ACS chemical neuroscience · 2024
Discovery of New Highly Potent Histamine H3 Receptor Antagonists, Calcium Channel Blockers, and Acetylcholinesterase Inhibitors.
СтатьяНазвание и аннотация: Перевод в очереди
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Malek Rim, Sałat Kinga, Totoson Perle, Karcz Tadeusz, Refouvelet Bernard, Skrzypczak-Wiercioch Anna, Maj Maciej, Simakov Alexey, Martin Helene, Siwek Agata, Szałaj Natalia, Godyń Justyna, Panek Dawid, Więckowska Anna, Jozwiak Krzysztof, Demougeot Celine, Kieć-Kononowicz Katarzyna, Chabchoub Fakher, Iriepa Isabel, Marco-Contelles José, Ismaili Lhassane
Аннотация
At present, one of the most promising strategies to tackle the complex challenges posed by Alzheimer's disease (AD) involves the development of novel multitarget-directed ligands (MTDLs). To this end, we designed and synthesized nine new MTDLs using a straightforward and cost-efficient one-pot Biginelli three-component reaction. Among these newly developed compounds, one particular small molecule, named 3e has emerged as a promising MTDL. This compound effectively targets critical biological factors associated with AD, including the simultaneous inhibition of cholinesterases (ChEs), selective antagonism of H3 receptors, and blocking voltage-gated calcium channels. Additionally, compound 3e exhibited remarkable neuroprotective activity against H2O2 and Aβ1-40, and effectively restored cognitive function in AD mice treated with scopolamine in the novel object recognition task, confirming that this compound could provide a novel and innovative therapeutic approach for the effective treatment of AD.