Discovery of\nNew Highly Potent Histamine H<sub>3</sub> Receptor Antagonists, Calcium\nChannel Blockers, and Acetylcholinesterase\nInhibitors

At present, one of the most promising strategies to tackle\nthe\ncomplex challenges posed by Alzheimer’s disease (AD) involves\nthe development of novel multitarget-directed ligands (MTDLs). To\nthis end, we designed and synthesized nine new MTDLs using a straightforward\nand cost-efficient one-pot Biginelli three-component reaction. Among\nthese newly developed compounds, one particular small molecule, named <b>3e</b> has emerged as a promising MTDL. This compound effectively\ntargets critical biological factors associated with AD, including\nthe simultaneous inhibition of cholinesterases (ChEs), selective antagonism\nof H<sub>3</sub> receptors, and blocking voltage-gated calcium channels.\nAdditionally, compound <b>3e</b> exhibited remarkable neuroprotective\nactivity against H<sub>2</sub>O<sub>2</sub> and Aβ<sub>1–40</sub>, and effectively restored cognitive function in AD mice treated\nwith scopolamine in the novel object recognition task, confirming\nthat this compound could provide a novel and innovative therapeutic\napproach for the effective treatment of AD.