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 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 mu M), potent affinity against...

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Published inJournal of medicinal chemistry Vol. 62; no. 24; pp. 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, Godyn, Justyna, Panek, Dawid, Malawska, Barbara, Gluch-Lutwin, Monika, Mordyl, Barbara, Siwek, Agata, Chabchoub, Fakher, Marco-Contelles, Jose, Kiec-Kononowicz, Katarzyna, Egea, Javier, de los Rios, Cristobal, Ismaili, Lhassane
Format Journal Article
LanguageEnglish
Published WASHINGTON Amer Chemical Soc 26.12.2019
American Chemical Society
Subjects
Chemical Sciences
Chemistry, Medicinal
Life Sciences & Biomedicine
Medicinal Chemistry
Organic chemistry
Pharmacology & Pharmacy
Science & Technology
SWISS-MODEL
DONEPEZIL
BUTYRYLCHOLINESTERASE
TARGET-DIRECTED LIGANDS
ACETYLCHOLINESTERASE
ANTIOXIDANT
STRATEGY
MEMANTINE
FLUORESCEIN
DERIVATIVES
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Summary: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 mu M), potent affinity against hH3R (K-i = 565 +/- 62 nM), a moderate but selective hBuChE inhibition (IC50 = 7.83 +/- 0.10 mu M), strong antioxidant power (3.6 TE), and ability to restore cognitive impairment induced by lip opolysaccharide.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.9b00937