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

• Published in: European journal of medicinal chemistry Vol. 174; pp. 116 - 129
• Main Authors: Oliveira, Catarina, Bagetta, Donatella, Cagide, Fernando, Teixeira, José, Amorim, Ricardo, Silva, Tiago, Garrido, Jorge, Remião, Fernando, Uriarte, Eugenio, Oliveira, Paulo J., Alcaro, Stefano, Ortuso, Francesco, Borges, Fernanda
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 15.07.2019; Elsevier
• Subjects: Acetylcholinesterase; Alzheimer's disease; Benzoic acid; Chemistry, Medicinal; Cholinesterase inhibitors; Life Sciences & Biomedicine; Nitrones; Oxidative stress; Pharmacology & Pharmacy; Science & Technology; Spin traps; Benzoic acid; Oxidative stress; BChE; FDA; Km; BBB; TPA; Ch; SAR; ACh; BCh; HBA; ATCI; CNS; t-BHP; ChEIs; clogP; log BB; HBD; Acetylcholinesterase; TNB2; Nitrones; Spin traps; nrotb; Alzheimer's disease; tPSA; AChE; AD; DTNB; OS; Vmax; BTCI; DIPEA; EDTA; Cholinesterase inhibitors; PCC; ChEs; NEAA; ROS; HBSS; ATP; Ki; CHOLINESTERASE; BUTYRYLCHOLINESTERASE; PROTEIN; PERMEABILITY; ALZHEIMERS-DISEASE; GLIDE; TRANSPORT; ACCURATE DOCKING; DRUGS; ASSAYS
• ISSN: 0223-5234; 1768-3254; 1768-3254
• DOI: 10.1016/j.ejmech.2019.04.026

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. [Display omitted] •A small library of non-cytotoxic benzoic based amide nitrones were obtained.•Only nitrones with tert-butyl moiety effectively and selectively inhibited AChE.•Molecular docking studies provided insights into the enzyme-inhibitor interactions.•Compound 33 is highlighted as a non-competitive toward AChE (IC50 = 8.3 μ0.3 μM; Ki 5.2 μM).•Compound 33 was able to prevent t-BHP-induced oxidative stress in SH-SY5Y differentiated cells.