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

Rim MalekRaquel L ArribasAlejandra Palomino-AntolinPerle TotosonCeline DemougeotTereza KobrlovaOndrej SoukupIsabel IriepaIgnacio MoraledaDaniel Diez-IriepaJustyna GodyńDawid PanekBarbara MalawskaMonika Głuch-LutwinBarbara MordylAgata SiwekFakher ChabchoubJosé Marco-ContellesKatarzyna Kiec-KononowiczJavier EgeaCristóbal de Los RíosLhassane Ismaili
Published in: Journal of medicinal chemistry (2019)
New tritarget small molecules combining Ca2+ channels blockade, cholinesterase, and H3 receptor inhibition were obtained by multicomponent synthesis. Compound 3p has been identified as a very promising lead, showing good Ca2+ channels blockade activity (IC50 = 21 ± 1 μM), potent affinity against hH3R (Ki = 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.
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