Exploring the Potential of Indole-3-acetic Acid Arylhydrazone Hybrids for Parkinson’s Disease Treatment: A Comprehensive Evaluation of Neuroprotective, MAOB Inhibitory, and Antioxidant Properties

In the current study, a small series of five indole-3-acetic acid-derived arylhydrazone hybrids were synthesized and subjected to comprehensive evaluation of their neuropharmacological and radical-scavenging properties. Minimal neurotoxic effects were observed across diverse subcellular fractions, with particular emphasis on the compound 3a bearing a 2,3-dihydroxy moiety, exhibiting superior neuroprotective effects against H₂O₂-induced oxidative stress by preserving the cell viability up to 68%. Noteworthy neuroprotection was observed in 6-OHDA-induced neurotoxicity using isolated rat brain synaptosomes, with compounds 3b and 3c displaying prominent effects. Compound 3a demonstrated robust neuroprotective and antioxidant effects in models of tert-butyl hydroperoxide-induced oxidative stress on isolated rat brain mitochondria and nonenzyme-induced lipid peroxidation using isolated rat brain microsomes (Fe/AA). All compounds exhibited MAOB inhibition within the range of 0.130-0.493 μM, with compounds 3d, 3e, and 3a showing notable selectivity against hMAOB. Molecular docking studies further validated ligand binding within MAOB active sites. The derivatives demonstrated scavenging activity and antioxidant effects against various ROS types, with compound 3a consistently exhibiting the most potent activity. Structural modifications exerted discernible effects on scavenging capabilities and antioxidant effects, underscoring their potential therapeutic implications in neuroprotection and oxidative stress mitigation.