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
  • 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.