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Eur J Med Chem. 2019 Oct 15;180:613-626. doi: 10.1016/j.ejmech.2019.07.051. Epub 2019 Jul 17.

A novel class of multitarget anti-Alzheimer benzohomoadamantane‒chlorotacrine hybrids modulating cholinesterases and glutamate NMDA receptors.

Author information

1
Laboratory of Pharmaceutical Chemistry (CSIC Associated Unit), Faculty of Pharmacy and Food Sciences, Institute of Biomedicine (IBUB), University of Barcelona, Av. Joan XXIII 27-31, E-08028, Barcelona, Spain.
2
Department of Pharmacy and Pharmaceutical Technology and Physical-Chemistry, Faculty of Pharmacy and Food Sciences, Institute of Nanoscience and Nanotechnology (IN2UB), University of Barcelona, Av. Joan XXIII 27-31, E-08028, Barcelona, Spain.
3
Department of Pharmacy and Biotechnology, Alma Mater Studiorum University of Bologna, Via Belmeloro 6, I-40126, Bologna, Italy.
4
Department for Life Quality Studies, Alma Mater Studiorum University of Bologna, Corso D'Augusto 237, I-47921, Rimini, Italy.
5
Department of Pharmacology, Therapeutics, and Toxicology, Autonomous University of Barcelona, E-08193, Bellaterra, Spain.
6
Pharmacology Unit, Faculty of Medicine and Health Sciences, Universitat Rovira i Virgili, C/St. Llorenç 21, E-43201, Reus, Spain.
7
Laboratory of Pharmaceutical Chemistry (CSIC Associated Unit), Faculty of Pharmacy and Food Sciences, Institute of Biomedicine (IBUB), University of Barcelona, Av. Joan XXIII 27-31, E-08028, Barcelona, Spain. Electronic address: svazquez@ub.edu.
8
Laboratory of Pharmaceutical Chemistry (CSIC Associated Unit), Faculty of Pharmacy and Food Sciences, Institute of Biomedicine (IBUB), University of Barcelona, Av. Joan XXIII 27-31, E-08028, Barcelona, Spain. Electronic address: dmunoztorrero@ub.edu.

Abstract

The development of multitarget compounds against multifactorial diseases, such as Alzheimer's disease, is an area of very intensive research, due to the expected superior therapeutic efficacy that should arise from the simultaneous modulation of several key targets of the complex pathological network. Here we describe the synthesis and multitarget biological profiling of a new class of compounds designed by molecular hybridization of an NMDA receptor antagonist fluorobenzohomoadamantanamine with the potent acetylcholinesterase (AChE) inhibitor 6-chlorotacrine, using two different linker lengths and linkage positions, to preserve or not the memantine-like polycyclic unsubstituted primary amine. The best hybrids exhibit greater potencies than parent compounds against AChE (IC50 0.33 nM in the best case, 44-fold increased potency over 6-chlorotacrine), butyrylcholinesterase (IC50 21 nM in the best case, 24-fold increased potency over 6-chlorotacrine), and NMDA receptors (IC50 0.89 μM in the best case, 2-fold increased potency over the parent benzohomoadamantanamine and memantine), which suggests an additive effect of both pharmacophoric moieties in the interaction with the primary targets. Moreover, most of these compounds have been predicted to be brain permeable. This set of biological properties makes them promising leads for further anti-Alzheimer drug development.

KEYWORDS:

Acetylcholinesterase inhibitors; Brain permeability; Butyrylcholinesterase inhibitors; Multi-target-directed ligands; Multitarget compounds; NMDA antagonists

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