Design, Synthesis, and Biological Evaluation of Novel Heterocyclic Scaffolds Targeting Neurodegenerative Disorders

Abstract

Neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease remain major public health challenges due to their progressive nature and lack of curative therapies. These diseases are driven by multifactorial mechanisms including oxidative stress, protein aggregation, neurotransmitter imbalance, and mitochondrial dysfunction. In this context, heterocyclic compounds have emerged as promising multitarget-directed ligands (MTDLs) capable of modulating several pathological pathways simultaneously. This study focuses on the design, green synthesis, and biological evaluation of novel heterocyclic scaffolds—including aurones, phenoselenazines, quinoline analogs, and chromenone hybrids—for their potential neuroprotective activity.

Using a structure-guided approach and green chemistry techniques, compounds were synthesized via microwave-assisted condensation, selenium-catalyzed oxidative coupling, and multicomponent reactions. In vitro screening revealed potent inhibition of acetylcholinesterase (AChE), monoamine oxidase-B (MAO-B), and β-secretase (BACE-1), along with robust antioxidant and anti-aggregation effects. Cell-based assays on SH-SY5Y neuroblastoma cells confirmed significant neuroprotection under oxidative stress. Molecular docking supported strong target binding and favorable pharmacokinetic profiles. These findings underscore the therapeutic promise of these scaffolds as lead candidates for neurodegenerative disease drug development.