Joao_2021_ChemMedChem__

Reversible acetylcholinesterase (AChE) inhibitors are key therapeutic tools to modulate the cholinergic connectivity compromised in several degenerative pathologies. In this work, four new alkyl esters of homarine were synthesized and screened in Electrophorus electricus AChE and rat brain AChE-rich fraction. Results showed that all homarine alkyl esters are able to inhibit AChE by a competitive inhibition kinetic model. The effectiveness of AChE inhibition increases with the alkyl side chain length of the homarine esters, being HO-C 16 (IC 50 = 7.57+/-3.32 microM and K i = 18.96+/-2.28 microM) the most potent inhibitor. The fluorescence quenching studies confirmed that HO-C 16 is the compound with higher selectivity and affinity for the tryptophan residues in the catalytic active site of AChE. Preliminary cell viability studies showed that homarine esters display no toxicity for human neuronal SH-SY5Y cells. Thus, the long-chain homarine esters emerge as new anti-cholinesterase agents, with potential to be considered for therapeutic applications development.