Benzoic acid-derived nitrones: A new class of potential acetylcholinesterase inhibitors and neuroprotective agents

• Type: Article in International Scientific Journal
• Date: 2019

Authors

Oliveira, C (Author) Other; Bagetta, D (Author) Other; Fernando Cagide (Author) FCUP; Teixeira, J (Author) Other; Amorim, R (Author) Other; Silva, T (Author) Other; Garrido, J (Author) Other; Fernando Remiao (Author) FFUP; Uriarte, E (Author) Other; Oliveira, PJ (Author) Other; Alcaro, S (Author) Other; Ortuso, F (Author) Other; Fernanda Borges (Author) FCUP

Journal

Title: European Journal of Medicinal Chemistry

Vol. 174

Pages: 116-129

ISSN: 0223-5234

Publisher: Elsevier

Indexing

ISI Web of Knowledge - 38 Citations

Scopus - 39 Citations

Other information

Authenticus ID: P-00Q-GJE

DOI: 10.1016/j.ejmech.2019.04.026

Abstract (EN): The discovery of new chemical entities endowed with potent and selective acetylcholinesterase (AChE) and/or butyrylcholinesterase (BChE) inhibitory activity is still a relevant subject for Alzheimer's disease therapy. Therefore, a small library of benzoic based amide nitrones (compounds 24 to 42) was synthesized and screened toward cholinesterase enzymes. SAR studies showed that the tert-butyl moiety is the most favourable nitrone pattern. In general, tert-butyl derivatives effectively inhibited AChE, being compound 33 the most potent (IC50 = 8.3 +/- 0.3 mu M; Ki 5.2 mu M). The data pointed to a non-competitive inhibition mechanism of action, which was also observed for the standard donepezil. None of compounds showed BChE inhibitory activity. Molecular modelling studies provided insights into the enzyme-inhibitor interactions and rationalised the experimental data, confirming that the binding mode of nitrones 33 and 38 towards AChE has the most favourable binding free energy. The tert-butylnitrones 33 and 38 were not cytotoxic on different cell lines (SH-SY5Y and HepG2). Moreover, compound 33 was able to prevent t-BHP-induced oxidative stress in SH-SY5Y differentiated cells. Due to its AChE selectivity and promising cytoprotective properties, as well as its appropriate drug-like profile pointing toward blood-brain barrier permeability, compound 33 is proposed as a valid lead for a further optimization step. (C) 2019 The Authors. Published by Elsevier Masson SAS.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 14