New Dual Small Molecules for Alzheimer's Disease Therapy Combining Histamine H 3 Receptor (H3R) Antagonism and Calcium Channels Blockade with Additional Cholinesterase Inhibition

New tritarget small molecules combining Ca channels blockade, cholinesterase, and H3 receptor inhibition were obtained by multicomponent synthesis. Compound has been identified as a very promising lead, showing good Ca channels blockade activity (IC = 21 ± 1 μM), potent affinity against hH3R ( = 565...

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Published in:Journal of medicinal chemistry 2019-12, Vol.62 (24), p.11416-11422
Main Authors: Malek, Rim, Arribas, Raquel L, Palomino-Antolin, Alejandra, Totoson, Perle, Demougeot, Celine, Kobrlova, Tereza, Soukup, Ondrej, Iriepa, Isabel, Moraleda, Ignacio, Diez-Iriepa, Daniel, Godyń, Justyna, Panek, Dawid, Malawska, Barbara, Głuch-Lutwin, Monika, Mordyl, Barbara, Siwek, Agata, Chabchoub, Fakher, Marco-Contelles, José, Kiec-Kononowicz, Katarzyna, Egea, Javier, de Los Ríos, Cristóbal, Ismaili, Lhassane
Format: Article
Language:English
Subjects:
Chemical Sciences
Medicinal Chemistry
Organic chemistry
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Summary:New tritarget small molecules combining Ca channels blockade, cholinesterase, and H3 receptor inhibition were obtained by multicomponent synthesis. Compound has been identified as a very promising lead, showing good Ca channels blockade activity (IC = 21 ± 1 μM), potent affinity against hH3R ( = 565 ± 62 nM), a moderate but selective hBuChE inhibition (IC = 7.83 ± 0.10 μM), strong antioxidant power (3.6 TE), and ability to restore cognitive impairment induced by lipopolysaccharide.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.9b00937