contributions A.W. designed the studies, analyzed the combined data, and revised and prepared the final version of the manuscript. N.S. and I.G. wrote the initial draft of the manuscript. A.B. performed in silico predictions of compounds’ metabolism. G.L. performed in vitro studies of metabolic stability, influence on cytochrome P450 (CYPs) isoenzyme activity, and cytotoxicity on HEK-293 and HepG2 cell lines. K.K.-K. supported in vitro studies. Ò .M.B.-A and M.C. carried out the synthesis of PF9601N, ASS234, and contilisant. J.M-C. planned and supervised the synthesis of the target ligands. F.L.-M. supported the research project. A.R. and E.R. performed the in silico toxicological screening of molecules, participated in writing/original draft preparation, and critically revised the manuscript. V.F.A. and A.G.R. performed the toxicological experiments in vitro. J.E. and A.G.R. participated in writing/original draft preparation and critically revised the manuscript
NO National Science Centre Poland
NO Agencia Estatal de Investigación (España))
DS Docta Complutense
RD 16 dic 2025