Synthesis and biological evaluation of 4-hydroxy-methylpiperidinyl-N-benzyl-acylarylhydrazone hybrids designed as novel multifunctional drug candidates for Alzheimer’s disease
| Autor: | Sarah, Macedo Vaz, Matheus, de Freitas Silva, Graziella, Dos Reis Rosa Franco, Marcos, Jorge R Guimarães, Fernanda, Motta R da Silva, Newton, Gonçalves Castro, Isabella, Alvim Guedes, Laurent E, Dardenne, Marina, Amaral Alves, Rafael, Garrett da Costa, Gabriela, Beserra Pinheiro, Letícia, Germino Veras, Márcia, Renata Mortari, Letizia, Pruccoli, Andrea, Tarozzi, Cláudio, Viegas |
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| Rok vydání: | 2022 |
| Předmět: |
Amyloid beta-Peptides
Molecular Structure Organic Chemistry Clinical Biochemistry Hydrazones Pharmaceutical Science Ligands Biochemistry Antioxidants Neuroblastoma Structure-Activity Relationship Neuroprotective Agents Piperidines Alzheimer Disease Drug Design Drug Discovery Acetylcholinesterase Humans Molecular Medicine Cholinesterase Inhibitors Molecular Biology |
| Zdroj: | Bioorganic & Medicinal Chemistry. 71:116952 |
| ISSN: | 0968-0896 |
| Popis: | The search for new drug candidates against Alzheimer's disease (AD) remains a complex challenge for medicinal chemists due to its multifactorial pathogenesis and incompletely understood physiopathology. In this context, we have explored the molecular hybridization of pharmacophore structural fragments from known bioactive molecules, aiming to obtain a novel molecular architecture in new chemical entities capable of concomitantly interacting with multiple targets in a so-called multi-target directed ligands (MTDLs) approach. This work describes the synthesis of 4-hydroxymethyl)piperidine-N-benzyl-acyl-hydrazone derivatives 5a-l, designed as novel MTDLs, showing improved multifunctional properties compared to the previously reported parent series of N-benzyl-(3-hydroxy)piperidine-acyl-hydrazone derivatives 4. The new improved derivatives were studied in silico, regarding their mode of interaction with AChE enzyme, and in vitro, for evaluation of their effects on the selective inhibition of cholinesterases, cellular antioxidant, and neuroprotective activities as their cytotoxicity in human neuroblastoma (SH-SY5Y) cells. Overall, compound PQM-181 (5 k) showed the best balanced selective and non-competitive inhibition of AChE (IC |
| Databáze: | OpenAIRE |
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