Novel tacrine-based multi-target directed Ligands: Enhancing cholinesterase inhibition, NMDA receptor antagonism, and CNS bioavailability for Alzheimer's disease treatment

作者：Barbora Svobodová, Zuzana Moravcová, Anna Misiachna, Gabriela Nováková, Aleš Marek, Vladimír Finger, Jitka Odvarkova, Jaroslav Pejchal, Jana Žďárová Karasová, Jakub Netolický, Marek Ladislav, Martina Hrabinová, Ales Sorf, Ľubica Múčková, Lenka Fikejzlová, Markéta Benková, Martin Novák, Lukáš Prchal, Jan Čapek, Jiří Handl, Tomáš Roušar, Katarzyna Ewa Greber, Krzesimir Ciura, Martin Hořák, Ondřej Soukup, Jan Korábečný · 发表于：European Journal of Medicinal Chemistry · 年份：2025 · DOI：10.1016/j.ejmech.2025.117678 · 被引用次数：6 · 研究领域：Cholinesterase and Neurodegenerative Diseases、Computational Drug Discovery Methods、Nicotinic Acetylcholine Receptors Study

Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder for which current treatments provide only symptomatic relief, primarily through cholinesterase (ChE) inhibition and N -methyl- d -aspartate receptor (NMDAR) antagonism. To improve therapeutic efficacy and safety, we designed and synthesized 16 novel tacrine derivatives modified at position 7 with various (hetero)aryl groups or deuterium substitution. Initially, in silico screening predicted favorable CNS permeability and oral bioavailability. Subsequent in vitro evaluations demonstrated significant inhibitory potency against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), with derivatives 5i and 5m displaying particularly promising profiles. Metabolic stability assessed using human liver microsomes revealed enhanced stability for compound 5e , whereas 5i and 5m underwent rapid metabolism. Notably, compound 7 showed improved metabolic stability attributed to deuterium incorporation. The newly synthesized compounds were further tested for antagonistic activity on the GluN1/GluN2B subtype of NMDAR, with compound 5m exhibiting the most potent and voltage-independent inhibition. The ability of these compounds to permeate the blood-brain barrier (BBB) was confirmed through in vitro PAMPA assays. In preliminary hepatotoxicity screening (HepG2 cells), most derivatives exhibited higher cytotoxicity than tacrine, emphasizing the ongoing challenge in hepatotoxicity management. Based on its overall favora...