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Benzoic Acid-Derived Nitrones: A New Class of Potential Acetylcholinesterase Inhibitors and Neuroprotective Agents

Benzoic Acid-Derived Nitrones: A New Class of Potential Acetylcholinesterase Inhibitors and Neuroprotective Agents

Catarina Oliveira, Donatella Bagetta, Fernando Cagide, José Teixeira, Ricardo Amorim, Tiago Silva, Jorge Garrido, Fernando Remião, Eugenio Uriarte, Paulo J Oliveira, Stefano Alcaro, Francesco Ortuso, Fernanda Borges

Eur J Med Chem. 2019 Jul 15;174:116-129.

PMID: 31029943

Abstract:

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 μM; Ki 5.2 μM). 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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AS23109	Benzoate Standard for IC			Price

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