2. Academic Validation
  3. Structure-based design of novel donepezil-like hybrids for a multi-target approach to the therapy of Alzheimer's disease

Structure-based design of novel donepezil-like hybrids for a multi-target approach to the therapy of Alzheimer's disease

  • Eur J Med Chem. 2022 Jul 5:237:114358. doi: 10.1016/j.ejmech.2022.114358.
Leonardo Brunetti 1,  Rosalba Leuci 2,  Antonio Carrieri 2,  Marco Catto 2,  Sara Occhineri 2,  Giuseppe Vinci 2,  Lucia Gambacorta 3,  Hanna Baltrukevich 4,  Sílvia Chaves 5,  Antonio Laghezza 2,  Cosimo Damiano Altomare 2,  Paolo Tortorella 2,  M Amélia Santos 5,  Fulvio Loiodice 2,  Luca Piemontese 6
Affiliations

Affiliations

  • 1 Department of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, via E. Orabona 4, 70125, Bari, Italy; Centro de Química Estrutural, Institute of Molecular Sciences, Departamento de Engenharia Química, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1, 1049-001, Lisboa, Portugal.
  • 2 Department of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, via E. Orabona 4, 70125, Bari, Italy.
  • 3 Institute of Science of Food Production-ISPA, Research National Council-CNR, Via Amendola, 122/O, 70126, Bari, Italy.
  • 4 Department of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, via E. Orabona 4, 70125, Bari, Italy; Faculty of Pharmacy, Chair of Technology and Biotechnology of Medical Remedies, Jagiellonian University Medical College in Krakow, Medyczna 9, 30-688, Kraków, Poland.
  • 5 Centro de Química Estrutural, Institute of Molecular Sciences, Departamento de Engenharia Química, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1, 1049-001, Lisboa, Portugal.
  • 6 Department of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, via E. Orabona 4, 70125, Bari, Italy. Electronic address: luca.piemontese@uniba.it.
PMID: 35462163 DOI: 10.1016/j.ejmech.2022.114358
Abstract

Alzheimer's disease (AD) is a widespread multifactorial aging-related pathology, which includes cholinergic deficit among its main causes. Following a multi-target design strategy, the structure of the approved drug donepezil was taken as the starting point for generating some new potential multi-functional compounds. Therefore, a series of twenty molecular hybrids were synthesized and assayed against three different Enzymes, namely the well-established targets acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), and the innovative one fatty acid amide hydrolase (FAAH). In silico studies confirmed the interaction of benzylpiperidine and the benzylpiperazine isostere with the catalytic anionic site (CAS) of AChE, while the aryloxycarbonyl portion appeared to be important for the interaction with the peripheral site (PAS). A QSAR study was carried out on AChE inhibition data, which revealed that the inhibition potency seems to depend upon the length of the spacer and the number of polar atoms. The docking poses of selected compounds within BChE and FAAH were also calculated. Furthermore, pharmacokinetics and drug-likeness properties were assessed by chemoinformatic tools. Several piperidine derivatives (in particular compound 10) showed interesting profiles as multi-target directed agents, while the lead piperazine derivative 12 (SON38) was found to be a more potent and selective AChE Inhibitor (IC50 = 0.8 nM) than donepezil, besides being able to bind bivalent copper cations (pCu = 7.9 at physiological pH). Finally, the selected lead compounds (10 and 12, SON38) did not show significant cytotoxicity on SH-SY5Y and HepG2 cells at the highest tested concentration (100 μM) in a MTT assay.

Keywords

Acetylcholinesterase; Alzheimer's disease; Butyrylcholinesterase; Chelating agents; Docking; Donepezil; FAAH; Multifunctional drugs; Neurodegeneration; QSAR.

Figures
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z