New Dual Small Molecules for Alzheimer’s Disease Therapy Combining Histamine H₃ Receptor (H3R) Antagonism and Calcium Channels Blockade with Additional Cholinesterase Inhibition

Abstract

New tritarget small molecules combining Ca²⁺ channels blockade, cholinesterase, and H3 receptor inhibition were obtained by multicomponent synthesis. Compound <b>3p</b> has been identified as a very promising lead, showing good Ca²⁺ channels blockade activity (IC₅₀ = 21 ± 1 μM), potent affinity against hH3R (<i>K</i>_i = 565 ± 62 nM), a moderate but selective hBuChE inhibition (IC₅₀ = 7.83 ± 0.10 μM), strong antioxidant power (3.6 TE), and ability to restore cognitive impairment induced by lipopolysaccharide.