Akademik Veri Yönetim Sistemi
Journal of Molecular Structure, cilt.1359, 2026 (SCI-Expanded, Scopus)
This study aimed to design, synthesize, and biologically evaluate a series of para-dicyanophenoxy-substituted benzoate esters ((2,3-dicyano)phenoxy- and (3,4-dicyano)phenoxy-para substituted benzoic acids thymyl, benzyl, isobutyl, and methyl esters) to identify potent and selective monoamine oxidase B (MAO-B) inhibitors. Particular emphasis was placed on elucidating the effects of ester substituent type and substitution position on MAO inhibition, selectivity, and enzyme–ligand interactions relevant to the symptomatic treatment of Parkinson's disease. In this study, four (2,3-dicyano)phenoxy- and four (3,4-dicyano)phenoxy-substituted benzoic acid esters containing thymyl, benzyl, isobutyl, and methyl groups were synthesized via esterification reactions, characterized, and their inhibitory effects on recombinant human MAO-A and MAO-B were assessed using p-tyramine as a substrate. The reference inhibitor selegiline showed a strong MAO-B inhibitory activity (IC₅₀ = 0.019 µM) with a high selectivity index (>3000), providing a benchmark for the evaluation of the synthesized compounds. All compounds showed selective inhibition toward MAO-B, with IC50 values ranging from 0.210 to 1.966 µM. Compound 7 was selected for detailed kinetic characterization. An enzyme kinetics study revealed a mixed, reversible inhibition mechanism for 7, with a Ki value of 0.1388 µM. Molecular docking studies supported the experimental findings, showing favorable binding interactions within the MAO-B active site. The results demonstrate that beta-substitüe phthalonitrile derivatives, particularly those bearing isobutyl benzoate substituents (compound 7), represent promising lead structures for the development of selective MAO-B inhibitors. The strong inhibitory potency, high selectivity, reversible inhibition profile, and favorable pharmacokinetic properties suggest that this compound may serve as a valuable candidate for further optimization in the discovery of drugs for Parkinson's disease.