Homarine Alkyl Ester Derivatives as Promising Acetylcholinesterase Inhibitors

Abstract

Reversible acetylcholinesterase (AChE) inhibitors are key therapeutic tools to modulate the cholinergic connectivity compromised in several degenerative pathologies. In this work, four alkyl esters of homarine were synthesized and screened by using 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 mode. The effectiveness of AChE inhibition increases with the alkyl side chain length of the homarine esters, being HO-C₁₆ (IC₅₀ =7.57±3.32 μM and K_i =18.96±2.28 μM) the most potent inhibitor. The fluorescence quenching studies confirmed that HO-C₁₆ 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.

Keywords: Acetylcholinesterase inhibitors; Drug discovery; Fluorescence spectroscopy; Homarine alkyl esters; Structure-activity relationships.