Isatin-based benzyloxybenzene derivatives as monoamine oxidase inhibitors with neuroprotective effect targeting neurogenerative disease treatment

Abstract

Eighteen isatin-based benzyloxybenzaldehyde derivatives from three subseries, ISB, ISFB, and ISBB, were synthesized and their ability to inhibit monoamine oxidase (MAO) was evaluated. The inhibitory activity of all synthesized compounds was found to be more profound against MAO-B than MAO-A. Compound ISB1 most potently inhibited MAO-B with an IC₅₀ of 0.124 ± 0.007 μM, ensued by ISFB1 (IC₅₀ = 0.135 ± 0.002 μM). Compound ISFB1 most potently inhibited MAO-A with an IC₅₀ of 0.678 ± 0.006 μM, ensued by ISBB3 (IC₅₀ = 0.731 ± 0.028 μM), and had the highest selectivity index (SI) value (55.03). The three sub-parental compounds, ISB1, ISFB1, and ISBB1, had higher MAO-B inhibition than the other derivatives, indicating that the substitutions of the 5-H in the A-ring of isatin diminished the inhibition of MAO-A and MAO-B. Among these, ISB1 (para-benzyloxy group in the B-ring) displayed more significant MAO-B inhibition when compared to ISBB1 (meta-benzyloxy group in the B-ring). ISB1 and ISFB1 were identified to be competitive and reversible MAO-B inhibitors, having K_i values of 0.055 ± 0.010, and 0.069 ± 0.025 μM, respectively. Furthermore, in the parallel artificial membrane penetration assay, ISB1 and ISFB1 traversed the blood–brain barrier in the in vitro condition. Additionally, the current study found that ISB1 decreased rotenone-induced cell death in SH-SY5Y neuroblastoma cells. In docking and simulation studies, the hydrogen bonding formed by the imino nitrogen in ISB1 and the pi–pi stacking interaction of the phenyl ring in isatin significantly aided in the protein–ligand complex's stability, effectively inhibiting MAO-B. According to these observations, the MAO-B inhibitors ISB1 and ISFB1 were potent, selective, and reversible, making them conceivable therapies for neurological diseases.