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 <b>3a</b> 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 <b>3b</b> and <b>3c</b> displaying prominent effects. Compound <b>3a</b> demonstrated robust neuroprotective and antioxidant effects in models of <i>tert</i>-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 <b>3d</b>, <b>3e</b>, and <b>3a</b> 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 <b>3a</b> 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.