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

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

  • J Med Chem. 2019 Dec 26;62(24):11416-11422. doi: 10.1021/acs.jmedchem.9b00937.
Rim Malek 1 2,  Raquel L Arribas 3 4,  Alejandra Palomino-Antolin 4 5 6,  Perle Totoson 7,  Celine Demougeot 7,  Tereza Kobrlova 8 9,  Ondrej Soukup 8 9,  Isabel Iriepa,  Ignacio Moraleda,  Daniel Diez-Iriepa 10,  Justyna Godyń 11,  Dawid Panek 11,  Barbara Malawska 11,  Monika Głuch-Lutwin 11,  Barbara Mordyl 11,  Agata Siwek 11,  Fakher Chabchoub 2,  José Marco-Contelles 10,  Katarzyna Kiec-Kononowicz 11,  Javier Egea 4 5 6,  Cristóbal de Los Ríos 3 4,  Lhassane Ismaili 1
Affiliations

Affiliations

  • 1 Neurosciences Intégratives et Cliniques EA 481, Pôle de Chimie Organique et Thérapeutique , Université Bourgogne Franche-Comté, UFR Santé , 19, Rue Ambroise Paré , F-25000 Besançon , France.
  • 2 Laboratory of Applied Chemistry: Heterocycles, Lipids and Polymers , University of Sfax , B. P 802, 3000 Sfax , Tunisia.
  • 3 Servicio de Farmacología Clínica, Instituto de Investigación Sanitaria , Hospital Universitario de la Princesa , C/Diego de León, 62 , 28006 Madrid , Spain.
  • 4 Instituto Teofilo Hernando , Universidad Autónoma de Madrid , C/Arzobispo Morcillo, 4 , 28029 Madrid , Spain.
  • 5 Molecular Neuroinflammation and Neuronal Plasticity Laboratory, Research Unit , Hospital Universitario Santa Cristina , 28009 Madrid , Spain.
  • 6 Instituto de Investigación Sanitaria , Hospital Universitario de la Princesa , 28006 Madrid , Spain.
  • 7 EA4267 PEPITE , Université Bourgogne Franche-Comté , F-25030 , Besançon , France.
  • 8 Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences , University of Defence , CZ-500 01 Hradec Kralove , Czech Republic.
  • 9 Biomedical Research Center , University Hospital CZ-500 05 Hradec Kralove , Czech Republic.
  • 10 Laboratory of Medicinal Chemistry, IQOG, CSIC , Juan de la Cierva 3 , 28006 Madrid , Spain.
  • 11 Faculty of Pharmacy , Jagiellonian University Medical College , Medyczna 9 , 30-688 Kraków , Poland.
PMID: 31724859 DOI: 10.1021/acs.jmedchem.9b00937
Abstract

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.

Figures