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

Add time:07/12/2019    Source:sciencedirect.com

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.

We also recommend Trading Suppliers and Manufacturers of 2-Amino-4-nitro-5-methoxybenzoic Acid (cas 196194-99-7). Pls Click Website Link as below: cas 196194-99-7 suppliers

Prev:Biochemical characterization and substrate profiling of a reversible 2,3-dihydroxybenzoic acid decarboxylase for biocatalytic Kolbe-Schmitt reaction
Next:Design, synthesis and identification of novel substituted 2-amino thiazole analogues as potential anti-inflammatory agents targeting 5-lipoxygenase)